Essentials in Ophthalmology - Oculoplastics and Orbit - Aesthetic and Functional Oculofacial Plastic Problem-Solving in the 21st Century ( GK Krieglstein ).pdf

Essentials in Ophthalmology

Oculoplastics and Orbit R. F. Guthoff J. A. Katowitz Editors

Essentials in Ophthalmology

Glaucoma

G. K. Krieglstein Series Editors

Cataract and Refractive Surgery

R. N. Weinreb

Uveitis and Immunological Disorders Vitreo-retinal Surgery Medical Retina Oculoplastics and Orbit Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics Cornea and External Eye Disease

Editors Rudolf F. Guthoff James A. Katowitz

Oculoplastics and Orbit Aesthetic and Functional Oculofacial Plastic Problem-Solving in the 21st Century

With 181 Figures, Mostly in Colour and 18 Tables

Foreword

The Essentials in Ophthalmology series represents an unique updating publication on the progress in all subspecialties of ophthalmology. In a quarterly rhythm, eight issues are published covering clinically relevant achievements in the whole field of ophthalmology. This timely transfer of advancements for the best possible care of our eye patients has proven to be effective. The initial working hypothesis of providing new knowledge immediately following publication in the peer-reviewed journal and not waiting for the textbook appears to be highly workable. We are now in the third cycle of the Essentials in Ophthalmology series, having been encouraged by read-

ership acceptance of the first two series, each of eight volumes. This is a success that was made possible predominantly by the numerous opinion-leading authors and the outstanding section editors, as well as with the constructive support of the publisher. There are many good reasons to continue andstill improve the dissemination of this didactic and clinically relevant information.

G.K. Krieglstein R.N. Weinreb

Series Editors

Preface

This third volume of Oculoplastic and Orbital Surgery promises to challenge the reader with stimulating new concepts at the cutting edge of this subspecialty. A variety of innovative techniques is described in this volume, covering both cosmetic and functional aspects of oculoplastic and orbital surgery. Pearls in cosmetic and oculofacialplastic surgery are presented in great detail, based on extensive experience. Rather than presenting merely anecdotal solutions, specific steps are outlined for problem solving in this rapidly evolving field. The latest therapies in the management of capillary hemangiomas, periorbital infections, and orbital and periorbital malignancies using specific targeted therapies demonstrate the increasingly important interaction between ophthalmic plastic surgery and the broad field of modern oncology.

Appearance issues are also discussed in relation to managing ophthalmic anomalies in congenital anophthalmic and microphthalmic patients. Controversies in enucleation techniques, implant selection, and implant preparation are presented, and the role of pegging an implant to ultimately improve prosthesis motility is critically evaluated. It is our hope, as with the previous two volumes, that this presentation of the latest concepts and management techniques for a variety of problem areas in the field of oculoplastic surgery will be of value for both comprehensive ophthalmologists and subspecialists with a particular interest in this field.

Rudolf F. Guthoff James A. Katowitz

Contents

2.4.4

Chapter 1 Ocular Adnexal Lymphoproliferative Disease Timothy J. Sullivan 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Antigen Stimulation . . . . . . . . . . . Immunosuppression . . . . . . . . . . . . . . . . . . . Pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features. . . . . . . . . . . . . . . . . . . . . . . . Imaging Findings . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positron Emission Tomography . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follicular Lymphoma . . . . . . . . . . . . . . . . . . . Mantle Cell Lymphoma . . . . . . . . . . . . . . . . . Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . Immunotherapy. . . . . . . . . . . . . . . . . . . . . . . . Radioimmunotherapy . . . . . . . . . . . . . . . . . . Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5 2 3 3 4 4 7 8 9 9 9 11 11 11 12 12 13 13 13 14

Chapter 2 Pearls in Cosmetic Oculofacial Plastic Surgery Jonathan A. Hoenig 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.4 2.4.1 2.4.2 2.4.3

General Introduction . . . . . . . . . . . . . . . . . . . The Aging Process and Facial Analysis. . . Endoscopic Brow Lift . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Browlift Anesthesia Pearls . . . . Endoscopic Browlift Surgical Procedure Pearls . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Browlift Postoperative Care Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Blepharoplasty . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Evaluation . . . . . . . . . . . . . . . . . . . . . . Upper Blepharoplasty Anesthesia Pearls . . . . . . . . . . . . . . . . . . . . . .

21 22 23 23 26 26 27 29 29 29 30

2.5.1 2.5.2 2.5.3 2.5.4

Upper Blepharoplasty Surgical Procedure Pearls . . . . . . . . . . . . . . . . . . . . . . . Lower Blepharoplasty, Fillers, and Midface Augmentation . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Evaluation . . . . . . . . . . . . . . . . . . . . . . Lower Blepharoplasty Anesthesia Pearls . . . . . . . . . . . . . . . . . . . . . . Lower Blepharoplasty Surgical Procedure Pearls . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30 33 33 33 37 38 44

Chapter 3 Current Concepts in the Management of Idiopathic Orbital Inflammation Katherine A. Lane and Jurij R. Bilyk 3.1 3.2 3.2.1 3.2.2 3.2.3 3.3 3.3.1 3.3.2 3.3.3 3.4 3.4.1 3.4.2 3.4.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . What Is the Diagnosis? . . . . . . . . . . . . . . . . . Pitfalls of Diagnosis. . . . . . . . . . . . . . . . . . . . . A Diagnostic Corticosteroid Trial? . . . . . . . The Question of Biopsy . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . Special Circumstances. . . . . . . . . . . . . . . . . . Pediatric IOIS. . . . . . . . . . . . . . . . . . . . . . . . . . . Sclerosing Pseudotumor . . . . . . . . . . . . . . . Tolosa–Hunt Syndrome. . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47 47 48 54 56 56 57 58 58 60 60 60 62 63

Chapter 4 Lacrimal Canalicular Inflammation and Occlusion: Diagnosis and Management David H. Verity and Geoffrey E. Rose 4.1 4.2

4.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology, Anatomy, Physiology, and Pathophysiology of the Canalicular System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infective Causes. . . . . . . . . . . . . . . . . . . . . . . .

67

67 69

x

Contents

4.3.1 4.3.2 4.4 4.4.1 4.4.2 4.4.3 4.5 4.5.1 4.5.1.1 4.5.1.2 4.5.2 4.5.3 4.5.3.1 4.5.3.2 4.5.4 4.6 4.6.1

4.6.2

Periocular Herpes Simplex Infection . . . . Bacterial Canaliculitis. . . . . . . . . . . . . . . . . . . Systemic Inflammatory Disease . . . . . . . . . Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . Ocular Cicatricial Pemphigoid . . . . . . . . . . Drug Eruptions (Stevens–Johnson Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iatrogenic Causes . . . . . . . . . . . . . . . . . . . . . . Systemic Drugs . . . . . . . . . . . . . . . . . . . . . . . . 5-Fluorouracil (5-FU) . . . . . . . . . . . . . . . . . . . Docetaxel (Taxotere) . . . . . . . . . . . . . . . . . . . Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . Topical Ophthalmic Treatments . . . . . . . . . Preservative-Related Chronic Conjunctivitis . . . . . . . . . . . . . . . . . . . . . . . . . . Mitomycin C Therapy. . . . . . . . . . . . . . . . . . . Lacrimal Stents and Plugs . . . . . . . . . . . . . . The Surgical Approach to Managing Canalicular Disease. . . . . . . . . . . . . . . . . . . . . Surgical Technique for Dacryocystorhinostomy with Retrograde Canaliculostomy. . . . . . . . . . . . Placement of a Jones Canalicular Bypass Tube. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69 70 70 70 70

5.7.3.1 5.7.3.2 5.7.4 5.7.4.1 5.7.4.2

71 71 71 71 72 72 73

5.7.4.3 5.7.4.4

73 73 73 74

74 75 76

Chapter 5 Orbitofacial Neurofibromatosis 1: Current Medical and Surgical Management William R. Katowitz and James A. Katowitz 5.1 5.2 5.3 5.4 5.4.1 5.4.2 5.4.3 5.5 5.5.1 5.5.2 5.6 5.6.1 5.6.2 5.7 5.7.1 5.7.2 5.7.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Manifestations of NF1 . . . . . . . . . . Orbitofacial Tumors in NF1 . . . . . . . . . . . . . Neurofibromas . . . . . . . . . . . . . . . . . . . . . . . . . Malignant Peripheral Nerve Sheath Tumors . . . . . . . . . . . . . . . . . . . . . . . . . Optic Pathway Gliomas . . . . . . . . . . . . . . . . . Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The NF1 Gene . . . . . . . . . . . . . . . . . . . . . . . . . . Overlapping NF1-Like Phenotype (SPRED1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Neurofibromatosis Type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical Management of Neurofibromas . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Management of Orbitofacial Tumors in NF1 . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Timing of Surgery . . . . . . . . . . . . . . . . . . . . . . Periorbital Involvement . . . . . . . . . . . . . . . .

5.8

81 81 83 83 83 84 84 84 84 84 84 85

85 85 86 86 87 87 87 90 92

Chapter 6 Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System in External Dacryocystorhinostomy Ludwig M. Heindl, Anselm G. M. Jünemann, and Leonard M. Holbach 6.1 6.2 6.3 6.4 6.5

79 79 79 80 80

The Upper Eyelid . . . . . . . . . . . . . . . . . . . . . . . The Lower Eyelid and Midface . . . . . . . . . . Orbital Involvement . . . . . . . . . . . . . . . . . . . . Proptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proptosis Due to Orbital Neurofibromas . . . . . . . . . . . . . . . . . . . . . . . . . Proptosis Due to Optic Nerve Glioma . . . Orbital Enlargement with Dystopia and Hypoglobus . . . . . . . . . . . . . . . . . . . . . . . The Natural History of NF1 Tumor Growth from Birth to Senescence . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.5.1 6.5.2 6.5.3 6.5.4 6.5.5 6.5.6 6.5.7

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Anatomy of the Lacrimal Drainage System . . . . . . . . . . . . . . . . . . . . . . . Basic Diagnostics for Disorders of the Lacrimal Drainage System. . . . . . . . Selective Lacrimal Sac Biopsy in External Dacryocystorhinostomy . . . . . Definitive Treatment and Prognosis of Lesions Affecting the Lacrimal Drainage System . . . . . . . . . . . . . . . . . . . . . . . Case A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95 96 97 97

99 99 99 100 100 101 101 101 103

Chapter 7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients Michael P. Schittkowski and Rudolf F. Guthoff 7.1 7.2 7.2.1 7.2.2 7.3 7.3.1 7.3.2 7.3.3 7.3.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and Methods . . . . . . . . . . . . . . . . . . Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Family History. . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy History. . . . . . . . . . . . . . . . . . . . . .

105 106 106 106 106 106 106 106 107

Contents

7.3.5 7.3.6 7.3.7

7.3.8 7.3.9 7.4 7.4.1 7.4.2 7.4.3 7.4.3.1 7.4.3.2 7.4.3.3 7.4.3.4 7.5

Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Associated Systemic and Ocular Diseases . . . . . . . . . . . . . . . . . . . . . . . . Developmental Anomaly and Potential Visual Capacity of the Fellow Eye in Unilateral Disease. . . . . . . . . Neuroradiological Findings (Brain MRI). . Nasolacrimal System Findings . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obstetric and Family History. . . . . . . . . . . . Associated Pathologies . . . . . . . . . . . . . . . . . Ophthalmological Findings in Unilateral Disease. . . . . . . . . . . . . . . . . . . . Neuroradiological Findings . . . . . . . . . . . . . Systemic Diseases . . . . . . . . . . . . . . . . . . . . . . Nasolacrimal Duct Findings. . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107 107

8.4.3 110 111 111 112 112 112 113 113 113 114 114 115 116

Chapter 8 Brow Suspension in Complicated Unilateral Ptosis: Frontalis Muscle Stimulation via Contralateral Levator Recession Markus F. Pfeiffer 8.1 8.2 8.2.1 8.2.2

8.2.3 8.2.4 8.2.5

8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5

8.3.6 8.4 8.4.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of Complicated Ptosis . . . . . . . Compensatory Eyebrow Elevation . . . . . . Examples of Complicated Unilateral Ptosis with Insufficient Compensatory Brow Elevation . . . . . . . . . . . . . . . . . . . . . . . . . Innervation Patterns of the Frontalis Muscle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Checklist of Preoperative Evaluation of Complicated Ptosis . . . . . . . . . . . . . . . . . . Planning Partial or Total Levator Muscle Recession Combined with Unilateral or Bilateral Brow Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Technique of Levator Muscle Recession . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Approach to the Levator. . . . . . . . . . . . . . . . Partial Levator Recession . . . . . . . . . . . . . . . Total Levator Recession. . . . . . . . . . . . . . . . . The Lid-Lowering Effect and Eyelid Symmetry: Evolution of the Eyelid Level After Levator Recession . . . . . . . . . . . Undercorrection and Overcorrection. . . . Surgical Technique of Brow Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials for Brow Suspension . . . . . . . . . .

8.4.1.1 8.4.1.2 8.4.2

117 117 117

118

8.4.4 8.4.5

118 119 119 119 119 119

121 121 121 122 122 122 123

Chapter 9 Modern Concepts in Orbital Imaging Jonathan J. Dutton 9.1 9.2 9.3 9.3.1 9.3.2 9.3.3 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.4.6 9.4.7 9.4.8 9.4.9 9.4.10 9.5

118 118

Nonautogenous Materials . . . . . . . . . . . . . . Autogenous Fascia Lata . . . . . . . . . . . . . . . . Our Technique of Harvesting Autogenous Fascia Lata . . . . . . . . . . . . . . . . Mechanical Principals of Brow Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Lid Approach. . . . . . . . . . . . . . . . . . . . Fascia Implantation . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9.6 9.7 9.7.1 9.7.1.1 9.7.1.2 9.7.1.3 9.7.2 9.7.3

Computerized Tomography . . . . . . . . . . . . Three-Dimensional Imaging . . . . . . . . . . . . Magnetic Resonance Imaging . . . . . . . . . . The T1 Constant. . . . . . . . . . . . . . . . . . . . . . . . The T2 Constant. . . . . . . . . . . . . . . . . . . . . . . . Creating the MR Image . . . . . . . . . . . . . . . . . Imaging of Common Orbital Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adenoid Cystic Carcinoma. . . . . . . . . . . . . . Cavernous Hemangioma . . . . . . . . . . . . . . . Dermoid Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . Fibrous Dysplasia . . . . . . . . . . . . . . . . . . . . . . Lymphangioma . . . . . . . . . . . . . . . . . . . . . . . . Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myositis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optic Nerve Glioma . . . . . . . . . . . . . . . . . . . . Pseudotumor . . . . . . . . . . . . . . . . . . . . . . . . . . Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . Diffusion MRI (Diffusion-Weighted Imaging) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positron Emission Tomography . . . . . . . . . Orbital Ultrasound . . . . . . . . . . . . . . . . . . . . . Physics and Instrumentation. . . . . . . . . . . . Topographic Echography . . . . . . . . . . . . . . . Quantitative Echography . . . . . . . . . . . . . . . Kinetic Echography. . . . . . . . . . . . . . . . . . . . . Extraocular Muscles . . . . . . . . . . . . . . . . . . . . Optic Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

125 129 129 130 131 131 134 134 134 134 135 136 136 136 138 139 139 140 141 142 142 143 143 143 145 146 146

Chapter 10 Management of Periorbital Cellulitis in the 21st Century Michael P. Rabinowitz and Scott M. Goldstein

121 121

10.1 10.2

121 121

10.3 10.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . The Infection: Stages, Symptoms, and Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology. . . . . . . . . . . . . . . . . . . . . . . . . . .

149 149 151 151

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10.5 10.5.1 10.5.2 10.6 10.7 10.8 10.9

Changing Pathogens and Resistance. . . . CA-MRSA Versus Hospital-Acquired MRSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Orbital MRSA. . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of Orbital Cellulitis . . . . . . . . . . Medical Treatment of Orbital Cellulitis . . Surgical Treatment of Orbital Cellulitis . . Prevention of Orbital Cellulitis after Orbital Fracture . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

152 152 153 154 155 156 158 159

Chapter 11 Current Concepts in the Management of Capillary Hemangiomas: Steroids, Beta-Blockers, or Surgery François Codère and Julie Powell Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Phases . . . . . . . . . . . . . . . . . . . . . . . . . Etiology, Histology, and Classification . . . Differential Diagnosis of Infantile Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Ocular Complications . . . . . . . . . . . . . . . . . . 11.3 Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.1 Angiography. . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4 Management . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.1 Active Nonintervention. . . . . . . . . . . . . . . . . 11.4.2 Indications for Treatment . . . . . . . . . . . . . . . 11.5 Modalities of Treatment . . . . . . . . . . . . . . . . 11.5.1 Steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.1.1 Topical Steroids . . . . . . . . . . . . . . . . . . . . . . . . 11.5.1.2 Intralesional Corticosteroid Injection. . . . 11.5.1.3 Oral Corticosteroids . . . . . . . . . . . . . . . . . . . . 11.5.2 Interferon-Alfa . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.3 Vincristine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.4 Laser. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.5 Embolization. . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.6 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5.7 Beta-Blockers: A New Promising Modality of Treatment. . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 11.1.1 11.1.2 11.1.3

161 161 161 162 163 163 164 165 165 165 165 165 165 165 166 166 167 167 167 167 168 170

Chapter 12 Evaluation and Management of Metastatic Orbital Tumors Alejandra A. Valenzuela and Alan A. McNab 12.1 12.2 12.3 12.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . Biological Behavior and Timing of Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . Lateralization . . . . . . . . . . . . . . . . . . . . . . . . . .

12.5 12.6 12.7 12.8 12.9 12.9.1 12.9.2 12.9.3 12.9.4 12.9.5 12.10 12.11 12.11.1 12.11.2 12.11.3 12.11.4 12.12

13.1 13.2 13.3 13.4 13.5

176 177 178 178 178 179 179 179 180 180 180 180 180 181 181 181

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Rituximab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yttrium-90-Labeled Ibritumomab Tiuxetan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imatinib Mesylate . . . . . . . . . . . . . . . . . . . . . . Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

187 188 189 190 191 192

Chapter 14 Controversies in Enucleation Technique and Implant Selection: Whether to Wrap, Attach Muscles, and Peg? David R. Jordan and Stephen R. Klapper 14.1 14.2 14.3 14.4

14.6

174 174

174 175

Chapter 13 Targeted Therapy in the Treatment of Orbital and Periorbital Malignancies Aaron Savar and Bita Esmaeli

14.5

173 173

Localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features. . . . . . . . . . . . . . . . . . . . . . . . Imaging and Patterns of Orbital Metastatic Disease . . . . . . . . . . . . . . . . . . . . . Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Types of Orbital Metastases . . . Breast Carcinoma . . . . . . . . . . . . . . . . . . . . . . Lung Carcinoma . . . . . . . . . . . . . . . . . . . . . . . Prostatic Cancer. . . . . . . . . . . . . . . . . . . . . . . . Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carcinoid Tumor . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . Hormonal Therapy . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis and Survival . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14.7 14.8 14.9

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Porous Orbital Implants . . . . . . . . . . . . . . . . Orbital Implant Selection in Adults. . . . . . Orbital Implant Selection in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Volume Considerations in Orbital Implant Selection . . . . . . . . . . . . Orbital Implant Wrapping and Attaching Extraocular Muscles . . . . . Which Wrap to Use . . . . . . . . . . . . . . . . . . . . . To Peg or Not to Peg Porous Implants . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

195 196 199 200 201 202 203 204 206 206

Contents

15.4 15.4.1 15.4.2 15.4.3

Chapter 15 Non-surgical Volume Enhancement with Fillers in the Orbit and Periorbital Tissues: Cosmetic and Functional Considerations Ana M. Susana Morley and Raman Malhotra 15.1 15.2 15.2.1 15.2.2 15.2.3 15.2.4 15.3 15.3.1 15.3.2 15.3.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology and Presentation . . . . . . . . . . . . . . Etiology of Orbital Volume Loss . . . . . . . . . Etiology of Periorbital Volume Loss . . . . . Features of Orbital Volume Loss. . . . . . . . . Features of PeriOorbital Volume Loss. . . . Background to Injectable Soft-Tissue Fillers . . . . . . . . . . . . . . . . . . . . . . . Historical Perspective on Volume Replacement. . . . . . . . . . . . . . . . . . . . . . . . . . . Advantages of Injectable Soft-Tissue Fillers . . . . . . . . . . . . . . . . . . . . . . . Complications of Injectable Soft-Tissue Fillers . . . . . . . . . . . . . . . . . . . . . . .

213 213 213 213 214 215 215 215

15.5 15.5.1 15.5.2 15.5.3 15.5.4 15.6 15.6.1 15.6.2 15.6.3 15.7

215 215

Index

Types of Injectable Soft-Tissue Filler. . . . . Collagen Fillers. . . . . . . . . . . . . . . . . . . . . . . . . Hyaluronic acid Fillers . . . . . . . . . . . . . . . . . . Semipermanent Injectable Soft-Tissue Fillers . . . . . . . . . . . . . . . . . . . . . . . Treatment Areas . . . . . . . . . . . . . . . . . . . . . . . Orbit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Eyelid and Brow . . . . . . . . . . . . . . . . . Tear Trough . . . . . . . . . . . . . . . . . . . . . . . . . . . . Temple and Brow . . . . . . . . . . . . . . . . . . . . . . Other Periorbital Uses of Injectable Soft-Tissue Fillers . . . . . . . . . . Upper Eyelid Loading . . . . . . . . . . . . . . . . . . Lower Eyelid Elevation. . . . . . . . . . . . . . . . . . Treatment of Cicatricial Ectropion. . . . . . . Future Developments . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

216 216 216 216 217 217 220 220 223 225 226 226 226 226 227

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

xiii

Contributors

Jurij R. Bilyk

Anselm G.M. Jünemann

Oculoplastic and Orbital Surgery Service, Wills Eye Institute, 840 Walnut St., Philadelphia, PA 19107, USA

Department of Ophthalmology and Eye Hospital, University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany

François Codère

James A. Katowitz

Department of Ophthalmology, Hôpital Ste-Justine, Université de Montréal, 3175 Côte Ste-Catherine, Montreal, Quebec, Canada, H3T 1C5

Children’s Hospital of Philadelphia, Division of Ophthalmology, R.D. Wood Ambulatory Care Building 34th Street Civic Center Blvd. Philadelphia, PA 19104, USA

Jonathan J. Dutton Department of Ophthalmology, University of North Carolina, Chapel Hill, NC 27599-7040, USA

Bita Esmaeli Section of Ophthalmology, Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1445, Houston, Texas 77030, USA

William R. Katowitz Oculoplastic Surgery, Children’s Hospital of Philadelphia Division of Ophthalmology, 34th Street Civic Center Blvd. Philadelphia, PA 19104, USA

Stephen R. Klapper

Scott M. Goldstein

Klapper Eyelid and Facial Plastic Surgery, 11900 North Pennsylvania Street, Suite 104, Carmel, IN 46032, USA

Oculoplastic Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, PA, USA

Katherine A. Lane

Department of Opthalmology, Rostock University, Doberaner Straβe 140, 18055 Rostock, Germany

Department of Ophthalmology, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104, USA

Ludwig M. Heindl

Raman Malhotra

Department of Ophthalmology and Eye Hospital, University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany

Queen Victoria Hospital, Corneoplastic Unit, Holtye Road, East Grinstead, RH19 3DZ, West Sussex, UK

Jonathan A. Hoenig

Alan A. McNab

9735 Wilshire Blvd. #308, Beverly Hills, CA 90212, USA

Royal Victorian Eye and Ear Hospital, Orbital, Lacrimal and Plastic Clinic, Suite 216, 100 Victoria Parade, East Melbourne 3002, Victoria, Australia

Rudolf F. Guthoff

Leonard M. Holbach Department of Ophthalmology and Eye Hospital, University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany

David R. Jordan University of Ottawa Eye Institute, 301 O’Connor Street, Ottawa, Ontario, Canada, K2P 1V6

Ana M. Susana Morley Queen Victoria Hospital, Corneoplastic Unit, East Grinstead, West Sussex, UK St. Thomas’ Hospital, Department of Ophthalmology, Westminster Bridge Rd., London SE1 7EH, UK

xvi

Contributors

Markus J. Pfeiffer

Timothy J. Sullivan

Augenklinik Herzog Carl Theodor, Nymphenburger Str.43, 80335 München, Germany

University of Queensland, Eyelid, Lacrimal and Orbital Clinic, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia

Julie Powell Division of Pediatric Dermatology, Hôpital Ste-Justine, Université de Montréal, 3175 Côte Ste-Catherine, Montreal, Quebec, Canada, H3T 1C5

Michael P. Rabinowitz Wills Eye Institute, Oculoplastic Service, Thomas Jefferson University, Philadelphia, PA, USA

Alejandra A. Valenzuela Orbital, Lacrimal and Oculoplastic Clinic, Department of Ophthalmology and Visual Sciences, Division of Neurosurgery, QEII Health Sciences Centre, Dalhousie University, Room 2035, 2W Victoria Building, 1276 South Park Street, Halifax, NS, B3H 2Y9, Canada

David H. Verity Geoffrey E. Rose Moorfields Eye Hospital, Adnexal Service, City Road, London EC1V 2PD

Aaron Savar Department of Head and Neck Surgery, Section of Ophthalmology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Michael P. Schittkowski Georg-August University, University Medical Center Goettingen, Department of Ophthalmology, Section for Strabismus, Neuroophthalmology and Oculoplastic Surgery R.-Koch-Str. 40 D 37075 Goettingen, Germany

Moorfields Eye Hospital, City Road, London EC1V 2PD, UK Lacrimal Clinic, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK

Chapter 1

Ocular Adnexal Lymphoproliferative Disease

1

Timothy J. Sullivan

Core Messages ■

■

Lymphoma is the most common orbital malignancy, usually presenting clinically with a short history of painless swelling, proptosis, or a salmon patch. The incidence of ocular adnexal lymphoproliferative disease Ocular adnexal lymphoproliferative disease (OALD) is increasing at 6% per year. The majority of adnexal lymphomas are extranodal marginal zone lymphoma (EMZL) or mucosa-associated lymphoid tissue (MALT). Chronic antigen stimulation and immunosuppression, including ultraviolet (UV) irradiation, contribute to pathogenesis. Improvements in molecular genetic techniques have led to more accurate diagnosis. Advances in imaging mean our ability to stage the presence and extent of systemic involvement has increased.

Summary for the Clinician ■ ■

■

MALT lymphoma is the most common OALD. MALT arises in response to chronic antigen stimulation, and increasing genetic aberrations lead to malignancy. Molecular genetic testing with polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) is being routinely performed to complement morphological findings to allow more rapid accurate diagnosis of OALD.

Malignant lymphomas represent neoplastic proliferation of cells predominantly located in lymphoid tissues. Lymphoma can be broadly divided into non-Hodgkin lymphoma (NHL; 70%) and Hodgkin disease (30%) [145]. There are 65,000 new cases of NHL annually as well as 19,000 deaths each year in the United States [83].

■

■

Computed tomographic (CT) images usually show homogeneous, well-circumscribed lesions, molding to the globe, of greater than brain density with moderate enhancement. Magnetic resonance imaging (MRI) lesions are isointense to extraocular muscles on T1- and T2-weighted images and show moderate enhancement with gadolinium. Positron emission tomography (PET) scanning provides improved detection of the presence and extent of systemic involvement. While radiotherapy remains the mainstay of treatment, management approaches are undergoing major changes. Treatments directed to reduce chronic antigen stimulation or to use immunotherapy or radioimmunotherapy result in greater response to treatment as well as improved quality of life and survival.

The annual incidence for mature B-cell neoplasms, which form the largest subgroup of lymphoma, ranges from 15/100,000 in the United States, Europe, and Australia to only 1.2/100,000 in China [61]. While the overall incidence of lymphoma has been increasing annually by 3–4% per year for many decades [22, 48], the rate of extranodal disease has been increasing at a greater rate [36, 50]. Within the extranodal subgroup, OALD has shown the greatest increase in incidence at a rate of up to 6.3% per year [106, 116, 137]. OALD represents a spectrum, ranging from benign reactive lymphoid hyperplasia (RLH) to malignant ocular adnexal lymphomas (OALs). Almost all OALs are B-cell NHLs. OALD disease has provided many challenges for the clinician and pathologist. Because of limitations in pathological techniques and understanding, previous workers were unable to correlate clinical behavior with pathological diagnosis in between 20% and 50% of cases [77, 114, 115]. This mismatch applied to both benign-appearing

2

1

1

Ocular Adnexal Lymphoproliferative Disease

lesions, which followed an aggressive course, and frankly malignant orbital lesions on histology, which failed to disseminate [94, 96]. With the discovery in the early 1970’s [74, 75, 155], that separate B- and T- lymphocyte subsets existed and also through insights gained with electron microscopy [78], pathologists began to understand that lymphoma comprised many distinct entities. Unfortunately, however, despite these advances, they were still unable to correlate clinical behavior with morphological appearance. This only came with an appreciation of immunophenotype and the use of the cluster of differentiation (CD) nomenclature [37, 54, 74, 77, 94–97]. The first CD discovered was B1, now known as CD20, a pan B-cell marker and target for monoclonal antibody therapy. The application of molecular genetics to pathological specimens [76, 80, 98, 108–110] has finally given pathologists the ability to precisely define the genetic aberrations underlying these lesions. Shortly after extranodal lymphomas of MALT were described elsewhere in the body [62, 68, 71, 72], similar lesions were recognized in the orbit [76, 79] but had probably been described in the orbit prior to the systemic recognition of this entity [78]. Since the early descriptions of MALT lymphoma, a greater appreciation of the importance of this entity in the ocular adnexa has developed, where it constitutes the majority of primary OALs [8, 15, 26, 84, 104, 113, 117, 153, 154]. There were also problems of applicability of existing classification schemes to OALD because of an inability to incorporate extranodal lesions. Fortunately, the classification in current use, the World Health Organization (WHO) modification of the Revised European American Lymphoma Classification, recognizes both extranodal disease and marginal zone MALT lymphomas and is designed to accommodate new entities as further diagnostic progress elucidates additional subtypes [69, 73]. OAL may be a primary process, arising within adnexal structures, but it may also be secondary from primary lesions elsewhere in the body. Less commonly, the adnexa may be involved by direct extension from primary lesions in adjacent structures such as the sinuses. OAL is usually subdivided into orbital, eyelid, conjunctival, and lacrimal sac lesions. Most large series confirmed that EMZL of MALT comprise one half to two thirds of OALs in Western countries and up to 90% in Asian communities, where the incidence of follicular lymphoma (FL) is very low. Other common indolent lesions include follicular (FL) and lymphoplasmacytic lymphoma, while the two more common aggressive lesions are the diffuse large B-cell lymphoma (DLBCL) and Mantle cell lymphoma (MCL). Less commonly, other non-Hodgkin B-cell lesions (e.g., small cell lymphoma)

may occur, and T- and NK (natural killer) cell lymphomas also occur rarely [27, 149, 156].

1.1

Pathogenesis

Lymphomas represent a malignant, clonal proliferation of lymphocytes, although clonality does not always constitute malignancy. The various lymphoma subtypes largely correspond to clonal proliferations of cells arrested at specific stages of lymphocyte development. This process begins in the marrow with precursor B lymphoblasts, which undergo immunoglobulin VDJ recombination to become surface immunoglobulin-positive naïve B cells [99]. These recirculating naïve B cells are found in blood, primary lymphoid follicles, and follicle mantle zones. Exposure to antigen leads to transformation to blast cells, which migrate into the center of the primary follicle, establishing the germinal center by filling the follicular dendritic cell meshwork, where they are now known as centroblasts. BCL-6 is necessary for germinal center formation, and then its downregulation is important for further lymphocyte development [21]. Here, the cells undergo somatic mutations of the immunoglobulin variable region gene and BCL-6 as part of the normal immune response, eventually becoming centrocytes. Centrocytes interact with surface molecules to differentiate into memory B cells or plasma cells. The memory B cells are found in the marginal zone of the lymph follicle, whereas plasma cells home to marrow [61]. There is site specificity for the homing of postgerminal center B cells, orchestrated by adhesion molecules and cytokines [122, 130]. Thus, MALT-derived B cells home to their specific MALT and nodal B cells to specific lymph nodes. Corresponding to these stages of development, EMZL and lymphoplasmacytic lymphoma arise from memory B cells and FLs and DLBCLs from the germinal center, whereas MCL arises from mature naïve B cells, found in the mantle region of the lymph node. A range of chromosomal translocations, deletions, and mutations occurs during the different phases of lymphocyte development, eventually establishing a clone of malignant cells. The clinical behavior of the tumor usually reflects the behavior of the normal cell counterpart. This corresponds to the lymphocyte stage at which the abnormal cell has accumulated sufficient genetic abnormalities to proliferate without control or avoid programmed cell death, constituting malignancy. Malignant cell clones that have low turnover produce indolent lymphomas such as MALT and FL, whereas cell stages that are more active will give rise to more aggressive lesions such as MCL or DLBCL. A small percentage of the low-grade lymphomas will

1.3

undergo transformation to a higher-grade lesion, for example, follicular and MALT lesions can transform into DLBCL. The most common OAL is the MALT lymphoma. Although the orbit itself has no lymph nodes or true lymphatic drainage system, studies have confirmed the presence of small lymphatic channels associated with the optic nerve [55, 56]. There is also a well-established ocular MALT system extending from the lacrimal gland, encompassing the conjunctival tissues, and including the lacrimal drainage apparatus. This can be broken down into the conjunctiva-associated lymphoid tissue and lacrimal drainage-associated lymphoid tissue (CALT and LDALT, respectively) with an overall designation of eyeassociated lymphoid tissue (EALT) [92, 93]. Lymphoid follicles from these tissues participate in the normal immune response to antigens with production of antibodies and effector plasma cells. While most OAL is MALT derived, presumably arising from these tissues, lymphocytes destined to reside in the EALT system pass through the normal lymphocyte development cycle, and this may explain why we see other primary B-cell lymphomas in the ocular adnexal region. Lymphomas originating in ocular adnexal tissues can have systemic lymphoid involvement of the marrow and other tissues. Conversely, systemic lymphomas may involve adnexal tissue secondarily. Primary ocular adnexal T- and NK cell lymphomas may also be seen, but are less common, possibly reflecting the fewer gene rearrangements that occur in their normal development compared to B lymphocytes [89].

1.2 Chronic Antigen Stimulation Chronic antigen stimulation and infectious agents have an important role in pathogenesis of lymphomas. Chronic low-grade infection and inflammation may induce and promote carcinogenesis, altering DNA and providing a carcinogenic environment bathed in cytokines and growth factors [131]. Ocular adnexal MALT often develops in a setting of chronic inflammation [44] (Fig. 1.1) and has been shown to be associated with Chlamydia psittaci and a number of other pathogens [1, 41, 133]. There is considerable regional variability with a number of studies showing no association with Chlamydia [34, 66, 159]. There may be different pathogens in different regional locations predisposing to the development of ocular adnexal MALT lymphoma. For example, the hepatitis C virus (HCV) has been detected in a small number of patients with ocular adnexal MALT [43]. In contrast, analysis of 49 cases of ocular adnexal MALT lymphoma from Florida

Immunosuppression

3

Fig. 1.1 Clinical image showing conjunctival MALT lymphoma that had arisen in response to chronic antigen stimulation from chronic conjunctival inflammation

with PCR techniques using universal bacterial primers failed to detect bacterial DNA [107]. Chlamydia causes chronic infections with inhibition of apoptosis and tumorogenic immunomodulatory effects that predispose to lymphoma formation [14, 112, 138]. The chronic systemic infection may be present for years, providing long-term chronic antigen stimulation. The pathogen may elaborate antigens that lead to molecular mimicry, allowing the organism to be tolerated, while other factors contribute to chronic antigen stimulation of both humoral and cell-mediated responses, creating an environment suitable for development of ocular adnexal MALT lymphoma. Ocular adnexal Mucosa Associated Lymphoid Tissue (MALT) lymphomas show a limited number of similar VH gene segments, and analysis of the mutations in these VH gene segments also suggests chronic antigen stimulation plays a role in their development [9].

1.3

Immunosuppression

Immunosuppression has long had an association with lymphoma development, which was underlined by increased incidence of lymphoma paralleling the AIDS era [58]. Lymphoma associated with immunosuppression tends to have a high prevalence of Epstein–Barr virus (EBV), defects in immunoregulation, as well as abnormal immunoglobulin and T-cell receptor gene rearrangement during lymphopoiesis [46] Disorders of immunity such as primary congenital immune deficiency, ataxia telangiectasia, and Wiscott–Aldridge syndrome all predispose to lymphoma development. Immunosuppressive therapy after organ transplantation is associated with a high rate of lymphoma, often with reduced latency and aggressive behavior [23, 91]. Interestingly, environments with high

4

1

1

Ocular Adnexal Lymphoproliferative Disease

UV light exposure such as Australia and Florida have high rates of both nonmelanoma skin cancer and lymphoma, suggesting a common role in immunosuppression from UV light in these tumors [7, 106]. There is good epidemiological support for this hypothesis, but mechanisms remain unclear [2, 65, 86, 129].

1.4

Pathology

The MALT-type OAL resembles MALT lymphoma elsewhere, comprised of morphologically small marginal zone cells, monocytoid cells, with occasional immunoblasts, centroblasts, and small lymphocytes (Fig. 1.2). There may be some plasmacytic differentiation and infiltration of epithelial tissues with malignant cells to form so-called lymphoepithelial units (Fig. 1.3 and 1.4). Dutcher bodies Periodic Acid-Schiff (PAS+ pseduointranuclear inclusions) are seen in about 25% of cases. Immunohistochemically, the cells are CD20 and CD79a+ and CD5 (95%), CD10, and CD23– [62, 68, 70–72]. Follicular lymphoma recapitulates the normal follicle formation with tumor cells but with poor definition, absence of mantle zone, and effacement of normal architecture with tumor cells (Fig 1.5). These cells are of two types, small cleaved centrocytes and larger noncleaved centroblasts. They are positive for pan B-cell markers CD19, CD20, CD22, and CD79a; are Bcl2+; and express germinal center markers BCL6, CD38, and CD10, but are CD5 and CD43− [11]. DLBCL diffusely involves tissues with a monotonous proliferation of large neoplastic B cells with large nuclei, which most commonly resemble centroblasts. Again, they are usually positive for pan B-cell markers CD19,

Fig. 1.3 MALT lymphoma. Hematoxylin and eosin ×400 showing a well-formed lymphoepithelial unit

Fig. 1.4 MALT lymphoma. Cytokeratin stain ×400 highlighting the epithelial component in a lymphoepithelial unit

CD20, and CD79a and may be CD5+, although they do not express cyclin D1, in contrast to MCL. Mantle cell lymphoma can show somewhat nodular patterns but with loss of normal architecture and infiltration by abnormal centrocyte-like cells, without blast forms (Fig. 1.6). They have a characteristic immunophenotype with CD5+ and CD43+ and BCL6 and CD10– (Fig. 1.7). They are all bcl2 and cyclin D1+ (Fig. 1.8). T-cell lesions include a broad range of subtypes but are typically CD20− and CD3+.

1.5 Fig. 1.2 MALT lymphoma. Hematoxylin and Eosin ×400 showing predominantly small marginal zone cells and monocytoid cells with occasional centroblasts and small lymphocytes

Cytogenetics

The acquisition of genetics aberrations in lymphocytes causes clonal cell proliferation and suppression of apoptotic mechanisms, immune suppression, and altered cell signaling functions, which result in tumor initiation,

1.5

Cytogenetics

5

promotion, and growth. The delicate balance between oncogenes and tumor suppressor genes becomes altered, leading to lymphoid malignancy. Certain cytogenetic abnormalities are characteristically seen in different lymphoma types. The first abnormality to be detected was the 8;14 translocation seen in Burkitt’s lymphoma, using standard karyotypic methods. Since that time, there have been many advances in molecular genetics, allowing more refined diagnosis of OALDs. Molecular testing is important to establish clonality and to establish a diagnosis. This is relevant in OALD to differentiate between small B-cell lymphomas (such as MALT, FL, chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) MCL). Certain cytogenetic abnormalities may also point to prognosis or response to particular treatments.

Conventional cytogenetics, usually performed with cell culture of a single-cell suspension from a mechanically disrupted lymph node, is not always rewarding due to difficulty in establishing a culture, low mitotic rates for many of the chronic and indolent lesions, and a poor response to mitogens. Southern blot methods are used but are labor intensive and time consuming, restricting their use in a routine setting. PCR techniques are usually the initial molecular diagnostic test in most pathology laboratories for assessment of lymphoid lesions. They can be performed quickly using DNA or RNA as templates, on small amounts of tissue, which may be fresh, fixed, or archival [143]. FISH uses labeled DNA probes that hybridize to sequences of interest, allowing detection of structural and numerical chromosomal abnormalities. There are a wide variety of commercially available FISH probes that are routinely used in lymphoma diagnosis in most laboratories [16]. Multiple chromosomal targets can be assessed with multicolor FISH (M-FISH) and spectral karyotyping (SKY). Comparative genome hybridization (CGH) permits analysis of DNA sequence copy number to detect loss or gain across the genome. Complementary DNA (cDNA) microarray testing allows gene expression profiling of lymphomas, which may be useful to correlate clinical behavior, response to treatment, and prognosis with improved lymphoma diagnosis [143]. Not all of these modalities are currently in routine laboratory use, but they will have increasing importance as more data are assembled on their application. Looking at OALD, the most common lesion is the EMZL of MALT type. These lymphomas show a range of cytogenetic abnormalities that vary from those seen in MALT lesions elsewhere in the body. These include t(11;18)(q21;q21) of the API2 and MALT1 genes (occurs in 0–10% ocular adnexal MALT lymphoma); t(14;18)

Fig. 1.6 Mantle cell lymphoma histology. Hematoxylin and eosin ×400, showing loss of normal architecture and infiltration by abnormal centrocyte-like cells

Fig. 1.7 Mantle cell lymphoma histology ×400 showing strongly positive CD5 immunostain

Fig. 1.5 Follicular lymphoma histology. Hematoxylin and eosin ×400, showing effacement of normal architecture with tumor cells. Most cells are small cleaved centrocytes, with occasional larger noncleaved centroblasts

6

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Ocular Adnexal Lymphoproliferative Disease

(q32;q21) of the IGH and MALT1 genes (occurs in 7–11% ocular adnexal MALT lymphoma); t(1;14)(p22;q32) of the Bcl-10 and IGH genes (not reported to occur in ocular adnexal MALT lymphoma); and t(3;14)(p14;q32) of the FOXP1 and IGH genes (not reported to occur in ocular adnexal MALT lymphoma) [136]. These different abnormalities result in activation of the transcription factor NF-κB (nuclear factor kappa B), which upregulates various proliferation genes in B cells [87]. Other abnormalities seen include trisomy 3 (occurs in 40–60% of ocular adnexal MALT lymphoma) and trisomy18 (occurs in 14–50% of ocular adnexal MALT lymphoma) [146]. The incidence of these cytogenetic abnormalities varies greatly, with MALT lymphomas derived from different tissues (e.g., gastric, lung, skin, and ocular adnexa [101]. Interestingly, given the low percentage of ocular adnexal MALT lymphomas showing the aberrations common in other MALT lymphomas, there may be other as-yetundiscovered abnormalities associated with this entity. Follicular lymphoma develops from centrocytes and centroblasts of the germinal centers that fail to undergo apoptosis because BCL2 expression is preserved as a result of the initial t(14;18) chromosomal rearrangement [61]. Additional genetic alterations occur, leading to FL, which may have a better or worse prognosis, depending on which secondary alterations take place [11]. We have already learned that BCL6 plays an important role in germinal center formation and subsequent lymphocyte development. Failure to downregulate BCL6 after affinity maturation may be lymphomagenic [21, 81]. BCL6 is necessary for survival of human DLBCL cells. DLBCL commonly shows alterations of the BCL6 gene at the 3q27 locus, but other complex karyotypes may be seen [51]. These different abnormalities may explain the

morphologically and immunohistochemically different centroblastic and immunoblastic subtypes of DLBCL [51]. There are at least three distinct entities grouped together under the DLBCL banner based on distinct chromosomal imbalances. These are germinal center B-cell-like (best prognosis), activated B-cell-like (intermediate-to-poor prognosis), and a poor prognosis non-germinal center B-cell-like (non-GCB-like) non-ABC-like subgroup [32]. Mantle cell lymphoma develops from a combination of dysregulation of cell proliferation and survival pathways with a high level of chromosome instability. The genetic hallmark of MCL is the t(11;14)(q13;q32) translocation that juxtaposes CCND1, at chromosome 11q13, to the immunoglobulin (Ig) heavy chain gene at chromosome 14q32 [82]. CCND1 is a proto-oncogene that encodes cyclin D1, resulting in cyclin D1 overexpression. This translocation occurs in the bone marrow in an early B cell at the pre-B stage of differentiation when the cell is initiating the Ig gene rearrangement with the recombination of the VDJ segments. The cell of origin is a mature B cell found in the mantle region of normal lymphoid follicles. Although the initial translocation occurs in immature B cells in the marrow, the oncogenic advantage is realized only when additional genetic aberrations occur as the cell matures into a naïve pregerminal center B cell [82, 139]. Diagnosis of this small cell lymphoma can be confirmed by immunohistochemical staining for cyclin D1 and with FISH techniques (Fig. 1.9) [24]. T-cell malignancies comprise two main groups: precursor T-cell lymphoblastic neoplasms, derived from maturing thymocytes, and peripheral T-cell lymphomas (PTCLs), arising from mature postthymic T cells (Figs. 1.10 and 1.11). Physiological T-cell development is regulated by numerous oncogenes and oncogenic pathways, suggesting a balance between normal differentiation and malignant transformation [4]. The molecular pathogenesis of T-cell lymphomas is still poorly understood, but it is recognized that there are often complex karyotypic abnormalities present [3].

Summary for the Clinician ■ ■

■

Fig. 1.8 Mantle cell lymphoma histology ×400 showing strongly positive cyclin D1immunostain

OAL usually presents with a short history (5–7 months) of painless proptosis or a salmon patch. MRI and CT are both useful, with MRI showing soft tissue involvement better and CT showing bone changes better. PET scanning has an important role in the systemic staging of OAL, but CT and MRI show the orbital disease better.

1.6

1.6

Fig. 1.9 Mantle cell lymphoma diagnosed rapidly by FISH using an IGH/CCND1 dual-color, dual-fusion translocation probe. The IGH probe is labeled with spectrum green, and the CCND1 probe is labeled with spectrum orange. The mantle cells can be seen as background shadows containing the t(11;14) (q13;q32) translocation shown by the fused green/orange nuclei (arrows)

Clinical Features

7

Clinical Features

Patients with OALD may present with a range of symptoms and signs. Proptosis, eyelid swelling, a palpable mass or conjunctival salmon patch, are common [35, 149]. Less frequently, patients may show visual disturbance (e.g., diplopia, visual loss), pain, or inflammation and occasionally dacryocystitis [85, 149] (Figs. 1.12 and 1.13). Pain and inflammation tend to be associated with more aggressive histologies. The typical patient is in the sixth or seventh decade, and there may be a history of autoimmune disease or thyroid eye disease [45, 85, 120, 149]. There does not appear to be any sex predilection, with some series having almost equal sex distribution [85] and others showing a slight female [45, 149] or male [35] predominance.

Fig. 1.12 Clinical appearance of left orbital MALT lymphoma showing left proptosis Fig. 1.10 NK T-cell lymphoma histology showing tumor invading small vessel. Hematoxylin and eosin ×400

Fig. 1.11 NK T-cell lymphoma histology CD56 stain ×400

Fig. 1.13 Clinical appearance of mantle cell lymphoma showing right conjunctival salmon patch

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1.7 Imaging Findings

1

The classic descriptions of early articles on the CT appearance of OALD are still current. Yeo et al. stated that these lesions molded or plastered themselves to preexisting orbital structures, such as the globe, extraocular muscles, lacrimal gland, or bony orbital walls, without eroding bone or enlarging the orbit (Fig. 1.14). Where lymphoid tumors abutted orbital fat, they adopted a streaky profile, presumably due to irregular infiltration reflecting involvement of microfascial structural elements [158]. The molding pattern has also been described as “puttylike” or having a pancake contour, following the fascial planes of the orbit [63, 134]. Other typical CT features include circumscription, homogeneity, greater than brain density, and moderate enhancement. Atypical appearances that show an infiltrative pattern, are inhomogeneous, or have calcification or bone changes may also be seen [147] (Fig. 1.15). Investigators have generally been unable to correlate clinical behavior with imaging appearance [126, 147, 152]. One study showed a statistically significant association between the CT appearance of molding and indolent histology [147]. Bone destruction has been associated with DLBCL by a number of authors [84, 134, 147]. Magnetic resonance imaging studies are complementary to CT, possibly showing extraorbital extension and central nervous system (CNS) involvement better than CT but not showing bony changes as well as CT. OALD lesions are usually isointense to extraocular muscle on both T1-and T2-weighted MRI images and show moderate enhancement with gadolinium in the majority of cases [35, 134, 147] (Figs. 1.16 –1.18). The imaging features of PET are considered in the staging section.

Fig. 1.16 T1-weighted MRI showing follicular lymphoma R lacrimal gland with no response to systemic chemotherapy

Fig. 1.14 Coronal CT MALT lymphoma showing molding of left lacrimal gland to the globe

Fig. 1.17 T2-weighted fat saturation MRI follicular lymphoma R lacrimal gland from the same patient as Fig. 1.16

Fig. 1.15 Coronal CT DLBCL arising in the right lacrimal sac showing the bone destruction commonly seen in DLBCL

1.10 Treatment

9

1.9 Positron Emission Tomography

Fig. 1.18 T1-weighted fat saturation MRI with gadolinium, follicular lymphoma R lacrimal gland from the same patient as Figs. 1.16 and 1.17. Post rituximab, showing good response to immunotherapy, having failed chemotherapy

1.8 Staging Although a diagnosis of OALD might be suspected on the basis of clinical findings and imaging studies, tissue analysis using the techniques described is necessary for confirmation and to allow classification of the lymphoma. Once a diagnosis of OALD has been established, the patient should be referred to an oncology center familiar with the management of hematological malignancy. Systemic investigation and staging, according to the Ann Arbor system, should be performed [17]. This is also true of reactive lymphoid hyperplasia (RLH) and atypical lymphoid hyperplasia (ALH) as a proportion of these will have systemic involvement with lymphoma. A full medical history, including any prior hematological malignancy, autoimmune disease, or history of thyroid eye disease should be taken. Clinical examination should include palpation of lymph nodes, liver, and spleen. Blood tests, including complete blood counts with cytologic examination, protein electrophoresis, lactate dehydrogenase, and beta-2-microglobulin levels; evaluation of renal and hepatic function; and serology for HCV and HIV infections. Bone marrow analysis is mandatory, and many advocate bilateral iliac crest samples. Chest radiographs and imaging of the cervical region, thorax, abdomen, and pelvis should be performed. While this has previously been performed utilizing CT images, increasingly, combined PET–CT scans are being used for initial staging.

The role of PET in staging, restaging, treatment monitoring, and follow-up of lymphoma is well accepted but is constantly evolving [6, 67]. Nearly all PET scanners sold currently are combined PET–CT scanners, giving functional and anatomic correlation and a diagnostic advantage over either PET or CT alone [5]. PET utilizes the decay physics of positron-emitting isotopes, with 18F-fluorodeoxyglucose (18F-FDG) the most common PET tracer [88]. Increased glucose metabolism is a hallmark of malignancy, and this can be quantified by fluorine-18 labeling of FDG, a glucose analogue, which becomes trapped within tumor cells. Positron emission by 18F is then detected by the PET scanner [6]. The application of PET to extranodal disease such as OALD, including EMZL and MALT lymphoma, is still being defined [52, 123] (Fig. 1.19). There are a small number of studies reporting the application of PET to OALD [18, 57, 128, 147, 151]. PET is superior to CT in detecting systemic disease associated with OALD and can result in the upstaging of disease by detecting systemic disease not detected by conventional imaging, which may have implications for treatment and outcome (Fig. 1.20). PET does have some limitations in detecting disease in the orbit due to the small volume of orbital disease as well as background physiological uptake of the extraocular muscles and the frontal lobes [147, 151]. One important role of PET is in the distinction between viable tumor and necrosis or fibrosis in residual masses [88]. PET has also been shown to have a role as an adjunct to conventional imaging in evaluating the response to treatment in OALD [57].

1.10 Treatment There are currently no universally accepted guidelines for the management of OALD. Treatment options for many decades mainly consisted of external beam radiotherapy

Summary for the Clinician ■ ■ ■

■

Long-term follow-up showed there is an overall 25% mortality with OAL. Radiotherapy remains the most common treatment for primary OAL. The advent of immunotherapy has seen a major change in treatment of OAL and is being used alone or in combination with systemic chemotherapy. Radioimmunotherapy offers even more targeted therapy and is currently under investigation.

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1

Fig. 1.19 PET CT scan showing right lacrimal gland FDFG avid MALT lymphoma (cursors)

and chemotherapy. There has been a paradigm shift last 5 years since 2004 with the application of immunotherapy and radioimmunotherapy to the management of lymphoma. There is no doubt that the management approach in 5 years will be very different from that in the recent past. General principles of management should be evidence based, considered broadly, and then applied to the individual case. There are factors that relate to the patient (e.g., age, comorbidities, performance) and to the tumor (histological type, stage, and site of involvement) as well as the impact on the eye from treatment that will influence the management approach [44, 144]. Ocular adnexal disease can be broadly divided into more indolent lymphoma subtypes (e.g., MALT, follicular, small cell lymphoma) and aggressive disease processes (DLBCL, MCL, and T- and NK cell lesions). There are international prognostic indicators for aggressive disease and for FL [135, 141]. Various clinical, histopatholoical, immunophenotypic, and other markers have been found to influence the prognosis and outcome of OALD. Assessing 326 patients with OAL, Jenkins et al. found that a greater than 1-year history of adnexal involvement was associated with less likelihood of disseminated disease [85]. They also found

extraorbital spread and tumor-related death were more common with bilateral adnexal disease, a finding confirmed by other authors [35, 149]. This is in contrast to earlier studies in which bilateral adnexal disease was not felt to have had an effect on extraorbital spread [76]. Advanced age, stage at presentation, aggressive histology, and tumor growth cell fraction are also associated with a poorer prognosis [26–28, 84, 85, 149]. Decaudin et al. recommend combined immunotherapy and chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone, R-CHOP) if there are perjorative prognostic factors present, radiotherapy if there are no perjorative factors but there is visual threat, and a range of treatments can be considered if there are no perjorative factors and no visual threat. These treatments include radiotherapy, immunotherapy with the monoclonal anti-CD20 antibody, rituximab, chlorambucil, antimicrobial therapy, and a “wait-and-see” approach for the elderly and frail with comorbidities [33]. Before looking at individual treatment modalities, some comments are relevant for different lymphoma categories. One emerging principle of management in the management of MALT lymphoma is to reduce or

1.13 Radiotherapy

11

disease should be treated with involved field radiotherapy (IFRT), and the addition of chemotherapy does not change survival. If disease is widespread, palliation is the aim, and initial management may be conservative. Treatment is initiated when there is bulky disease (>7 cm), more than three nodal groups are involved, or the patient has B symptoms or symptomatic splenomegaly [140]. Usually, this will be with combined rituximab and chemotherapy. Locoregional IFRT may be considered and is appropriate for ocular adnexal involvement. Radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab is also possible and is currently being evaluated. Advanced multiply relapsed disease may be treated with autologous stem cell transplant. Newly diagnosed DLBCL patients are treated with curative intent. While cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) is the preferred chemotheraputic regime, R-CHOP has been shown to improve survival in a number of randomized controlled trials [25, 47, 60, 124, 125].

1.12

Fig. 1.20 PET scan showing systemic involvement with MALT lymphoma

eliminate the chronic antigen stimulus and eradicate any local infective cause. This has been shown to be of benefit in gastric MALT lymphoma with elimination of Helicobacter pylori resulting in regression or remission in 50–80% of patients [157]. Because the association with Chlamydia and other infective agents is not as clear in ocular adnexal MALT lymphoma, blind anti-Chlamydia therapy is not recommended but could be considered if a chlamydial infection has been proved in geographical areas where associated chlamydial infection has been demonstrated [1, 41, 59, 66].

1.11

Mantle Cell Lymphoma

The majority of ocular adnexal cases are secondary. R-CHOP for systemic MCL is associated with a 50% response rate, with duration of effect of less than 2 years. This lesion usually requires aggressive treatment with alternating or sequential non-cross-reacting chemotherapy regimes, giving a remission rate of 90%. Despite consolidation treatment with chemotherapy and autologous stem cell transplantation, overall 5-year disease-free survival is around 50% [40, 84, 90, 100, 102, 149]. One promising recent report of 21 cases of orbital or adnexal MCL found 80% 5-year survival in patients treated with rituximab and chemotherapy compared with an 8% 5-year survival in patients not treated with rituximab [127]. T-cell lymphomas are a diverse group of poorly understood entities that may rarely behave moderately aggressively and be curable, but more commonly they are aggressive and associated with a poor outcome. The ocular adnexa may be involved secondarily or less frequently as a primary process [27, 84, 149, 156].

Follicular Lymphoma

Because FL can transform into DLBCL with accumulated genetic mutations, staging is critical to identify whether this has occurred. 18F-FDG PET has a special role when the most intense focus on PET should be biopsied to look for any such transformation. If the process has not transformed, staging is important. Localized

1.13

Radiotherapy

Having said all this, radiotherapy is currently the most common first-line treatment for primary OALD (Figs. 1.21 and 1.22). Superficial conjunctival and anterior orbital lesions are usually treated with electron beams,

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1.14

Chemotherapy

For primary OALD, chemotherapy has been used at either end of the behavior spectrum for low-grade disease and for aggressive disease. Chlorambucil is often used alone for low-grade disease in elderly patients [10]. More aggressive histologies are usually treated with CHOP or similar regimes [84, 85, 149]. While overall response rates are good, local recurrence is around 30% [142].

1

1.15 Fig. 1.21 Clinical image left orbital MALT lymphoma at presentation

Immunotherapy

Immunotherapy includes interferon and a range of monoclonal antibodies. There are limited reports of the use of interferon for OALD, with good response in the short follow-up time [13, 103] (Figs. 1.23 and 1.24). The use of monoclonal antibodies, most commonly the anti-CD20 antibody rituximab, has underpinned the paradigm shift in lymphoma management in the last decade. Anti-CD20 antigens are expressed by all B cells and 90% of B-cell lymphomas throughout most stages of B-cell development, except at the very early pre-B-cell stage and with plasma cell differentiation. Rituximab contains human IgG1 and κ-constant regions with murine variable regions. The antibody kills CD20-positive cells using human complement and immune effector cells, augmenting complement-mediated lysis and antibodydependent cell-mediated cytotoxicity (ADCC), activating apoptosis and having a direct antiproliferative effect. Rituximab as a single agent has been used to treat indolent FL, was initially approved for use in relapsed or

Fig. 1.22 Clinical image of same patient following 30-Gy external beam radiotherapy

whereas deeper orbital tissues are usually treated with photon beams. This achieves a local control of 85–100%, which may be dose related. Patients receiving less than 30 Gy had an 81% 5-year local control rate compared with 100% if the dose was more than 30 Gy [53]. There is a risk of distant spread of up to 25% over 10 years [53, 144]. One study showed a statistically significant reduction in distant spread (using Cox multivariate analysis) with a radiotherapy dose above 20 Gy [149]. This was highly significant for indolent lymphomas and approached significance for aggressive lymphomas. Complications of radiotherapy include immediate soft tissue effects on the affected skin, conjunctiva, and ocular surface. Later complications, which are dose related, include xerophthalmia, cataract, retinopathy, and optic neuropathy.

Fig. 1.23 Clinical image left orbital follicular lymphoma at presentation

1.18 The Future

Fig. 1.24 Clinical image of same patient following single course of rituximab monotherapy with complete response and no recurrence in long-term follow-up

refractory FL [64, 105, 111], but has also shown benefit for marginal zone lymphoma, and lymphoplasmacytic and small cell lymphoma [20, 49, 118, 150]. Rituximab in combination with chemotherapy has been demonstrated to improve response rates, event-free survival, progression-free survival, and overall survival in both FL and DLBCL [29, 30]. Initial reports of the use of rituximab for OALD confirmed the good overall response seen for most B-cell lymphomas elsewhere, with a generally low side-effect profile, mainly consisting of flulike symptoms [12, 38, 42, 119, 148]. Monoclonal antibody treatment of OALD needs further study to elucidate its role as a single agent; in combination with chemotherapy regimes; for initial treatment, relapsed, or refractory disease; or as maintenance therapy for OALD.

13

Administration approval for FL and transformed NHL that failed or relapsed from prior therapies, including rituximab and standard chemotherapy [19]. They have shown benefit as initial therapy, in sequential therapy with chemotherapy, and as consolidation therapy [31]. Further advances with pretargeted regimens and with fractionated therapy are currently being studied [121, 132]. Their application to OALD probably parallels that of other sites. Following favorable use of the modality in one patient [38], Esmaeli et al. reported the exciting early findings of a pilot study of the use of 90Y ibritumomab tiuxetan (Zevalin) as front-line treatment in 12 patients with early-stage extranodal indolent lymphoma of the ocular adnexa (nine MALT, three FL) [39]. Ten had a complete response, and two had a partial response, with a radiotherapy dose one tenth that of standard external beam radiotherapy. All patients experienced transient pancytopenia, but none had myelosuppression.

1.17

Outcome

The majority of OALs are indolent, with patients enjoying a good quality of life in remission after treatment. Ophthalmologists need to be aware, however, that there is significant morbidity and mortality the longer the followup. The overall mortality with long-term follow-up for OAL is roughly 20–25% from pooled data [8, 26, 28, 53, 84, 85, 149]. The mortality varies, depending on the histological type of lymphoma, being lower for the more indolent lymphomas (EMZL 10%, follicular 20–25%), and higher for the more aggressive lesions (DLBCL 40–45%, MCL and T- and NK cell lymphoma 75–100%) [27, 84, 85, 102, 127, 149, 156].

1.18 The Future 1.16

Radioimmunotherapy

Conjugating a monoclonal antibody with a radioisotope allows the delivery of radiotherapy to tumor cells that bind the antibody as well as neighboring tumor cells that may not express the antigen, yet minimizing radiation to normal tissues. While a number of agents are currently under study or development, two radioimmunoconjugates, yttrium-90 ibritumomab tiuxetan (Zevalin, BiogenIDEC Pharmaceuticals, San Diego, CA, USA) and iodine-131 tositumomab (Bexxar, GlaxoSmithKline, Philadelphia, PA, USA) have U.S. Food and Drug

Management of these disorders is entering an exciting epoch based on an improved understanding of the molecular basis and pathophysiology of the different lymphomas. Moving in tandem with improved diagnosis are improvements in imaging for more accurate initial staging and monitoring. Simple specific treatments designed to reduce chronic antigen stimulus may become available as we understand the basic disease mechanisms better. More complex therapies based on immunotherapy and radioimmunotherapy will emerge and it is hoped improve both patient quality of life and survival while reducing treatment-related complications.

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Chapter 2

Pearls in Cosmetic Oculofacial Plastic Surgery

2

Jonathan A. Hoenig

Core Messages ■

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Analyze the Face in Layers: Aging occurs in the skin, muscle, fat, and bony layers. The key for successful and consistent results is to define the anatomic problem and select procedures that address these problems. Do not sacrifice function for beauty. It is imperative that the patient and surgeon come to an understanding that function always supersedes beauty. The eyelids are unique in that they serve a vital function: to protect the eye. It is sometimes difficult for the patient to understand that, for example, the wrinkles that are still present after surgery are in actuality the skin necessary for eyelid closure. Endoscopic Brow Lift: The goal of a brow lift is less about lifting and more about contouring the shape of the brow. In women, the brow is elevated in a superior/medial vector. In men, the brow is elevated superiorly so that the brow becomes

2.1

General Introduction

Twenty years ago, life for the oculoplastic surgeon was relatively simple. If a patient presented with a problem, there were limited options to address the problem. As surgeons, we were good at removing tissue: fat, muscle, and skin. For example, if a patient presented with lower eyelid “bags,” the fat was always removed, while the skin would either be removed or be resurfaced. Most patients were treated in a similar manner despite significant anatomic differences. Most surgeons and patients were relatively happy with the surgical results. The reality is that we did not know any better. Then came the Internet. The Internet allowed patients and physicians to share and gather information. We all became more sophisticated. A variety of injectable fillers came on the market. Our whole philosophy of the aging process suddenly changed.

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■

straight and forms a T configuration with the nose. Upper Blepharoplasty: An upper blepharoplasty procedure cannot cure brow ptosis. If the brow is ptotic, correct the brow. The goal of upper blepharoplasty is definition and subbrow fullness. Blepharoplasty is not about how much skin and fat you take out but how much tissue you leave in. Preserving the pretarsal and preseptal orbicularis is necessary for proper eyelid function. Lower Blepharoplasty: The goal of lower blepharoplasty is restoration of the youthful contour of the eyelid and midface. This consists of a vertically short lower eyelid and a full, convex midface. Analysis of the lower eyelid involves the relationship between the globe and inferior orbital rim projection, orbital fat protrusion, and midfacial fat loss and skin elasticity versus excess.

Today, we are blessed with an array of options to rejuvenate the periocular region. There are multiple surgical and nonsurgical options. However, with all the various options, confusion ensues. What technique do we use to rejuvenate the lower eyelids? Do we use filler or fat? Who needs a transcutaneous blepharoplasty, and who is a better candidate for a transconjunctival incision? I often hear, “What about a midface lift, doctor?” “My friend read on the Internet that to fix lower eyelid bags you need to put in an orbital rim implant.” “How about a laser or a peel?” The combination of solutions can get dizzying. This chapter summarizes my personal experience and philosophy on what techniques seem to be the most effective. Many of these ideas are based on work described by others. The purpose of this chapter is to show the reader and surgeon my path through the mountain of options that are now available. The chapter is organized into sections for brow lifts, upper blepharoplasty, and lower

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blepharoplasty (which also includes information on fillers and midface augmentation).

2

2.2 The Aging Process and Facial Analysis The face is created in layers. The sturdiest of these layers is the skeletal bones. The contour and configuration of these bones truly defines the facial shape and soft tissue positions. In many instances, prominent bony contours act as a scaffold and prevent soft tissue descent. This is an important concept since augmenting the bones and deep tissues with implants, fat, or fillers will lift the face to some degree (Fig. 2.1). The outermost layer of the face is the skin, which bears the brunt of environmental exposure. Between the bones and skin lay fat and muscular layers. In general, there are superficial and deep muscular layers known as the SMAS (superficial musculoaponeurotic system) and DMAS (deep musculoaponeurotic system) [32, 31, 46]. Aging occurs in all four layers: bone, muscle, fat, and skin. As we age, we lose bone around the eyes and mouth [30]. The vertical height of the orbit elongates, and the inferior orbital rim and maxillary face retrude [35]. There is also loss of bone in the mandible, and it also has a loss of its vertical dimension (Fig. 2.2). The muscles of the face stretch and become ptotic, resulting in jowls and neck laxity. There is loss of fat in the eyelid region, cheeks, and buccal space (Fig. 2.3). Some patients gain fat in the jowl region and neck. Finally, the skin undergoes significant changes [25]. The skin thins by losing dermal thickness.

a

Fig. 2.1 (a and b) Two patients who are of the same age. Patients with prominent bony contour have less soft tissue ptosis. The heart-shaped face is considered more youthful than the rectangular-shaped face

The dermal collagen becomes irregular and disorganized. Clinically, the skin has an increase in pigmented spots and wrinkles. Analyzing the face in layers and defining the problem in each layer is paramount to designing a specific individualized solution for each patient. This approach allows the surgeon to decide which procedure and treatment are needed for each patient. I like to compare facial surgery to building a house. When a house is constructed or repaired, the contractor looks at the foundation, internal beams, walls, and finally the paint. This is analogous to

Fig. 2.2 Loss of bone in the mandible contributes to the appearance of a jowl (arrow). This prejowl sulcus is often due to loss of bone in this region

b

2.3 Endoscopic Brow Lift

a

23

b

Fig. 2.3 (a) Overall loss of facial fat, especially in the temples, buccal space, and jawline. (b) Loss of fat in the periorbital region with gain of fat in the submentum

the face: We analyze the bones, muscles, fat, and skin. We all understand the concept that rebuilding the foundation of the house does little for the outside paint. Similarly, removing protruding eyelid fat in a patient with significant skin changes does little to improve the skin. I find it helpful to have workup sheets available for the evaluation of the patient. This forces the surgeon to analyze the various layers and come up with specific solutions. Table 2.1 is an example of my facial analysis workup sheet.

Summary for the Clinician ■

■ ■ ■

Analyze the face in layers: skin, muscle fat, and bone. Remember, aging occurs in all of these layers. A prominent underlying skeleton acts as a scaffold to support the soft tissue. Define the problem. Design a solution that addresses the specific anatomic abnormality.

2.3 2.3.1

Endoscopic Brow Lift Introduction

The reestablishment of the structural integrity of the eyebrow is fundamental to achieving an aesthetically acceptable surgical result for cosmetic and functional periocular surgery [41]. Patients often present to the aesthetic

surgeon complaining of excess upper eyelid skin and request blepharoplasty. However, when the eyebrows are raised to their normal position, there is often less redundant upper eyelid skin than anticipated, and the required amount of skin removal during blepharoplasty is significantly reduced [40, 47]. Malposition of the eyebrows can often be overlooked. Many patients reflexively raise the eyebrows with their frontalis muscles to lift the eyebrow and eyelid tissue out of the visual axis. These patients develop furrows in the forehead region due to the constant contraction of the frontalis muscles (Fig. 2.4). It is the surgeon’s task to ensure that the patient’s frontalis muscles are completely relaxed prior to assessing the eyebrow position and excess upper eyelid skin. The eyebrow region ages by deflation as well as descent. As we age, we lose volume in the subbrow fat pad known as the ROOF (retro orbicularis oculi fat) [29]. This deflation contributes to the hooding that occurs in the brow and upper eyelid region (Fig. 2.5). The forehead and eyebrows are also under the constant influence of downward forces of both gravity and the periorbital protractor muscles (orbicularis oculi, procerus, and corrugator and depressor supercilii). These downward forces are opposed by the elevating action of the frontalis muscle. In time, this constant “tug-of-war” between the downward and upward forces leads to a series of wrinkles in the forehead and downward displacement of the eyebrows and eyelids. The lateral portion of the brow tends to descend in an inferomedial vector due in part to the lack of frontalis muscle in this

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Table 2.1. Jonathan Hoenig, M.D. New Patient Consultation

2

CHIEF COMPLAINT HISTORY OF PRESENT ILLNESS:

MAJOR CONCERNS:

PHYSICAL EXAMINATION Scalp: Hair Density Forehead: Brow Ptosis Glabella Rhytids Bony Contour: EYELIDS: Ptosis:

Length of Forehead

01234 01234  Normal  None

 OD

Forehead Rhytids: Solar Damage:  Abnormal  OS

MRD1 Lower Eyelids: Laxity: Retraction: Fat Herniation: Orbicularis Strength:

Periorbital Rhytids:

EYELID cont. Skin Excess: Other: Lesions: PHOTOS/DRAWINGS

CM

PF

01234 01234

LF

 Responds to Neosynephrine

 None

 OD _____

 OS _____

 None

 OD _____ mm

 OS_____mm

 None

 OD 1 2 3 4

 OS 1 2 3 4

Upper Eyelid: Lower Eyelid

 OD 0 1 2 3 4

 OS 0 1 2 3 4

 OD 0 1 2 3 4

 OS 0 1 2 3 4

Static: Dynamic:

 OD 0 1 2 3 4

 OS 0 1 2 3 4

 OD 0 1 2 3 4

 OS 0 1 2 3 4

Upper Lower  Ectropion

 OD 0 1 2 3 4

 OS 0 1 2 3 4

 OD 0 1 2 3 4

 OS 0 1 2 3 4

 Entropion

2.3 Endoscopic Brow Lift

25

Table 2.1. (continued) MIDFACE Infraorbital bony status: Infraorbital Soft Tissue Dent Central Midfacial Contour Lateral Midfacial Contour Festoons: NASOLABIAL FOLD JOWLS PARACHUTE NECK LIPOMATOSIS PLATYSMAL BANDS SKIN LAXITY

 Normal

 Hypoplasia

 None

1234

-4 -3 -2 -1 0 1 2 3 4 -4 -3 -2 -1 0 1 2 3 4  None

Right: Right: Right: Right: Right: Right:

 Preseptal

01234 01234 01234 01234 01234 01234

MIMETIC MUSCLE STRENGTH/NEURO Frontal: R 0 1 2 3 4 L01234 Zygomatic: R 0 1 2 3 4 L01234 Buccal R01234 Mandibular R 0 1 2 3 4 L01234 SKIN Fitzpatrick Classification Glagou Classification  Lentigines  Acne Rosacea

Left: Left: Left: Left: Left: Left:

123456 1234  Actinic Keratoses:  Scars:

portion of the brow as well as the sphincter action of the orbicularis oculi muscles [14]. There are many methods to raise the ptotic brow [19]. However, it is important for the surgeon to understand that the purpose of a brow lift is partly to raise the brow but more important to reshape the contour of the brow. Most

 Malar

 Normal

 Abnormal

 Normal

 Abnormal

V-3  Normal

 Normal

 Mounds

01234 01234 01234 01234 01234 01234

SENSORY V-1 V-2 L01234 G Auricular

IMPRESSION: PLAN: Common Risks  Bleeding  Bruising  Scarring  Submandibular Gland Ptosis  Change of Vision  Loss of Vision  Eyelid Malposition  Tearing  Persistent Wrinkles  Persistent Swelling  Changes in Skin Color  Asymmetry  Change in Shape of Eyes or Face

 Orbital

 Abnormal

 Abnormal

 Acne Vulgaris:  Pigmentary Disturbances

 Persistent Droopiness  Loss of Fat  Infection  Contour Irregularities  Need for Additional fat  Skin Necrosis  Persistent Neck Prominence  Visible Submandibular Glands  Extrusion or Infection of Implant  Sensory and Motor Nerve Damage  Loss of Hair  Persistent Droopiness  Unrealized Expectations

female patients benefit from elevation of the lateral half of the brow only, thereby restoring the youthful arch of the brow. Men, on the other hand, require a straight brow that is less arched and sits lower than the female brow. The endoscopic forehead lift has now become the most popular method of raising the eyebrows and forehead.

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2.3.2 Endoscopic Browlift Anesthesia Pearls Many facial surgical procedures can be performed under local anesthesia. The endoscopic brow lift, however, is typically performed with intravenous sedation due to the difficulty in anesthetizing the glabella region.

2

Fig. 2.4 This patient has significant dermatochalasis, eyelid ptosis, and brow ptosis. The brow ptosis can be overlooked since the patient reflexively raises his eyebrows to pull the skin out of his visual axis. Note the deep wrinkles of his forehead. The horizontal lines are due to frontalis contraction. The vertical lines are sleep lines. These lines form when a pillow pushes his forehead tissues medially when sleeping face down

(a) Avoid Bleeding: Use 50–100 ml of tumescent anesthesia [24] to balloon up the scalp and forehead tissues. This compresses the blood vessels, separates out the layers, and reduces the chances of bleeding and nerve damage. The anesthetic is placed in a ring pattern starting from just above the ears, across the coronal line, and across the brows. (b) Tractional Nerve Pain: As the brow is released and elevated, there is traction on the sensory nerves. The traction extends to the posterior orbit, and the patient will feel pain and will be quite uncomfortable. To avoid the pain, perform supraorbital, supratrochlear, zygomaticotemporal, and zygomaticofacial nerve blocks with Septocaine® or Marcaine®. Extend the supraorbital block into the anterior, superior orbit. (c) Decrease the Amount of Sedatives: Have the anesthesiologist sedate the patient with propofol and then add 20–30 mg ketamine IV [2]. The ketamine will act synergistically with the propofol and allow the anesthesiologist to use less sedative. Giving the propofol first will reduce the potential ketamine side effect of bad dreams.

2.3.3 Endoscopic Browlift Surgical Procedure Pearls

Fig. 2.5 Deflation of the sub-brow fat pad (ROOF) contributes to the aging appearance of the brow. Reinflation of this region restores the more youthful three-dimensional contour of the eyebrow

This procedure can achieve elevation of the eyebrows and reduction of forehead furrows and glabellar folds. The aesthetic success of the endoscopic approach is similar to a coronal lift without the need for a large incision. Pearls of the endoscopic lift are separated into three sections: anesthesia, surgical procedure, and postoperative care.

(a) Vertical Incisions: Make all the incisions vertical and not horizontal. Vertical incisions, unlike horizontal ones, are almost never visible [19] (Fig. 2.6). (b) Lacrimal Retractors: Use a lacrimal retractor to keep the incisions open. The retractors will compress the edge of the incisions, thereby reducing the bleeding. The retractors make it easy to insert the endoscope and prevent blood from getting on the lens (Fig. 2.7). (c) Blind Dissection: 90% of the surgery can be performed without the use of an endoscope. Blind, subperiosteal dissection can be performed centrally until 2 cm above the brow. Laterally, dissection along the deep temporalis fascia can be performed easily with just headlight illumination. (d) Periosteal Elevators: A suction elevator with a “lipdown” configuration is an excellent tool to dissect along the deep temporalis fascia and for the blind subperiosteal dissection (Fig. 2.8).

2.3 Endoscopic Brow Lift

27

Fig. 2.8 Elevators with a downward curvature help dissect in the subperiosteal plane Fig. 2.6 Five vertical incisions are typically made in the temples and central and paracentral scalp

pull is determined. In general, the brow is pulled posteriorly and shifted medially. This allows elevation of the tail of the brow without getting the surprised look. (h) Fat Transfer: Aging of the brow is mostly due to ptosis but also can be due to deflation of the subbrow fat pad. Adding fat in the subbrow plane will restore the three-dimensional contour of the brow and give a more natural look [26] (Fig. 2.10).

2.3.4

Fig. 2.7 Standard lacrimal retractors are used to keep the scalp incisions open, which reduces bleeding and prevents hair from getting dragged into the wound

(e) Adequate Release: The key to getting a good lift is to free the attachments of the brow along the lateral orbit [45]. Superiolateral to the lateral canthus, a tendonous attachment of the orbicularis is noted. Use a standard facelift scissors to cut this tendon. This will elevate the lateral brow. (f) The Central Brow: Do not overelevate the central brow. This will result in a surprised look. Aggressive release or excision of the corrugator muscle will cause the medial brow to drift upward. I usually do not cut the periosteum medial to the supratrochlear nerves (Fig. 2.9). (g) Up-and-In Vector: After the entire scalp is mobile and the brow is ready for fixation, the direction of

Endoscopic Browlift Postoperative Care Pearls

(a) Postop Nausea: Nausea after a brow lift is often attributed to the anesthesia. I find that patients with a short forehead (short distance between the brows and the hairline) are more likely to get nauseous no matter what kind of anesthesia is used. Identify these patients prior to surgery and give them antiemetics. I ask the patients to place a scopolamine patch in the posterior auricular region a day before surgery and keep it in place for 48 h [27]. (b) Dressings: Head wraps or other pressure dressings do little to prevent swelling or bruising. All they do is make the patient feel uncomfortable. A loose dressing can be used to hold drains in place, if used. (c) Drains: I rarely use drains. However, when there is some oozing of the veins in the supraorbital region, a small drain is used and will reduce the bruising. I use a modified butterfly tubing, in which I cut additional small holes along the length of the tube. The butterfly tube is placed just above the brow and is brought out through the temporal incision.

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a

b

2

Fig. 2.9 (a) Pre operative photo of brow lift patient . The goal of surgery in the early to mid 1990’s was to release the entire brow and pull the brow as high as possible. (b) Release of the central glabella periosteum and aggressive resection of the procerus muscle lead to over-elevation of the central brow

a

b

c

d

Fig. 2.10 (a and b) Pre and post-operative photos of patient who underwent brow lift, blepharoplasty with insertion of fat to the sub-brow region. (c and d): Pre and post-operative photos of patient who underwent brow lift, insertion of fat to the sub-brow region without a blepharoplasty

2.4

(d)

(e)

(f)

(g)

It is then attached to a red-top blood collection tube. Showering: Have patients shower and wash their hair on postop day 2. This will get the incisions clean and make the patients feel much better. Strict Salt Avoidance: Canned foods, Asian food, and Mexican food all have high sodium content. Eating these in the early postop period will result in a lot of swelling. Sleeping Pattern: Have patients sleep on the back for the first 2 weeks after surgery. Sleeping on the side or on the stomach will cause the edema to settle in the eye region. A cervical pillow, available at most back stores, will help the patients unaccustomed to sleeping on the back. Botox®: Inject Botox in the glabella region within the first week of surgery. This will weaken the brow depressors and prevent the brow from getting pulled down during the first 3 months after surgery. This will increase the longevity of the browlift results [4]. During the first postoperative week, the brow and forehead region is typically numb, and the patients do not mind the injections.

Summary for the Clinician: Endoscopic Brow Lift ■ ■ ■ ■ ■ ■ ■

Tumesce the incisions and supraorbital region. Use Septocaine for nerve blocks, propofol and ketamine intravenously. Make short, vertical incisions. Add volume: Learn how to inject fat. Shift the forehead up and in. Botox the brow depressors postop. Identify the short-forehead patients; have them use scopolamine.

2.4 2.4.1

Upper Blepharoplasty Introduction

The upper eyelid forms the lowest portion of the forehead/eyebrow/eyelid continuum. As noted, it is extremely important to take into account brow position before deciding on the degree of “laxity” of the upper eyelids. The eyelids are unique in that they are regarded in both their aesthetic and functional sense. It is imperative that the surgeon prioritize function over beauty.

Upper Blepharoplasty

29

2.4.2 Patient Evaluation Patients presenting for blepharoplasty are evaluated in a similar manner to those patients presenting for brow lift. The eyelids are evaluated in layers: skin, muscle, fat, and bone. The skin of the eyelid is extremely thin and stretches over time. When considering the amount of skin that is “redundant,” it is important to keep in mind that there is a minimal amount of skin that is necessary to ensure proper eyelid function [39]. Patients with prominent eyes will require more skin since the eyelid has to cover a greater convex surface. It is also imperative that the surgeon keep in mind that the degree of dermatochalasis is based on brow position. Due to gravitational effects, the position of the eyebrow will be lower when the patient is upright. When the patient is supine, the brow will be in a higher position, thus requiring more skin for the eyelids to close properly. This is the reason why many patients who seem to have enough eyelid skin when we evaluate them in our office actually have nocturnal lagophthalmus. The most important concept in blepharoplasty is not about how much skin you take out but how much you leave. Remember also that a blepharoplasty cannot cure brow ptosis. The orbicularis oculi is separated into three portions: pretarsal, preseptal, and orbital. The pretarsal and preseptal portions of the eyelid are needed for proper eyelid closure [36]. Removal of too much orbicularis oculi muscle will affect blinking and lead to dry eyes. For this reason, currently we remove less muscle during blepharoplasty than we did in the past. The upper eyelid fat pockets contribute to the fullness of the upper eyelids [34]. In decades past, a hollow upper lid with a high lid crease was considered aesthetically pleasing. Fullness is now in vogue and considered a sign of youth. It is the role of the surgeon to decide how much upper eyelid fat to remove. In general, I remove a moderate amount of the medial fat pad while removing little to none of the central eyelid fat pad. The sub-brow fat pad known as the ROOF is evaluated. As we age, there is deflation of this fat, which contributes to the apparent redundancy of the eyebrow and eyelid skin. Reinflating this fat pad improves the threedimensional contours of the brow and eyelids. Hyaluronic acid fillers and fat are often used as substrates [10]. The bones of the orbit consist of the zygoma and the frontal bone. It is important to carefully evaluate the bony contour of the superior orbit. Asymmetries are noted as well as convexities and concavities of the bone. The larger the bone is, the greater the foundational effects the bone exerts on the overlying soft tissue. Thus, it is common to

30

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Pearls in Cosmetic Oculofacial Plastic Surgery

see one brow higher than another due to more prominent bone on the side with the higher eyebrow. These asymmetries are difficult to correct by manipulating the soft tissue. The only long-standing solution is to correct the bony asymmetry. Upper blepharoplasty is a technically simple surgery. There are only a handful of upper blepharoplasty techniques that are utilized [8]. However, blepharoplasty is often combined with other procedures, such as volume enhancement of the subbrow, brow-lifting and brow-stabilizing techniques, ptosis repair, lacrimal gland repositioning [23], and upper eyelid crease formation. Knowing when these adjunct procedures are necessary is the key to achieving great results. The pearls of upper blepharoplasty are separated into those for anesthesia and procedures.

(b)

2.4.3 Upper Blepharoplasty Anesthesia Pearls Upper blepharoplasty can easily be performed under local anesthesia. For patients who are anxious, 10 mg of diazepam is given orally 45 min prior to surgery [18]. I find it helpful for the patients to cooperate during surgery by opening and closing their eyes. (c) (a) Topical Anesthesia: Use a topical anesthetic to blunt the pain of the local injection [33]. A combination of tetracaine, lidocaine, and prilocaine cream is placed on the eyelid for 30 min prior to the procedure. (b) Local Anesthetic Choice: I prefer to use articaine (Septocaine) to inject the upper eyelids. Articaine is a dental anesthetic that is pH balanced and stings much less than lidocaine. It gives a dense block and is longer lasting than lidocaine. However, it takes several minutes to take effect. (c) Timing of Local Anesthetic Injection: I prefer to inject the local anesthetic prior to marking the upper eyelid. This puts the skin on stretch and gives me an accurate idea of the amount of eyelid skin. Since the pretarsal skin is on stretch, the location of the anticipated lid crease becomes more accurate.

(d)

2.4.4 Upper Blepharoplasty Surgical Procedure Pearls (a) Marking: The proposed new lid crease height is marked with a thin marking pen. The proposed skin incision is an ellipse that is greater in vertical dimension laterally. Typically in women, the inferior portion of the incision is marked at 9–10 mm. In a man,

(e)

it is marked at 8 mm. In an Asian, depending on the tarsal height, it is 6–7 mm [6]. The inferior border of the eyebrow skin is marked. The eyebrow skin is thicker than the eyelid skin, and the junction between the eyebrow and eyelid skin can be easily determined. Do not use the inferior brow cilia as a guide since many women pluck these hairs. Measure 13–15 mm inferior to the eyebrow/eyelid junction. This point will be the superior portion of the incision. This will guarantee that a minimum of 23–25 mm of eyelid skin will be left in the eyelid after the blepharoplasty. In a more prominent eye, more skin is left than a deeper-set eye. Skin/Muscle Excision: Traditionally, blepharoplasty involved removing the same amount of skin and muscle, usually in an en bloc fashion. Currently, none or a minimal amount of orbicularis oculi is removed. Thus, the skin is first excised and dissected off of the underlying muscle. If the goal of surgery is to volumize the region inferior to the superior orbital rim, no muscle is removed [8]. Fat can also be injected in the subbrow region. If a more sculpted look is desired, a small portion of the preseptal orbicularis is removed across the eyelid, usually more in the lateral portion of the lid. Crease Formation in the Lateral Third of the Lid: Defining the contour of the lateral portion of the lid is key to achieving aesthetically acceptable results in blepharoplasty. In patients with brow ptosis, elevating the lateral portion of the brow will improve the contour of the lateral portion of the lid. In patients with minimal brow ptosis or those who refuse a brow lift, redefining the contour of the orbital rim will mitigate the illusion of hooding. This can be achieved by suturing the superior cut edge of the orbicularis to the arcus marginalis in the lateral third of the lid [50]. These sutures support the subbrow fat pad and invaginate the skin and orbicularis so that they follow the contour of the orbital rim (Fig. 2.11). Management of Excess Lateral Skin: Often, there is excess skin in the lateral portion of the lid. To address this “dog-ear,” many surgeons extend the incision laterally toward the thicker lateral canthal skin. However, dissection and skin excision in the thick lateral orbital region often result in a visible scar. To manage the extra skin an “M-”plasty is used that reduces the length of the extended scar by 50% [1, 7, 47] (Fig. 2.12). Volumizing the Brow: Increasing the volume of the brow results in a more aesthetically pleasing contour of the upper eyelid. The deflation of the subbrow fat pad contributes to the dermatochalasis of the upper

2.4

a

d

g

b

e

Upper Blepharoplasty

31

c

f

h

Fig. 2.11 (a, b, and c) The arcus marginalis is identified, and a suture is placed between the arcus and the superior cut edge of the orbicularis. (d) A second buried suture is placed laterally. (e) These sutures stabilize the brow and prevent descent. (f) The wound is closed. (g, h) Pre- and postoperative results of patient undergoing this procedure

eyelid. Fat is suctioned from a donor region, usually the abdomen, and 1–1.5 ml of fat are injected into the subbrow region through the open blepharoplasty incision (Fig. 2.13). (f) Do Not Neglect the Ptosis: Upper eyelid ptosis not only results in drooping of the upper eyelid but also changes in the lid crease as well as changes in the brow position. When patients have upper eyelid ptosis, they

compensate for the ptosis by raising their eyebrows. This must be taken into account prior to undertaking a blepharoplasty. Furthermore, addressing the ptosis will add fullness to the upper eyelids. In general, it is easier and more predictable to perform a posterior ptosis repair than an anterior ptosis repair. If a patient responds to epinephrine, then he or she is a candidate for the posterior approach [37] (Fig. 2.14).

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b

a

“M” Plasty

Ellipse

2

c

d

Fig. 2.12 (a) Upper blepharoplasty incision closed with lateral M plasty. (b) The M plasty reduces the scar length by 50% compared to a standard ellipse. (c and d) Pre- and postoperative patient who underwent upper blepharoplasty. The patient has excess lateral skin, which would force the incision to extend lateral to the canthus. The M plasty keeps the scar within the orbital region

a

b

c

Fig. 2.13 (a) Fat is transferred to the suborbicularis region of the subbrow with multiple passes using a cannula. (b and c) Pre- and postoperative results of blepharoplasty and fat transfer

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

a

33

b

Fig. 2.14 Pre- and postoperative internal ptosis repair. Note the improvement in the hollowness of the upper lid and improvement of the lid crease

Summary for the Clinician: Upper Blepharoplasty ■ ■ ■ ■ ■

Remember: The upper eyelid is a continuum of the forehead. You cannot cure brow ptosis with a blepharoplasty. Preserve the orbicularis. Leave at least 23 mm of skin. Add volume: Use fat to augment the subbrow region.

2.5

2.5.1

Lower Blepharoplasty, Fillers, and Midface Augmentation Introduction

The lower eyelid forms the upper portion of the eyelid/ midface continuum. The midface contributes to the overall contour and shape of the eyelids. Ideally, the lower eyelid follows the contour of the globe until it reaches the inferior orbital rim. At this point, there is a slight concavity. As we follow the lid inferiorly, it becomes more convex. As we age, however, the lower eyelid “lengthens,” and the concavities and convexities change [15]. The goal of lower blepharoplasty is to restore the youthful contour of the lower eyelid and midface [20, 21] (Fig. 2.15). Lower blepharoplasty is not about removing

fat, skin, or muscle. Removal of this tissue may be a means to achieve this goal but not its primary purpose. The lower eyelids are unique in that they are regarded in both their aesthetic and functional senses. It is imperative that the surgeon prioritize function over beauty.

2.5.2 Patient Evaluation Patients presenting for blepharoplasty are evaluated in a similar manner to those patients presenting for all other facial procedures. The eyelids are evaluated in layers: skin, muscle, fat, and bone. The skin of the eyelid is extremely thin and stretches over time. When considering the amount of skin that is “redundant,” it is important to keep in mind that there is a minimum amount of skin that is necessary to ensure proper eyelid function. Patients are evaluated by putting the lower eyelid on maximal stretch. This involves having the patient open his or her mouth and looking up. The degree of skin excess is then assessed. Again, patients with prominent eyes will require more skin since the eyelid has to cover a greater convex surface. It is important to differentiate between loss of skin elasticity and actual skin excess. Loss of skin elasticity will result in rhytids, and skin may appear redundant. It is tempting to remove this skin. However, removal of this skin may result in lid retraction if there is truly no skin excess. It is often better to laser or peel the skin to improve the elasticity than to remove the skin (Fig. 2.16).

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a

b

2

c

d

Fig. 2.15 (a, b) The youthful eyelid/midface complex involves a short eyelid and a single midfacial convexity. (c, d) The aged midface involves a long lower eyelid and a double convexity of the midface

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

a

b

35

c

Fig. 2.16 (a) Patient appears to have extra lower eyelid skin (b) Excess lower eyelid skin determination: maximal skin stretch can be achieved by having patients open their mouth while looking up. (c) When the skin is in maximal stretch there is little excess noted

Laxity of the orbicularis results in sagging of the lower eyelid and a generalized aged appearance. The pretarsal and preseptal orbicularis are vital for proper eyelid function and position. Laxity of the orbicularis results in bowing of the lower eyelid, lid retraction, and festoon formation [12]. Traditional lower blepharoplasty involved removal of preseptal orbicularis and skin. The removal of this vital muscle invariably resulted in lid retraction to some degree. In some cases, the lids became cicatrized to the orbital rim, resulting in severe retraction and ectropion (Fig. 2.17). Once the muscle was removed, it was difficult to attain proper lid height and contour without extensive surgery, such as midface lifting or insertion of hard palate grafts [38]. As oculoplastic surgeons, we manage many of the complications of lower blepharoplasty. In the 1980s, the trend toward limited skin and muscle excision emerged, and transconjunctival blepharoplasty became popular [3] (Fig. 2.18). The transconjunctival blepharoplasty, however, only addressed the orbital fat and neglected the orbicularis laxity. The addition of pinch skin removal or laser resurfacing of the skin improved the skin but still did not address the underlying orbicularis [5]. Currently, in patients with skin and orbicularis issues, an orbicularis oculi plication blepharoplasty is performed. This procedure is described in Section 2.5.4. Protrusion of the orbital fat results in fullness of the eyelids above the inferior orbital rim. This fullness is exacerbated by concavities of the midface, where loss of the suborbicularis oculi fat (SOOF) is common. I like to give the following analogy to the patients: The eyelid/

Fig. 2.17 Severe lid retraction and ectropion resulting from aggressive removal of skin and orbicularis during transcutaneous blepharoplasty

midface is similar to a hill and a valley. If one is standing in a deep valley next to a hill, then the hill will appear higher. Once the valley is filled, the hill appears less high. Thus, removal of protruding fat (hill) in the face of a concavity inferior to the fat (valley) will create an even larger

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a

2

b

Fig. 2.18 (a and b) Transconjunctival blepharoplasty combined with laser resurfacing: Pre and Postoperative photos

Fig. 2.19 This patient has mild fat protrusion and significant infraorbital hollowness. The concavity extends from the medial to lateralmost portion of the eyelid. Removal of protruding orbital fat in this patient will make the hollowness worse

concavity (greater valley). It is imperative that the blepharoplasty surgeon evaluate the contours of the lower eyelid and decide if fat removal, fat addition, or fat repositioning is indicated (Fig. 2.19). The inferior orbital rim and bony midface are evaluated. The contours of these bones significantly contribute to eyelid position [13]. The relationship between the anterior corneal surface and the inferior orbital rim is evaluated in the sagittal plane. Patients are grouped into three categories: negative vector (the globe projects anterior to the rim), neutral vector (the globe is in line with the inferior rim), and positive vector (the globe projects posterior to the rim) [11] (Fig. 2.20). Patients with a negative vector configuration have less midfacial support and are more at risk for lid malpositions and contour irregularities after transconjunctival fat removal or transcutaneous blepharoplasty. Patients with prominent eyes and severe negative vector configuration may benefit from midface implants and a midface lift (Fig. 2.21). The question of fat removal versus fat preservation and repositioning is daunting [17]. I have abided by the

following general principals and have managed to get consistent results: In patients with a prominent eye, negative vector, and orbital fat protrusion, a fat-repositioning procedure is performed [42]. In patients with a deeperset eye, positive vector, and orbital fat protrusion, fat removal is acceptable (Table 2.2). The lower eyelids are probably the most difficult region of the face to rejuvenate. Attaining excellent and consistent results in lower eyelid surgery is dependent on proper evaluation of the anatomic problems and proper solutions to address these problems. Since there are so many anatomic variations among patients, there are multiple procedures that are available for lower eyelid rejuvenation. Often, a patient may require multiple procedures within the context of “blepharoplasty” to address each anatomic abnormality. For example, lower lid fat repositioning may be combined with orbicularis suspension and skin excision. Transconjunctival blepharoplasty may be combined with hyaluronic fillers and a chemical peel [22]. The pearls of lower blepharoplasty are separated into anesthesia and procedure sections.

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

a

b

37

c

Fig. 2.20 (a, b, and c) From left to right: positive vector, neutral vector, and negative vector. The negative vector patients are more at risk of complications of blepharoplasty. Fat is rarely removed in these patients. Fat repositioning or midface augmentation is more effective

2.5.3 Lower Blepharoplasty Anesthesia Pearls Lower blepharoplasty is usually performed under local anesthesia with or without intravenous sedation. Patients who prefer to have the procedure in the office are given 10 mg of diazepam orally 45 min prior to surgery. I find it necessary for the patients to cooperate during surgery by opening and closing the mouth (for skin excision) and moving the eyes.

Fig. 2.21 Severe midface retrusion with a very prominent eye. This patient would benefit from a midface lift with implants

(a) Topical Anesthesia: A combination of tetracaine, lidocaine, and prilocaine cream is placed on the eyelid for 30 min prior to the procedure. (b) Local Anesthetic Selection: Similar to the upper eyelids, I prefer to use articaine as the anesthetic when injecting the lower eyelids [43]. Articaine gives a dense block and even allows me to perform midface dissection with minimal discomfort. Due to potential permanent paresthesia, articaine should not be injected directly into the nerve or the region of the infraorbital foramen.

Table 2.2 Fat Removal Neutral or Positive Vector(Bone) Good SOOF and Subcutaneous Fat layers(Fat) ■ Can be Combined with Orbicularis Lifting(Muscle) ■ Can Be Combined with Skin Excision or Resurfacing(Skin) ■ Pure Transconjunctical Blepharoplasty Represents only 10 to 15% of My Cases

Fat Transposition

■

■

■

■ ■ ■ ■ ■

Negative Vector(Bone) Thin SOOF and Subcutaneous Fat layers(Fat) Abundant Extruding Orbital Fat Can be Combined with Orbicularis Lifting(Muscle) Can Be Combined with Skin Excision or Resurfacing(Skin) Pure Transconjunctical Blepharoplasty Represents 15% of Cases

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2.5.4 Lower Blepharoplasty Surgical Procedure Pearls

2

(a) Infralash Muscle Plication Blepharoplasty: This procedure is a modification of that described by Fagien [9]. Patients with true excess skin and laxity of the orbicularis are candidates for this procedure. The procedure is also useful in the management of festoons. Step 1: The lower eyelid skin and muscle are reinjected with dilute lidocaine with epinephrine to balloon up the skin. Step 2: Two traction sutures are placed through the gray line of the lower eyelid. The sutures are clamped to the towels on the forehead, thereby putting the lower eyelid on stretch. Step 3: A number 15 blade is used to make an incision from medial to lateral. Laterally, the incision extends about a centimeter and is angled slightly inferiorly. It can be hidden in a rhytid in this region. Step 4: The assistant places two fingers on the skin of the lower eyelid/cheek junction, thereby putting the eyelid on maximal stretch. Step 5: Scissors are used to dissect the skin off the underlying muscle. The dissection proceeds until the inferior orbital rim is reached. It is important to stay superficial and not to damage the underlying muscle. Pinpoint bleeding is cauterized at this point. If fat reposition or fat excision is necessary, it is performed at this point of the procedure. A small horizontal incision is made through the orbicularis, and the septum is buttonholed. Midface dissection can easily be performed through this small hole. Fat excision is also quite easy to perform through this hole. After the fat manipulation is completed, the orbicularis is closed with several 6–0 buried Vicryl sutures. The traction sutures are now released. Step 6: The degree of lower eyelid laxity is assessed. In 70% of cases, a lateral canthal plication suture is placed to tighten the lower eyelid margin. If severe laxity exists, a tarsal strip is performed. It is imperative that the lower eyelid hug the globe. The suture is replaced until the proper tension and proper position of the eyelid are achieved. Step 7: The orbicularis is grasped at a point inferomedial to the canthus. The muscle is then pulled superolateral and folded on itself. If this elevates the orbicularis in the desired manner, a buried, 5–0 PDS

suture is then placed from this portion of the orbicularis to the periosteum just lateral to the canthus. Multiple sutures are placed progressively laterally, thereby securing the orbicularis to the periosteum. The imbrication of the orbicularis adds fullness to the lateral lower eyelid, where a crescent typically forms during the aging process. Step 8: The skin is pulled superiorly and laterally, and the patient is asked to open his or her mouth and look superiorly. A pilot cut is then made through the skin at the lateral canthal region. Skin is conservatively excised lateral to medial. Very little skin is excised medially. The skin is then closed in the subciliary region. The skin lateral to the canthus is similarly excised. If a dog-ear is noted, an M-plasty can be performed (Fig. 2.22). (b) Transconjunctival Fat Repositioning: The transconjunctival approach for fat repositioning is utilized in patients with minimal or no skin/muscle issues. The techniques of fat repositioning have been described in the past [16, 17, 28]. The following are some tips that will make the procedure easier (Fig. 2.23): Step 1: A transconjunctival incision is made with a fine-tipped cautery. The incision extends through the lower eyelid retractors. Step 2: Cotton-tipped applicators are used to dissect to the inferior orbital rim. The arcus marginalis becomes visible. If the lateral fat pocket is prolapsing but is not large enough to reposition, it is excised at this point in the surgery. Step 3: The cutting cautery is then used to cut through the arcus marginalis. Step 4: A Senn retractor is helpful for the midface dissection. The dissection plane is a combination of preperiosteal and subperiosteal. Subperiosteal dissection proceeds for about 1.5 cm medial and lateral to the location of the infraorbital nerve. It is not necessary to disinsert the origin of the levator labii superioris muscle that overlies the infraorbital nerve. Blunt dissection with cotton-tipped applicators is performed on the anterior surface of the muscle. Step 5: The fat pockets are dissected free from their attachments to create a rectangular pedicle. Two 4–0 gut sutures are tied together. The suture is passed through the leading edge of the fat and locked at the medial and lateral poles (similar to what is performed in strabismus surgery).

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

a

b

d

g

39

c

e

h

f

i

Fig. 2.22 (a) The lid is put on stretch with a traction suture placed through the margin. (b) A skin flap created until the orbital rim is reached (c) A suture is placed to plicate the canthal tendon (d) Orbicularis muscle is pulled superior/lateral and sutured to the periosteum. Several sutures are sequentially placed. (d) Excess skin is removed by making a pilot cut at the canthus. The excess skin is removed medial and lateral to this vertical incision after having the patient look up and open their mouth (f and g) Pre- and postoperative patient who underwent muscle plication blepharoplasty (h and i) Pre- and post operative patient who underwent muscle plication blephaoplasty, fat injections and upper blepharoplasty

Step 6: The suture is then passed through the midface tissues and exits the skin. It is tied over a Telfa bolster. The medial, the central, and if necessary the lateral fat pockets are rotated into place as described. After the sutures are placed, it is important to check for ocular motility. If too much tension is placed on the fat, dimpling occurs on the exit site of the suture in attempted downgaze. If this occurs, the fat is further freed from its attachments until no movement is noted on the skin. Step 7: I find it helpful to place Microfoam tape on the lower eyelids and keep it in place for 5 to 7 days. This significantly reduces swelling and bruising. The

tape and sutures are cut on the seventh postoperative day. (c) Lower Eyelid Fillers or Fat: Many patients now present wanting a quick fix to their problems with minimal downtime and low chance of complications. The introduction of the hyaluronic acid fillers (e.g., Restylane®, Juvederm®) has allowed us to achieve these goals. The purpose of the lower eyelid fillers is to fill in the concavities of the infraorbital region [44]. This region begins at the inferior orbital rim and ends inferiorly at the lid cheek junction. Medially, the skin is extremely thin and is often discolored. The “dark circles” that many patients complain about are due to

40

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Pearls in Cosmetic Oculofacial Plastic Surgery

a

b

c

2

d

g

e

f

h

i

Fig. 2.23 Transconjunctival approach for fat repositioning. (a) Surgeon’s view. Orbital fat is pushed posteriorly and the arcus marginalis is visualized. (b) Subperiosteal dissection is performed. (c) Medial and lateral pockets are dissected, and a double-armed 4–0 gut suture is passed along the leading edge with locking bites at the medial and lateral poles. (d) Senn retractor is placed in the subperiosteal pocket (e) Sutures are brought out through the skin and tied over a telfa bolster. (f and g) Pre- and postoperative photos of patient who underwent transconjunctival fat repositioning. (h and i) Pre- and postoperative photos of another patient who underwent transconjunctival fat repositioning

the red color of the orbicularis muscle that shines through the thin, tan skin. The combination of these colors gives a purple appearance. There is minimal or no SOOF in this region of the eyelid. As we proceed laterally, the skin thickens slightly. Many patients

have an indentation in the inferolateral portion of the lid. It is important that the patients understand that the filler will only fill in the concavity (valley). It may camouflage the protruding fat (hill) but will not remove it.

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

1. Choice of Fillers: I prefer to use Restylane under the eyes since clinically Restylane appears to be less hydrophilic than Juvederm. One of the problems with the hyaluronic fillers is that they absorb fluid. In some patients, a secondary fluid bag can develop inferior to where the filler is placed. This seems to occur less with Restylane than with Juvederm. 2. Anesthesia: I prefer to use a topical anesthetic that consists of lidocaine, tetracaine, and prilocaine. The anesthetic is placed on the lower eyelids and left in place for 20 min. Some patients will swell from the local anesthetic, which may result in a false sense of fullness. 3. Needle Choice: The Restylane box comes with a 30-gauge needle. I prefer to use a 32-gauge needle since it allows me to be more precise with the amount of filler that I place. It takes greater pressure to inject through a 32-gauge needle. The needle must be securely tightened to the syringe so it does not pop off during the injection. 4. Vertical Strands: The Restylane is injected vertically from the superior portion of the cheek to the lower eyelid. Multiple vertical strands are placed deep to the orbicularis. In patients with a deep tear trough deformity, a small amount of filler is placed directly under the skin (Fig. 2.24). 5. Undercorrect: It is important that one undercorrect the lower eyelid region. The filler will absorb fluid and puff out over the first few weeks after the filler is placed. I typically have the patient return in 2–3 weeks and place a little more filler if necessary (Fig. 2.25). 6. Avoid Bruising: As with all procedures, we ask our patients to refrain from aspirin products, nonsteroidal anti-inflammatory medications, fish oils, and other herbal supplements for 10 days prior to the procedure. 7. Postprocedure Management: Patients are asked to avoid salt and high-sodium foods and to sleep on the back. At the 2-week follow-up visit, the eyelids are reassessed. If there are contour irregularities due to too much filler placement, dilute hyaluronidase can be used. I like to dilute the hyaluronidase and mold the filler. Full-strength hyaluronidase will take away all of the filler, which is unnecessary. (d) Midface Implants: There are many patients who present for lower eyelid bags who have significant midface retrusion. These patients have prominent globes, inferior orbital rim recession, or midfacial concavities (Fig. 2.26).

41

Fig. 2.24 Restylane is placed from the thicker cheek skin to the eyelid. Vertical strands are placed deep to the orbicularis

These patients appear to have significant bags of their lower eyelids. However, when the face is analyzed, one realizes that the protruding fat is in the same sagittal plane as the anterior corneal surface. The abnormality lies in the recessed inferior orbital rim and midface. Thus, the abnormality is a bony one. The best management of this problem is to augment the inferior orbital rim and midface [11, 48]. There are several implants that are available. The implants vary in thickness and material. The solid silicone tear trough implant (Implantech) is used in patients with a moderate tear trough deformity and thin skin. The implant is inserted subperiosteally, and the midface tissues are elevated over the implant. The medpore (Porex) orbital rim implants have a greater anterior projection. They come in several designs and sizes and vary depending on the degree of cheek augmentation [49]. They are also inserted subperiosteally and are secured in place with screw fixation, and the midface is elevated over the implant (Fig. 2.27).

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a

b

2

Fig. 2.25 (a) Photo prior to Restylane to lower eyelids. (b) Photo of Restylane to lower eyelids with overcorrection on the left side. There is fullness medially just inferior to the tear trough region

a

b

Fig. 2.26 (a) Significant midface retrusion: The globe is a centimeter anterior to the inferior orbital rim. (b) Lower midface concavity: The inferior orbital rim is in a good position, while the subrim is deficient

2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation

a

b

c

d

43

Fig. 2.27 (a and b) Pre and post-operative photos of patient who underwent midface implants and midface lift. (c and d) Pre and post-operative photos of another patient who underwent midface implants and lift

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Summary for the Clinician: Lower Blepharoplasty ■

2

■ ■ ■ ■ ■

Define the anatomic abnormality: think layers. Learn how to do peels. To add volume use filler fat or implants. It is okay to excise skin but not muscle. Reposition fat in negative vector patients. For a bony abnormality, think a bony solution: implant.

References 1. Asken S (1994) A modified M plasty. J Derm Surg Oncol 12(4):369–373 2. Badrinath S, Avramov MN, Shadrick M, et al. (2000) The use of ketamine-propofol combination during monitored anesthesia care. Anesth Analg 90:858–862 3. Baylis HI, Long JA, Groth MJ (1989) Transconjunctival lower eyelid blepharoplasty. Technique and complications. Ophthalmology 96(7):1027–1032 4. Carruthers, J Carruthers A (2009) The adjunctive usage of botulinum toxin. Derm Surg 24(11):1244–1247 5. Carter SR, Seiff SR, Choo PH, Vallabhanath P (2001) Lower eyelid laser rejuvenation: a randomized, prospective clinical study. Ophthalmol 108(3):437–441 6. Chen WP (1987) Asian blepharoplasty. J Ophthal Plast Reconstr Surg 3:135–140 7. Courtiss EH, Webster RC, White MF (1974) Use of double W plasty in upper blepharoplasty. Plast Reconstr Surg 53(1):25–28 8. Fagien S (2002) Adavanced rejuvenate upper blepharoplasty. Enhancing aesthetics of the upper periorbita. Plast Reconstr Surg 110:278–284 9. Fagien S (2007) Lower blepharoplasty: blending the lid cheek junction with orbicularis muscle and lateral retinacular suspension. In: Fagien S (ed) Putterman’s cosmetic and oculoplastic surgery. Elsevier, New York, Chap 15 10. Finn J, Cox S (2007) Fillers in the periorbital complex. Facial Plast Surg Clin North Am 15(1):123–132 11. Flowers RS (1993) Tear trough implants for the correction of tear trough deformity. Clin Plast Surg 20(3):403–415 12. Furnas DW (1993) Festoons, mounds and bags of the eyelids and cheek. Clin Plast Surg 20(2):367–385 13. Goldberg RA, Relan A, Hoenig JA (1999) Relationship of the eye to the bony orbit, with clinical applications. Aust N Z J Ophthalmol 6:398–403 14. Gunter JP, Antrobus SD (1997) Aesthetic analysis of the eyebrows. Plast Reconstr Surg 99:1807–1816

15. Hamra SR (1992) Repositioning of the orbicularis oculi muscle in composite rhytidectomy. Plast Reconstr Surg 90:14–22 16. Hamra ST ( 1995) Arcus marginalis release and orbital fat repositioning in midface rejuvenation. Plast Reconstr Surg 92(2):354–362 17. Hamra ST (1996). The role of orbital fat preservation in facial aesthetic surgery. A new concept. Clin Plast Surg 23(1):17–28 18. Harley DH, Collins DR (2008) Patient satisfaction after blepharoplasty performed as office surgery using oral medication with the patient under local anesthesia. Aesthetic Plast Surg 32(1):77–81 19. Hoenig JA (2005) Comprehensive management of eyebrow and forehead ptosis. Otolaryngol Clin North Am 38: 947–984 20. Hoenig JA, Shorr, NS, Shorr J (1997) The suborbicularis oculi fat in aesthetic and reconstructive surgery. Int Ophthalmol Clin 37:179–191 21. Hoenig JA, Shorr NS, Goldberg R (1998) The versatile SOOF lift in oculoplastic surgery. Facial Plast Clin 6(2): 205–219 22. Hoenig JA, Shorr NS, Morrow DM (2007) Chemical peel: eyelid and facial skin rejuvenation. In: Fagien S (ed) Putterman’s cosmetic and oculoplastic surgery. Elsevier, New York, Chap 21 23. Horton CE, Carraway JH, Potenza AD (1978) Treatment of a lacrimal gland bulge in blepharoplasty by repositioning the lacrimal gland. Plast Reconstr Surg 61(5):701–702 24. Klein JA (1990) Tumescent technique for regional anesthesia permits lidocaine dose of 35 mg/kg for liposuction. J Dermatol Surg Oncol 16:248–263 25. Kligman AM, Lauker RM (1988) Cutaneous aging: the difference between intrinsic aging and photoaging. J Cutan Aging Cosmet Dermatol 1:5–11 26. Kranendonk S, Obagi S (2007) Autologous fat transfer for periorbital rejuvenation: indications, techniques and complications. Dermatol Surg 33(5):572–578 27. Kranke P, Morin A, Roewer N, et al (2002) The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systemic review. Anesth Analg 95:133–143 28. Loeb R (1981) Fat pad sliding and fat grafting for leveling lid depressions. Clin Plast Surg 8:757–776 29. May JW, Fearson J, Zingarelli P (1990) Retro-orbicularis oculi fat (ROOF) resection on aesthetic blepharoplasty a six year study in 63 patients. Plast Reconstr Surg 86: 682–289 30. Mendelson BC, Hartley W, Scott, M (2007) Age-related changes of the orbit and midcheek and implications for facial rejuvenation. Aesthetic Plast Surg 31:419–423 31. Millard JF, Cornette de St Cyr B, Sheflan M (1991) The subperiosteal bicoronal approach to total facelifting: the DMAS—deep musculoaponeurotic system. Aesthetic Plast Surg 15:285–291

References 32. Mitz V, Peyronie M (1976) The superficial musculoaponeurtic system (SMAS) in the parotid and cheek area. Plast Reconstr Surg 58:80–88 33. Moody BR, Hold JB (2006) Anesthesia for office-based oculoplastic surgery. Dermatol Surg 31(7):766–770 34. Persichetti P, Di Lella F, Delfino F (2004) Adipose compartments of the upper eyelid: anatomy applied to blepharoplasty. Plast Reconstr Surg 113:373–378 35. Pessa JE (2000) An algorithm of facial aging: verification of Lambros’s theory by three dimensional stereolithography, with reference to the pathogenesis of midfacial aging, sclera show, and the lateral suborbital tera trough deformity. Plast Reconstr Surg 106:479–488 36. Porter JD, Burns LA, May PJ (1989) Morphological substrate for eyelid movements: Innervation and structure of primate levator palpebrae superioris and orbicularis oculi muscles. J Comp Neurol 287:64–81 37. Putterman AM, Urist MJ (1975) Muller’s muscle-conjunctival resection: technique for treatment of blepharoptosis. Arch Ophthalmol 93:619–623 38. Shorr NS (1997) Madame butterfly procedure: total lower eyelid reconstruction in three layers utilizing a hard palate graft: management of the unhappy post-blepharoplasty patient with round eye and sclera show. Int J Aesthetic Restor Surg 3: 3–26 39. Shorr NS, Cohen MS (1991) Cosmetic blepharoplasty. Ophthalmol Clin North Am 4(1):17–33 40. Shorr N, Enzer Y (1992) Considerations in aesthetic surgery. J Dermatol Surg Oncol 18:1081–1095

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41. Shorr N, Hoenig JA (1995) Brow lift. In: Levine M (ed) Manual of oculoplastic surgery. Butterworth-Heinrmann, Newton, MA 42. Shorr N, Hoenig JA, Goldberg RA (1999) Fat preservation to rejuvenate the lower eyelid. Arch Facial Plast Surg 1(1): 38–39 43. Steele EA, Ng JD, Poissant TM, et al. (2009) Comparison of injection pain of articaine and lidocaine in eyelid surgery. Ophthal Plast Reconstr Surg 25(1):13–15 44. Steinsapir KD, Steinsapir SM (2006) Deep-fill hyaluronic acid for the temporary treatment of the naso-jugal groove: a report of 303 consecutive treatments. Ophthal Plast Reconstr Surg 22(5):344–348 45. Steinsapir K, Shorr N, Hoenig JA, et al. (1998) Endoscopic forehead lift. Ophthal Plast Reconstr Surg 14:107–118 46. Stuzin JM, Baker TJ, Gordon HL (1992) The relationship of the superficial and deep facial fascias: the relevance to rhytidectomy and aging. Plast Reconstr Surg 89: 441–449 47. Webster RC, Fanous N, Smith RC (1979) Blepharoplasty: when to combine it with eyebrow, temple or coronal lift. J Otolaryngol 8:339–343 48. Yaremchuk MJ (2001) Infraorbital rim augmentation. Plast Reconstr Surg 107(6):1585–1592 49. Yaremchuk MJ (2005) Making the concave midface convex. Aesthetic Plast Surg 29(3)141–148 50. Zarem HA, Resnick JL, Carr RM, Wooton DG (1997) Browpexy: lateral orbicularis muscle fixation as an adjunct to upper blepharoplasty. Plast Reconstr Surg 10:1258–1261

Chapter 3

Current Concepts in the Management of Idiopathic Orbital Inflammation

3

Katherine A. Lane and Jurij R. Bilyk

Core Messages ■

■ ■

■

Idiopathic orbital inflammatory syndrome (IOIS) is a nonspecific inflammation of orbital tissue with no identifiable local or systemic cause. Inflammation is often categorized based on its anatomic location. Because there is no imaging study or laboratory test that can rule in or rule out IOIS, the syndrome remains one of exclusion. Classically, the signs and symptoms of IOIS are extremely responsive to corticosteroid therapy.

3.1

Introduction

Idiopathic orbital inflammatory syndrome is also known as orbital pseudotumor and is a constellation of clinical findings consistent with nonspecific inflammation of orbital tissues with no identifiable local or systemic cause. It is important to note that over the past century this has been a diagnosis in transition as improving diagnostic capabilities have steadily narrowed the once broad and expansive term “idiopathic.” For example, serologic tests and immunologic markers can now distinguish sarcoidosis, Wegener granulomatosis (WG), xanthogranulomatosis, and lymphoid hyperplasia, among others. The classic presentation of IOIS includes the abrupt onset, often over the course of hours, of periorbital pain associated with edema, erythema, and chemosis. Other protean features include proptosis, diplopia, and visual changes. When supported by positive findings on appropriate imaging studies and in the absence of any attributable cause, this clinical presentation is considered by some to be diagnostic. These signs and symptoms most likely represent the clinical manifestations of a variety of autoimmune and cell-mediated processes [18] for which the triggers have yet to be determined. IOIS is a heterogeneous disease process that can involve virtually any orbital tissue individually or in combination. Although there have been many classification schemes

■

■

Typical treatment doses are 1 mg/kg/day. Patients whose disease is “steroid resistant” are considered atypical. An orbital biopsy should be attempted in patients who present in an atypical fashion, in patients who do not respond to corticosteroid treatment, and in patients with recurrent episodes of inflammation. Patients with steroid-resistant IOIS may be responsive to low-dose orbital radiation or immunomodulating agents.

proposed, one of the most commonly employed is based on the anatomic location of inflammation: myositis, dacryoadenitis, peribulbar inflammation (posterior scleritis, tenonitis), and inflammation of the orbital fat, the orbital apex, or the cavernous sinus (presumed Tolosa– Hunt syndrome, THS) [11, 57, 60] (Figs. 3.1 and 3.2).

Summary for the Clinician ■ ■

■

IOIS is a diagnosis of exclusion. The classic presentation of IOIS includes the abrupt onset, often over the course of hours, of periorbital pain associated with edema, erythema, and chemosis and sometimes diplopia, proptosis, and vision loss. IOIS is commonly subclassified by anatomic location.

3.2 What Is the Diagnosis? One of the enduring controversies concerning IOIS lays in the question of what, precisely, is the diagnosis? Is “inflammation” a valid diagnosis, or is it merely a tissue response due to some other process [49] not yet

48

3 Current Concepts in the Management of Idiopathic Orbital Inflammation

3

Fig. 3.1 Idiopathic orbital inflammatory syndrome (IOIS) classification by anatomic location: (a) dacryoadenitis; (b) myositis; (c) tenonitis

elucidated by available testing? In addition, the literature is fraught with examples of masquerade syndromes, some either vision or life threatening. These are difficult issues to address. The fact that the diagnosis of IOIS is most comfortably made after its complete and sustained resolution underscores the healthy caution that should be used in considering the diagnosis of IOIS in any particular patient.

3.2.1 Pitfalls of Diagnosis Although the constellation of signs and symptoms of IOIS, as outlined, are considered suggestive of IOIS, there is no single variable that is pathognomonic. IOIS remains a diagnosis of exclusion. As such, other potential causes must be evaluated and ruled out based on clinical suspicion (Fig. 3.3).

3.2

What Is the Diagnosis?

49

Fig. 3.2 IOIS classification by anatomic site: (a) Orbital apical inflammation. (b) posterior scleritis. Note the thickened sclera on B-scan ultrasonography (left). The characteristic squared-off edge between the sclera and optic nerve insertion is known as the “T sign.” (c) Tolosa–Hunt syndrome. Note the asymmetric enlargement and enhancement of the right cavernous sinus (arrow)

Thyroid eye disease (TED) is the most common cause of proptosis in adults and is an important consideration in a patient who presents with suspected myositis. TED may occur in a euthyroid patient as the initial presentation of immune-mediated disorder that may also subsequently affect the thyroid gland or after clinical control of thyroid disease has been established. Typically, patients with TED will have other manifestations of the disorder,

including eyelid retraction, lateral flare, or a von Graeffe sign (lid lag in downgaze) (Fig. 3.4). In contrast, patients with the myositis variant of IOIS typically have eyelid edema [personal data; 60] or ptosis [personal data]. Patients with either TED or IOIS may have pain, proptosis, or diplopia. However, these symptoms tend to have a slow and insidious onset in TED in contradistinction to the explosive symptomatology in IOIS. Radiographically,

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3 Current Concepts in the Management of Idiopathic Orbital Inflammation

LYMPHOPROLIFERATIVE DISEASE (INCLUDING LYMPHOMA)

PRIMARY MALIGNANCY OR METASTASIS

IDIOPATHIC ORBITAL INFLAMMATION

INFECTION (FUNGAL, AFB, PARASITIC), MISCELLANEOUS (AMYLOID, ETC)

ATYPICAL INFLAMMATION (SARCOIDOSIS, WEGENER GRANULOMATOSIS)

Fig. 3.3 Differential diagnosis. The constellation of signs and symptoms of IOIS overlaps significantly with other categories of pathology, especially when they manifest with a significant inflammatory component

Fig. 3.4 The inflammatory phase of thyroid eye disease (TED). Note the lid edema, chemosis, and proptosis, which are often seen in IOIS. However, upper eyelid retraction and bilateral presentation are distinctly atypical for IOIS

TED patients may have an expansion of the orbital fat compartment, or they may have unilateral or bilateral fusiform enlargement of the extraocular muscles (EOMs) that spares the tendonous insertions and tends to affect the rectus muscles in a generally predictable frequency: inferior > medial > superior > lateral [20, 39] (Fig. 3.5). An isolated, enlarged lateral rectus muscle would be uncommon in TED. In contrast, EOM involvement in IOIS is often unilateral and can affect any portion of the muscle, including the tendonous insertion onto the globe [11]. “Spillover” of inflammation into adjacent structures (orbital fat, lacrimal gland, Tenon fascia, or posterior sclera) is also a common feature of IOIS. Acute bacterial cellulitis has an abrupt onset, is quite painful, and is often associated with a prior history of paranasal sinusitis, dental disease, or trauma [30]. Patients may be febrile and have an elevated white blood cell count, in contrast to patients with IOIS. Since it may be life threatening, orbital cellulitis must be the initial consideration in any patient presenting with acute orbital inflammation. In most cases, the results of orbital imaging are helpful in distinguishing between the two diagnoses: Orbital cellulitis frequently occurs as a complication of acute bacterial cellulitis, and sinus opacification is usually obvious on CT, as opposed to the relatively clear paranasal sinuses seen in IOIS (Fig. 3.6). A history of penetrating trauma should also be sought in all patients to rule out the possibility of direct bacterial inoculation or the presence of an infected and possibly occult foreign body. Patients with suspected bacterial orbital cellulitis should be hospitalized and started on broad-spectrum intravenous antibiotics. The growing specter of resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), may complicate this treatment. Except in young children, who may exhibit sterile subperiosteal abscesses [12], an attempt should be made to drain orbital

Fig. 3.5 CT of TED. Axial image (left) shows marked enlargement of the medial rectus muscles with characteristic sparing of the tendonous insertions. On coronal imaging (right) note that the right inferior and medial rectus muscles are more enlarged than the lateral

3.2

What Is the Diagnosis?

51

a1

a2

a3

a4

b1

b2

b3

Fig. 3.6 Both children presented with acute proptosis, pain, and diplopia. External ophthalmoplegia is present on exam. (a) CT reveals opacification of the left maxillary (asterisk) and ethmoid (green arrow) sinuses along with a subperiosteal collection (red arrow). These findings are consistent with sinusitis and an adjacent subperiosteal orbital abscess. (b) In this patient with IOIS, the paranasal sinuses are clear, but a poorly circumscribed opacification is present in the retrobulbar space

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collections and to reestablish sinus drainage. On occasion, a clear distinction between pediatric IOIS and orbital cellulitis cannot be made based on clinical and radiographic evidence. For example, patients may present with acute orbital inflammatory signs and mild-tomoderate sinus mucosal thickening, mild fever, and minimally elevated white cell count. In such cases, it is prudent to admit the child and first treat with 24–48 h of broadspectrum antibiotics before instituting corticosteroid therapy. Prompt resolution on corticosteroids is typically indicative of IOIS. Sarcoidosis is a chronic systemic disease characterized by noncaseating granulomatous inflammation that can involve the lungs, skin, lymph nodes, and orbit. As in IOIS, there is no single finding or laboratory test that is diagnostic of sarcoidosis. Diagnosis relies on the combination of a compatible clinical picture involving at least two organ systems, histologic evidence of noncaseating granulomas, and the exclusion of other possible causes [23]. Orbital involvement occurs in up to 22% of patients with known systemic disease [23, 43], but ophthalmic symptoms can often herald the discovery of systemic disease. Within the orbit, sarcoidosis can unilaterally or bilaterally involve the lacrimal gland, the EOMs and other soft tissues, and the optic nerve (Fig. 3.7). The most common orbital complaint in a large series of biopsy-proven sarcoidosis was that of a slowly progressing mass (88.5%), followed by proptosis (42%), discomfort as opposed to pain (30.8%), ptosis (27%), and restricted extraocular motility (23%) [43]. Radiologically, the lacrimal gland exhibits a well-defined homogeneous

Fig. 3.7 Orbital sarcoid. Note the poorly defined mass in the anterior portion of the medial orbit (arrow). Unlike IOIS, orbital sarcoid often presents in an indolent fashion, but acute signs may occur. Because of the long list of potential diagnoses, biopsy is necessary for definitive diagnosis

enlargement, and bilateral involvement is common; orbital involvement can manifest as a discrete mass or diffuse process involving more than two orbital quadrants; and EOMs may be involved, often in conjunction with adjacent orbital or lacrimal gland involvement [43]. Angiotensinconverting enzyme (ACE) is produced by sarcoid granuloma cells and may be elevated in up to 66% of patients diagnosed with sarcoidosis [23]. Chest imaging is also helpful in the workup. While the diagnosis of IOIS should not be considered in the presence of known systemic sarcoidosis, there is some confusion in the ophthalmic literature regarding the diagnosis of solitary orbital sarcoid. This entity was reviewed by Mombaerts and colleagues, who presented a series of 7 patients and reviewed 30 more in the literature. All patients presented with unilateral signs of inflammation or mass effect and demonstrated noncaseating granulomas on biopsy [35]. None were found to have systemic sarcoidosis. These cases may represent idiopathic granulomatous orbital inflammation [35, 43], although thorough investigation must first rule out other potential causes. Specific immunologic and microbiologic tests include the beryllium lymphocyte proliferation test, tests for antineutrophil cytoplasmic antibodies (ANCA) for WG and related vasculitis, serologic and skin tests for fungal infections, and rapid culture for mycobacteria. The distinction between solitary orbital sarcoid and idiopathic granulomatous inflammation (IOIS) may be academic as both are diagnoses of exclusion and are treated in a similar manner [43]. Wegener granulomatosis classically consists of necrotizing granulomatous inflammation of the upper or lower respiratory tract; necrotizing granulomatous vasculitis, usually affecting small vessels; and focal segmental glomerulonephritis [28]. As with sarcoidosis, no single finding or laboratory test is diagnostic. A patient is said to have WG if at least two of the following criteria are present: (1) nasal inflammation or oral ulcers; (2) abnormal chest radiograph; (3) hematuria or red cell casts present on urinary analysis; or (4) granulomatous inflammation on biopsy. Ocular involvement is seen in 52–61% of all patients at some point during the disease course [45]. Cases of WG involving the orbit are commonly part of a more limited form of the disease that affects the ear, nose, throat, and chest but spares the kidneys [6, 42]. As opposed to the systemic form, which rapidly progresses to multisystem damage and renal failure, this “limited” form may have a chronic remitting course [6, 28]. The pathophysiological features of orbital WG frequently result from direct spread of the disease process from the sinonasal region [58]. Alternatively, there may be a solid

3.2

What Is the Diagnosis?

53

Fig. 3.8 Wegener granulomatosis. Top left: A patient presented with acute inflammatory changes suggestive of anterior scleritis. Biopsy and serology confirmed WG. Top right: A different patient with saddle nose deformity and severe globe restriction on the left. CT (bottom) demonstrates severe bone destruction of the nasal and sinus anatomy and complete absence of the medial orbital walls. Such findings would be extremely atypical for IOIS

inflammatory mass or evidence of inflammatory myositis, necrotizing scleritis, corneal ulceration, uveitis, retinal vasculitis, or an optic neuropathy [42, 58]. The most common manifestations of WG in one large orbital series [58] were sinusitis (66%), proptosis (69%), and nasolacrimal duct obstruction (52%). Others included the presence of conjunctival granulomas and dacryoadenitis. Interestingly, only 6 of 20 patients with orbital mass or proptosis had ocular pain associated with the orbital involvement. Also in contrast with IOIS, WG often exhibits bilateral disease [42]. Radiologically, WG can show bone destruction, which would be distinctly unusual in IOIS (Fig. 3.8). In addition, while the vast majority of the pathological processes that occur in the retrobulbar space, both neoplastic and inflammatory, appear hyperintense on T2-weighted technique, WG lesions tend to appear hypointense [7]. This distinction is thought to be related to the abundance

of fibrocollagenous tissue present in these granulomatous lesions. It should be noted, however, that chronic inflammation as seen in long-standing IOIS may also appear hypointense on T2 images [2]. While cANCA testing is highly sensitive in systemic WG, it may be negative in 32% of patients with the sino-orbital variant of WG [58]. The final major category in the differential diagnosis of IOIS is that of a neoplasm. In adults, neoplastic disorders of the orbit tend to be primary tumors, often of neurogenic, lymphoproliferative, or vascular origin [47]. Imaging studies may reveal a mass lesion, bony changes, or extension into or from adjacent spaces such as the sinonasal or intracranial cavities. As opposed to IOIS, the tempo of onset is rarely explosive. Patients more often present in a subacute or chronic manner with proptosis, EOM dysmotility, signs of orbital congestion, or a palpable mass. In a large study from China, Yan et al [59]

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compared patients with IOIS to those with lymphoma and found that more patients with lymphoid tumors had a palpable mass than did patients with IOIS (90% vs. 65%, p < .0001). They also noted that patients with IOIS were more likely to present with lid swelling (55% vs. 40%, p = .014); eyelid or conjunctival congestion (42% vs. 24%, p = .001); and pain (24% and 1%, p < .0001), among others. Two entities that may mimic IOIS in the pediatric population need to stressed. Rhabdomyosarcoma presents with rapidly progressive orbital signs (proptosis, globe malposition) in the absence of acute inflammation (pain, erythema, etc.), but on occasion, inflammation may also be present [53]. Conversely, a ruptured dermoid cyst presents with an intense inflammatory orbital reaction that may mimic cellulitis or IOIS [53]. Tumors metastatic to the orbit are rare, representing 7–10% of all orbital neoplasms [47, 53]. Similar to IOIS, diplopia, ocular motility limitation, proptosis, or globe dystopia and the presence of a palpable mass are common signs and symptoms of metastasis to the orbit [14, 16]. However, the tempo of onset tends to be less acute than in IOIS (Fig. 3.9). Common primary sites include breast, prostate, lung, and kidney. Of note, orbital metastasis may be the presenting sign of systemic cancer in as many as 25–30% [14, 53] of patients. Certainly, in any patient with a known history of cancer, the diagnosis of IOIS should be made with extreme caution. Even if biopsy of the involved tissue may appear inflammatory, the possibility of an acute or chronic inflammatory reaction surrounding a metastatic lesion should also be considered.

3.2.2 A Diagnostic Corticosteroid Trial? Despite patient age, duration of symptoms, or tissue type involved, one of the most consistent findings in patients with IOIS is an exquisite sensitivity to corticosteroids. It is common to observe near-complete resolution of a patient’s signs and symptoms after the first dose or two of oral or intravenous steroids (Fig. 3.10). Some have advocated that such a rapid and significant response to corticosteroids be considered diagnostic of IOIS [29]. Others counter that any type of reactive inflammation, be it due to tumor, infection, systemic vasculitis, or hematological malignancy, will demonstrate clinical improvement with systemic steroids, and that therefore a “steroid response” cannot be used as a diagnostic test for IOIS [34, 49]. There are also numerous examples in the literature of patients with IOIS who “fail” corticosteroid therapy. Care must be taken in interpreting these steroid failures, however, as steroid resistance may be multifactorial. For example, inadequate dosage may result in incomplete resolution of

Summary for the Clinician ■ ■

■

■

■

■

■

IOIS is a diagnosis of exclusion. Patients with TED may present with periorbital pain, proptosis, and diplopia that is slow in onset and accompanied by characteristic eyelid findings, such as upper eyelid retraction and lateral flare. Acute bacterial cellulitis has an abrupt onset, is painful, and is often associated with a prior history of sinusitis, dental disease, or trauma. Patients are often febrile with an elevated white blood cell count. Orbital imaging usually distinguishes infection from IOIS. Sarcoidosis is a chronic systemic disease characterized by noncaseating granulomatous inflammation involving at least two organ systems. Within the orbit, sarcoidosis can involve the lacrimal gland, the EOMs and other soft tissues, and the optic nerve. On occasion, isolated orbital sarcoid may occur with no serologic or chest abnormality. WG is a chronic systemic disease characterized by necrotizing granulomatous inflammation of the upper or lower respiratory tract; necrotizing granulomatous vasculitis, usually affecting small vessels; and focal segmental glomerulonephritis. Cases involving the orbit may be part of a more limited form of the disease and may present with sinusitis, proptosis, nasolacrimal duct obstruction, conjunctival granulomas, or dacryoadenitis. cANCA may be negative in the limited form of WG. Primary orbital tumors often present with the insidious onset of proptosis, orbital congestion, or diplopia. Tumors metastatic to the orbit are rare but may present in a manner similar to IOIS. Orbital biopsy should be strongly considered in any patient with a known history of cancer who presents with suspected IOIS.

a patient’s symptoms and thus may be interpreted as treatment failure. The standard oral dose for suspected IOIS is between 1.0 and 1.5 mg/kg/day or approximately 80 mg of prednisone a day for a 70-kg adult. In addition, corticosteroids that are tapered too rapidly may predispose a patient to significant symptomatic flares, which may also be misconstrued as “steroid failures.” The literature addressing the use of corticosteroids in the diagnosis of IOIS is limited. Mombaerts et al examined the efficacy of systemic corticosteroids in a group

3.2

What Is the Diagnosis?

55

Fig. 3.9 Metastatic breast carcinoma. A T1-weighted postcontrast MRI with fat suppression of a patient who presented with an indolent progressive external ophthalmoplegia. Despite the presence of bilateral orbital infiltrates (arrows) and a history of breast cancer, the patient was treated with an 18-month course of oral corticosteroids for presumed IOIS. Subsequent referral diagnosed bilateral metastatic breast carcinoma to the orbits, which responded to chemotherapy

Fig. 3.10 A patient with suspected IOIS based on clinical exam and imaging (see Fig. 3.6b) on presentation (left) and after 2 days of oral corticosteroid therapy. Note the dramatic improvement in external signs

of patients with IOIS that excluded all patients with inflammatory myositis or dacryoadenitis [34]. Of the 27 patients in this study who were initially treated with corticosteroids, only 78% of patients demonstrated an initial response to a single course of oral corticosteroids. With this relatively low sensitivity rate and the low specificity of corticosteroids, they concluded that the response to corticosteroids should not be used as a diagnostic test of IOIS. However, when the same group examined patients with the myositis variant of IOIS, all patients responded to oral corticosteroids. However, 50% of initial responders experienced symptomatic recurrence, and all of these cases were defined as a steroid failure [33].

Certainly, in a patient who presents in a manner classic for IOIS, an immediate and near-complete response to systemic corticosteroids may allow the clinician to feel more comfortable with the presumptive diagnosis. This adequate response to empiric therapy does not mean that continued vigilance is not necessary, however. In addition, one cannot conclude that an initially successful corticosteroid regimen is diagnostic of IOIS if the patient cannot be easily tapered off of the steroids, or if he or she experienced a recurrence of symptoms. Such a case would be considered “atypical,” and alternative diagnoses should be sought, be it through a biopsy of the involved tissue or through further systemic workup.

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Summary for the Clinician ■

3 ■

■

IOIS is classically exquisitely sensitive to corticosteroids. Patients who do not quickly respond to adequate steroid therapy are considered “atypical.” Corticosteroid therapy should be considered a failure only if adequately dosed and tapered. Relapse is common if steroid therapy is tapered too quickly. Atypical cases of suspected IOIS either at presentation or after failed corticosteroid therapy should undergo further workup, including tissue biopsy.

3.2.3 The Question of Biopsy The role of orbital biopsy in the diagnosis of IOIS is controversial and has been debated extensively in the literature. Briefly, some experts posit that an orbital biopsy should be attempted in all patients prior to the initiation of steroid treatment of IOIS, provided the tissue in question is easily accessible, arguing that “inflammation” is not a diagnosis but may be a sign of a potentially dangerous underlying tissue process [49] (Fig. 3.9). Others counter that orbital exploration may expose the typical IOIS patient to unnecessary surgical risk (Fig. 3.11). In one study of IOIS in pediatric patients, those who underwent orbital biopsy were more likely to experience “serious residua from their disease,” such as decreased visual

acuity, persistent proptosis, and EOM pareses and restriction [36]. These clinicians concluded that orbital biopsy should be reserved for patients with an atypical presentation, those who do not experience an immediate and sustained response to corticosteroids, and those whose symptoms recur. Close inspection of the arguments from both camps, however, reveals that in clinical practice the chasm between them may be quite narrow and possibly nonexistent. For example, both agree that in the case of orbital myositis or an inflammatory lesion located at the orbital apex, the benefits of histopathologic confirmation should be carefully weighed against the possibility of iatrogenic damage [46]. In a similar vein, while the advocates for biopsy may argue that there is an unacceptably high incidence of malignancy in cases of lacrimal gland masses [47, 53], in many cases IOIS and lacrimal gland tumors can be distinguished by the history (tempo of onset, associated symptoms, etc.), clinical exam, and results of radiologic studies. In cases that may be uncertain, few would argue with the legitimacy of biopsy. In addition, any atypical variable (e.g., a subacute or smoldering onset, lack of associated pain, bony destruction on imaging), recurrent episodes of inflammation, or a history of local or distant malignancy should prompt a biopsy in most cases.

Summary for the Clinician ■

■

■

Some experts believe that an orbital biopsy should be attempted in all patients prior to the initiation of steroid treatment of IOIS. Others recommend an orbital biopsy only in select patients who (1) present in a manner atypical for IOIS; (2) fail to respond to corticosteroid therapy; or (3) experience recurrent disease. Proposed algorithms for the management of typical and atypical IOIS cases are listed in Figs. 3.12 and 3.13, respectively.

3.3 Treatment

Fig. 3.11 Levator injury after orbital biopsy. Note the significant right eyelid ptosis with poor levator function in this patient who underwent orbitotomy for biopsy of the levator–superior rectus complex. Biopsy was consistent with IOIS. Eyelid function did not improve, and final correction required two additional surgeries

The inflammation in IOIS results from the escalation of a series of cascading enzymatic processes that occurs in target tissues as a result of some unknown inciting factor. Localized cellular damage can lead to the activation of phospholipases, which mediate the release of arachidonic acid and perpetuate the cascade of inflammatory mediators in an explosive fashion. While an in-depth discussion of inflammation is beyond the scope of this text,

3.3

Treatment

57

TYPICAL IOI (onset, symptoms, imaging)

Systematic Corticosteroids

Rapid and sustained response

Poor response or recurrence despite adequate dosage and taper

Poorly tolerated side effects

Gradual taper over 6−8 weeks

Biopsy

Specific inflammation (granulomatous, vasculitic)

Nonspecific inflammation Cosider intraorbital steroids, NSAIDs, XRT (? Biopsy)

Tailored systemic work-up Neoplasia Rheumatology consultation for immunosuppressants

Fig. 3.12 Proposed management algorithm for typical IOIS (Modified from ref. 18)

ATYPICAL IOI (onset,symtoms,imaging) Blopsy if feasible Lower threshold for lacrimal gland, anterior orbital tissue, or discreet orbital mass

Nonspecific inflammation

Higher threshold for orbital apex,Eom or optic nerve shealth

Neoplasia

Specific Inflammation (granulomatous, vasculitic)

Systematic Corticosteroids Tailored systemic work-up

Rheumatology conultation for immunosuppressants/modulars

Fig. 3.13 Proposed management algorithm for atypical IOIS (Modified from ref. 18)

some knowledge of this inflammatory cascade is necessary to understand the treatment options available for patients with IOIS.

3.3.1

Corticosteroids

Corticosteroids inhibit the cascade of inflammation and the immune response at virtually every level via the

suppression of proinflammatory cytokines. The effect is a nonspecific and global immune suppression. Herein lies the argument against the use of corticosteroids as part of the diagnostic algorithm for IOIS, as discussed. Nevertheless, in clinical practice, corticosteroids remain the mainstay of treatment for IOIS at present [18, 33, 34, 36, 46, 60]. The most common route of administration of corticosteroids in the treatment of IOIS is oral, at a starting dosage of 1.0–1.5 mg/kg/day. Parenteral steroids may also

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be employed, usually in cases of IOIS-related optic neuropathy. The initial dose is tapered over the course of weeks to months, as dictated by the patient’s symptoms. While too rapid a taper may predispose the patient to rebound inflammation, a prolonged steroid taper will expose the patient to some of the more serious treatmentrelated side effects. Weight gain, gastritis, cushingoid facies, and mood swings are commonly cited effects. Corticosteroid treatment can also exacerbate or induce diabetes, hypertension, glaucoma, and cataract in susceptible patients. In light of the significant side effects of systemic therapy, some authors advocate local intraorbital injection of triamcinolone acetonide in cases of inflammatory masses or dacryoadenitis [15]. It should be noted that this is an off-label use of the medication, and it carries with it the inherent risk of retinal vasculature embolization of particulate matter. A review of the literature reveals numerous examples of “steroid-resistant” IOIS as well as outright steroid failures. Direct comparison of published studies is difficult, however, as inclusion criteria and treatment protocols are inconsistent at best. For example, Mombaerts et al reported a low cure rate (37%) and a high recurrence rate (52%) of IOIS treated with corticosteroids; however, patients with myositis and lacrimal gland involvement were excluded from analysis [34]. In a separate study looking only at patients with idiopathic inflammatory myositis, the authors reported that all patients responded well to corticosteroid therapy, but symptoms recurred in 50% with prolonged follow-up [33]. In Yuen and Rubin’s study [60], 69% of patients were managed with corticosteroids alone and a further 9% with the addition of a nonsteroidal anti-inflammatory drug (NSAID) to manage residual symptoms, for a total of 78%. An incomplete resolution of symptoms was noted in approximately 30%, and these patients were designated steroid failures.

3.3.2

Radiation

Radiotherapy is effective treatment for IOIS, especially in patients who are steroid responsive but intolerant of steroid-related side effects. The studies demonstrating efficacy of radiation therapy are somewhat dated and, as is the problem with many studies concerning IOIS, are difficult to compare due to different inclusion criteria and treatment measures. For example, Sergott et al [51] showed a response in 15 of 21 patients (72%) with a dose of 1,000– 2,000 cGy over 10–15 days. Orcutt et al [40], on the other hand, showed a 75% treatment effect at doses of 2,500 cGy over 15 days. Gunalp et al [17] reported successful results

of radiation treatment in 9 of 14 (64%) of patients who failed to respond to corticosteroid therapy. Fortunately, the side effects of low-dose orbital radiation in the range of 1,000–2,500 cGy are rare. The eyelids tolerate approximately 5,000–6,000 cGy before exhibiting significant signs of radiation dermatitis and eyelid scarring. Similar doses induce lacrimal gland atrophy, radiation retinopathy, and optic neuropathy. At the lower end, punctate keratopathy and conjunctivitis are noted with dosages of between 3,000 and 4,000 cGy. A radiation cataract may develop at 2,000 cGy [1]. However, these radiation dosage associations are averages; certain patients, such as those with vasculopathic risk factors (hypertension, diabetes mellitus, etc.), may be more at risk for adverse events related to radiation therapy.

3.3.3 Other Agents Following a lead from rheumatologists and dermatologists, there has been a growing interest among orbital specialists in the use of immunomodulating agents in the treatment of IOIS. Although corticosteroids remain a first-line treatment, immunosuppressive agents, including antimetabolites (e.g., methotrexate [MTX], azathioprine); alkylating agents (e.g., cyclophosphamide, chlorambucil); T-cell inhibitors (e.g., cyclosporine, tacrolimus); and biologics (e.g., infliximab, etanercep) it are increasingly used as steroid-sparing alternatives. Methotrexate is an antimetabolite that interferes with intracellular folic acid metabolism during DNA and RNA synthesis. It is a cytotoxic agent that is used in combination with other chemotherapeutic agents in the treatment of many types of cancers. Lower doses of MTX have been shown to be very effective for the management of rheumatoid arthritis, Crohn disease, and psoriasis [24]. Several small studies have addressed the usefulness of MTX in the treatment of orbital inflammatory disease. Both Shah et al [52] and Smith and Rosenbaum [55] showed that MXT (7.5–25 mg/week) had some benefit in patients with noninfectious orbital inflammatory disease, including IOIS, who had failed to respond to systemic corticosteroids or orbital irradiation. Azithroprine is also an antimetabolite that works by inhibiting purine synthesis. Like MTX, it has been used in the treatment of various rheumatologic and dermatologic conditions (i.e., rheumatoid arthritis, inflammatory bowel disease, pemphigus, systemic lupus erythematosis), but its efficacy in terms of orbital disease is limited to a small number of case reports [9]. Alkylating agents slow or stop cell growth by forming cross-links between DNA strands, inducing apoptosis. Examples include cyclophosphamide (Cytoxan), a mainstay

3.3

in the treatment of systemic lupus erythematosus (SLE), and chlorambucil, used only in very refractive cases of rheumatoid arthritis. There are limited data on the use of these agents for IOIS, and the results are at times conflicting. Leone and Lloyd [29] successfully treated two patients with cytoxan (200 mg/day plus corticosteroids), while Mombaerts et al [34] found that two patients with steroid-resistant IOIS demonstrated no response to a similar regimen. Chorambucil has proven useful as an alternative to radiotherapy in the treatment of orbital and adnexal lymphoma [3], but there is little information in the peer-reviewed literature addressing its use in the treatment of IOIS. Cyclosporine and mycophenolate mofetil (CellCept) are T-cell inhibitors. These agents prevent the transcription of interleukin 2 and inhibit lymphokine production, reducing the function of effector T cells. Cyclosporine is available in systemic formulations as well as topical preparations, well known to ophthalmologists by the brand name Restasis®. Similar to the previously mentioned agents, use of these T-cell inhibitors by the rheumatologic and dermatologic communities (e.g., for rheumatoid arthritis, inflammatory bowel disease, polymyositis) has pioneered their use in orbital disease. There are several case reports that suggested that cyclosporine may have a role in the treatment of steroid-resistant IOIS. Diaz-Llopis and Menezo [10] controlled the symptoms of one patient with low-dose cyclosporine (starting dose 5 mg/kg, maintenance dose 2 mg/kg) for 10 months prior to a recurrence. Sanchez-Roman et al [50] successfully treated one patient with recurrent myositis who became intolerant of steroid-related side effects with low-dose cyclosporine. With similar success, Bielory and Frohman [4] reviewed a small series of four patients with granulomatous optic neuropathy and orbitopathy and noted stabilization in two and improvement in the other two with low-dose cyclosporine therapy. Hatton et al [19] reported on the successful use of mycophenolate mofetil in four patients with refractory IOIS and in one patient with brittle diabetes for whom corticosteroids were contraindicated. Finally, biologic agents are the newest addition to the armamentarium of drugs available to treat the various rheumatologic diseases. The development of these agents grew out of a more complete understanding of the immune response and its dysregulation. As opposed to the global immune suppression achieved by some of the previously discussed agents, biologics target specific cell surface and soluble molecules to intercept the immune cascade at a specific point with fewer side effects than traditional immunomodulatory agents. Examples of such targets include tumor necrosis factor alpha (TNF-a), interleukin 2, and T-cell surface markers that supply costimulatory signals.

Treatment

59

Anti-TNF-a agents such as etanercept and infliximab have shown considerable efficacy in treating a diverse group of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. There are a number of factors that suggest that TNF-a may play an important role in the treatment of orbital inflammation [25]: It is found in orbital connective tissue of patients with TED but not in normal controls. Furthermore, the levels of TNF-a messenger RNA (mRNA) seem to correlate with the size of EOMs in patients with TED. Paridaens et al [41] reported an improvement in soft tissue changes such as conjunctival chemosis and redness in ten consecutive patients with active TED treated prospectively with entercept studied the effects of etanercept. These medications have also been used with some success in the treatment of ocular inflammatory diseases such as uveitis and scleritis [37]. Promising results have also been observed in patients with IOIS. Garrity et al [13] reviewed data from three centers where infliximab was used to treat patients with IOIS who failed conventional treatments such as steroids, radiation, and other anti-inflammatory agents. Symptomatic improvement was reported in six of seven patients, and three experienced complete resolution. More recently, several small case series have confirmed these earlier successes [32, 44].

Summary for the Clinician ■ ■

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Treatment of IOIS involves interrupting the inflammatory cascade. Corticosteroids remain the mainstay of treatment for IOIS. They are often started at a dose of 1 mg/kg/day and tapered over the course of weeks to months, according to a patient’s symptoms. NSAIDs may be useful adjuncts during the tail end of the corticosteroid taper. Patients who do not respond to corticosteroid therapy are often considered “atypical,” and biopsy of the affected tissue should be attempted, if accessible. Low-dose 1500-2000 cGy orbital radiation has shown efficacy in the treatment of steroidresistant IOIS. Immunomodulating agents have demonstrated efficacy in the treatment of rheumatologic, dermatologic, and uveitic inflammation. The results of a small number of case series and case reports suggest that these agents may be useful in select patients with IOIS.

60 3.4 3.4.1

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3 Current Concepts in the Management of Idiopathic Orbital Inflammation

Special Circumstances Pediatric IOIS

Pediatric IOIS comprises between 6% and 16% of all IOIS in published series [5, 7, 34, 60]. While the signs and symptoms of IOIS are generally consistent across all age groups, a number of large studies have ascribed several features of pediatric IOIS that are thought to be atypical in the adult population: (1) the presence of constitutional symptoms; (2) accompanying anterior chamber reaction; and (3) the presence of bilateral disease [34, 36]. The differential diagnosis of IOIS in children includes orbital cellulitis and trauma as well as such potentially lethal entities as rhabdomyosarcoma and neuroblastoma, among others. While “classic” IOIS in a child may be approached in a manner similar to that used in adults, a high degree of suspicion should be maintained. As in the adult population, any patient with atypical presentation or recurrent disease should undergo orbital biopsy of the involved tissue. The treatment algorithm for pediatric IOIS is also similar to that of the adult population. However, certain aspects deserve mention. Corticosteroids should be administered based on a weight-based formula, typically at a dosage of 1 mg/kg/day for oral prednisone. Steroidrelated side effects, such as increased appetite, weight gain, gastritis, headache, and mood swings are common in children, and the classic cushingoid appearance may develop quickly. Corticosteroids also have an effect on linear growth, especially with prolonged therapy [8]. Fortunately, corticosteroids also inhibit closure of epiphyseal plates [22]. Once the steroids are tapered, children often experience rebound growth, allowing them to rejoin previous growth curves and attain normal adult height. Other known complications of steroid use, such as hypertension, diabetes, glaucoma, and cataract, are rare in the pediatric population [8, 22]. The data with regard to other treatment modalities are sparse for pediatric IOIS. Radiation therapy is generally avoided in children due to fears of inducing bony hypoplasia, soft tissue deformities, and secondary tumors, such as are seen in children receiving radiation for retinoblastoma and rhabdomyosarcoma. Although the dosages in the treatment are much lower (2,000 cGy vs. 5,000– 6,000 cGy), there are no studies in the literature documenting a “safe” dosage. Anecdotally, we have treated two patients, ages 11 and 15, with orbital radiation. Both have been followed for more than 4 years, and neither has experienced any treatment-related side effects. Methotrexate, cyclosporine, and etanercept have been used with much success in the treatment of pediatric

uveitis [54] and rheumatologic diseases [38]. These agents may also be employed in the treatment of children with refractory IOIS or in those who become intolerant of steroid-related side effects, although there is very little published to support this use. Consultation and comanagement with a pediatric rheumatologist familiar with the use of these steroid-sparing and immunomodulating agents are recommended.

Summary for the Clinician ■

■

■

The signs and symptoms of IOIS in the pediatric population are similar to those of adults. The presence of bilateral disease, constitutional symptoms, and an accompanying anterior chamber reaction may be more common in children. Peripheral eosinophilia may also be present. Corticosteroid dosages for treatment of IOIS should be calculated based on the child’s weight (1 mg/kg/day). Therapeutic management of pediatric IOIS should be managed in conjunction with pediatricians or pediatric rheumatologists familiar with the dosages and side effects of treatment regimens.

3.4.2

Sclerosing Pseudotumor

Idiopathic sclerosing orbital inflammation (ISOI) is a rare cause of orbital inflammation that some consider a distinct clinicopathological entity [48]. It is characterized by a chronic, slowly progressive course and lacks the acute onset frequently associated with IOIS. Common signs and symptoms of ISOI include a dull pain, proptosis, EOM restriction with diplopia, and mild-to-moderate inflammation [21, 48]. Within the orbit, the superior and lateral portions, particularly the lacrimal gland, tend to be affected more often; however, up to 50% of patients may present with an apical mass [21, 48]. The disease is often unilateral but may be bilateral and asymmetric (Fig. 3.14). On imaging, ISOS is characterized by a homogeneously enhancing mass with irregular margins, which may obliterate adjacent structures such as EOMs, the lacrimal gland, or bone. The masses are deeply hypointense on T2-weighted sequences. Histopathologically, normal anatomic structures are replaced by broad areas of fibrosis with a sparse inflammatory infiltrate of lymphocytes, plasma cells, histiocytes, eosinophils, and neutrophils [21, 48]. This characteristic picture is also seen in retroperitoneal fibrosis, a condition with which ISOI may be associated [31]. Calcification may also be present [61].

3.4

Special Circumstances

61

Fig. 3.14 Idiopathic sclerosing orbital inflammation. Top left: Indolent, slowly progressive left external ophthalmoplegia with no response to systemic corticosteroids. Top right: Orbital exploration revealed a dense infiltrate. Bottom left: Histopathology shows a dense, monotonous, fibrous infiltrate with a paucity of inflammatory cells. Bottom right: CT of a sequential ISOI in another patient who underwent exenteration of the left orbit for intractable pain after failing oral corticosteroids, antimetabolite therapy, radiation, and surgical debulking. Unfortunately, she developed an identical progressive orbital process on the contralateral side several years later that resulted in compressive optic neuropathy

Summary for the Clinician ■

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■

IOSI may be a distinct clinicopathological entity characterized by broad areas of fibrosis with a sparse inflammatory infiltrate of lymphocytes, plasma cells, histiocytes, eosinophils, and neutrophils, which replace normal anatomic structures. Common signs and symptoms include a dull pain, proptosis, EOM restriction with diplopia, and mild-to-moderate inflammation ISOI is usually less responsive to corticosteroids than IOIS. Surgical debulking combined with immunomodulating agents may slow the course of this chronic, often progressive, disease.

In contrast to IOIS, which shows a dramatic response to corticosteroid treatment, a more aggressive regimen is often required to control the progression of ISOI. Hsuan et al [21] reviewed the largest series of patients in the literature (n = 31) from five regional centers. While the majority of patients received oral prednisolone, only nine had a “good” response with marked improvement. Eleven patients had a “partial” response with significant but limited improvement, and seven had minimal or no benefit. The authors noted a trend toward greater improvement in patients with shorter duration of disease. Cyclophosphamide and azithioprine were used with some success in patients who did not respond well to steroids or those who experienced steroid intolerance. Radiotherapy was ineffective; however, surgical debulking did result in symptomatic relief in three of four patients.

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3 Current Concepts in the Management of Idiopathic Orbital Inflammation

3.4.3 Tolosa–Hunt Syndrome

3

Tolosa–Hunt syndrome (THS) is an idiopathic, painful ophthalmoplegia characterized by one or more episodes of periorbital or hemicranial pain and variably combined with ipsilateral cranial nerve palsies, oculosympathetic paralysis, or sensory loss in the distribution of the ophthalmic and occasionally the maxillary division of the trigeminal nerve. In 2004, the International Headache Society redefined the diagnostic criteria of THS specifying that granuloma, as demonstrated by magnetic resonance imaging (MRI) or biopsy, is required for diagnosis [56]. Some may argue that this change makes the inclusion of the THS in a discussion of IOIS more controversial. The histopathology, however, is no different from that of idiopathic orbital granulomatous inflammation dubbed “orbital sarcoid,” as discussed. In addition, like IOIS, the symptoms of THS are extremely sensitive to treatment with corticosteroids. The resolution of pain and paresis within 72 hours of starting corticosteroid therapy is, in fact, part of the new diagnostic criteria for the syndrome [56]. The characteristic findings of THS on MRI include lesions that enlarge the cavernous sinus, are isointense on T1-weighted images, and enhance markedly with contrast. In a literature review based on the new 2004 inclusion criteria, MRI detected a lesions in 7 (47%) of 15 patients with a normal computed tomographic (CT) scan,

demonstrating the importance of proper imaging in patients with suspected THS. These lesions diminished or disappeared during follow-up (range 1 week to 1 year) [27]. In our experience, the pain associated with THS responds rapidly to corticosteroids, but the cranial neuropathy has a distinct lag in resolution, usually taking several weeks. In addition, THS anecdotally appears to recur with greater frequency than IOIS and may be sequentially bilateral (Fig. 3.15). This atypical behavior of THS understandably produces a necessary underlying clinical trepidation in the treating physician and should always result in close follow-up over the long term with serial imaging. With improvements in modern imaging, a tissue biopsy is rarely sought to establish the diagnosis of THS. Neurosurgical biopsy of the dural wall of the cavernous sinus is a technically difficult operation and exposes the patient to significant iatrogenic risks. Therefore, the procedure is generally considered one of “last resort” in patients with rapidly progressive neurological deficits, lack of steroid responsiveness, or persistent abnormalities on neuroimaging studies [26]. As is the case with IOIS, the differential diagnosis of cavernous sinus inflammation is long and includes many potentially serious conditions. While the updated inclusion criteria may help to rule out painful ophthalmoplegia caused by intracranial tumors and vascular anomalies that would be visible on MRI, signal

Fig. 3.15 Tolosa–Hunt syndrome. T1-weighted postcontrast MRI with fat suppression of a patient with acute onset periocular pain, ptosis, and external ophthalmoplegia. MRA was unremarkable. Note enlargement and enhancement of the right cavernous sinus (arrow). Pain resolved rapidly with oral corticosteroids. The external ophthalmoplegia resolved over several weeks. Repeat imaging showed resolution of the abnormality

References

63

Fig. 3.16 Perineural invasion of squamous cell carcinoma (SCCA). A patient with a known history of SCCA of the forehead with 4 months of progressive pain and external ophthalmoplegia initially diagnosed as trochleitis by MRI. Repeat MRI demonstrated enlargement and enhancement of the cavernous sinus “consistent with Tolosa–Hunt syndrome.” Failure to respond to several weeks of corticosteroids prompted referral. Subsequent supraorbital nerve biopsy confirmed the diagnosis of SCCA

Summary for the Clinician ■

■

■

Tolosa–Hunt syndrome is an idiopathic painful ophthalmoplegia consisting of periorbital or hemicranial pain, variably combined with ipsilateral cranial nerve palsies, oculosympathetic paralysis, and sensory loss in the distribution of the trigeminal nerve. The resolution of pain and paresis within 72 h of starting corticosteroid therapy is part of the diagnostic criteria for the syndrome. Resolution of cranial neuropathy and external opthalmoplegia may lag by several weeks. Tolosa–Hunt syndrome is a diagnosis of exclusion. Because of the difficulties with obtaining a tissue specimen, a high index of suspicion must be maintained to rule out masquerade syndromes. A thorough systemic workup, adequate imaging with contrast-enhanced MRI, and close follow-up over an extended period of time are essential.

characteristics of meningioma, lymphoma, aneurysm, and sarcoidosis may be confused with THS. Furthermore, the inflammation sometimes associated with meningioma, aneurysm, etc may result in temporary improvement with corticosteroid therapy. One particular entity of concern is perineural extension of facial squamous cell carcinoma into the cavernous sinus. Actinic changes of the face, a history of skin cancer, or enhancement of the supra- or infraorbital nerves intraorbitally on MRI make this diagnosis more likely (Fig. 3.16). Like IOIS, THS remains a diagnosis of exclusion and requires a high index of suspicion and extended follow-up.

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32. Miquel T, Abad S, Badelon I, et al (2008) Successful treatment of idiopathic orbital inflammation with infliximab: an alternative to conventional steroid-sparing agents. Ophthal Plast Reconstr Surg 24:415–417 33. Mombaerts I, Koornneef L (1997) Current status in the treatment of orbital myositis. Ophthalmology 104: 402–408 34. Mombaerts I, Schlingemann RO, Goldschmeding R, et al (1996) Are systemic corticosteroids useful in the management of orbital pseudotumors? Ophthalmology 103:521–528 35. Mombaerts I, Schlingemann RO, Goldschmeding R, et al (1996) Idiopathic granulomatous orbital inflammation. Ophthalmology 103:2135–2141 36. Mottow L, Jakobiec F, Smith M (1978) Idiopathic inflammatory orbital pseudotumor in early childhood I: Clinical characteristics. Arch Ophthalmol 96:1410–1417 37. Murphy CC, Ayliffe WH, Booth A, et al (2004) Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 111: 352–356 38. Niehues T, Lankisch P (2006) Recommendations for the use of methotrexate in juvenile idiopathic arthritis. Pediatr Drugs 8:347–356 39. Nugent RA, Belkin RI, Neigel JM, et al (1990) Graves orbitopathy: correlation of CT and clinical findings. Radiology 177:675–682 40. Orcutt J, Garner A, Henk J, et al (1983) Treatment of idiopathic inflammatory orbital pseudotumors by radiotherapy. Br J Ophthalmol 67:570–574 41. Paridaens D, van den Bosch WA, van der Loos TL, et al (2005) The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye 19:1286–1289 42. Perry SR, Rootman J, White VA (1991) The clinical and pathologic constellation of Wegener granulomatosis of the orbit. Ophthalmology 104:683–1694 43. Prabhakaran VC, Saeed P, Esmaeli B, et al (2007) Orbital and adnexal sarcoidosis. Arch Ophthalmol 125:1657–1662 44. Prendiville C, O’Doherty M, Moriarty P, et al (2008) The use of infliximab in ocular inflammation. Br J Ophthalmol 92:823–825 45. Reinhold-Keller E, Beuge N, Latza U, et al (2000) An interdisciplinary approach to the care of patients with Wegener’s granulomatosis. Long-term outcome in 155 patients. Arthritis Rheum 43:1021–1032 45. Rootman J, Nugent R (1982) The classification and management of acute orbital pseudotumors. Ophthalmology 89:1040–1048 47. Rootman J, Chang W, Jones D (2003) Distribution and differential diagnosis of orbital disease. In: Rootman J (ed) Diseases of the orbit: a multidisciplinary approach, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 48. Rootman J, McCarthy M, White V, et al (1994) Idiopathic sclerosing inflammation of the orbit: a distinct clinicopathologic entity. Ophthalmology 101:570–584

References 49. Rose GE (2007) A personal view: probability in medicine, levels of (un)certainty, and the diagnosis of orbital disease (with particular reference to orbital “pseudotumor”). Arch Ophthalmol 125:1171–1172 50. Sanchez-Roman J, Varela-Aguilar JM, Bravo-Ferrer J, et al (1993) Idiopathic orbital myositis: treatment with cyclosporine. Ann Rheum Dis 52:84–85 51. Sergott R, Glaser J, Charyulu K (1981) Radiotherapy for idiopathic inflammatory orbital pseudotumor: indications and results. Arch Ophthalmol 99:853–856 52. Shah SS, Lowder CY, Schmitt MA, et al (1992) Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology 99:1419–1423 53. Shields JA, Shields CL, Scartozzi R (2004) Survey of 1,264 patients with orbital tumors and simulating lesions: the 2002 Montgomery Lecture, part 1. Ophthalmology 111: 997–1008 54. Smith J (2002) Management of uveitis in pediatric patients: special considerations. Pediatr Drugs 4:183–189

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55. Smith JR, Rosenbaum JT (2001) A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 85:1220–1224 56. The International Classification of Headache Disorders ICHD-II (2004) Cephalalgia 24(Suppl 1):131 57. Weber AL, Jakobiec FA, Sabates NR (1996) Pseudotumor of the orbit. Neuroimaging Clin North Am 6:73–91 58. Woo TL, Francis IC, Wilcsek GA, et al (2001) Australasian orbital and adnexal Wegener’s granulomatosis. Ophthalmology 108:1535–1543 59. Yan J, Wu Z, Li Y (2004) The differentiation of idiopathic inflammatory pseudotumor from lymphoid tumors of orbit: analysis of 319 cases. Orbit 23:245–254 60. Yuen SJ, Rubin PA (2003) Idiopathic orbital inflammation: distributions, clinical features and treatment outcome. Arch Ophthalmol 121:491–499 61. Zakir R, Manners RM, Ellison D, et al (2000) Idiopathic sclerosing inflammation of the orbit: a new finding of calcification. Br J Ophthalmol 84:1322–1324

Chapter 4

Lacrimal Canalicular Inflammation and Occlusion: Diagnosis and Management

4

David H. Verity and Geoffrey E. Rose

Core Messages ■

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Canalicular inflammation may lead to loss of compliance and stenosis, with lacrimal symptoms occurring despite anatomical patency. Microbial canaliculitis is frequently overlooked, leading to a delay in diagnosis and management. Failure adequately to remove canalicular stones and debris is a common cause for persistent canaliculitis. Canalicular epithelial inflammation due to primary herpes simplex infection is a common cause of canalicular, or common canalicular, occlusion. Subepithelial canalicular inflammation—as seen with lichen planus (LP)—may lead to a more severe and extensive annular fibrosis and carries a poor prognosis. Systemic chemotherapeutic agents, including radioiodine, 5-fluorouracil (5-FU), mitomycin C (MMC), and docetaxel, may injure the canalicular epithelium, the evidence suggesting active concentration of these agents by the lacrimal outflow structures.

4.1

Introduction

Canaliculitis, either epithelial or pericanalicular inflammation, has many underlying causes with rather characteristic clinical patterns. Although certain etiologies, such as herpetic canaliculitis, are rapidly progressive, others are insidious and frequently pass unrecognized until the onset of lacrimal symptoms. Inflammation, either within the epithelium or deep to its basement membrane, leads to scarring with a reduction of both longitudinal compliance and cross-sectional area of the affected canaliculus; these changes result in impaired function of both the active pumping mechanism and the static drainage (Table 4.1). This review considers idiopathic, infective, and iatrogenic causes of canalicular inflammation and obstruction, but canalicular trauma—comprehensively reviewed elsewhere—is excluded [24, 27].

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The surgical approach to canalicular occlusion depends on the extent of disease. Dacryocystorhinostomy (DCR) with retrograde canaliculostomy is the preferred surgery for proximal and midcanalicular occlusion. The indication for primary placement of a Jones canalicular bypass tube is the total absence of all distal canalicular and common canalicular structures, with this ascertained during open lacrimal surgery. The indication for secondary Jones tube placement is a functional failure after primary DCR with retrograde canaliculostomy. A canalicular bypass tube should be sutured such that the tube flange is held clear of the healing carunculectomy site; the function is not to prevent prolapse of the tube. As such, an encirclage suture is required only during primary placement of a bypass tube, when carunculectomy has just been performed.

4.2 Embryology, Anatomy, Physiology, and Pathophysiology of the Canalicular System The lacrimal drainage pathway arises, at day 32, from a thickening of the ectoderm in the naso-optic fissure. This ectoderm descends into the surrounding mesoderm and forms a cord that extends from the developing eyelids to the nasal space, the cord subsequently forming a lumen by disintegration of the central ectoderm. The lacrimal puncta, ampullae, and canaliculi form the proximal, high-resistance, elements of the lacrimal drainage system: Measuring 0.3 mm in diameter, the puncta lie within the lacrimal papillae and drain into the vertical ampullae, each being 1–2 mm in length and 2.5 mm in width. The horizontal canaliculi are about 6 mm long in the upper lid and 8 mm in the lower, have an internal diameter of about 0.4 mm, and are surrounded

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4 Lacrimal Canalicular Inflammation and Occlusion: Diagnosis and Management

Table 4.1. Canalicular inflammation: etiology Infection 1. Chronic staphylococcal lid disease

4

2. Periocular herpes simplex infection 3. Bacterial and fungal canaliculitis Systemic inflammatory diseases 1. Lichen planus 2. Ocular cicatricial pemphigoid 3. Drug eruptions (Stevens–Johnson syndrome) Iatrogenic causes 1. Chemotherapeutic agents ■ 5-Fluorouracil ■ Taxanes: docetaxel (taxotere) and paclitaxel

2. Local radiotherapy 3. Topical treatment ■ Preservative related ■ Mitomycin C

4. Lacrimal stents and plugs

by the muscle of Duverney–Horner, which is one element of the physiological lacrimal pump. In about 80% of individuals, the upper and lower canaliculi unite to form the common canaliculus, which—with a diameter of about 0.6 mm—runs medially for 2–3 mm before angulating anteriorly to enter the sac. The internal opening of the common canaliculus lies near the midpoint of the sac, at the level of the lower border of the medial canthal tendon, and the anterior angulation of the common canaliculus (about 60°) as it passes through the lateral wall of the sac forms, in part, the physiological “valve” of Rosenmüller; in addition to punctal apposition on lid closure, the valve helps to prevent the retrograde flow of tears [33].

a

b

These structures are lined by a stratified squamous epithelium, with a change to pseudostratified, nonciliated columnar epithelium—similar to that found in the upper respiratory system—occurring near the common canaliculus (Fig. 4.1a). The canaliculi form a low-conductance conduit, with tear delivery to the lacrimal sac being dependent on the active “compression pump” mechanism of the pretarsal orbicularis oculi. Thus, physiological pump failure, anatomical misalignment, and canalicular stenosis or obstruction may all lead to lacrimal symptoms, examples being facial palsy, ectropion, and herpetic canalicular block, respectively. Depending on the rate of tear clearance, symptoms include a troublesome awareness of wet or moist eyelids, impaired vision due to a raised tear meniscus (Fig. 4.1b), a “wicking” of the tear meniscus onto the skin at the lateral canthus (Fig. 4.1c), and frank epiphora, with this frequently associated with a secondary eczema of the eyelids. The relative contribution of the upper and lower canaliculi to tear drainage varies between individuals, and most reports suggest that a single canaliculus is adequate for basal tear drainage [18] but will not cope with drainage during reflex lacrimation.

Summary for the Clinician ■ ■

■

In about 80% of individuals, the upper and lower canaliculi unite to form the common canaliculus. Physiologic pump failure, anatomic misalignment, and canalicular stenosis or obstruction may all lead to lacrimal symptoms. Most reports suggest that a single canaliculus is adequate for basal tear drainage.

c

Fig. 4.1 (a) Histology of cross section of healthy canaliculus showing stratified squamous epithelium (hematoxylin and eosin, ×20); (b) delayed spontaneous clearance of 2% fluorescein from the conjunctival sac of left eye due to upper and lower herpetic canalicular block with medial overflow; (c) lateral “wicking” of the tear meniscus

4.3 Table 4.2. Causes of nontraumatic canalicular obstruction and their approximate incidence Cause of canalicular obstruction

Average annual caseload (%)

Postherpetic

8/23 (35%)

Iatrogenic

6/23 (26%)

Cicatricial conjunctival diseasea

6/23 (26%)

5-Fluorouracil chemotherapy

2/23 (9%)

Lichen planus

1/23 (5%)

Based on cases presenting to Moorfields Eye Hospital over an 8-year period a Including risk factors such as topical glaucoma therapy, severe blepharitis

There are many causes for canalicular dysfunction (Table 4.2), and symptoms vary according to the extent, severity, and duration of the underlying disease. Unfortunately, irreversible canalicular fibrosis is often present at presentation due to delayed diagnosis (e.g., retained punctal plugs or stents), misdiagnosis (as with chronic canaliculitis [34]), or the rapid onset of disease (herpes simplex canaliculo-conjunctivitis). Restoration of canalicular function is hampered by the challenge of providing effective immunosuppression for local disease,

Infective Causes

69

such as ocular cicatricial pemphigoid, and the very small caliber of the canaliculi, with surgery failing due to both annular fibrosis and disruption of the dynamic (lacrimal “pump”) function of the orbicularis oculi muscle.

4.3

Infective Causes

Severe ocular surface infections can cause canaliculitis either by a direct infection or by spillover of the toxic tear film from an “upstream” hyperacute conjunctivitis.

4.3.1

Periocular Herpes Simplex Infection

Apart from trauma, primary periocular infections with herpes simplex virus (Fig. 4.2a) are probably the most common cause of canalicular obstruction (Fig. 4.2b). In 160 patients presenting with lacrimal symptoms after primary herpetic blepharo-conjunctivitis, canalicular block was typically unilateral and significantly more common in women [10, 20]. Primary open lacrimal surgery-DCR with anterograde or retrograde intubation—was undertaken in 94 eyes, of which fewer than a quarter required subsequent bypass tube insertion, emphasizing the role for primary canalicular surgery before resorting to placement of a glass bypass tube.

a

b

c

d

Fig. 4.2 Microbial canaliculitis. (a) Primary periocular herpes simplex infection: blepharoconjunctivitis with vesicles; (b) probe identifying proximal lower canalicular block; (c) Actinomyces canaliculitis with large granuloma bulging out of punctum; (d) expression of stones and debris after canaliculotomy

70 4.3.2

4

4 Lacrimal Canalicular Inflammation and Occlusion: Diagnosis and Management

Bacterial Canaliculitis

Numerous microbes may infect the canalicular epithelial surface (Table 4.3), but the most characteristic is due to Actinomyces species. Such patients usually present after many months of a painless chronic discharge at the medial canthus, this typically being misdiagnosed as conjunctivitis, chalazion, or nasolacrimal duct obstruction [1, 3]. Although rare, microbial canaliculitis may also lead to chronic or recurrent nasolacrimal obstruction in children [26], and may also be a cause of blood-stained tears. Typically, there is swelling with mild inflammation, centered on the midcanaliculus, and the characteristically stringy yellow discharge at a pouting punctum (Fig. 4.2c). Pressure over the canaliculus may lead to discharge of pus or gritlike “granules,” but in most cases the debris is typically not expressible (unlike that of a lacrimal sac mucocele). Actinomyces, especially A. israelii, is a cast-forming gram-positive filamentous anaerobe that can be difficult to isolate, and the organism has a propensity for colonizing hollow spaces and forming “stones,” such as canaliculiths (Fig. 4.2d). In all but the mildest cases, Actinomyces canaliculitis is resistant to topical antibiotics alone. Antibiotic syringing of the affected canaliculus is well described [23], but this tends to be ineffective [35] and, more importantly, carries the risk of microbial dissemination into the lacrimal sac and nasolacrimal duct. Definitive treatment entails canaliculostomy with expression of all inflammatory and infective debris; a 6-mm incision is made along the conjunctival border of the affected canaliculus, and the canalicular contents are expressed with firm pressure on either side of its walls. Although a large chalazion spoon may be used to curette stones, this instrument is best avoided as it is liable to damage the severely inflamed canalicular mucosa and result in canalicular occlusion. Chronic infection may lead

Table 4.3. Microbial isolates in canaliculitis Actinomycetes spp. Arcanobacterium haemolyticum Eikenella corrodens

to gross distension of the canaliculus by the large number of stones, all of which require removal. The canaliculotomy incision heals spontaneously, and the patient should be placed on a week’s course of a topical antibiotic, such as ofloxacin; because the incision lies along, rather than across, the canaliculus, ring contracture is rare and postoperative epiphora most unusual [1]. Recurrence of symptoms is a likely indication of persistent canalicular stones, and a further canaliculotomy should be performed if necessary; occasionally, such recurrent infection is centered on the lacrimal sac rather than the canaliculi.

4.4 4.4.1

Systemic Inflammatory Disease Lichen Planus

Lichen planus (LP), an idiopathic autoimmune disease of the skin and oral or genital mucosa, may rarely affect conjunctiva [15, 28] and lead to severe canalicular obstruction [10, 22]. Etiological mechanisms include autoreactive T cells to keratinocytes and activated tissue matrix metalloproteinases and mast cells. Systemic lesions show suband intraepithelial lymphocytic infiltration with degeneration of basal keratinocytes, and although conjunctival disease is less well characterized, case reports describe reticular subconjunctival scarring, forniceal shortening, and symblepharon formation. These features resemble those seen in ocular cicatricial pemphigoid [21, 25], but immune complex deposition within the conjunctival basement membrane—pathognomonic for ocular cicatricial pemphigoid—is absent in LP. Canalicular LP leads to extensive bilateral, bicanalicular occlusion in three quarters of patients with symptomatic disease [10]; these changes probably reflect inflammation within the subepithelial substantia propria of the canaliculus, with consequent deep fibrosis “throttling” the canaliculus (Fig. 4.3a). LP patients with proximal or midcanalicular block are offered DCR with retrograde canaliculostomy [36] but are warned of the high likelihood of requiring secondary placement of a Jones bypass tube.

Haemophilus aphrophilus Lactococcus lactis cremoris Molluscum contagiousuma Mycobacterium chelonae Nocardia asteroides Propionobacterium propionicum Staphylocococcus spp. a

Primary involvement of the conjunctiva or cornea by molluscum is rare and is often associated with HIV infection

4.4.2

Ocular Cicatricial Pemphigoid

Distal spillover of the severe conjunctival inflammation of ocular cicatricial pemphigoid will often cause proximal canalicular blockage (Figs. 4.3c, d). Retention of inflammatory debris will, in some cases, be associated with an exacerbation of ocular surface disease, and consideration will be given to the reestablishment of tear drainage; in

4.5 Iatrogenic Causes

a

b

c

d

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Fig. 4.3 (a) Inflammatory sequelae of lichen planus, identifying complete destruction of the epithelium (chevrons), dense subepithelial fibrotic changes (short arrow), and lymphocytic infiltrate (long arrow) (hematoxylin and eosin, original magnification ×20); (b) Stevens–Johnson syndrome presenting with severe pseudomembranous conjunctivitis; (c) advanced bilateral ocular cicatricial pemphigoid demonstrating bilateral medial ankyloblepharon and punctal occlusion; (d) magnified view of left eye showing severe synblepharon and medial ankyloblepharon completely obstructing punctum (arrow shows probable location)

most cases, these patients will require DCR and retrograde canaliculostomy, with occasional later placement of a glass bypass tube.

4.4.3 Drug Eruptions (Stevens–Johnson Syndrome) Stevens–Johnson syndrome (SJS), the bullous form of erythema multiforme, is an acute and self-limiting inflammatory disorder of the skin and mucous membranes. Severe, and often hemorrhagic, conjunctivitis with pseudomembrane formation may occur in over half of patients (Fig. 4.3b), with the resultant subepithelial fibrosis leading to conjunctival symblepharon, cicatricial entropion, loss of limbal stem cells, and obliteration of the lacrimal gland ductules. These changes reduce production of tear-film mucin and aqueous tears, making any punctal or canalicular occlusion less troublesome; indeed, in one study, objective evidence for lacrimal outflow disease was noted in most cases, although none required surgery, presumably due to the simultaneous reduction in the quantity of tear film [37]. Other authors have reported significant lacrimal outflow obstruction

requiring surgery, with this occurring at the level of the common canaliculus in one case and at both the canaliculi and nasolacrimal duct in another patient [2].

4.5

Iatrogenic Causes

Canalicular or pericanalicular inflammation may arise from a number of iatrogenic causes, with these typically due to systemic medications or local radiotherapy.

4.5.1

Systemic Drugs

4.5.1.1 5-Fluorouracil (5-FU) A potent inhibitor of DNA synthesis, 5-FU is widely used in the management of systemic malignancy, with rapidly proliferating tissues, including normal epithelial surfaces, most affected. Healthy canalicular epithelium may be affected in about 6% of patients, with this leading to punctal narrowing and focal or diffuse canalicular stenosis; over a quarter of these individuals require DCR with placement of a bypass tube [14].

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4 Lacrimal Canalicular Inflammation and Occlusion: Diagnosis and Management

There are two putative mechanisms for canalicular damage: First, bathing of the puncta and canaliculi in 5-FU secreted into the tears may lead to chronic mucosal inflammation per se. Second, 5-FU may damage rapidly proliferating canalicular epithelium, causing chronic inflammation and fibrosis within the underlying substantia propria. These theories are similar to those proposed for the canalicular stenosis associated with docetaxel (Taxotere , v.i.), discussed below.

4.5.1.2 Docetaxel (Taxotere)

and syringing (followed by a short course of topical steroids) appear adequate to prevent problems in most patients on a ie every 3 weeks dosing schedule. Docetaxel is, however, an increasingly used chemotherapy, and with a trend toward weekly dosing to reduce systemic complications, lacrimal complications are set to increase. Treating physicians should counsel patients about the risk of lacrimal problems and seek appropriate early referral if symptoms arise.

4.5.2

Docetaxel is a semisynthetic taxane used in the treatment of advanced solid malignancies, especially those of breast, prostate, and non-small cell lung cancers. It is secreted into the tears [13] and may lead to canalicular stenosis or occlusion, with this troublesome side effect related to both the dosing frequency and total cumulative dose. Histological studies have shown fibrosis within the mucosal lining of the lacrimal drainage apparatus [11]. Clinical features of docetaxel toxicity include symptomatic punctal and canalicular stenosis or occlusion in up to a half of patients while on a weekly dosing schedule [12, 32]. Temporary canalicular intubation has been recommended for patients on weekly therapy, but probing

a

b

d

e

Radiotherapy

Due to their propensity to invade the medial orbit, tumors at the medial canthus carry a relatively worse prognosis, and Mohs surgery is now the preferred approach in managing such basal or squamous cell carcinomas. Historically, radiotherapy has often been used in this location, with almost universal canalicular occlusion (Fig. 4.4a). In 1981, Call and Welham described 13 patients with severe epiphora following radiotherapy for medial basal cell carcinomas, all of whom had complete obstruction of both upper and lower canaliculi; 12 were successfully managed by DCR and insertion of a Jones tube, and 1 settled with canaliculo-DCR for a common canalicular block [6].

c

Fig. 4.4 (a) Radiation treatment for medial canthal BCC causing canalicular occlusion and requiring subsequent DCR and secondary bypass tube (note lash loss and depigmentation); (b) drop sensitivity to unpreserved chloramphenicol with secondary canaliculitis and epiphora; (c) silicone stent-induced canalicular inflammation with developing granuloma (arrow) and medial canthal staphylococcal infection; (d) medial canthal granuloma secondary to monocanalicular stent; (e) impacted intracanalicular plug at the entrance of the common canaliculus to the sac. Note the inflamed sac mucosa due to recurrent episodes of dacrocystitis

4.5 Iatrogenic Causes

Systemic radioiodine (131I) is used for the management of thyroid carcinoma and has well-documented ocular side effects, including xerophthalmia and chronic conjunctivitis [31]. Symptomatic lacrimal outflow obstruction is less well recognized, occurring in at least 5% of patients, with the distal nasolacrimal duct more commonly affected than the canalicular systems [5]1; whether this effect is mediated by local toxicity from passive flow of 131I into the tears or is due to active uptake by the sodium–iodide symporter (known to exist in both lacrimal and thyroid gland) remains uncertain, although at least one report supported the latter mechanism [4].

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Canalicular disease has been reported in 3/14 (21%) patients receiving topical MMC for 2 weeks [16], although another report found punctal stenosis in only 14/100 eyes of 91 patients who received the drop for 1 week (of which only 1 required lacrimal surgery), suggesting that symptomatic canalicular stenosis occurs only rarely and may be related to duration of topical therapy [17]. To reduce canalicular toxicity, some authors advocate temporary punctal occlusion with removable plugs while using MMC drops, which has the additional advantages of increasing drug bioavailability on the ocular surface.

4.5.4 Lacrimal Stents and Plugs 4.5.3 Topical Ophthalmic Treatments 4.5.3.1 Preservative-Related Chronic Conjunctivitis Lacrimal canalicular occlusion may occur after exposure to topical ocular medications, with one study reporting obstruction as little as a month after beginning treatment [21]. Outflow obstruction is most commonly observed 2–5 mm from the lacrimal punctum, with other associated findings including symblepharon, keratinization of the medial canthal tissues, and cicatricial medial entropion. Canalicular occlusion may follow a chronic inflammatory response to drop preservatives and, if a patient has symptoms of dry eye, features suggestive of chronic allergy (e.g., skin changes, ocular redness or irritation, and a conjunctival papillary response) (Fig. 4.4b) should not be confused with those of aqueous insufficiency.

4.5.3.2 Mitomycin C (MMC) Therapy Topical MMC is proven in the treatment of ocular surface malignancy, such as intraepithelial carcinoma, primary acquired melanosis with atypia, superficial conjunctival malignant melanoma, and sebaceous carcinoma with pagetoid spread. Transient side effects of MMC include an allergic reaction in a third of patients in addition to kerato-conjunctivitis and punctate epithelial keratopathy.

1

A lower dose 131I is used in controlling hyperthyroidism (therapeutic activity 10–15 mCi 131I) compared to managing thyroid carcinoma (30–200 mCi 131I), which in the context of metastatic disease may require substantial cumulative activities (up to 300 mCi 131I).

All foreign bodies within the lacrimal outflow tract, including stones, stents, and plugs, incite a mucosal inflammatory response. At about a month after lacrimal surgery, silicone stents typically cause medial canthal irritation and mucus production due to punctal and canalicular inflammatory changes; when stent removal is delayed beyond 3 months, frank exophytic granulomas may occur (Fig. 4.4c, d). Thus, even the most inert of materials is capable of inciting mucosal inflammation, with secondary submucosal fibrosis and risk of canalicular stricture. Although the vast majority of lacrimal plugs are not used appropriately, a variety of punctal and canalicular plugs are available to treat symptoms of true aqueous insufficiency. Self-degrading collagen plugs are effective for a few weeks, and silicone punctal plugs, which are reasonably well tolerated, are best used to identify those patients in whom permanent outflow occlusion would be appropriate. Other materials include a flexible thermosensitive acrylic material (SmartPlug) that molds to the internal contour of the ampullae, but none is without complication, and all may cause canaliculitis [8, 9, 29, 30]. Intracanalicular plugs have been advocated for the treatment of dry eye for some years, but these tend to migrate into the nasolacrimal sac, be held up at the entrance to the sac (Fig. 4.4e), or become embedded through the common canalicular wall. The presence of a chronic intracanalicular foreign body can fuel a gross conjunctival inflammatory response, and the retrograde discharge of purulent debris further compromises the ocular surface. Indeed, intracanalicular plugs were the cause of lacrimal outflow symptoms in 6% of eyes in one series, with the high prevalence possibly reflecting practice within one particular catchment population [19]; over a quarter of eyes in this study had persistent epiphora after plug removal or reparative lacrimal surgery, presumably due to persistent canalicular stenosis.

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Summary for the Clinician ■

4 ■ ■ ■ ■ ■

■ ■ ■

■

There are many causes for canalicular dysfunction, and symptoms can vary according to the severity and duration of the underlying disease. Local infective causes can include herpes simplex and bacterial canaliculitis. Systemic inflammatory causes include LP, ocular cicatricial pemphigoid, SJS. Topical medications can be a cause of canalicular obstruction. Radiation can have a secondary effect that causes an obstruction. Systemic medications such as Taxotere can also lead to canalicular scarring. Proper dosing can reduce the incidence of this. Topical ophthalmic treatments can cause canalicular scarring. Medications with preservatives can induce chronic inflammation. MMC therapy used for the treatment of ocular surface malignancy can produce canalicular disease in approximately 21% of patients. Lacrimal stents and plugs may sometimes incite a mucosal inflammatory response, which may lead to secondary fibrosis and the risk of canalicular stenosis.

4.6 The Surgical Approach to Managing Canalicular Disease A micropunctoplasty, such as the three-snip procedure, is useful if punctal stenosis is present with a patent canaliculus and nasolacrimal duct or extreme punctal stenosis prevents canalicular assessment. The purpose is to remove the posterior wall of both the punctal ampulla and 1–2 mm proximal canaliculus, although recent evidence suggests that removal of the posterior ampullary wall alone, without disruption of the canaliculus, may be preferable [7]. In performing a standard punctoplasty, a punctum seeker may be required first to identify and enter the lacrimal punctum, which may then be further dilated with the wider-tipped Nettleship dilator. Three incisions are then made with either a pair of fine Westcott or Vannas scissors; a vertical incision is made through the most posterolateral part of the punctum and ampulla, a second along the avascular superior margin of the canaliculus, and the third removes the flap of tissue thus created.

For complete punctal occlusion, the tip of a 19-gauge needle is inserted bevel up and obliquely—under microscopic illumination—into the punctal “hill” at an angle almost in line with the (presumed) canalicular lumen. The cutting edge of the needle is advanced medially while slowly rotating to bevel down to open the proximal canaliculus. Failure to identify the mucosal-lined lumen signifies a more extensive block, and the patient should be offered open lacrimal drainage surgery with retrograde intubation (discussed in the next section). If there is complete closure of the canaliculi, external DCR with retrograde intubation should be offered. Although resistance to outflow may appear to be limited to a small segment of a canaliculus (or canaliculi), DCR is advocated for three reasons: First, the full extent of canalicular disease is impossible to determine by probing and may be limited to only a short proximal segment. Second, bypassing the physiological resistance of the nasolacrimal duct with DCR reduces the overall resistance to tear flow, and this will aid drainage, even if canalicular dynamics remain impaired. Third, it is known that some patients will require a secondary bypass tube—even if the reconstructed anastomosis is anatomically patent—and this is best achieved after prior open DCR and carunculectomy.

4.6.1 Surgical Technique for Dacryocystorhinostomy with Retrograde Canaliculostomy If canalicular occlusion occurs within the proximal 7 mm, DCR with retrograde canaliculostomy is the procedure of choice; this marsupializes the healthy distal canaliculus into the conjunctival sac. The extent of canalicular block is established only at surgery, and since a healthy common canaliculus is required to perform retrograde canaliculostomy, the patient should be warned of the possible need for a primary glass bypass tube in the event that no common canaliculus is found. In all cases, carunculectomy should be performed as later placement of a bypass tube is more successful within a previously healed carunculectomy bed. A large osteotomy should be created as this allows versatility in the positioning of any subsequent Jones canalicular bypass tube. After suturing of the posterior mucosal flaps, the internal common canalicular opening is entered retrogradely using a “1”-gauge Bowman probe that has been bent perpendicularly at about 8–9 mm from its end. The probe is passed as far laterally as possible along each canaliculus, and a 1- to 2-mm fenestration is created in the canalicular wall overlying the tip of the probe (Fig. 4.5a); the “pseudopuncta” are intubated, and the DCR is completed in a standard

4.6

a

The Surgical Approach to Managing Canalicular Disease

b

75

c

Fig. 4.5 (a) DCR with retrograde canaliculostomy: “1” probe (chevron) with a perpendicular bend at its end, is placed retrograde into the canaliculus, and canaliculostomy performed with an E11 blade over most lateral part of upper canaliculus to create pseudopunctum (long arrow), this being medial to normal punctum (short arrow). (b) Primary placement of Jones bypass tube: passage of a “bullhorn” dilator through the medial tissues and (c) passage of the glass tube into the tract over a “1” probe

fashion. If only the common canaliculus is present, its lateral end should be opened into the carunculectomy bed; in this case, and others where only a single canaliculus is retrievable, the returning end is passed through the heavily scarred annulus of the opposite punctum and forced medially through the lid tissues.2 This last manœuvre is assisted by passing a large-bore needle through the tissue first to create a track that enters the upper part of the opened sac, remote from the common canalicular opening. The patient should be reviewed at about 1 week for removal of sutures and again at 3–4 weeks after surgery for removal of the silicone intubation; by this time, the pseudopunctum will typically have completely healed. “Cheese wiring” of the pseudopuncta will occur within a month if neither end of the stent is returning to the nose through a healthy collagen annulus, and such intubation should be removed at about 3 weeks after surgery.

4.6.2 Placement of a Jones Canalicular Bypass Tube3 Primary or secondary placement of a Jones canalicular bypass tube is required if no functioning canalicular tissue is present, with the tube designed to act as a sump drain, permitting gravitational tear flow from the medial tear lake into the nose, aided by the slight subatmospheric pressure in the nose that occurs during inhalation. Primary placement of a tube during DCR is undertaken after posterior mucosal suturing; the tube requires a 30° downward tilt for optimum drainage, with the distal

2 Monocanalicular stenting is unlikely to stay in place because of the absence of a normal annulus at the pseudopunctum. 3 This is sometimes referred to as a canaliculo-dacrocystorhinostomy or CDCR.

end lying free within the nasal space, somewhat in front of the middle turbinate, and the proximal end positioned hard behind the lower lid margin and immediately posterior to the medial canthal tendon. The mouth of the tube should lie neither too deeply (where it may abut the epibulbar surface) nor too anteriorly (where it will lie proud of the tear lake). After primary placement, the tube should be held somewhat laterally—by passing a 6–0 nylon suture three times around the neck of the tube— with each end of the suture passed through the skin beneath the lower canaliculus and tied over a bolster (fig 4.1c); the tube end is thereby lifted clear of the caruncular bed while conjunctival healing occurs in this area. Secondary placement of a Jones bypass tube is best accomplished by using a Nettleship dilator to pierce the epithelium at the exact desired position and a track forced through to the nose using the smallest end of the doubleended (“bullhorn”) dilators supplied with commercial tube sets (Fig. 4.5b). An appropriate tube (commonly 11 mm, with a 3.5-mm flange) is placed onto a “1”-gauge lacrimal probe that is passed along the dilated track, and the tube is forced along the track using the end of the thumbnails (Fig. 4.5c); the use of any form of instrument on the tube flange tends to shatter it. The positions of the ocular and nasal ends of the tube should be checked after withdrawing the “1” probe and spontaneous flow of saline verified. Since the patient will previously have had a carunculectomy, the bed of which will have healed, a suture need not be placed around the neck of the tube. Nasal examination, preferably with endoscopy, although a headlight and speculum are often adequate, aids secondary placement of bypass tubes. Placement is best performed under a short general anesthetic as the vasoconstriction of nasal local anesthesia creates an atypically capacious nasal space and leads to the misguided nasal positioning of the bypass tube.

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Summary for the Clinician

4

The surgical management depends on the location and the severity of canalicular obstruction, and may include: ■ Punctoplasty ■ DCR with retrograde canaliculostomy ■ Canalicular Pyrex bypass tubes (possibly the only effective solution for severe canalicular obstruction)

References 1. Anand S, Hollingworth K, Kumar V, Sandramouli S. Canaliculitis (2004) The incidence of long-term epiphora following canaliculotomy. Orbit 23:19–26 2. Auran J, Hornblass A, Gross ND (1990) Stevens–Johnson syndrome with associated nasolacrimal duct obstruction treated with dacrocystorhinostomy and Crawford silicone tube insertion. Ophthalmic Plast Reconstr Surg 6:60–63 3. Briscoe D, Edelstein E, Zacharopoulos I, et al (2004) Actinomyces canaliculitis: diagnosis of a masquerading disease. Graefes Arch Clin Exp Ophthalmol 242:682–686 4. Brockmann H, Wilhelm K, Joe A, Palmedo H, Biersack H-J (2005) Nasolacrimal drainage obstruction after radioiodine therapy: case report and a review of the literature. Clin Nucl Med 30:543–545 5. Burns JA, Morgenstern KE, Cahill KV, Foster JA, Jhiang SM, Kloos RT (2004) Nasolacrimal obstruction secondary to I(131) therapy. Ophthal Plast Reconstr Surg 20:126–129 6. Call NB, Welham RA (1981) Epiphora after irradiation of medial eyelid tumors. Am J Ophthalmol 92:842–845 7. Chak M, Irvine F (2009) Rectangular 3-snip punctoplasty outcomes: preservation of the lacrimal pump in punctoplasty surgery. Ophthal Plast Reconstr Surg 2:134–135 8. Chen SX, Lee GA (2007) SmartPlug in the management of severe dry eye syndrome. Cornea 26:534–538 9. Dutton JJ, Fowler WC, Gilligan P (2008) Mycobacterium chelonae canaliculitis associated with SmartPlug use. Ophthal Plast Reconstr Surg 24:241–243 10. Durrani OM, Verity DH, Meligonis G, Rose GE (2008) Bicanalicular obstruction in lichen planus: a characteristic pattern of disease. Ophthalmol 115:386–389 11. Esmaeli B, Burnstine MA, Ahmadi MA, Prieto VG (2003) Docetaxel-induced histologic changes in the lacrimal sac and the nasal mucosa. Ophthal Plast Reconstr Surg 19:305–308 12. Esmaeli B, Hidaji L, Adinin RB, et al (2003) Blockage of the lacrimal drainage apparatus as a side effect of docetaxel therapy. Cancer 98:504–507

13. Esmaeli B, Hortobagyi G, Esteva F, et al (2003) Canalicular stenosis secondary to weekly docetaxel: a potentially preventable side effect. Ann Oncol 13:218–221 14. Fezza JP, Wesley RE, Klippenstein KA (1999) The treatment of punctal and canalicular stenosis in patients on systemic 5-FU. Ophthalmic Surg Lasers 30:105–108 15. Hahn JM, Meisler DM, Lowder CY, Tung RC, Camisa C (2000) Cicatrizing conjunctivitis associated with paraneoplastic lichen planus. Am J Ophthalmol 129:98–99 16. Khong JJ, Muecke J (2006) Complications of mitomycin C therapy in 100 eyes with ocular surface neoplasia. Br J Ophthalmol 90:819–822 17. Kopp ED, Seregard S (2004) Epiphora as a side effect of topical mitomycin C. Br J Ophthalmol 88:1422–1424 18. Linberg JV, Moore CA (1988) Symptoms of canalicular obstruction. Ophthalmology 95:1077–1079 19. Mazow ML, McCall T, Prager TC (2007) Lodged intracanalicular plugs as a cause of lacrimal obstruction. Ophthal Plast Reconstr Surg 23:138–142 20. McLean CJ, Rose GE (2000) Postherpetic lacrimal obstruction. Ophthalmology 107:496–499 21. McNab AA (1998) Lacrimal canalicular obstruction associated with topical ocular medication. Aust N Z J Ophthalmol 26:219–223 22. McNab AA (1998) Lacrimal canalicular obstruction in lichen planus. Orbit 17:201–202 23. Mohan ER, Kabra S, Udhay P, Madhavan HN (2008) Intracanalicular antibiotics may obviate the need for surgical management of chronic suppurative canaliculitis. Indian J Ophthalmol 56:338–340 24. Naik MN, Kelapure A, Rath S, Honavar SG (2008) Management of canalicular lacerations: epidemiological aspects and experience with Mini-Monoka monocanalicular stent. Am J Ophthalmol 145:375–380 25. Neumann R, Dutt CJ, Foster CS (1993) Immunohistopathologic features and therapy of conjunctival lichen planus. Am J Ophthalmol 115:494–500 26. Park A, Morgenstern KE, Kahwash SB, Foster JA (2004) Pediatric canaliculitis and stone formation. Ophthal Plast Reconstr Surg 20:243–246 27. Reifler DM (1991) Management of canalicular laceration. Surv Ophthalmol 36:113–132 28. Rhee MK, Mootha VV (2004) Bilateral keratoconjunctivitis associated with lichen planus. Cornea 23:100–105 29. Rumelt S, Remulla H (1997) Silicone punctal plug migration resulting in dacryocystitis and canaliculitis. Cornea 16:377–379 30. Scheepers M, Pearson A, Michaelides M (2007) Bilateral canaliculitis following SmartPLUG insertion for dry eye syndrome post LASIK surgery. Graefes Arch Clin Exp Ophthalmol 245:895–897

References 31. Solans R, Bosch JA, Galofre P, et al (2004) Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy. J Nucl Med 42:738–743 32. Tsalic M, Gilboa M, Visel B, Miller B, Haim N (2006) Epiphora (excessive tearing) and other ocular manifestations related to weekly docetaxel: underestimated doselimiting toxicity. Med Oncol 23:57–61 33. Tucker NA, Tucker SM, Linberg JV (1996) The anatomy of the common canaliculus. Arch Ophthalmol 114:1231–1234 34. Varma D, Chang B, Musaad S (2005) A case series on chronic canaliculitis. Orbit 24:11–14

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35. Vécsei VP, Huber-Spitzy V, Arocker-Mettinger E, Steinkogler FJ (1994) Canaliculitis: difficulties in diagnosis, differential diagnosis and comparison between conservative and surgical treatment. Ophthalmologica 208: 314–317 36. Wearne MJ, Beigi B, Davis G, Rose GE (1999) Retrograde intubation dacryocystorhinostomy for proximal and midcanalicular obstruction. Ophthalmology 106:2325–2328 37. Wright P, Collin JR (1983) The ocular complications of erythema multiforme (Stevens Johnson syndrome) and their management. Trans Ophthalmol Soc U K 103: 338–341

Chapter 5

Orbitofacial Neurofibromatosis 1: Current Medical and Surgical Management

5

William R. Katowitz and James A. Katowitz

Core Messages ■

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Neurofibromatosis type 1 (NF1) is an inherited disorder that predisposes a patient to acquired neoplasms. There are many challenges to the management of NF1 associated orbitofacial neurofibromas and optic pathway gliomas. New understanding of intracellular pathways, specifically the role of neurofibromin as a negative regulator of Ras, an intracellular signaling protein, may allow future treatment to target NF1-associated tumors. While chemotherapy protocols to treat optic pathway gliomas (OPGs) have been somewhat effective, the medical treatment of plexiform neurofibromas to date has been less successful.

5.1

Introduction

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder occurring with an estimated incidence of 1 in 3,000 live births [16]. The propensity for tumor progression and skeletal abnormalities in this disease present both functional and cosmetic challenges for both patients and the physicians treating them. This is most evident in patients disfigured by NF1 involving the orbits and face. This chapter summarizes the clinical findings, updates current clinical trials, and describes surgical techniques useful in the treatment of NF1 tumors involving the orbit and adjacent tissues.

5.2

Nomenclature

The first published case report describing the findings in NF1 was published by Von Recklinghausen in1882 [43]. There have since been numerous terms used to describe

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■

■

A multidisciplinary approach is essential for treating patients with NF1 and should include genetic counseling and testing for both patients and their families. Early intervention can better control expansion of soft tissues and possibly reduce bony orbital expansion. Periorbital surgical techniques for managing tumors involving the orbit and adnexal structures can often spare more invasive neurosurgical approaches in the orbitofacial rehabilitation of NF1 patients. Orbital exenteration can be avoided in almost every instance.

the involvement of the orbit and face. Orbitotemporal neurofibromatosis has been the most common [12]. Other terms are orbitopalpebral neurofibromatosis [35], orbitofacial neurofibromatosis [46], oculofacial neurofibromatosis [10], and cranio-orbital-temporal neurofibromatosis [18]. Orbitofacial neurofibromatosis is perhaps the most inclusive term for the oculoplastic surgeon since it highlights the potential involvement of NF1 tumors affecting not only the orbit, eyelids, and temporalis region but also facial structures above and below the orbits.

5.3

Clinical Manifestations of NF1

NF1 is caused by a germline-inactivating mutation in the NF1 gene on chromosome 17 that results in deregulated cell growth. This abnormal growth manifests in various soft tissue and bony abnormalities, often producing major orbitofacial deformities [50]. The lesions most disfiguring in orbitofacial NF1 are neurofibromas and optic gliomas.

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Orbitofacial Neurofibromatosis 1: Current Medical and Surgical Management

Table 5.1. Diagnostic Criteria for NF1 National Institutes of Health Diagnostic Criteria for NF1 [37]

5

Two or more of the following features signify the presence of NF1 in a patient: Six or more café-au-lait macules (>0.5 cm at largest diameter in prepubertal individuals or >1.5 cm in individuals past puberty) Axillary freckling or freckling in inguinal regions Two or more neurofibromas of any type or ≥1 plexiform neurofibroma Two or more Lisch nodules (iris hamartomas) A distinctive osseous abnormality A first-degree relative with NF1 diagnosed using these criteria National Institutes of Health Diagnostic Criteria for NF1 [37]

Other manifestations include café-au-lait macules; axillary and inguinal freckling; malignant peripheral nerve sheath tumors; Lisch iris nodules; skeletal dysplasia, including the absence of the greater sphenoid wing; neurocognitive defects; and cardiovascular abnormalities. Ocular findings can manifest as proptosis, glaucoma, buphthalmos, and vision loss. Lee et al. described additional periorbital sequelae of brow ptosis, lateral canthal disinsertion, conjunctival and lacrimal gland infiltration, as well as lower and upper eyelid infiltration with ptosis [28]. The National Institute of Health diagnostic criteria for NF1 are listed in Table 5.1 [36].

5.4 5.4.1

Plexiform neurofibromas typically are congenital, with 50% of the tumors occurring in the head and neck [36]. They exhibit an earlier growth phase than the localized form, with the most rapid growth occurring before the onset of puberty. A study identified the presence of growth hormone receptors on plexiform neurofibromas, which suggests that their propensity to grow may be further induced by hormonal signals [8]. Plexiform neurofibromas grow along the length of a nerve and may arise from multiple nerve fascicles. External plexiform neurofibromas (i.e., not within the cranium) occur in approximately 30% of patients with NF1 [33]. These tumors can cause pain, localized pruritis, and neurologic deficits in addition to severe disfigurement and amblyopia [38]. Plexiform neurofibromas carry a 4–5% rate of malignant transformation [11]. In contrast to the localized neurofibroma, the plexiform type is not well circumscribed and usually infiltrates local tissues. This makes complete resection of this tumor very challenging and often impossible. Tarsal thickening, an S-shape lid deformity and overgrowth of the eyelid are induced by this tumor (Fig. 5.1). The diffuse form of neurofibromas is not ensheathed in repeating perineura as is found in plexiform neurofibromas [29]. Diffuse neurofibromas also appear early in young patients as with the plexiform neurofibromas. One distinguishing characteristic from the plexiform type is the inability to palpate discrete tumors. Diffuse neurofibromas often present as a thickening of tissues, such as the tarsus and levator muscle often seen in NF1 lid deformities. These tumors are highly infiltrative, bleed heavily, and are virtually impossible to completely remove (Fig. 5.2).

Orbitofacial Tumors in NF1 Neurofibromas

The NF1 tumors affecting the orbit include neurofibromas and OPGs. Neurofibromas are benign tumors that arise from peripheral nerve sheaths and are composed of Schwann cells, endoneural fibroblasts, and perineural cells [29]. The multicellular histology of the neurofibroma distinguishes it from the schwannoma, which is a pure proliferation of Schwann cells. Neurofibromas can be subdivided into localized, plexiform, or diffuse. Localized neurofibromas are associated with NF1 in approximately 10% of cases [25]. They can present in the orbit, causing proptosis in adults, usually young to middle aged. These lesions often behave like isolated schwannomas, although they can present as multiple lesions within the orbit and can cause pain if involving a sensory nerve. The tumors are not encapsulated but can often be removed intact because they are well circumscribed [29].

Fig. 5.1 A 4-year-old boy with NF1 and right upper eyelid S-shape deformity from plexiform neurofibroma in the upper eyelid

5.4 Orbitofacial Tumors in NF1

a

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Fig. 5.2 (a) Plexiform neurofibroma of the upper eyelid. (b) Diffuse neurofibroma of the upper eyelid. Notice the infiltration of the levator muscle by neurofibroma (From Katowitz [23]. With permission from Springer)

value for differentiating benign plexiform neurofibromas from malignant peripheral nerve sheath tumors [14].

5.4.2 Malignant Peripheral Nerve Sheath Tumors Malignant peripheral nerve sheath tumors are aggressive spindle cell tumors that are also called malignant schwannomas or neurofibrosarcomas. These tumors present in the orbit and eyelids and usually arise from branches of the trigeminal nerve [29]. They typically arise from plexiform neurofibromas; however, a large study of 1,475 NF1 patients found that 36% of the 30 cases of malignant peripheral nerve sheath tumors occurred in patients with no known history of neurofibromas [24]. The lifetime risk of developing this tumor is 10% in NF1 patients [13]. Although fluorodeoxyglucose positron emission tomographic (PET) scans have generally been of little value in evaluating optic nerve gliomas in the orbit, they may be of

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5.4.3

Optic Pathway Gliomas

Optic pathway gliomas can extend from the orbit to the chiasm and optic tract (Fig. 5.3). OPGs are low-grade pilocytic astrocytomas that occur in approximately 15–20% of patients with NF1 [30, 31]. Other central nervous system gliomas associated with NF1 can also occur in the cerebellum, diencephalon, and brain stem at a rate of 3.5% [15]. OPGs in NF1 typically occur before the age of 10 and are usually located along the optic nerve. In contrast, sporadic gliomas not associated with NF1 are typically chiasmal or prechiasmal [31]. This common

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Fig. 5.3 (a) An 8-year-old girl with NF1 and a blind proptotic left eye. (b) T1-weighted MRI reveals an optic nerve glioma within the orbit

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belief has been challenged by Singhal et al., who found a significant involvement of the chiasm in NF1-associated OPG as compared to sporadic cases (10 of 17 cases with NF1 and 6 of 17 sporadic OPGs) [44]. Symptoms can include proptosis, vision loss, and hypothalamic involvement, resulting in precocious puberty. There are reports of progression of OPGs, although the common belief is that this occurs more frequently in sporadic cases [50]. When considering outcomes, the term progression, from an orbital surgeon’s perspective, needs clarification. In this regard, it is useful to review the neurooncology perspective, particularly as it applies to NF1. There are several categories that can be used to describe the clinical status of OPGs from initial diagnosis to remission or cure. Remission is most commonly used to describe a positive response to medical therapy. While spontaneous remissions can occur in NF1 OPGs, this is rarely, if ever, observed in sporadic OPGs [41]. Recurrence of tumor describes evidence of tumor after an apparent tumor-free period. Progression of tumor describes growth of an existing mass. This can be observed either clinically (i.e., increasing proptosis), for example, or by serial imaging studies demonstrating an increase in volume or expansion of the lesion. For the orbital surgeon, the major concern has related to the possibility of “retrograde progression,” particularly regarding optic nerve gliomas growing posteriorly from the orbital apex through the bony optic canal toward the chiasm [2, 22]. Management paradigms for treating NF1 orbital tumors and particularly optic nerve glioma have been somewhat controversial. A common assumption has been that these lesions represent hamartomas with early and then static growth. The traditional concepts have been that (1) NF1-related gliomas act more benignly, (2) optic nerve gliomas without chiasmatic involvement do not later spread into the chiasm, and (3) surgical removal to prevent spread is unnecessary. Studies, however, indicated that there may be some cases when retrograde progression can occur. Singhal et al. reported one case of an NF1-associated glioma that had affected the left optic nerve and was excised. Nine years later, the optic glioma recurred in the chiasm [44]. A report by Walrath et al. demonstrated retrograde growth in a non-NF1 patient [47]. Progression from prechiasmal to chiasmal to postchiasmal disease was demonstrated on serial magnetic resonance imaging (MRI) scans. Of significance, clinically, with treatment using confocal radiation and intravenous steroids, vision was regained from no light perception (NLP) to 20/20. Because of disfiguring proptosis, however, an excisional biopsy was done. The histopathology confirmed that the tumor was a benign pilocytic astrocytoma. Of major

interest, however, were the results of histochemical studies, which revealed evidence of a mindbomb homolog (MIB-1 LI) [6]. This homolog is an antibody that recognizes Ki 67, a protein active during all phases of the cell cycle. Increased levels of Ki 67 have been found to be consistent with aggressive tumor behavior in OPGs [7, 47]. The normal value for Ki 67 in benign pilocytic astrocytomas is less than 1%. In this patient, however, the specimen revealed an average of 2.8%, with some areas as high as 7%. The importance of this case is not only that active growth in the tumor was observed both clinically and histologically but also that the tumor responded to therapy with a dramatic improvement in vision. These findings do not conform with the concept of a hamartoma. An accompanying editorial by Miller in the same journal emphasized that it is “inaccurate to consider such lesions to be hamartomas and equally inappropriate to recommend no treatment for lesions that show evidence of clinical or imaging progression” [34]. Walrath and his coauthors further suggested that early biopsy with histochemical studies may possibly provide prognostic information regarding timing and extent of surgical resection [47]. This assertion is supported by the histologic findings by Burstine et al. [6], who performed quantitative analysis of proliferative activity of 14 optic nerve gliomas using the silver nucleolar organizing region technique and found 6 of 14 gliomas positive. A similar finding was observed in other malignant tumors. In addition, the analysis was equivocal regardless of location or NF1 association. First-line therapy for OPGs includes appropriate imaging and chemotherapy [39]. Although chemotherapy regimens vary depending on the institution, a new protocol (Children’s Oncology Group Chemotherapy Protocol CCG-A9952) has completed a phase III randomized study of carboplatin and vincristine compared to thioguanine, procarbazine, lomustine, and vincristine in children with progressive low-grade astrocytoma [4]. Although the results of this study have not yet been published, it does appear from other reports that the effectiveness of chemotherapy for chiasmal gliomas has been greatly improved, with 5-year survival rates of over 70% [44]. Radiation for chiasmal lesions has not been recommended for children under 5 years of age because of damage to the brain and hypothalamus. Because of the success rates with chemotherapy, however, the use of radiation even in older patients is no longer recommended [26]. Surgical intervention is usually reserved for gliomas that either respond poorly to chemotherapy or radiation or are associated with severe proptosis causing vision loss or a marked cosmetic deformity. This is discussed more fully in other sections of this chapter.

5.5

5.5

Genetics

5.5.1 The NF1 Gene Neurofibromatosis type 1 is caused by a germline mutation in the NF1 gene on chromosome 17q11.2. The gene is autosomal dominant. Most NF1 patients are born with one intact and one defective allele from a germline mutation. When a “second hit” occurs to the intact allele in somatic cells, those cells become vulnerable to tumor growth [48]. Roughly 50% of newly diagnosed cases of NF1, however, occur in patients with no known family history of NF and are presumed new mutations [45]. An estimated 5% of individuals with NF1 have a more severe phenotype due to a complete deletion of the NF1 gene. Genetic testing is now able to detect nearly 95% of all cases. (A publicly funded posting of labs that test for NF1 is available at www.genetests.org.) The protein product of the NF1 gene is neurofibromin. This is a guanosine triphosphatase-activating protein for Ras (a component of the signal transduction pathway for cell growth initiation). It has been shown that the loss of neurofibromin leads to the unsuppressed activity of the intracellular protein Ras with increased cell growth [9]. Neurofibromin has also been suggested to play a role in the tumor suppressor gene TSC2 as well as the growth pathway mTOR [21].

SPRED1 is a newly discovered gene with an acquired mutation that can lead to a NF1 clinical presentation without the loss of the neurofibromin gene. The SPRED1 gene is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of Ras intracellular signaling [40]. The first description of this autosomal

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dominant disorder was made in 2007 in a patient with café-au-lait spots, axillary freckling, and macrocephaly [5]. A report found the SPRED1 mutation in 5% (3/61) of patients with the NF1 phenotype but with no identifiable NF1 mutation [40]. This publication underscores our incomplete understanding of the determinative biologic factors in patients who present with the constellation of clinical findings associated with NF1. Figure 5.4 depicts a patient with a lower eyelid neurofibroma and an ispilateral sphenoid wing dysplasia but without any other characteristic findings of NF1. Genetic testing was positive for the SPRED1 mutation in this patient but negative for the NF1 gene mutation.

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5.5.2 Overlapping NF1-Like Phenotype (SPRED1)

Genetics

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Orbitofacial neurofibromas is an accurate term to describe the multi-focal location of these tumors in relation to the eye. Neurofibromas can occur as localized, plexiform, or diffuse, although the last two are more common in NF1. OPGs should be considered proliferating tumors and not hamartomas. Remission is most commonly used to describe a positive response to medical therapy. Recurrence of tumor describes evidence of tumor after an apparent tumor-free period. Progression of tumor describes growth of an existing mass. NF1 is caused by a mutation to the neurofibromin gene; however, the newly discovered SPRED1 mutation can cause a NF1-like phenotype without an abnormal neurofibromin gene.

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Fig. 5.4 (a) A 4-year-old boy with no known history of NF1 has a palpable mass in the left lower eyelid. (b) A lower eyelid mass is removed through a subciliary incision. Biopsy revealed a plexiform neurofibroma. NF1 gene testing was negative for NF1, but the patient was positive for the SPRED1 mutation. (c) Six months postoperative

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Management of Neurofibromatosis Type 1

Summary for the Clinician ■

Introduction

Due to the variable clinical manifestations of NF1, treatment must be tailored to the patient and not the disease. A multidisciplinary approach is important for optimizing patient care by incorporating the diagnostic and management skills of other medical services such as genetics, neurooncology, ophthalmology, neuroophthalmology, plastic surgery, otolaryngology, orthopedics, general surgery, and developmental psychiatry/psychology.

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First-line therapy for OPGs is proper imaging and chemotherapy. Medical therapy for neurofibromas is currently under clinical trials; however, initial data do not point to a home run therapy. and surgery should always be considered a primary treatment.

5.7 Surgical Management of Orbitofacial Tumors in NF1 5.7.1

5.6.2

Medical Management of Neurofibromas

Although there has been some success in treating OPGs with chemotherapy or radiation, the management for optic nerve gliomas in the orbit has been primarily surgical when treatment for severe proptosis has been determined necessary. For plexiform neurofibromas, however, because of their marked vascularity, numerous chemotherapeutic agents are being tested as potential treatments. A clinical trial with alfa-interferon has had poor results [50]. Thalidomide has also had poor results with plexiform neurofibromas but has shown more promise in treating malignant peripheral nerve sheath tumors [17]. AZD2171, a small molecule VEGF-like vascular endothelial growth factor (VEGF) receptor, is currently under phase I study [3]. Tipifarnib, a drug specifically targeting tumor cells, is also currently in phase II trials. This is a farnysyl transferase inhibitor that affects intracellular Ras activity and has shown some promise in phase I trials in both children and adults [49]. The antifibrotic agent pirifenidone (5-methyl-1-phenyl2-[1H]-pyridone) is now in phase II trials. This medication attenuates cytokine release by fibroblasts thus weakening the cellular support of neurofibromas [1]. At the Children’s Hospital of Philadelphia, the effectiveness of methotrexate with Velban for suppressing NF1 tumor growth is currently being evaluated as well as an NF consortium study using rapamycin. Although there is as yet no published data, anecdotally, however, it appears that there may be some slowing of growth but little evidence of regression [4]. Unfortunately, to date an effective “home run” medical regimen has not been found for managing plexiform neurofibromas [4]. For this reason, surgical debulking and reconstruction still remain the best option for orbitofacial rejuvenation from the disfiguring tumors associated with NF1. The following section outlines our current approach to the surgical management of orbitofacial tumors associated with NF1.

Introduction

Surgical intervention to help restore function and improve cosmesis in patients with orbitofacial involvement of neurofibromatosis has been well described in the literature. Jackson et al., in their series of 24 patients with NF1, defined three treatment groups [19]: 1. Orbital soft tissue involvement with a seeing eye 2. Orbital soft tissue and significant bony involvement with a seeing eye 3. Orbital soft tissue and significant bony involvement with a blind or absent eye Lee et al., in their series of 33 patients with NF1, elaborated on this classification by describing additional findings to these treatment groups [28]: 1. 2. 3. 4. 5.

Brow ptosis Upper lid infiltration with ptosis Lower lid infiltration Lateral canthal disinsertion Conjunctival and lacrimal gland infiltration

5.7.2 Timing of Surgery It is critical to recognize the emotional stress and psychosocial implications of NF1 deformities not only on the affected individuals but also on their families and friends. Social withdrawal due to disfigurement and chronic pain must be considered when evaluating the need for and timing of surgical intervention. Some authors suggest delaying intervention if possible due to the higher rate of “recurrence” in younger patients. In the periorbital region, these tumors really do not represent recurrences, however, but rather continued progression of sheath and cutaneous tumors in particular. In our experience, most families are extremely motivated to begin treatment, including surgical intervention, even though cautioned

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Surgical Management of Orbitofacial Tumors in NF1

regarding the continuing need for multiple surgical corrections in most instances [28]. We have observed significant improvements in patients’ social interactions after surgery that have definitely outweighed a more conservative approach to defer intervention until postadolescent years. In addition, the preservation of vision is also an important factor since surgery can often help to reduce the amblyogenic influence on a patient’s visual development. The indication for a diagnostic biopsy may sometimes be an important consideration as well, requiring surgical intervention in certain clinical situations. Efforts to correct orbitofacial deformities are very challenging from both functional and aesthetic perspectives. Regarding ptosis surgery, in particular, Jackson et al. stated [19]: The most unsatisfactory part of the procedure is the ptosis correction. This frequently requires repeat surgery, and even after this, there may be incomplete lid elevation. Indeed, most patients require multiple procedures to treat tumor progression, as well as repeat procedures for the mechanical type of ptosis caused by NF1. It is important to counsel patients and families of the strong possibility that multiple procedures may be required in any effort to approach a normal appearance through orbitofacial rehabilitation surgery. The reality of tumor “recurrence,” specifically plexiform neurofibroma, is well documented. A 20-year review published by the neurofibromatosis clinic at the Children’s Hospital of Philadelphia reviewed 121 patients who had 302 procedures. The overall freedom from tumor progression was 54%. The main risk factors for progression were (1) tumors of the head/neck/face, (2) less-extensive progression, and (3) affected children less than10 years of age [38]. The risk of tumor progression, however, should not be considered a deterrent to surgical intervention when one weighs the overall psychological, aesthetic, and often functional benefits of orbitofacial rehabilitation for NF1 deformities. Some authors have actually advocated the need for exenteration in part to prevent tumor progression but also to decrease the risk of malignant transformation [12, 32]. It is our belief, however, that this permanently disfiguring procedure can be avoided in almost all circumstances with acceptable results.

5.7.3 Periorbital Involvement 5.7.3.1

The Upper Eyelid

The classic appearance of an upper eyelid S-shape deformity frequently occurs in NF1 patients with neurofibroma infiltration of the upper eyelid (Fig. 5.1). This can

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involve any of the eyelid tissues from the dermis, orbicularis, levator complex, tarsus, and conjunctiva. Sometimes, the lid may become thickened and heavy with tumor, causing ptosis of the upper eyelid. The term bag of worms often used to describe plexiform neurofibromas is appropriate as these tumors can be readily palpated in the upper lid. They represent sheath abnormalities occurring in multiple nerve fibers in the upper eyelid tissues. When approaching the management of NF1-induced ptosis in children, one must always be cognizant of the amblyogenic risk of ptosis as well as possible anisometropia from induced astigmatism. In our experience, we usually find an anterior approach for NF1-induced ptosis most useful because tumor debulking is most commonly required. In general, patients with moderate or better levator function have a good functional result with an anterior levator resection. With advancing age, as plexiform and diffuse neurofibromas grow, the anterior lid crease approach for ptosis repair can be extended to permit wedge resection and re-formation of the lateral canthal angle. A periosteal flap is often useful. Frontalis suspension surgery is reserved for those patients with poor levator function (4 mm or worse). In patients under the age of 5, we prefer a silicone frontalis sling passed in a rhomboid fashion with two brow stab wounds (medial fixation of sling over a silicone sleeve). In patients older than 5 years, the ideal sling material is autogenous fascia lata.

5.7.3.2

The Lower Eyelid and Midface

Some patients may present with an isolated mass of the lower eyelid with or without a known diagnosis of NF1. Figure 5.4 illustrates how a lower eyelid/upper midface mass may be removed through a subciliary incision with minimal morbidity. A patient in France underwent a lower and midface transplant for a massive plexiform neurofibroma. On 1-year follow-up, after two episodes of clinical rejection (at 1 month and at 2 months), the patient had acceptable sensory and motor innervation of the transplanted territory [27]. This treatment represents a potential new horizon for allotransplantation that certainly warrants further research. While most cases of adnexal deformity due to NF1 can be managed by lessdrastic measures, there may be a place for facial transplantation in the patient who has not had the benefit of early debulking and reconstruction, including subsequent follow-up procedures, and presents as an adult with extraordinarily gross deformities difficult to manage from both a functional and aesthetic perspective using more conventional techniques.

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5.7.4 Orbital Involvement 5.7.4.1 Proptosis

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Orbital enlargement resulting from growth of an optic nerve glioma or neurofibomas is common. It may also be due to bony cranial abnormalities, typically sphenoid wing dysplasia. The last results in the classic finding of

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pulsatile proptosis in the patient with NF1. In addition, buphthalmos, which is often secondary to congenital glaucoma associated with NF1, can lead to pseudoproptosis from an increased axial length. It is not uncommon for patients with significant orbital involvement to have a cluster of findings, including sphenoid wing dysplasia, proptosis, ptosis, buphthalmos with a blind eye, and an optic nerve glioma or orbital neurofibroma (Fig. 5.5).

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Fig. 5.5 (a) Neonatal picture of infant with NF1 tumors present at birth. (b) T2 MRI demonstrates neurofibromas present in orbit and lids as well as a buphthalmic globe causing proptosis from an increased axial length as well as intraorbital masses. (c) Child at age 2½ years postenucleation at another institution with a significant recurrence of proptosis and lid deformity secondary to a marked increase in tumor growth. (d) MRI now shows orbital implant surrounded by an increase in neurofibromas extending into the upper lid. (e) Lid crease incision used to debulk upper lid and orbital tumors with wedge resection of one third lateral lid and canthal reconstruction; note thickening of lateral tarsal lid margin due to infiltration of diffuse type of neurofibroma. (f) Resection of levator muscle infiltrated with plexiform and diffuse neurofibromas. (g) Four years postoperative. (h) MRI postop debulking and lid reconstruction with prosthesis in place

5.7

Surgical Management of Orbitofacial Tumors in NF1

A multidisciplinary approach is best for the NF1 patient afflicted with these complicated disfiguring problems. Even after neurooncological evaluation and treatment, it is often necessary to intervene surgically to rehabilitate a patient’s appearance. For the child with gross orbital and periorbital deformities, this may be of even greater concern to the family than the preservation of the eye on the affected side despite the opportunity for a reasonable visual potential. The surgeon must thoroughly discuss the realistic limits to keeping a proptotic eye versus complete resection (enucleation, etc.) with subsequent socket reconstruction. The approach to the proptotic patient with NF1 may require craniofacial or neurosurgical collaboration depending on the need to reach a specific area of the orbit. For posterior apical lesions or the repair of certain bony abnormalities of the orbit and cranium, a transcranial neurosurgical approach may be warranted. Other options for treating proptosis in NF1 are usually available to avoid unnecessarily aggressive intervention, such as orbital exenteration for rehabilitation. As stated, we strongly reject use of this technique except for an extremely unusual case for which malignancy is of documented concern. With a carefully staged approach to multiple surgeries, reasonable results can be achieved to optimize ocular prosthesis retention with acceptable or even good cosmesis in many cases.

5.7.4.2 Proptosis Due to Orbital Neurofibromas Patients with orbital neurofibromas, particularly of the plexiform type, may benefit from possible reduction of tumor with additional chemotherapy. To this date, however, no chemotherapy regimen has proven effective in completely reducing orbital neurofibromas [4]. The main effect, as stated, has been possible slowed growth. At this time, for patients with significant orbital involvement, surgery remains the most hopeful modality for addressing issues of painful proptosis or disfigurement. Patients may suffer from exposure due to proptosis and from orbital or periorbital discomfort secondary to their orbitofacial neurofibromas. The surgeon must obtain adequate imaging in such cases to delineate the presence of any intracranial extension as well as any additional intracranial tumors or other pathology.

5.7.4.3

Proptosis Due to Optic Nerve Glioma

The medical management and controversies regarding tumor classification of OPGs in NF1 have been addressed in this chapter. In addition to medical management,

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Fig. 5.6 Optic nerve glioma excision: lateral approach. Gliomas can often be excised via a lateral orbitotomy as demonstrated above. Glioma visible in front of retractor (see arrow). Removal of the lateral wall in children may not be necessary due to the shallow orbit in this age group (From Katowitz [23]. With permission from Springer)

tumor resection may be considered. This is both to treat disfiguring proptosis and to remove a lesion that could potentially grow posteriorly. Gliomas of the orbital optic nerve causing proptosis can often be removed by a lateral approach, especially in children, for whom the orbit is shallower and removal of the orbital bone can be avoided (Fig. 5.6). Gliomas directly behind the globe can sometimes be removed by an anterior approach combined with enucleation (Fig. 5.7). For posterior lesions where there is severe proptosis or real concern regarding retrograde progression, a superior transcranial neurosurgical approach may be required (Fig. 5.8).

5.7.4.4 Orbital Enlargement with Dystopia and Hypoglobus Early involvement of NF1 tumors can lead to orbital enlargement (Fig. 5.9). This can present a significant surgical dilemma for reconstruction. Debulking of tumor from the orbit early in life may decrease the stimulus for asymmetric growth to some degree but is usually not sufficient to control this effectively. Orbital bony enlargement, while a problem, is often less noticeable than the soft tissue deformities usually associated with this. For the casual observer, the increase in orbital volume is actually hidden. The periorbital soft tissue changes are what is noticeable, represented by a higher and often more prominent brow, a lengthened lid fissure with lid deformities secondary to tumor growth, as well as an associated mechanical ptosis. Bony sphenoid wing dysplasia or even aplasia permits visible pulsations transmitted from the brain through the orbital defect.

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Fig. 5.7 Optic nerve glioma excision: anterior approach. Gliomas can be excised using an anterior approach combined with enucleation if the tumor is adherent to the globe and not in the posterior orbit. (a) Marked proptosis with exposure problems. (b) Tumor visible after removing extraocular muscles. (c) Four years postoperative

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Fig. 5.8 Optic nerve glioma excision: superior approach. For posterior tumors, particularly if there is concern for retrograde progression, a transcranial neurosurgical approach may be utilized. (a) Left proptosis from optic nerve glioma. (b) MRI scan of tumor near bony canal entrance posteriorly. (c) Frontal lobe retracted and periorbita exposed after removing orbital roof. (d) Artist rendition of a superior orbitotomy with retraction of the levator muscle and superior rectus medially (From Katowitz [23]. With permission from Springer). (e) Ten years postoperative

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Surgical Management of Orbitofacial Tumors in NF1

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Fig. 5.9 Orbital enlargement with vertical dystopia and hypoglobus. (a) A 20-month old child presenting with ptosis of his left upper lid. (b) At 20 years of age, despite multiple efforts to debulk orbital and periorbital tumors, including enucleation with a dermis fat graft, he still has obvious dystopia and hypoglobus. Note the heavy tumors in his left cheek; note also the paste-on hairpiece used to cover hair loss over lateral cranium. (c) T2 MRI scan shows expansion of orbit in all directions secondary to tumor growth. This patient declined osteotomies at an earlier age. (d) CT scan reveals thin bony orbital structure that would be difficult to mobilize and support with bone grafts and hardware at this point in time; note also the posterior bony defect due to sphenoid bone dysplasia. (e) Tumor excision from cheek via a skin flap with rhytidectomy. Further ptosis and lid reconstruction also done. (f) One month postoperative with positive effect from rhytidectomy but persistent vertical dystopia. Paste-on hairpiece withheld to avoid contaminating rhytidectomy incision. (g) An appropriate base-down prism can be used to optically elevate orbit for a more symmetrical appearance

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Surgery to decrease the diameter of the bony orbital entrance or to significantly build up the orbital floor to reduce volume requires an experienced craniofacial surgical team. Because of the high vascularity of NF tumors, the risks of extensive blood loss is always a major concern. Surgery to alter the bony orbit is difficult but can be effective in selected cases [20, 42]. A major problem with early osteotomies to reduce the orbital rim diameter or to shift the orbit up, however, is in determining how progressive and destructive any given orbital process will become. The problem with deferring orbital bone surgery to a later adult stage is that over time, with the gradual expansion of soft tissue tumor growth, the bony rims become thin and brittle. This adds to the surgical difficulties given the propensity for major loss of blood in the NF1 patient. Another factor is that while most adult patients and parents of affected children accept the concept of multiple soft tissue procedures, they are usually more reticent to undergo major orbital bony reconstruction when presented with the risk–benefit ratios and the prolonged postoperative course of major craniofacial reconstruction. Elevation of the canthi rather than onlay grafts to the orbital floor or sectioning the orbital rims to achieve a smaller diameter is an alternative that can yield a reasonable result in many instances but may require wiring of the canthi into a higher position on the bony orbit. Even with this approach, there is a tendency for a downward drift over time. This is compounded by the gravitational pull of tumors in the cheek and lower face that can add to this downward drift. Care must be taken to protect the lacrimal drainage system during medial canthopexy, and bicanalicular silastic intubation may be of value for this purpose. Further support of the lower lid and canthi with an autogenous fascia lata sling can be a useful adjunct. When there is still a noticeable vertical dystopia, use of a basedown prism in spectacles can also produce a more symmetric appearance if the patient does not wish to proceed with craniofacial bony reconstruction for this aspect of orbitofacial rehabilitation (Fig. 5.9g).

Summary for the Clinician ■ ■

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It is not necessary to delay surgical intervention for disfiguring NF1 tumors. Patients and families often seek early intervention and are willing to tolerate the likelihood of multiple procedures. When approaching disfiguring proptosis, the surgeon must counsel the patient and family regarding the visual prognosis and weigh the overall benefit of removing an eye to rehabilitate a patient’s comfort, self-perception, and appearance. Orbital exenteration can be avoided except for cases of malignancy. Patients with NF1 require a lifetime of follow-up due to the tendency of tumor progression, recurrence, and involvement of other organ systems.

5.8 The Natural History of NF1 Tumor Growth from Birth to Senescence Growth or progression of NF1 tumors affecting the orbitofacial region is generally considered to begin in the first few years of life and then to advance more rapidly with natural growth spurts, slowing in the third decade of life. Unfortunately, there are no published studies documenting the long-term effects of NF1 in a large series of patients with multidecade follow-up. We have had a somewhat unusual opportunity, however, to observe the evolution and progression of NF1 tumors in such a patient over a period of more than 60 years (Fig. 5.10). What is evident from this case is that NF1 tumor growth does not always slow in progression after the second decade. Although we have photographic documentation of his appearance at 2 years of age, our direct experience with this patient began at age 37 when our surgical team first had the opportunity to evaluate him and then to perform

Fig. 5.10 NF1 tumor growth from birth to senescence. (a) Patient at age 2 with obvious NF1 tumor presentation. (b) Appearance 35 years later at age 37 after multiple procedures elsewhere. These included a neurosurgical excision of tumor involving cranial bone on the left side. (c) Coronal CT scan shows missing left cranial bone due to infected metal plate with subsequent removal. (d) Patient at 2 months after combined team approach for excision of tumors in scalp, cheek, and orbit, including enucleation with a dermis fat graft implant. (e) Transposition flap moved from lower to upper lid with lateral canthopexy. (f) Transposition flaps sutured into place. (g) Patient at 2 years postoperative (age 39); note that skin and cheeks are relatively free of tumor. (h) Patient now 20 years postprocedure (age 60); note the cutaneous neurofibromas now affecting both sides of his face as well as the deeper left cheek tumors. (i) Severe enophthalmic appearance due to presumed atrophy of orbital soft tissues. (j) Scan actually reveals healthy dermis fat graft placed 20 years previously with significant atrophy of the temporal lobe as the cause of the enophthalmos due to a direct communication of orbital contents through an aplastic sphenoid bone defect. (k) Large dermis fat graft from inguinal area has been placed in orbit to repair enophthamic appearance. (l) Patient at 2 months post-op and age 61 years. Note that despite orbital dystopia in this case, the canthi have remained in a relatively symmetrical position, possibly related to use of a fascia lata sling with canthopexy repair

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The Natural History of NF1 Tumor Growth from Birth to Senescence

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major orbitofacial tumor resection and reconstruction. Underscoring the problems with potential blood loss in the NF1 patient, his first procedure involved replacement of eight units of blood and then an additional four units postoperatively. At age 60, he presented with marked enopthalmos in his enucleated left socket, with his prosthesis lying flat in the socket, presumably due to orbital fat atrophy. Imaging, however, revealed this not to be due to atrophy of his dermis fat graft or orbital fat but to further atrophy of his temporal lobe, with the orbital contents herniating through the opening in his aplastic sphenoid bone. A large dermis fat graft from the inguinal region was placed to fill the upper lid sulcus and periorbit along with additional lid reconstruction to permit better positioning of his prosthesis. His appearance was further marred by the progression of cutaneous neurofibromas on both the right side of his face and his left as compared to his facial appearance 25 years earlier. This case illustrates that NF1 tumors, although they may well be benign initially, can continue to manifest in the orbit and elsewhere for decades. It must be recognized

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Patients who suffer from NF1 present with a varied course that often involves tumor progression. New understanding of intracellular pathways and abnormal genes may allow future treatments to better target these tumors. While some authors recommend deferring definitive reconstructive surgery until after puberty, we believe that early intervention can better control expansion of soft tissues and possibly reduce bony orbital expansion. Of major importance, in addition to functional concerns, is the need to recognize the value of orbitofacial rehabilitation from an appearance perspective. Improving appearance is usually of critical importance to both the patient and family. It is critical to counsel older patients and the parents of young children regarding the likely necessity for multiple reconstructive procedures in the effort to approach normal orbitofacial function and appearance. It is also critical that NF1 patients be followed carefully from a systemic medical perspective during the entire lifetime as there are numerous secondary problems related to NF1 that may become manifest at any time.

that the risks for secondary malignancy, whether in sheath tumors, in secondary central nervous system tumors, or in other more distant locations, are of real significance, particularly in NF1 patients, thus mandating careful follow-up evaluations [44].

References 1. Babovic-Vuksanovic D, Ballman K, Michels V, et al (2006) Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology 67(10):1860–1862 2. Balcer LJ, Liu GT, Heller G, Bilaniuk L, Volpe NK, Galetta SL, et al (2001) Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am J Ophthalmol 131:442–445 3. Batchelor TT, Sorensen AG, di Tomaso E, et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95 4. Bellasco J (2009) Children’s Hospital of Philadelphia. Personal correspondence 5. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1 like phenotype. Nat Genet 39(9):11120–1126 6. Burnstine MA, Levine LA, Louis DN, et al (1993) Nucleolar organizer regions in optic gliomas. Brain 116:1465–1476 7. Cummings TJ, Provenzale JM, Hunter SB, et al (1987) Magnetic resonance imaging in the evaluation of optic nerve gliomas. Ophthalmology 94:709–717 8. Cunha KS, Barboza EP, Fonseca EC (2008) Identification of growth hormone receptor in plexiform neurofibromas of patients with neurofibromatosis type 1. Clinics 63:39–42 9. Dasgupta B, Dugan LL, Gutmann DH (2003) The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes. J Neurosci 23(26):8949–8954 10. Dilenge D, Saraux H, Simon J, Calabro A (1965) Bilateral oculofacial form of neurofibromatosis. J Radiol Electrol Med Nucl 46:143–146 11. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM (1986) Malignant peripheral nerve sheath tumors. Cancer 57:2006–2021 12. Erb MH, Uzcategui N (2007) Orbitotemporal neurofibromatosis: classification and treatment. Orbit 26:223–228 13. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002) Malignant peripheral nerve sheath tumors in neurofibromatosis 1. J Med Genet 39(5):311–314

References 14. Ferner RE, Golding JF, Smith M, et al (2008) [18F]2-Fuoro-2deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study. Ann Oncol 19(2): 390–394 15. Ferner RE, Huson SM, Thomas N, et al (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44(2):81–88 16. Friedman JM, Riccardi VM (1999) Clinical and epidemiological features. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM (eds) Neurofibromatosis: phenotype, natural history, and pathogenesis, 3rd ed. Johns Hopkins University Press, Baltimore, MD, pp 29–86 17. Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC (2003) Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 60(1):130–132 18. Havlik RJ, Boaz J (1998) Cranio-orbital-temporal neurofibromatosis: are we treating the whole problem? J Craniofac Surg 9:529–535 19. Jackson IT, Carbonnel A, Potparic Z, Shaw K (1993) Orbitotemporal neurofibromatosis: classification and treatment. Plast Reconstr Surg 92(1):1–11 20. Jackson IT, Shaw K (1990) Tumors of the craniofacial skeleton including the jaw. In: McCarthy J (ed) Plastic surgery, vol 5. Saunders, Philadelphia, pp 3336–3411 21. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 102:8573–8578 22. Kaufman LM, Doroftei O (2006) Optic glioma warranting treatment in children. Eye 20:1149–1164 23. Kazim M, Katowitz JA (2002) Surgical approaches to the pediatric orbit. In: Katowitz JA (ed) Pediatric oculoplastic surgery. Springer-Verlag, New York, pp 511–532 24. King AA, Debaun MR, Riccardi VM, Gutmann DH (2000) Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am J Med Genet 93(5):388–392 25. Krohel GB, Rosenberg PN, Wright HE, et al (1985) Localized orbital neurofibromas. Am J Ophthalmol 100:458 26. Laithier V, Grill J, Le Deley MC, Ruchoux MM, Couanet D, Doz F, et al (2003) Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy– results of the first French prospective study for the French Society of Pediatric Oncology. French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21:4572–4578 27. Lantieri L, Meningaud JP, Grimbert P, Bellivier F, Lefaucheur JP, Ortonne N, Benjoar MD, Lang P, Wolkenstein P (2008) Repair of the lower and middle parts of the face by composite tissue allotransplantation in a

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patient with massive plexiform neurofibroma: a 1-year follow-up study. Lancet 372:639–645 Lee V, Ragge NK, Collin JR (2004) Orbitotemporal neurofibromatosis. Ophthalmology 111:382–388 Levin LA, Jakobiec FA (2008) Peripheral nerve sheath tumors of the orbit. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology, 2nd ed. Saunders, Philadelphia, pp 3156–3181 Listernick R, Charrow J, Greenwald M, Mets M (1994) Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr 125:63–66 Listernick R, Ferner RE, Liu GT, Gutmann DH (2007) Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 61(3):189–198 Madill KE, Brammar R, Leatherbarrow B (2007) A novel approach to the management of severe facial disfigurement in neurofibromatosis type 1. Ophthal Plast Reconstr Surg 23:227–228 Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Funsterer C (2006) MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology 48(3):160–165 Miller NR (2008) Optic pathway gliomas are tumors!. Ophthal Plast Reconstr Surg 24(6):433 Morax S, Herdan ML, Hurbli T (1988) The surgical management of orbitopalpebral neurofibromatosis. Ophthal Plast Reconstr Surg 4:203–213 Muir D, Neubauer D, Lim IT, Yachnis AT, Wallace MR (2001) Tumorigenic properties of neurofibromindeficient neurofibroma Schwann cells. Am J Pathol 158(2):501–513 National Institutes of Health Consensus Development Conference statement. Neurofibromatosis. Bethesda, MD, July 13–15, 1988. 1(3):172–178 Needle MN, Cnaan A, Dattilo J, Chatten J, Phillips PC, Schehat S, Sutton LN, Vaughan SN, Zackai EH, Zhao H, Molloy PT (1997) Prognostic signs in the surgical management of plexiform neurofibroma: the Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr 131(5): 678–682 Packer RJ, Ater J, Allen J, et al (1997) Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86(5): 747–754 Pasmant E, Sabbagh A, Hanna N, Masliah-Planchon J, Jolly E, Goussard P, Ballerini P, Cartault F, Barbarot S, Landman-Parker J, Soufir N, Parfait B, Vidaud M, Wolkenstein P, Vidaud D (2009) SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J Med Genet Apr 14 (Epub ahead of print) Phillips P (2009) Children’s Hospital of Philadelphia. Personal correspondence

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42. Posnick JC (2000) Other frequently seen craniofacial syndromes. In: Posnick JC (ed) Surgery in children and young adults. Saunders, Philadelphia, pp 503–527 43. Reynolds RM, Browning GG, Nawroz I, Campbell IW (2003) Von Recklinghausen’s neurofibromatosis type 1. Lancet 361(9368):1552–1554 44. Singhal S, Birch JM, Kerr B, Lashford L, Evans DG (2002) Neurofibromatosis type 1 and sporadic gliomas. Arch Dis Child 87:65–70 45. Stephens K, Kayes L, Riccardi VM, Rising M, Sybert VP, Pagon RA (1992) Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 88(3):279–282 46. Van der Meulen JC, Moscona AR, Vaandrager M, Hirshowitz B (1982) The management of orbitofacial neurofibromatosis. Ann Plast Surg 8:213–220

47. Walrath JD, Engelbert M, Kazim M (2008) Magnetic resonance imaging evidence of optic nerve glioma progression into and beyond the optic chiasm. Ophthal Plast Reconstr Surg 24:473–474 48. Ward BA, Gutmann DH (2005) Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol 32:221–228 49. Widemann BC, Salzer WL, Arceci RJ, et al (2006) Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol 24(3):507–516 50. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL (2009) Neurofibromatosis type 1 revisited. Pediatrics 123:124–133

Chapter 6

Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System in External Dacryocystorhinostomy

6

Ludwig M. Heindl, Anselm G. M. Jünemann, and Leonard M. Holbach

Core Messages ■

■

■

Differential diagnostic symptoms and signs in favor of a tumor of the lacrimal sac include a swelling above the medial canthal tendon, the presence of telangiectases in the skin overlying the mass, and the presence of serosanguinous discharge or a bloody reflux with atraumatic irrigation. All patients should be asked for a history of predisposing conditions, such as systemic diseases (e.g., lymphoma, Wegener granulomatosis, sarcoidosis) or neoplasms. External dacryocystorhinostomy (DCR) allows detailed inspection of the lacrimal sac and adequate tissue biopsy.

6.1

Introduction

Disorders of the lacrimal drainage system (Table 6.1), which cause epiphora, punctal discharge, or medial canthal swelling, are common ophthalmic complaints comprising approximately 3% of clinic visits in some series [8, 21]. The most common histopathologic findings in primary acquired nasolacrimal duct obstruction include chronic inflammation and fibrosis leading to occlusion of the lacrimal drainage system [7, 12, 13]. Secondary causes of dacryostenosis may be the result of neoplasms, systemic inflammatory diseases, infections, or trauma [2, 19]. Neoplasms that affect the lacrimal drainage system are rare, but potentially life-threatening, so early diagnosis and treatment are particularly important [17, 23]. Almost 500 primary lacrimal sac tumors have been reported and were malignant in about 55% of the cases [6, 9, 10, 17–19]. Epithelial neoplasms are most common (73%), including benign (squamous cell papilloma, transitional cell papil-

■

■

■

Lacrimal sac biopsy should be considered selectively in patients with atypical clinical or intraoperative findings or in those with a history of predisposing systemic diseases. Biopsy results may help to define the degree of active specific inflammation requiring further chemo- or immunotherapy postoperatively. Selective lacrimal sac biopsy permits early diagnosis of potentially life-threatening malignant tumors to determine further definitive management.

loma, mixed-cell papilloma, oncocytoma) and malignant (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, mucoepidermoid carcinoma, oncocytic adenocarcinoma) tumors [6, 9, 10, 17–19]. Mesenchymal tumors such as fibrous histiocytoma, fibroma, hemangioma, hemangiopericytoma, angiosarcoma, or lipoma are less common (14%), and the rarer tumors include lymphomas (8%), malignant melanomas (4%), and neural tumors (1%) (Table 6.2) [6, 9, 10, 17–19]. Secondary tumors originating in adjacent structures (paranasal sinuses, orbit, nose) may extend into the lacrimal sac [6, 9, 10, 17–19]. Metastatic neoplasms confined to the lacrimal sac are extremely rare, and most metastases also affect adjacent structures, such as the eyelid, nose, sinuses, and orbit [6, 9, 10, 17–19]. Inflammatory lesions, including nonspecific chronic inflammation (“pseudotumor”) or granulomatous disease, are not true neoplasms but may present as lacrimal sac masses and may be a sign of systemic diseases that require further medical treatment [6, 17–19].

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Table 6.1. Differential diagnosis of lacrimal drainage disorders Punctal causes of epiphora – Congenital punctal atresia

6

– Punctal ectropion in eyelid malposition – Acquired punctal stenosis due to age-related atrophic processes, chronic inflammation, cicatricial conjunctival disease, systemic chemotherapeutic agents Canalicular causes of epiphora – Congenital absence or fistula – Acquired intrinsic disorders: postherpetic infection (herpes simplex, varicella zoster); bacterial infection (e.g., Actinomyces, Chlamydia); trauma; postirradiation; pharmacological; intrinsic tumor (e.g., squamous papilloma, squamous cell carcinoma) – Acquired extrinsic disorders: compression or invasion and occlusion by adjacent tumor (e.g., basal cell carcinoma, squamous cell carcinoma, non-Hodgkin B-cell lymphoma) Lacrimal sac causes of epiphora – Congenital diverticulum or fistula (from sac to nose or cheek) – Acquired intrinsic disorders: inflammation (extension of primary acquired nasolacrimal duct obstruction, including dacryoliths, Wegener granulomatosis, sarcoidosis, allergy, hay fever, atopy), trauma, intrinsic tumor arising within the sac or the sac walls (Table 6.2) – Acquired extrinsic disorders: adjacent tumor compressing or invading the sac from the outside (e.g., basal cell carcinoma, squamous cell carcinoma, non-Hodgkin B-cell lymphoma, neurofibroma) Nasolacrimal duct causes of epiphora – Congenital nasolacrimal duct obstruction (delayed opening of valve of Hasner with or without dacryocele, craniofacial abnormality, rare nasolacrimal duct agenesis) – Primary acquired nasolacrimal duct obstruction (most common cause in adults) – Secondary acquired lacrimal obstruction, including trauma and tumors (as for sac and those extending from the maxillary sinus) Nasal causes of epiphora – Allergic rhinitis, severe rhinosinus disease (e.g., polyps), previous nasal surgery – Tumors spreading from nasal space or adjacent sinuses Source: Adapted from [8]

Table 6.2. Lacrimal sac tumors I. Epithelial tumors 1. Squamous cell papilloma 2. Transitional cell papilloma 3. Mixed-cell papilloma (exophytic or endophytic) 4. Oncocytic adenoma (oncocytoma) 5. Squamous cell carcinoma 6. Transitional cell carcinoma 7. Adenocarcinoma 8. Mucoepidermoid carcinoma 9. Oncocytic adenocarcinoma II. Nonepithelial tumors 1. Fibrous histiocytoma 2. Pyogenic granuloma 3. Neurilemmoma 4. Lymphoid tumors 5. Malignant melanoma 6. Angiosarcoma Source: Modified from [6]

The recognition and proper management of such lifethreatening lesions require an understanding of the anatomy and general diagnostic techniques of the lacrimal drainage system.

6.2 Surgical Anatomy of the Lacrimal Drainage System On lid closure, tears are wiped to the nasal bulbar conjunctiva and tear meniscus and are then drained through the superior and inferior lacrimal puncta, which are open only with open eyes, and canaliculi into the lacrimal sac and by a sort of “lacrimal peristalsis” into the nose (Fig. 6.1). The canaliculi start with a 2-mm vertical component and continue with a horizontal portion 8–10 mm long. The common canaliculus, 1–2 mm long, leads into the lacrimal sac. Its entry into the sac at the internal ostium is often partially covered by a mucosal flap, which is based anteriorly and also called “the valve of

6.4 Selective Lacrimal Sac Biopsy in External Dacryocystorhinostomy

Fig. 6.1 Schematic illustration of the lacrimal drainage system with approximate measurements (Redrawn from [8])

Rosenmüller.” The lacrimal sac lies in the fossa between the anterior (frontal process of maxilla) and posterior (lacrimal bone) lacrimal crest and is surrounded by the anterior and posterior limbs of the medial canthal tendon. The body of the sac measures 10–12 mm in vertical height, and 3–5 mm of the sac (fundus) lie above the internal ostium. The suture line in the lacrimal fossa runs vertically between the thin lacrimal bone and the thicker frontal process of the maxilla. It is mostly located one half of the way from the anterior to the posterior lacrimal crest. The sac leads into the bony nasolacrimal duct, which measures 12–15 mm in length and travels within the wall of the maxillary sinus and the lateral nasal wall. The duct extends for about 5 mm below the bony portion and opens beneath the inferior turbinate in the lateral wall of the nose. A mucosal valve (Hasner) usually prevents retrograde passage of mucus or air upward. The nasal entry site of a DCR lies at the anterior tip of the middle turbinate. The ethmoid sinus may extend to the lacrimal sac fossa. Bony removal of the lacrimal sac fossa may result in entry into the ethmoid sinus rather than into the nasal vault [8, 20].

97

typically worse in the winter months and windy weather. The eye can be sticky due to an expressible mucocele or collected dried tears. The vision can be blurred secondary to an elevated tear meniscus (prismatic effect, especially on downgaze, for example, when reading) or tear-splattered glasses. Chronic epiphora can induce red, sore lower lid skin, with secondary anterior lamella (vertical) shortening (mild cicatricial ectropion). Excessive wiping away of tears can cause or exacerbate a medial ectropion. Mucopurulent punctal discharge suggests stasis in the lacrimal sac or canaliculi, mostly secondary to nasolacrimal duct obstruction. Accumulation of inflammatory debris can result in dacryolithiasis in up to 15% of DCR surgeries. Lacrimal sac stones consist of dried mucus, lipid, and inflammatory cells and are more likely to be found in chronically inflamed sacs. Medial canthal swelling may be caused by an abscess, a dacryolith, or a tumor in the lacrimal sac. But, not all masses in the medial canthal area arise from the lacrimal sac (acute skin infection, acute ethmoiditis, ruptured dermoid cyst). Swellings below the medial canthal tendon are typical of dacryocystitis. Differential diagnostic signs in favor of a tumor of the lacrimal sac include a mass above the medial canthal ligament (absent in dacryocystitis), the presence of telangiectases in the skin overlying the mass (instead of the diffuse erythema of dacryocystitis) and the presence of serosanguinous discharge or a bloody reflux with atraumatic irrigation (both of which are not usually observed in dacryocystitis). All patients should be asked not only for their complaints, but also for the history of predisposing conditions, such as systemic diseases (e.g., lymphoma, Wegener granulomatosis, sarcoidosis), trauma, neoplasms, and dacryocystitis. In addition to a comprehensive ophthalmic examination, particularly with regard to ocular surface disease and eyelid and punctum position, the assessment of the lacrimal drainage system must include inspection, palpation, digital expression of lacrimal sac contents, and standard irrigation and probing of the nasolacrimal system. Imaging studies (dacryocystography, computed tomography (CT), magnetic resonance imaging) are reserved for selected patients with atypical symptoms and signs. Detailed history taking and nasal endoscopy must be performed by an otorhinolaryngologist to rule out intranasal pathology [8].

6.3 Basic Diagnostics for Disorders of the Lacrimal Drainage System Prior to clinical examination, it is helpful to ask the patient for severity, duration, and quality of symptoms. The most common symptoms indicating dysfunction of the lacrimal drainage system include epiphora, punctal discharge, and medial canthal swelling. Epiphora is

6.4

Selective Lacrimal Sac Biopsy in External Dacryocystorhinostomy

Although endonasal endoscopic DCR is gaining clinical popularity in the therapy of acquired dacryostenosis, the external DCR is regarded as the gold standard in terms of

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Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System

surgical success [4, 5, 14, 16]. In addition, the external approach allows an excellent possibility for inspection of the lacrimal sac (Fig. 6.2) and for biopsy (excisional or incisional with debulking) of abnormal-appearing findings. In view of lacrimal tumors mimicking symptoms and signs of primary acquired nasolacrimal duct obstruction, some lacrimal surgeons perform “routine” lacrimal sac biopsy during external or endonasal DCR [1, 3, 11–13, 15, 22]. Incidence rates for significant lacrimal sac pathologies that require further medical or surgical intervention varied between 0% and 14% of biopsy specimens obtained routinely during DCR [1, 3, 11–13, 15, 22]. Since recent clinicopathologic studies revealed significant histopathologic findings only in clinically suspicious cases [3, 11, 15], we suggest selective lacrimal sac biopsy during external DCR only for patients with atypical clinical or intraoperative findings rather than routine biopsy of all patients with primary acquired nasolacrimal duct obstruction. If lacrimal sac biopsy is not performed in all cases of primary acquired nasolacrimal duct obstruction, the risk of overlooking significant pathologies that require further medical or surgical intervention should be kept in mind. Therefore, we compared the long-term follow-up

of patients with and without lacrimal sac biopsy during external DCR. In our series of 421 consecutive patients undergoing external DCR with selective lacrimal sac biopsy, no significant difference was detectable between patients with and without biopsy regarding 5-year overall survival. None of the patients without biopsy developed clinical evidence of systemic inflammatory diseases (e.g., Wegener granulomatosis, sarcoidosis) or neoplasms of the lacrimal drainage system within follow-up. Our follow-up results are compatible with the findings of seven previously published series with routine lacrimal sac biopsy [1, 3, 11–13, 15, 22]. Here, only 7 of 1,294 specimens (0.5%) showed specific pathology that was definitely not suspected clinically, and only 1 of these (0.08%) was found to be malignant (lymphoma) [1, 3, 11–13, 15, 22]. Using selective lacrimal sac biopsy only in patients with atypical clinical or intraoperative findings, positive biopsy results could be found in 3.8% of 442 consecutive external DCR procedures: primary non-Hodgkin B-cell lymphoma (mucosa-associated lymphoid tissue, MALT) in one patient, secondary bilateral non-Hodgkin B-cell lymphoma (MALT) in one patient, squamous cell carcinoma in two patients, malignant melanoma in one patient, oncocytoma in one patient, pyogenic granuloma in three patients, Wegener granulomatosis in three patients (one bilateral), and sarcoidosis in two patients (one bilateral) (Table 6.3). Our results are compatible with the pooled data of seven previously published series with routine lacrimal sac biopsy [1, 3, 11–13, 15, 22] revealing significant pathology in 50 of 1,294 specimens (3.9%). In detail, significant lacrimal sac pathology was detected in 2 of 14 specimens (14.3%) in Linberg and McCormick’s series (one sarcoidosis, one leukemia) [12]; in 4 of 162 specimens (2.5%) in Tucker et al.’s series (two lymphoma, one sarcoidosis, one oncocytoma) [22]; in 10 of 302 specimens (3.3%) in Bernardini et al.’s series (four sarcoidosis, Table 6.3. Results of selective lacrimal sac biopsies

Fig. 6.2 External DCR allows an excellent possibility for inspection of the lacrimal sac and for taking biopsy samples of abnormal-appearing findings

Histopathology

No. of cases (% total)

Non-Hodgkin B-cell lymphoma (MALT)

3 (18%)

Squamous cell carcinoma

2 (12%)

Malignant melanoma

1 (6%)

Oncocytoma

1 (6%)

Pyogenic granuloma

3 (18%)

Wegener granulomatosis

4 (24%)

Sarcoidosis

3 (18%)

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6.5 Definitive Treatment and Prognosis of Lesions Affecting the Lacrimal Drainage System

three squamous papilloma, two lymphoma, one leukemia) [3]; in 31 of 377 specimens (8.2%) in Anderson and coworkers’ series (eight sarcoidosis, seven lymphoma, four papilloma, four lymphoplasmacytic infiltrate, two transitional cell carcinoma, one oncocytoma, one granular cell tumor, one adenocarcinoma, one poorly differentiated carcinoma, one plasmacytoma, one leukemia) [1]; and in 3 of 193 specimens (1.6%) in Merkonidis et al.’s series (two sarcoidosis, one transitional cell papilloma) [15]. No specific pathologies could be observed in 44 biopsy specimens by Mauriello et al. [13] and in 202 specimens by Lee-Wing and Ashenhurst [11]. In summary, the risk of overlooking significant pathologies in selective lacrimal sac biopsy can be minimized by detailed medical history, comprehensive clinical examination, and intraoperative inspection of the lacrimal sac during external DCR.

6.5

Definitive Treatment and Prognosis of Lesions Affecting the Lacrimal Drainage System

diagnosis is made, and the effectiveness of the treatment. However, long-term prognosis remains uncertain due to the paucity of reports with long-term follow-up. Therefore, no evidence-based clinical practice guidelines exist on the therapy of lesions affecting the lacrimal drainage system.

6.5.1

A 39-year-old female presented with epiphora and a right-sided firm lacrimal sac mass of 6-month duration (Fig. 6.3a). Detailed inspection of the lacrimal sac during external DCR revealed abnormal swelling. Incisional biopsy with surgical debulking demonstrated a primary MALT lymphoma of the lacrimal sac (Fig. 6.3b). The patient was treated successfully with radiotherapy (43 Gy), with no sign of local recurrence or systemic disease at 6-year follow-up.

6.5.2

Depending on the histopathologic diagnosis of the lacrimal sac biopsy, the anatomic extent of the lesion, and the outcome of clinical staging, further definitive treatment is individual and often multidisciplinary, including orbital exenteration, lateral rhinotomy, chemotherapy, radiotherapy, immunotherapy (e.g., interferon alpha), or systemic immunosuppression (Table 6.4). The prognosis for patients with lacrimal sac lesions depends on the pathologic characteristics of the process, the stage at which

Case A

Case B

Following an episode of dacryocystitis, a 56-year-old female with 8 months of epiphora was found to have a firm, incompressible medial canthal mass (Fig. 6.4a). External DCR with incisional biopsy disclosed an extensive squamous cell carcinoma (Fig. 6.4b). Further therapy included dacryocystectomy, excision of periosteum and nasolacrimal duct using lateral rhinotomy, radio- (59Gy) and chemotherapy (5-fluoruracil and cisplatin). Within 1 year after surgery, no local recurrence or metastatic disease could be observed.

Table 6.4. Principles of treatment for lesions affecting the lacrimal drainage system Non-Hodgkin lymphoma (n = 3)

Squamous cell carcinoma (n = 2)

Malignant Oncocytoma melanoma (n = 1) (n = 1)

Pyogenic granuloma (n = 3)

Wegener Sarcoidosis granulo- (n = 3) matosis (n = 3)

Incisional biopsy with debulking

3

2

1

–

–

4

3

Excisional biopsy

–

–

–

1

3

–

–

Orbital exenteration

–

1

1

–

–

–

–

Lateral rhinotomy

–

2

1

–

–

–

–

Chemotherapy

2

1

–

–

–

4

–

Radiotherapy

1

2

1

–

–

–

–

Immunotherapy

–

–

1

–

–

–

–

Systemic immunosuppression

–

–

–

–

–

4

3

100

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Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System

6

Fig. 6.3 Primary non-Hodgkin B-cell lymphoma (MALT) of the lacrimal sac (case A). (a) Firm mass of the right lacrimal sac with epiphora of 6-month duration in a 39-year-old female. (b) Histopathologic section (hematoxylin and eosin, original magnification ×50) revealing a MALT (mucosa-associated lymphoid tissue) lymphoma consisting of small lymphocytes and occasional blasts

Fig. 6.4 Squamous cell carcinoma of the lacrimal sac (case B). (a) A 56-year-old female with 8 months of epiphora and recurrent dacryocystitis showing a firm incompressible medial canthal mass. (b) Histopathologic section (hematoxylin and eosin, original magnification ×200) demonstrating a squamous cell carcinoma with nuclear atypia

6.5.3

Case C

A 68-year-old female presented with a 10-month history of right-sided epiphora, bloody tears, and medial canthal mass (Fig. 6.5a). CT revealed a soft tissue mass of the right lacrimal sac with widening of the bony nasolacrimal canal (Fig. 6.5b). A transcutaneous incisional biopsy confirmed the diagnosis of malignant melanoma (Figs. 6.5c and d). After staging, further therapy included orbital exenteration, lateral rhinotomy with en bloc resection of lacrimal drainage apparatus and adjuvant radioimmunotherapy. One year after surgery, no evidence of local recurrence or metastatic disease could be detected [9].

6.5.4

Case D

A 67-year-old female attended with an 8-month history of right-sided epiphora and recurrent dacryocystitis and having noticed a mass inferior to the medial canthus (Fig. 6.6a). Nasal space was unremarkable. Coronal CT scan revealed a circumscribed mass limited to the lacrimal sac and upper portions of the nasolacrimal duct (Fig. 6.6b). Lacrimal sac biopsy disclosed a benign oncocytoma (Figs. 6.6c and d). Excision of the whole mass was attempted using dacryocystectomy combined with canaliculorhinostomy and silicone tube intubation. No local recurrence could be seen within a follow-up of 5 years (including nasal endoscopy) [10].

6.5 Definitive Treatment and Prognosis of Lesions Affecting the Lacrimal Drainage System

101

Fig. 6.5 Malignant melanoma of the lacrimal sac (case C). (a) Right-sided, darkly pigmented mass inferior to the medial canthus with epiphora and bloody tears of 10-month duration in a 68-year-old female. (b) Coronal computed tomographic scan revealing a soft tissue, space-occupying lesion in the region of the right lacrimal sac in direct contact with the globe and inferior oblique muscle. Note the widening of the bony nasolacrimal canal. (c) Histopathologic section (periodic acid-Schiff, original magnification ×50) showing a malignant melanoma with intra- and extracytoplasmatic melanin granules as well as hemosiderin granules. (d) Immunohistochemical staining (HMB-45, original magnification ×400) demonstrating positive expression of the tumor cells for the melanoma-associated antigen HMB-45 (Adapted from [9])

6.5.5

Case E

Six months after endonasal DCR, a 63-year-old female was referred due to persistent epiphora and recurrent dacryocystitis (Fig. 6.7a). External DCR demonstrated a prominent mass of the lacrimal sac. Excisional biopsy revealed a pyogenic granuloma (Fig. 6.7b). Seven years after surgery, the patient reported complete resolution of the preoperative symptoms with a patent lacrimal drainage system on clinical irrigation.

6.5.6

Case F

A 70-year-old male with the history of Wegener granulomatosis presented with bilateral epiphora and recurrent dacryocystitis for 8 months (Fig. 6.8a). External DCR with incisional biopsy of the lacrimal sac and nasal mucosa showed necrotizing vasculitis with granuloma-

tous inflammation (Fig. 6.8b). After bilateral external DCR with silicone tube intubation and control of the systemic disease with endoxane and cyclosporine, the patient was free of symptoms and local recurrence within a follow-up of 32 months.

6.5.7

Case G

Following bilateral endonasal DCR for epiphora and dacryocystitis, 12 months later a 65-year-old female with the history of sarcoidosis was referred with recurrent bilateral dacryocystitis (Fig. 6.9a). The patient underwent bilateral external DCR with silicone tube intubation and—due to granulomatous inflammation compatible with active sarcoidosis in the incisional biopsy specimens from the lacrimal sac and nasal mucosa (Fig. 6.9b)—immunosuppressive treatment. The patient remained recurrence free at 1 year of follow-up.

102

6

Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System

6

Fig. 6.6 Benign oncocytoma of the lacrimal sac (case D). (a) Recurrent conjunctivitis and epiphora of the left eye for 6 years and left medial canthal swelling of 18-month duration in a 66-year-old woman. (b) Coronal computed tomographic scan showing a noncalcified, soft tissue, space-occupying process in the region of the left lacrimal sac. (c) Histopathologic section (periodic acidSchiff [PAS], original magnification ×100) revealing a solid tumor with numerous cystic spaces filled with PAS-positive amorphous material surrounded by proliferating epithelial cells with granular cytoplasm. (d) Electron microscopy (scale bar 1 mm) demonstrating oncocytes densely packed with mitochondria of various sizes and shapes (Adapted from [10])

Fig. 6.7 Pyogenic granuloma of the lacrimal sac (case E). (a) Persistent epiphora and recurrent dacryocystitis 6 months after endonasal DCR in a 63-year-old female. (b) Histopathologic section (hematoxylin and eosin, original magnification ×50) showing a pyogenic granuloma composed of granulation tissue with radiating capillaries

References

103

Fig. 6.8 Wegener granulomatosis involving the lacrimal sac (case F). (a) A 70-year-old male with a history of Wegener granulomatosis presenting with bilateral epiphora and recurrent dacryocystitis for 8 months. (b) Histopathologic section (hematoxylin and eosin, original magnification ×100) demonstrating granulomatous inflammation compatible with an active stage of Wegener granulomatosis

Fig. 6.9 Sarcoidosis involving the lacrimal sac (case G). (a) Persistent epiphora and dacryocystitis 12 months following bilateral endonasal DCR in a 65-year-old female with a history of sarcoidosis. (b) Histopathologic section (hematoxylin and eosin, original magnification ×100) revealing granulomatous inflammation with “naked granulomas” (arrows) compatible with active sarcoidosis

Summary for the Clinician ■

■

■

Clinical symptoms and signs as well as the history of predisposing systemic diseases may raise suspicion of significant lacrimal sac pathologies requiring further medical or surgical intervention. In addition, external DCR allows an excellent possibility for inspection of the lacrimal sac and for adequate tissue biopsy of abnormal-appearing findings. Selective lacrimal sac biopsy for atypical clinical or intraoperative findings allows early diagnosis and management of life-threatening lesions affecting the lacrimal drainage system.

References 1. Anderson NG, Wojno TH, Grossniklaus HE (2003) Clinicopathologic findings from lacrimal sac biopsy specimens obtained during dacryocystorhinostomy. Ophthal Plast Reconstr Surg 19:173–176 2. Bartley GB (1992) Acquired lacrimal drainage obstruction: an etiologic, classification system, case reports and a review of the literature. Part 1. Ophthal Plast Reconstr Surg 8: 237–242 3. Bernardini FP, Moin M, Kersten RC, Reeves D, Kulwin DR (2002) Routine histopathologic evaluation of the lacrimal sac during dacryocystorhinostomy. How useful is it? Ophthalmology 109:1214–1218

104

6

6

Clinicopathologic Features of Lesions Affecting the Lacrimal Drainage System

4. Boboridis KG, Bunce C, Rose GE (2005) Outcome of external dacryocystorhinostomy combined with membranectomy of a distal canalicular obstruction. Am J Ophthalmol 139: 1051–1055 5. Emmerich KH, Busse H, Meyer-Rüsenberg HW (1994) Dacryocystorhinostomia externa. Technique, indications and results [in German]. Ophthalmologe 91:395–398 6. Font RL (1996) Eyelids and lacrimal drainage system. In: Spencer WH (ed) Ophthalmic pathology, vol 4. Saunders, Philadelphia, pp 2412–2427 7. Heindl LM, Jünemann A, Holbach LM (2008) A clinicopathologic study of nasal mucosa in 350 patients with external dacryocystorhinostomy. Orbit 27(6):462–465 8. Heindl LM, Jünemann A, Holbach LM (2008) Lacrimal drainage system. In: Naumann GOH, Holbach L, Kruse FE (eds) Applied pathology for ophthalmic microsurgeons. Springer, Berlin, pp 45–48 9. Heindl LM, Schick B, Kämpgen E, Kruse FE, Holbach LM (2008) Malignant melanoma of the lacrimal sac [in German]. Ophthalmologe 105(12):1146–1149. (Epub ahead of print) 10. Kottler UB, Schlötzer-Schrehardt U, Holbach LM (2004) Epiphora and conjunctivitis for 6 years [in German]. Ophthalmologe 101:730–732 11. Lee-Wing MW, Ashenhurst ME (2001) Clinicopathologic analysis of 166 patients with primary acquired nasolacrimal duct obstruction. Ophthalmology 108:2038–2040 12. Linberg JV, McCormick SA (1986) Primary acquired nasolacrimal duct obstruction. A clinicopathologic report and biopsy technique. Ophthalmology 93:1055–1063 13. Mauriello JA, Palydowycz S, DeLuca J (1992) Clinicopathologic study of lacrimal sac and nasal mucosa in 44 patients

14. 15.

16. 17. 18. 19.

20.

21. 22.

23.

with complete acquired nasolacrimal duct obstruction. Ophthal Plast Reconstr Surg 8:13–21 McNab AA (1994) Manual of orbital and lacrimal surgery. Churchill Livingstone, Edinburgh, pp 75–86 Merkonidis C, Brewis C, Yung M, Nussbaumer M (2005) Is routine biopsy of the lacrimal sac wall indicated at dacryocystorhinostomy? A prospective study and literature review. Br J Ophthalmol 89:1589–1591 Olver J (2002) Colour atlas of lacrimal surgery. Butterworth Heinemann, Oxford, pp 94–114, 158–162 Parmar DN, Rose GE (2003) Management of lacrimal sac tumours. Eye 17:599–606 Pe’er JJ, Stefanyszyn M, Hidayat AA (1994) Nonepithelial tumors of the lacrimal sac. Am J Ophthalmol 118:650–865 Stefanyszyn MA, Hidayat AA, Pe’er JJ, Flanagan JC (1994) Lacrimal sac tumors. Ophthal Plast Reconstr Surg 10: 169–184 Thale A, Paulsen E, Rochels R, Tillmann B (1998) Functional anatomy of the human efferent tear ducts: a new theory of tear outflow mechanism. Graefes Arch Clin Exp Ophthalmol 236:674–678 Traquair HM (1941) Chronic dacryocystitis. Its causation and treatment. Arch Ophthalmol 26:165–180 Tucker N, Chow D, Stockl F, Codère F, Burnier M (1997). Clinically suspected primary acquired nasolacrimal duct obstruction. Clinicopathologic review of 150 patients. Ophthalmology 104:1882–1886 Valenzuela AA, McNab AA, Selva D, O’Donell BA, Whitehead KJ, Sullivan TJ (2006) Clinical features and management of tumors affecting the lacrimal drainage apparatus. Ophthal Plast Reconstr Surg 22:96–101

Chapter 7

Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients

7

Michael P. Schittkowski and Rudolf F. Guthoff

Core Messages ■

■ ■

■ ■

■ ■

■

Congenital clinical anophthalmos and blind microphthalmos are extremely rare conditions, with a prevalence rate of 1–20/100,000 newborns. Distribution of the conditions is approximately equal between males and females. Unilateral anophthalmos is encountered almost twice as frequently as bilateral anophthalmos. Microphthalmos is the least-common reason why patients present for surgery. With a single exception, the family histories were not positive for the conditions. The course of pregnancy itself was routinely unexceptional. Consanguinity and pathological chromosomal abnormalities point to the possible role of genetic factors, which are increasingly becoming the focus for research. As expected, obstetric delivery was not a determinant of the clinical condition. Comprehensive evaluation of each case requires a thorough ophthalmological examination supplemented by assessment by an experienced pediatrician. Associated systemic findings were more numerous in patients with anophthalmos (50%) than in

7.1

Introduction

Congenital clinical anophthalmos and blind microphthalmos are rare conditions with prevalence rates per 100,000 live births of between 1.1 [22] and 4 [2] for anophthalmos and between 2.2 [21] and 19.8 [11] for microphthalmos. In the course of developing and establishing a new treatment strategy for this special patient group using self-inflating, highly hydrophilic hydrogel expanders [8, 18, 19], we have treated a comparatively large patient population since 1997.

■ ■

■

■

■

those with microphthalmos (17.6%). There was no difference in the rate of developmental anomalies in unilateral and bilateral anophthalmos. Typically, the pathology is characterized by Goldenhar syndrome and clefting. Magnetic resonance imaging (MRI) is generally necessary to detect developmental cerebral anomalies. Nasolacrimal duct pathology was present in about 75% of the affected children. Canalicular stenoses were the most common finding. Twenty-five percent of patients with unilateral microphthalmos and 50% of patients with unilateral anophthalmos had anomalies in the fellow eye, chiefly in the form of coloboma, dermoid, sclerocornea, and glaucoma. On account of this pathology in a single eye, 2 (12.5%) of the patients with unilateral microphthalmos and 13 (34.2%) of the patients with unilateral anophthalmos, as well as all 20 patients with bilateral anophthalmos, were classified as legally blind. Therefore, the overall blindness rate was 17.6% in microphthalmos and 3.4 times higher (56.9%) in anophthalmos.

This chapter first investigates the frequency of systemic disease in these patients and identifies possible pathologies of the fellow eye in primarily unilateral disease.

Summary for the Clinician ■

Congenital clinical anophthalmos and blind microphthalmos are extremely rare conditions.

106 7.2

7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients

Patients and Methods

7.2.1 Patients

7

A prospective study was conducted of all patients with congenital clinical anophthalmos and blind microphthalmos who were treated at least once with a hydrogel expander in the Ophthalmology Department of the University of Rostock during the period after the first introduction of hydrogel expander therapy in September 1997 until May 2008. No exclusion criteria were defined for this study.

7.2.2

Examination

7.3

Results

7.3.1 Patient Data To date, 75 patients (35 girls and 40 boys) have been treated. The patient sample was composed as follows

Patients

Orbits

Unilateral congenital clinical anophthalmos

38

38

Bilateral congenital clinical anophthalmos

20

40

Unilateral blind microphthalmos

16

16

Bilateral blind microphthalmos

1

2

Total

75

96

In addition to a routine ophthalmological examination, the following specific patient data were collected: ■

■

■

■ ■

Details were elicited concerning the course of pregnancy and delivery, and these were supplemented by discharge summaries from previously treating hospitals if available. When taking the family history, special emphasis was placed on gathering information about developmental anomalies. The results of pediatric examinations were included to rule out associated systemic changes (syndromes, organ anomalies, metabolic disorders, etc.). Magnetic resonance imaging (MRI) was generally performed to exclude developmental cerebral anomalies. For the assessment of the nasolacrimal ducts, routine probing and irrigation of the nasolacrimal system was performed under anesthesia prior to first-time surgery, as has been described in detail elsewhere [20].

The workup for genetic diagnosis is part of another ongoing study and is therefore not discussed here.

Summary for the Clinician ■

Comprehensive evaluation of each case requires a thorough ophthalmological examination supplemented by assessment by an experienced pediatrician. MRI is generally necessary to detect for developmental cerebral anomalies.

Summary for the Clinician ■

Distribution of the conditions was approximately equal between males and females. Unilateral anophthalmos was encountered almost twice as frequently as bilateral anophthalmos. Microphthalmos was the least common condition.

7.3.2

Age

The age of the patients at initial presentation was between 1 and 90 months (median 4 months).

7.3.3

Family History Unilateral (n = 54)

Bilateral (n = 21)

Nothing of note, no siblings

39

14

Nothing of note, siblings healthy

12

7

Nothing of note, siblings unwell

2

0

■ One child with

postnatal middle cerebral artery infarction

107

7.3 Results

Summary for the Clinician

■ One twin sister

with iris coloboma Positive, no siblings

■

1

The course of pregnancy itself was routinely unexceptional.

0

■ One cousin of

father with bilateral anophthalmos

7.3.5

Spontaneous

Summary for the Clinician ■

Cesarean section

With a single exception, the family histories were not positive for the conditions.

(of which, before week 36)

■

Unilateral (n = 54)

Bilateral (n = 21)

48

16

■ One in vitro

■

■

■

Bilateral (n = 21)

35

19

19

2

(4)

0

As expected, obstetric delivery was not a determinant of the clinical condition.

7.3.6 Associated Systemic and Ocular Diseases

Noteworthy 6 findings

■

Unilateral (n = 54)

Summary for the Clinician

7.3.4 Pregnancy History

Nothing of note

Birth

fertilization, single umbilical artery One in vitro fertilization, midcycle bleeding Two with hypertension requiring treatment One with consanguinous parents, four previous miscarriages, mother with Pena–Shokeir syndrome (pseudotrisomy 18) One with three previous miscarriages, mother with partial transposition of chromosome 13 to 15

Unilateral (n = 54)

Bilateral (n = 21)

None/ocular findings only (Fig. 7.1)

24 (13 Anophthalmos and 11 microphthalmos patients)

11 (10 Anophthalmos and 1 microphthalmos patients)

None/but developmental anomaly of fellow eye (Fig. 7.2)

8 Anophthalmos ■ Two sclerocornea ■ One coloboma of iris, retina, choroid, and optic disc, with posterior pole involvement ■ One iris coloboma, retina intact ■ One nanophthalmos with questionable light perception ■ One aplasia of macula/optic disc

(No subdifferentiation possible because both eyes affected)

■ One with

■

■

■

■

acyclovir ingestion before pregnancy, single umbilical artery One with two previous early miscarriages One mother with acromegaly, history of pituitary adenoma, anterior pituitary lobe insufficiency One mother with a history of completed treatment for syphilis One with nicotine abuse

108

7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients

Microphthalmos

■ One complex

■ One central stromal

corneal scar

7

■ One paracentral lens

clouding, persistant hyperplastic primary vitreous (PHPV), aplasia of macula Unilateral (n = 54) Associated 14 disease; path- Anophthalmos ■ One clefting of ology of lip, upper jaw fellow eye and palate, ear (Fig. 7.3) cartilage missing (no deafness), corpus callosum hypoplasia; coloboma of iris, retina, and choroid in fellow eye ■ One retardation, labyrinthine deafness on affected side; sclerocornea, secondary glaucoma in fellow eye ■ One Goldenhar syndrome; contralateral clefting of lip, upper jaw, and palate, cleft tongue; auricular dysplasia; external auditory meatus absent; preauricular tags bilaterally; upper lid coloboma, lipodermoid of the limbus in fellow eye

Bilateral (n = 21) 10 ■ One external

■

■ ■

■ ■

■

auditory meatus absent unilaterally, labyrinthine deafness, bilateral talipes calcaneus One rudimentary sixth finger on both hands One plagiocephaly One septo-optic dysplasia, corpus callosum aplasia One Delleman syndrome One microcephaly, statomotor retardation, hearing loss One microcephaly, retardation

■

■

■

■

■

■

■ One agenesis of developmental corpus callosum, anomaly micrognathia, syndrome with respiratory hypertelorism, failure (died at bilateral clefting 16 months) of lip, upper jaw ■ One developmental delay, and palate, labyrinthine pre-auricular tag; anomaly Peters’ anomaly with secondary ■ One myelinization disorder glaucoma requiring treatment in fellow eye One Goldenhar syndrome; limbus dermoid, severe Sjögren syndrome symptoms with corneal vascularization in fellow eye One craniofacial dysmorphism; sclerocornea in fellow eye One hexadactyly, epilepsy; nanophthalmos of fellow eye One familial facial syndrome and additional sixth toe; dense corneal clouding in fellow eye One cerebral retardation, deafness, septal agenesis; pitting of optic disc in fellow eye One massive growth retardation; iris coloboma in fellow eye

7.3 Results

■ One central

motor disturbance, focal epilepsy due to complex cerebral anomaly; coloboma of iris, retina, choroid, and optic disc in fellow eye ■ One develop-

mental anomaly of labyrinth; nystagmus in fellow eye Microphthalmos ■ One unilateral

duplicate kidney; coloboma of iris, retina, and choroid in fellow eye, paracentral corneal turbidity ■ One epilepsy,

hemiparesis, unilateral hearing loss, developmental delay; PHPV, coloboma of iris, retina, and choroid in fellow eye

Fig. 7.1 Girl with right-sided anophthalmos in isolation, before and after completion of treatment

Associated disease; fellow eye unremarkable (Fig. 7.4)

109

Unilateral (n = 54)

Bilateral (n = 21)

8 Anophthalmos ■ Two clefting of lip, upper jaw, and palate ■ One oblique facial cleft ■ One subcortical cerebral atrophy with secondary ventricle enlargement, hypoplasia of the corpus callosum

(No subdifferentiation possible because both eyes affected)

■ One Goldenhar

syndrome; clefting of lip, upper jaw, and palate; deafness (suspected aplasia of cranial nerve VIII); congenital clubfoot bilaterally (pes equino-varus); developmental anomalies of extremities, chest, and vertebrae ■ One unilateral renal agenesis ■ One atrioseptal defect Microphthalmos ■ One atrioseptal defect, unilateral preauricular tag

110

7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients

Summary for the Clinician ■

7

There was no difference in the rate of developmental anomalies in unilateral and bilateral anophthalmos. Typically, the pathology is characterized by Goldenhar syndrome, facial clefting, and cerebral anomalies.

7.3.7 Developmental Anomaly and Potential Visual Capacity of the Fellow Eye in Unilateral Disease

Fig. 7.2 Sclerocornea affecting only eye (visual acuity: light perception) and status following two cyclophotocoagulation procedures for secondary glaucoma; other side (not shown) with anophthalmos and uncomplicated expander treatment

a

Developmental anomaly

Legally blind

Microphthalmos (n = 16) 4 (25%)

2 (12.5%)

Anophthalmos (n = 38)

13 (34.2%)

18 (47.4%)

b

Fig. 7.3 Girl with clinical anophthalmos on right side; the fellow eye has upper lid coloboma and lipodermoid of the limbus; general Goldenhar syndrome; preauricular tags bilaterally; clefting of lip, upper jaw, and palate on left side; cleft tongue; auricular dysplasia; external auditory meatus absent. (a) Initial findings. (b) Current findings with prosthesis and orbital expander on right side; upper lid coloboma on left side reconstructed

Fig. 7.4 MRI of a patient with anophthalmos on left side (orbital expander implanted, prosthesis inserted), ophthalmologically healthy right eye without gaze fixation due to complex developmental cerebral anomaly with subcortical cerebral atrophy, and resultant ventricular enlargement and hypoplasia of the corpus callosum

7.3 Results

Summary for the Clinician ■

111

Summary for the Clinician

Twenty-five percent of patients with unilateral microphthalmos and 50% of patients with unilateral anophthalmos had anomalies in the fellow eye, chiefly in the form of coloboma, dermoid, sclerocornea, and glaucoma.

■

Nineteen percent of the children were found to have pathological findings on MRI. Most frequently encountered and in clinical terms, the most serious were developmental anomalies of the corpus callosum; these were about four times more common in bilateral than in unilateral anophthalmos (21.4% vs 4.5%) but were not observed at all in microphthalmos.

7.3.8 Neuroradiological Findings (Brain MRI) 7.3.9 Table 7.1. History taking and previous findings in patients treated Unilateral (n = 54)

Bilateral (n = 21)

Normal for age

44

14

Pathological (Fig. 7.4)

5 Anophthalmos ■ One almost total hypoplasia of the corpus callosum, extreme enlargement of the lateral ventricles ■ One hypoplasia of the corpus callosum ■ One suprasellar hamartoma Microphthalmos ■ One minimally enlarged CSF spaces ■ One general reduction in cerebral volume

6 ■ One agenesis

of corpus callosum ■ One agenesis of corpus callosum, moderate ventricular enlargement ■ One agenesis of corpus callosum, small sella/ pituitary ■ One minimally enlarged CSF spaces ■ One small subarachnoid cyst Microphthalmos ■ One myelinization disorder

Findings still awaited

2

0

Findings not available (abroad)

3 (all anophthalmos)

1 (anophthalmos)

CSF cerebrospinal fluid

Nasolacrimal System Findings

Patients who had undergone extensive previous surgical procedures involving the nasolacrimal system—or with a history of manipulation performed elsewhere—were excluded from this assessment because otherwise it would not have been possible to differentiate between primary and secondary nasolacrimal system pathology (Table 7.1). Evaluable findings obtained during probing and irrigation of the nasolacrimal system were available for 61 of the 75 children (30 of 38 with unilateral anophthalmos, 18 of 20 with bilateral anophthalmos, and 13 of 17 with microphthalmos) (Fig. 7.5). Consequently, 80 a total of 96 affected orbits (83.3%) were considered here. In patients with unilateral anophthalmos/microphthalmos the contralateral healthy side was normally developed and freely irrigable, except for two cases with classic congenital stenosis of the lacrimal fold. Normal anatomy and irrigation outcome were noted in barely one quarter of cases with anophthalmos. Well over half of the patients showed an association with stenosis of both canaliculi, which could be probed for a distance of between 1 and 8 mm (mean 4 ± 1.9 mm). Eight children showed typical stenosis at the level of the valve of Hasner. Stenoses of one canaliculus (5%) and of the common canaliculus (6%) were comparatively rare. Other pathologies, such as aplasia of the lacrimal puncta or fistulas, were not observed.

Summary for the Clinician ■

Nasolacrimal duct pathology was present in about 75% of the children in the study sample. This primarily took the form of canalicular stenosis. Typical congenital stenosis of the lacrimal fold was not encountered more frequently than normal.

112

7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients Anophthalmos

Microphthalmos

7

normal UCB BCB CCB CNLDO

all patients

Fig. 7.5 Nasolacrimal duct findings in anophthalmos and microphthalmos. UCB unicanalicular block, BCB bicanalicular block, CCB common canalicular block, CNLDO congenital nasolacrimal duct obstruction

Developmental anomalies of the nasolacrimal system were detected rather less commonly in microphthalmos patients (see Fig. 7.5 for details).

7.4

Discussion

7.4.1 Patients With 40 boys and 35 girls, the male–female distribution of the patient sample in this study showed a slight overrepresentation of males, somewhat in excess of the normal boy-to-girl ratio (approximately 108:100) in newborns. Unilateral anophthalmos (38 patients) was present almost twice as commonly as bilateral anophthalmos (20 patients). With a single exception, the 17 patients with microphthalmos all showed unilateral pathology. There are only a small number of publications dealing systematically with investigations in a comparably large group of patients with congenital anophthalmos. The definitive article published by Collin’s group [23] studied a comparable population in terms of patient numbers, gender, and sample breakdown. However, that study included almost twice as many microphthalmos patients as anophthalmos patients, and this is a marked departure from the population described here, in which 3.4 times as many anophthalmos as microphthalmos patients were

treated. It is likely that patients with microphthalmos were managed better elsewhere with conformers or prostheses than those with clinical anophthalmos and therefore were not referred to us in Rostock for expander therapy; this theory would explain their marked relative underrepresentation. It is noteworthy that in unilateral disease anophthalmos was encountered about 50% more often on the right side (n = 32) than on the left (n = 22). In microphthalmos, the right-to-left ratio was balanced (n = 8:8). There is no known—or published—explanation for this.

Summary for the Clinician ■

Male–female distribution is almost balanced. It is not known why anophthalmos involves the right eye 1.5 times more often than the left eye.

7.4.2

Obstetric and Family History

The obstetric course was unremarkable for all children. There was no direct relationship between obstetric history and anophthalmos/microphthalmos. A history of abnormalities during pregnancy was reported for 11 of the 75 mothers. It has been suggested that the factors most likely to be implicated in the etiology are maternal

7.4

vitamin A deficiency, exposure to X-rays, and gestationalacquired infections [24]. In our own patients, for the majority of anomalies reported, there was no discernible link with the children’s anophthalmos/microphthalmos in terms of factors reported in the literature. In an Indian population, Hornby et al. [9] reported a consanguinity rate of 64% in 24 children with microphthalmos. In our own patients, consanguinity was established in only one child. Taken together with the described genetic findings in the parents and the single case with a positive family history, however, this points to the putative role of genetic factors. It seems clear that anophthalmos and microphthalmos have a complex and multifactorial etiology that includes chromosomal factors, such as duplications, deletions, and translocations, as well as monogenic causes. Among the monogenic causes, SOX2 on chromosome 3 has been identified as a principal gene that is responsible for 10–20% of (mainly bilateral) anophthalmos [6]. Other linked genes include PAX6, OTX2, CHX10, FOXE3, and RAX (for comprehensive discussion, see [24]). The detailed workup for genetic diagnosis in our own patients is the subject of another ongoing study and is therefore not covered in this article.

Summary for the Clinician ■

Consanguinity and pathological chromosome findings point to the involvement of genetic factors, which are becoming an increasing focus of research.

7.4.3.1

Ophthalmological Findings in Unilateral Disease

In 12 (75%) of the 16 patients with unilateral microphthalmos, the fellow eye was morphologically and functionally normal; the condition was limited to a single eye. The remaining four children (25%) displayed pathological changes in the fellow eye, and in two of these cases (12.5%) the changes were so severe that the children were categorized as legally blind. Twenty (70%) of 29 microphthalmos patients had a normal fellow eye in the study conducted by Tucker et al. [23]; the remainder displayed associated developmental anomalies of the fellow eye, although no information on visual acuity was provided. In the present study, in 20 (52.6%) of the 38 patients with unilateral anophthalmos, the fellow eye was healthy

113

and had normal visual function. Eighteen children (47.4%) were found to have an associated developmental anomaly of the fellow eye, such as coloboma or sclerocornea, with the result that 13 children (34.2%) were categorized as legally blind. The distribution statistics are largely consistent with the details for 14 anophthalmos patients presented in the previously cited study by Tucker et al. [23]. That publication provided no information on potential visual function. In their group of 24 Indian children with anophthalmos, Hornby et al. [9] did not find any patients with a normal fellow eye. However, the children were recruited only from blind schools, a fact that explains the absence of children with one healthy or sighted eye and ultimately rules out any comparison with the population in the present study. In summary, in terms of potential visual function, 46.7% of our study population were legally blind. When those children with obvious bilateral disease were left out of the calculation, the risk of blindness with presumed unilateral pathology was almost three times higher with anophthalmos than with microphthalmos. Previous publications have not referred to this aspect. It is therefore necessary to examine the fellow eye at an early stage to assess the potential development of visual acuity and, if appropriate, to initiate measures for its early promotion.

Summary for the Clinician ■

7.4.3 Associated Pathologies

Discussion

On account of this pathology in a single eye, 2 (12.5%) of the patients with unilateral microphthalmos and 13 (34.2%) of the patients with unilateral anophthalmos, as well as all of the patients with bilateral anophthalmos, were classified as legally blind. Therefore, the overall blindness rate was 17.6% in microphthalmos and 3.4 times higher (56.9%) in anophthalmos.

7.4.3.2

Neuroradiological Findings

In technical terms, MRI is superior to computed tomography (CT) for the assessment of cerebral findings [5, 7]. In our study sample, 15.9% of patients had findings consistent with associated cerebral pathology. These were encountered almost three times as often in bilateral anophthalmos (26.3%) as in unilateral anophthalmos (9.1%). The frequency of such findings in unilateral microphthalmos (12.5%) was comparable to that in unilateral

114

7

7 Systemic and Ophthalmic Anomalies in Congenital Anophthalmic or Microphthalmic Patients

anophthalmos. Our study sample included only one patient with bilateral microphthalmos, and consequently no further differentiation was possible. The most serious changes, detected in five anophthalmos patients, involved extreme hypoplasia—or complete agenesis—of the corpus callosum. This change affected 9.6% of the patients and was again far more common in bilateral (16.8%) than in unilateral (6.1%) disease. Septooptic dysplasia was reported to be associated with an increased rate of sudden death in children [3]. Among our patients, one child with bilateral anophthalmos and corpus callosum aplasia died unexpectedly at the age of 16 months. An association between anophthalmos and developmental anomalies of the corpus callosum has been described in individual case reports [1, 5]. In view of the frequent occurrence of associated cerebral developmental anomalies, it appears justifiable to recommend MRI examination for every child with these conditions.

Summary for the Clinician ■

The frequent occurrence of developmental cerebral anomalies, particularly those involving the corpus callosum, warrants MRI examination for all children affected.

7.4.3.3

Systemic Diseases

In their analysis of data from the Spanish Collaborative Study of Congenital Malformations in a series of 1,124,654 consecutive births, Bermejo and Martínez-Frías [2] noted 240 cases of anophthalmos (n = 47) or microphthalmos (n = 193). Only 9.6% of these defects occurred in isolation. The 90.4% occurring in conjunction with systemic diseases were subdivided into syndromes (32.9%) and multiple congenital anomalies (57.5%). Unfortunately, those authors did not undertake any further differentiation of concomitant systemic diseases to provide a basis for comparison. A far lower rate of systemic disease associations (39%) was reported by Mouriaux et al. [13] in their study in 7 anophthalmos and 35 microphthalmos patients; this figure is comparable to the 37.7% incidence calculated by Tucker et al. [23], who noted associated systemic diseases in 7 of 34 microphthalmos patients (20.6%) and in 22 of 43 anophthalmos patients (51.2%). These published statistics are consistent with our observations:

In our patient sample, 3 of 17 children with microphthalmos (17.6%) were found to have associated systemic diseases, although the pathology tended to be of a less serious nature. Associated systemic diseases were considerably more frequent in anophthalmos patients, with 29 of 58 children affected (50%); most commonly, these were developmental cerebral anomalies (n = 12), followed by (hemi-)facial anomalies (n = 9). The variable “unilateral versus bilateral” had no influence on absolute frequency. However, it is remarkable that the nature of the pathology is different. Unilateral anophthalmos was associated most commonly with clefting (seven patients), which was not detected at all in the surgically managed patients with bilateral anophthalmos. (To date, bilateral clefting of lip, upper jaw, and palate has been noted just once in a child with bilateral anophthalmos who did not undergo surgery because of the underlying presence of trisomy 13; see Fig. 7.6.) In the children with bilateral anophthalmos, there was a definite predominance (7 of 10 affected children) of cerebral anomalies, which were encountered far less commonly (23%) in unilateral anophthalmos. It has been postulated that a general malformation of the forebrain during embryological development might provide an explanation for the above-average incidence of the association between bilateral anophthalmos and developmental anomalies of the optic chiasm and corpus callosum [1, 10]. Meanwhile unilateral anophthalmos arises mainly in association with developmental anomalies of the first and second pharyngeal arches, such as Goldenhar syndrome. This suggests that the normal development of the mesenchyma, from which, for example, the maxilla and mandible are formed, is associated with the correct shaping of the eye and orbit, and that anomalies in this development may lead to degenerative (consecutive) anophthalmos [1].

Summary for the Clinician ■

Associated systemic findings were more numerous and more severe in patients with anophthalmos (50%) than in those with microphthalmos (17.6%).

7.4.3.4

Nasolacrimal Duct Findings

On the side affected by anophthalmos or microphthalmos, 80% of patients presented with stenosis of the nasolacrimal duct system. Canalicular (62%) and presaccal (11%) stenoses accounted for the largest proportion of

7.5 Conclusions

115

Fig. 7.6 Neonate with clinical anophthalmos and bilateral clefting of the lip, upper jaw, and palate; trisomy 13 confirmed after genetic diagnosis

these occlusions. Obstruction of the valve of Hasner, otherwise typical in this age group [12], played only a minor role in our patients even though the incidence of 8% was approximately consistent with the incidence for this age group, which is reported in the literature to be as high as 15% [14, 15, 17]. In 1887, Collins [4] supplemented the 30 anophthalmos cases published in the literature up to that time with 12 new cases and pointed out the occasional absence of the lacrimal puncta and canaliculi. The lacrimal puncta were always present in our patients. To date, there have been no comprehensive newer studies of the nasolacrimal duct system in anophthalmos. One case report has described an association between congenital stenosis of the valve of Hasner and congenital anophthalmos [16], but the results presented in our study suggest that this is rather the exception. So far, the high incidence of nasolacrimal duct anomalies has therapeutic implications only when there is classic congenital stenosis of the valve of Hasner that is successfully corrected in the course of diagnostic probing. Bearing in mind the possible presence of a pathogen reservoir, elimination of the obstruction should be performed so expander therapy is not jeopardized by infection-related complications. However, the vast majority (91.3%) of all stenoses were diagnosed in presaccal locations; because the development of inflammation is not to be expected, surgical management is indicated here only in troublesome epiphora [20].

Summary for the Clinician ■

Treatment appears to be necessary only in “classic” congenital stenosis.

7.5

Conclusions

If pathology is unilateral, patients with anophthalmos have a poorer prognosis than those with microphthalmos in terms of the potential visual capacity of the fellow eye. The consequence arising from the high incidence of associated developmental anomalies of the fellow eye is that a thorough ophthalmological examination must be a sine qua non for all affected children. Anophthalmos is also a poorer prognostic factor than microphthalmos in terms of its association with a wide range of systemic diseases. Patients with unilateral anophthalmos tend to display ipsilateral facial anomalies, whereas patients with bilateral anophthalmos are characterized mainly by intracranial anomalies. The consequence must be that every affected child should undergo a meticulous program of pediatric diagnosis that also includes neuroradiological examination. Because causal therapy is often not available, the recording of all findings enables a reliable prognosis to be established and, if appropriate, permits early initiation of specific measures to promote visual acuity.

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References

7

1. Albernaz VS, Castillo M, Hudgins PA, Mukherji SK (1997) Imaging findings in patients with clinical anophthalmos. Am J Neuroradiol 18(3):555–561 2. Bermejo E, Martínez-Frías ML (1998) Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med Genet 75(5): 497–504 3. Brodsky MC, Conte FA, Taylor D, Hoyt CS, Mrak RE (1997) Sudden death in septo-optic dysplasia. Report of 5 cases. Arch Ophthalmol 115(1):66–70 4. Collins ET (1887) On anophthalmos. Royal London Ophthalmic Hospital Reports. J Ophthal Med 40:429–455 5. Daxecker F, Felber S (1993) Magnetic resonance imaging features of congenital anophthalmia. Ophthalmologica 206(3):139–142 6. Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C, Vivian AJ, Williamson K, Van Heyningen V, Fitzpatrick DR (2003) Mutations in SOX2 cause anophthalmia. Nat Genet 33(4):461–463. (Epub 3 Mar 2003) 7. Frosini R, Papini M, Campana G, Giovannucci Uzielli ML (1981) Contribution of computerized tomography to the study of severe congenital ocular dysplasias. Study of a case of clinical anophthalmos. Ophthalmologica 183(2):72–76 8. Gundlach KKH, Guthoff RF, Hingst V, Schittkowski MP, Bier UC (2005) Expansion of the socket and the orbit for congenital clinical anophthalmia. Plast Reconstr Surg 116(5):1214–1222 9. Hornby SJ, Dandona L, Foster A, Jones RB, Gilbert CE (2001) Clinical findings, consanguinity, and pedigrees in children with anophthalmos in southern India. Dev Med Child Neurol 43(6):392–398 10. Jacquemin C, Mullaney PB, Bosley TM (2000) Ophthalmological and intracranial anomalies in patients with clinical anophthalmos. Eye 14(1):82–87 11. Kallen B, Robert E, Harris J (1996) The descriptive epidemiology of anophthalmia and microphthalmia. Int J Epidemiol 25(5):1009–1016 12. Katowitz JA, Welsh MG (1987) Timing of initial probing and irrigation in congenital nasolacrimal duct obstruction. Ophthalmology 94:698–705

13. Mouriaux F, Audo I, Defoort-Dhellemmes S, Labalette P, Guilbert F, Constantinides G, Pellerin P (1997) Management of congenital microphthalmos and anophthalmos. J Fr Ophthalmol 20(8):583–591 14. Müller F (1975) Erkrankungen der Tränenorgane. In: Velhagen K (ed) Der Augenarzt, 2nd ed, vol. 3. VEB Georg Thieme, Leipzig, pp 7–131 15. Noda S, Hayasaka S, Setogawa T (1991) Congenital nasolacrimal duct obstruction in Japanese infants: its incidence and treatment with massage. J Pediatr Ophthalmol Strabismus 28(1):20–22 16. Oguz H, Ozturk A, San I (2003) Congenital nasolacrimal duct occlusion with clinical anophthalmos: a possible new association. Ophthalmic Genet 24(3):181–185 17. Olver J (2001) Paediatric lacrimal surgery. In: Olver J (ed) Colour atlas of lacrimal surgery. Butterworth-Heinemann, Oxford, pp 69–90 18. Schittkowski MP, Gundlach KK, Guthoff RF (2003) Treatment of congenital clinical anophthalmos with high hydrophilic hydrogel expanders. Ophthalmologe 100(7): 525–534 19. Schittkowski MP, Guthoff RF (2006) Injectable self inflating hydrogel pellet expanders for the treatment of orbital volume deficiency in congenital microphthalmos: preliminary results with a new therapeutic approach. Br J Ophthalmol 90(9):1173–1177. (Epub 17 May 2006) 20. Schittkowski MP, Guthoff RF (2007) Results of lacrimal assessment in patients with congenital clinical anophthalmos or blind microphthalmos. Br J Ophthalmol 91(12): 1624–1626. (Epub 13 June 2007) 21. Shaw GM, Carmichael SL, Yang W, Harris JA, Finnell RH, Lammer EJ (2005) Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989–1997. Am J Med Genet A 137(1):36–40 22. Srsen S (1973) Congenital anophthalmos in two siblings. Acta Univ Carol Med Monogr 56:136–139 23. Tucker S, Jones B, Collin R (1996) Systemic anomalies in 77 patients with congenital anophthalmos or microphthalmos. Eye 10(3):310–314 24. Verma AS, Fitzpatrick DR (2007 Nov) Anophthalmia and microphthalmia. Orphanet J Rare Dis 26:47–54

Chapter 8

Brow Suspension in Complicated Unilateral Ptosis: Frontalis Muscle Stimulation via Contralateral Levator Recession

8

Markus J. Pfeiffer

Core Messages ■

■ ■ ■ ■

Ptosis with absent levator function and absent brow elevation cannot be corrected with brow suspension alone. Brow elevation can be stimulated by contralateral levator recession. Patients with individual (non-Hering) frontalis innervation must be excluded. Use the tape-down test to simulate the effect of levator recession. Partial levator recession requires precise adjustment.

8.1

Introduction

■ ■ ■

■

Total levator recession avoids the adjustment problem but requires bilateral suspension. High levator recession avoids the subsequent rise of the lid crease. Only autogenous fascia lata is free of graft complications and can be harvested from the age of 1 to 2 years. Oblique implantation creates the best eyelid motility.

orbicularis muscle more on the side of the ptosis (Figs. 8.1 and 8.2).

If there is no levator function, the eyelid can be elevated by brow suspension. In complicated cases of unilateral ptosis, there is no spontaneous compensatory brow elevation because the eye is amblyopic, nondominant, or deviated. These cases do not benefit from brow suspension alone. The majority of these cases, however, can be corrected if the contralateral eyelid is lowered to stimulate the bilateral brow elevation. The diagnostic evaluation of cases and the surgical procedures are explained.

8.2 8.2.1

Evaluation of Complicated Ptosis Compensatory Eyebrow Elevation

Unilateral ptosis usually causes a compensatory, involuntary elevation of the eyebrow on the side of the ptosis or on both sides [8]. The eyebrow on the side of the unilateral ptosis is commonly elevated more than the other eyebrow because patients tend to relax the antagonistic

Fig. 8.1 Right eye: ptosis without levator function and amblyopia. The minimal ptosis of the left eye stimulates the brow elevation (bilateral Hering innervation)

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stimulus of brow elevation is not transmitted to the side of the ptosis.

8

8.2.4

Checklist of Preoperative Evaluation of Complicated Ptosis

To correct a complicated unilateral ptosis by brow suspension and frontal muscle stimulation via contralateral levator recession, check the following preoperative conditions:

Fig. 8.2 Right eye postoperatively after unilateral brow suspension with autologous fascia lata. The correction of the ptosis was only possible because the right frontal muscle is stimulated by the left minimal ptosis

8.2.2

Examples of Complicated Unilateral Ptosis with Insufficient Compensatory Brow Elevation

1. The levator function is so far reduced that levator surgery is not possible or previous levator advancement has been ineffective. 2. The eye on the side of the ptosis is amblyopic, nondominant, or deviated. 3. There is no spontaneous elevation of the eyebrow on the side of the ptosis. 4. The eyebrow on the side of the ptosis can be elevated voluntarily. 5. The innervation pattern corresponds to Hering’s law on the opposite side of the ptosis, and there is no individual innervation. 6. The tape-down test on the opposite side of the ptosis (a moderate ptosis is simulated by taping the lid downward) stimulates bilateral brow elevation (Figs. 8.3 and 8.4).

Congenital dystrophic ptosis with amblyopia on the same side: Ptosis caused by third-nerve palsy Ptosis in combination with restricted ocular motility Ptosis caused by aberrant innervation Traumatic ptosis with amblyopia

8.2.3

8.2.5 Planning Partial or Total Levator Muscle Recession Combined with Unilateral or Bilateral Brow Suspension The levator can be recessed partially so far that the lid can be raised by compensatory brow elevation. The brow

Innervation Patterns of the Frontalis Muscle

We can differentiate three patterns of innervation of the frontal branch of the facial nerve. The type of pattern can be examined by asking the patient to elevate first the right and then the left eyebrow. In more than 98% of the cases, the frontal muscle is equally innervated on both sides (corresponding to Hering’s law), and both brows will be elevated if the patient is asked to raise the brow on one side. It is rare (2%) to find a patient with an individual innervation unilaterally or bilaterally. If the frontalis muscle on the contralateral side of the ptosis is innervated individually, we have to exclude these patients. Their ptosis cannot be corrected by brow suspension because the

Fig. 8.3 Right complicated ptosis after brow suspension. Absent compensatory brow elevation due to amblyopia

8.3

Surgical Technique of Levator Muscle Recession

Fig. 8.4 The tape-down test of the left upper lid shows that the right brow is only elevated if the left lid is lowered. A left levator recession is indicated

suspension is only necessary on the side of the original ptosis. The difficulty is to adjust the amount of recession precisely just to stimulate the brow elevation. An excessive recession will create a ptosis that cannot be compensated by the brow elevation. The difficulty of adjustment can be avoided if a total levator recession is performed to create a marked ptosis, which will be corrected with bilateral brow suspension.

Summary for the Clinician ■ ■ ■

Patients must be checked for amblyopia, unilateral dominance, or ocular deviation. The tape-down test predicts whether compensatory brow elevation can be expected. The Hering pattern of bilateral frontalis innervation must be present.

8.3 Surgical Technique of Levator Muscle Recession 8.3.1

Principle

The levator muscle is transsected in the level of the fornix posterior to the fusion of the aponeurosis into the levator muscle and anterior to the Whitnall ligament. The advantage of this high approach is the reduced horizontal extension of the levator incision (10 mm) and more effective recession of the levator [9]. (Alternatively, the aponeurosis and the Müller muscle can be transsected at a lower level, but the transsection must be carried out over 30 mm from the medial to the lateral canthus to be

119

Fig. 8.5 The ideal level of the levator recession is the high level because the incision is shorter and the effect on the subsequent rise of the skin crease is much less than the lower incision of the aponeurosis

effective and causes secondarily a much more pronounced rise of the lid crease; Fig. 8.5.)

8.3.2 Approach to the Levator The transcutaneous approach is recommended because it offers better exposure of the high portions of the levator complex near the Whitnall ligament and leaves the conjunctiva and the fornix intact. A typical blepharoplasty skin incision can be used to divide the orbicularis muscle and expose the orbital septum. The orbital septum should be opened widely over more than 25 mm to be able to retract the preaponeurotic fat pad and expose the surface of the levator complex.

8.3.3 Partial Levator Recession To localize the level of the incision, a malleable blunt spatula is introduced into the upper fornix. The upper margin of the spatula marks the incision line where the levator tissue is incised horizontally, leaving the underlying conjunctiva intact. The result is the formation of a gap with a width of about 12 mm in the levator sheath and significant lowering of the upper lid. To limit the amount of the recession, we can insert a patch of fascia lata into the gap (Figs. 8.5–8.11).

8.3.4 Total Levator Recession After introducing the spatula into the fornix, the levator is transsected horizontally at two levels, first at the level of the Whitnall ligament and then at the junction of the

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8

Fig. 8.6 Exposure of the levator after having opened the orbital septum. The spatula is introduced into the upper fornix up to the level of the Whitnall ligament

Fig. 8.9 The spacer tissue is introduced into the gap of the recessed levator

Fig. 8.7 The upper margin of the spatula marks the area of the levator transsection, which will be performed in the central third of the lid, leaving the conjunctiva intact

Fig. 8.10 Left congenital ptosis with amblyopia and without spontaneous brow elevation

Fig. 8.8 If no fascia lata had been extracted from the limb, the fascia of the subbrow fat pad (ROOF) could be harvested as spacer tissue

Fig. 8.11 After partial levator recession on the right side, the bilateral brow elevation is stimulated, and the left lid could be elevated via brow suspension

8.4

levator muscle and the aponeurosis. The tissue between the two incisions is removed completely, leaving the underlying conjunctiva intact. This will create a large gap of 6 mm in the levator complex and marked ptosis. The technique is also recommended to eliminate the synkinesis in Marcus Gunn ptosis [1].

Surgical Technique of Brow Suspension

121

risk (>30%) of degradation of the tissue [3]. Synthetic materials like silicone, polyester, nylon, polyethylene, PTFE (polytetrafluoroethylene), and polyglycolic acid are initially tolerated but carry a high risk (>30%) to be rejected after a period of 1/2 to 20 years [4, 5].

8.4.1.2 Autogenous Fascia Lata 8.3.5 The Lid-Lowering Effect and Eyelid Symmetry: Evolution of the Eyelid Level After Levator Recession After the partial levator recession, the immediate postoperative eyelid level tends to be low and will rise in the following 2 weeks. If the lid has reached the desired level earlier, the patient is asked to massage his lid downward to prevent undercorrection.

Only the transplantation of autologous fascia lata can guarantee a lifelong integration without complications like extrusion, degradation, or dislocation. Autologous fascia lata can be harvested from the age of 1 to 2 years through a small incision [7].

8.4.2 8.3.6

Undercorrection and Overcorrection

In partial recession, 80% of the patients finally reach a satisfactory eyelid level. Undercorrection (10%) and overcorrection (10%) are equally frequent. The undercorrected lid needs a repeated recession of the levator with a larger spacer tissue. Overcorrection (excessive recession) can be managed by ptosis surgery. The total recession surgery will usually create a marked ptosis without a tendency of undercorrection.

Summary for the Clinician ■ ■

■

Our Technique of Harvesting Autogenous Fascia Lata

Many different techniques of fascia lata harvesting are recommended. To minimize donor site morbidity, the incision should not extend 20 mm. I recommend the combination of a 20-mm incision at the lower third of the limb and a second 3-mm stab incision at a higher location in the distance of the required extraction length of the fascia [6, 10]. The lower incision of 20 mm serves as an approach to split the required width of the fascia in an upward direction toward the stab incision. The higher stab incision serves to extract the fascia with a slim 3-mm grasper instrument, which is introduced downward to the lower incision to grasp and extract the lower edge of the fascia (Figs. 8.12–8.14).

The high levator recession is more effective and does not affect the skin crease position. A total recession creates a total ptosis and avoids the adjustment problems of the partial recession, but bilateral suspension will be necessary. Partial recessions carry a 20% risk of over- or undercorrection, which will have to managed by secondary surgery.

8.4 Surgical Technique of Brow Suspension 8.4.1

Materials for Brow Suspension

8.4.1.1 Nonautogenous Materials Freeze-dried, irradiated allografts like dura mater, fascia lata, or fascia temporalis are effective initially for brow suspension. After a period of 3–6 months, there is a high

Fig. 8.12 The lower incision of 20 mm (right) serves as an approach to split the required width of the fascia in an upward direction toward the stab incision. The higher stab incision (left) serves to extract the fascia with a slim (diameter of 3 mm) grasper instrument, which is introduced down to the lower incision to grasp the lower edge of the fascia

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8

Fig. 8.13 The fascia is extracted through the stab incision

Fig. 8.15 Oblique fascia implantation between tarsus and brow via a skin crease incision creates the best eyelid motility and contour

8.4.4 Upper Lid Approach I recommend an open technique via a skin crease incision and two short stab incisions in the medial and lateral end of the brow. Sometimes, there is excessive tissue of the preseptal anterior lamella, which can be shortened moderately to improve the effect of the suspension. The orbital septum is opened widely to separate clearly the anterior and posterior lamella. The upper third of the anterior surface of the tarsus is exposed. Fig. 8.14 The fascia is split into strips of 2 × 70 mm

8.4.5 Fascia Implantation 8.4.3

Mechanical Principals of Brow Suspension

When the fascia bands are passed through the tissue and tightened, the cutaneous and subcutaneous tissue can be compressed only to a certain limit depending on the tissue volume. The shortening effect depends primarily on the involved tissue volume and much less on the tension of the fascia. In some cases, the anterior lamella is excessively stretched and has to be shortened by a blepharoplasty to reduce the volume of the tissues involved in the suspension. There are three sections of tissue connection in lid elevation: (1) frontalis muscle–brow; (2) brow–lid crease; (3) lid crease–lid margin. The first section above the brow usually shows good transmission of elevation and does not benefit from fascia implantation. The pretarsal and preseptal sections below the brow only show a loose connection dependent on the laxity of the anterior lamella. Oblique fascia implantation creates effective transmission with sufficient elasticity for sufficient lid closure (Fig. 8.15).

The fascia is split into 2 × 70 mm strips. The fascia needle is introduced into the stab incisions to emerge in the skin crease. Thus, the two bands of fascia are pulled up to the brow incisions through four separate tunnels in an oblique direction. The oblique direction of both loops (Crawford technique) provides better elasticity during lid closure than the single-loop technique (Fox pentagon). The loops are sutured in the center and the periphery to the upper third of tarsal plate [2]. The tightness is adjusted in the brow incision, where the ends of the loops are sutured together. We found that additional points of frontal fixation are not necessary. Further adjustment can be performed postoperatively by tightening or loosening the loops in the brow incision. Even after years, the effect of the suspension can be enhanced by shortening the preseptal anterior lid lamella inclusive of the integrated fascia, or it can be diminished by cutting the bands of fascia through a skin crease incision (Figs. 8.16–8.18).

References

123

Fig. 8.16 The two fascia loops run from the skin incision through the stab incisions of the brow

Fig. 8.18 Post-op: after right total levator recession and bilateral brow suspension with autogenous fascia lata

References

Fig. 8.17 Pre-op: left complicated congenital ptosis with amblyopia and without spontaneous brow elevation

Summary for the Clinician ■ ■ ■

Autogenous fascia lata is the “gold standard” and can be harvested from the age of 1 to 2 years. Oblique implantation through an “open sky approach” offers the best contour and motility. Over- or undercorrections are rare and can be managed by simple secondary surgery of the anterior lamella.

1. Cates CA, Tyers AG (2008 June) Results of levator excision followed by fascia lata brow suspension in patients with congenital and jaw-winking ptosis. Orbit 27(2):83–89 2. DeMartlaere SL, Blaydon SM, Cruz AA, Amato MM, Shore JW (2007 July–Aug) Broad fascia fixation enhances frontalis suspension. Ophthal Plast Reconstr Surg 23(4): 279–284 3. Fitzgerald MP, Edwards SR, Fenner D (2004 July–Aug) Medium-term follow-up on use of freeze-dried, irradiated donor fascia for sacrocolpopexa and sling procedures. Int Urogynecol J Pelvic Floor Dysfunct 15(4):238–242 4. Hersh D, Martin FJ, Rowe N (2006 July–Aug) Comparison of silastic and banked fascia lata in pediatric frontalis suspension. J Pediatr Ophthalmol Strabismus 16(4):212–218 5. Junceda-Moreno J, Suárez-Suárez E, Dos-Santos-Bernardo V (2005 Aug) Treatment of palpebral ptosis with frontal suspension: a comparative study of different materials. Arch Soc Esp Oftalmol 80(8):457–461 6. Kashkouli MB (2007 Sept) A novel technique for smallincision fascia lata harvesting without a fasciatome for the frontalis suspension procedure. Orbit 26(3):203–206 7. Leibovitch I, Leibovitch L, Dray JP (2003 Nov) Long-term results of frontalis suspension using autogenous fascia lata for congenital ptosis in children under 3 years of age. Am J Ophthalmol 136(5):866–871

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8. Matsuo K, Yuzuriha S (2008 Jan 11) Frontalis suspension with fascia lata for severe congenital blepharoptosis using enhanced involuntary reflex contraction of the frontals muscle. J Plast Reconstr Aesthet Surg 9. McNab AA, Galbraith JE, Friebel J, Caesar R (2004 July) Pre-Whitnall levator recession with hang-back sutures in

Graves orbitopathy. Ophthal Plast Reconstr Surg 20(4): 301–307 10. Naugle TC Jr, Fry CL, Sabatier RE, Elliot LF (1997 Sept) High leg incision fascia lata harvesting. Ophthalmology 104(9):1480–1488

Chapter 9

Modern Concepts in Orbital Imaging

9

Jonathan J. Dutton

Core Messages ■

■

■

■

■

Radiologic imaging is an important adjunct to the evaluation of any orbital disease and will contribute to establishing a likely diagnosis. Orbital imaging should not replace a careful physical examination to establish a differential diagnosis. Each imaging modality will contribute redundant data, but each also can provide unique information that may not be apparent with other imaging techniques. Computerized tomography (CT) utilizes X-rays to create a two-dimensional image in any plane; this is a uniparametric modality based only on tissue transparency to the passage of X-rays. Magnetic resonance imaging (MRI) is a multiparametric modality that utilizes atomic charac-

Radiographic examination is an important component in the evaluation of any patient with suspected orbital disease. Such studies contribute to narrowing the differential diagnosis and often provide guidance in planning the most appropriate medical therapy or surgical approach. CT scanning and MRI have largely replaced older techniques, although specialized studies may still be necessary to define certain lesions. Newer technologies, such as PET, are adding to our repertoire of useful modalities. All of the available imaging techniques may provide some redundant information, but they each also provide some unique information not seen with other modalities. Orbital imaging should therefore never be used as a replacement for a careful and complete clinical examination and the creation of an initial differential diagnosis. This is then used to decide the most appropriate imaging studies that will confirm or rule out suspected lesions.

■

■

teristics of tissue protons and their behavior in an external magnetic field; the image therefore reflects biochemical differences between tissues based on the molecular environment in which the proton is situated. Positron emission tomography (PET) is a newer technique that images tissues based on biological activity, most specifically the metabolism of fluoridated glucose in actively metabolizing tissues, such as tumors. Orbital ultrasound (echography) can provide nonradiologic but complementary examination techniques for the detection, differentiation, and measurement of orbital and periorbital lesions.

9.1 Computerized Tomography Computed tomography (CT) is an imaging technique that relies on the differential passage of X-rays through tissues, but unlike standard X-ray studies, CT can image soft tissues in addition to bone. Scans can be reconstructed in any plane through the body and contrast adjusted to maximize visualization of specific tissues. CT is the imaging modality of choice for showing details of bony structures or the location of foreign bodies but is less useful for differentiating details of the optic nerve or small lesions in the orbital apex. For these, MRI is superior. CT utilizes an array of thin, collimated X-ray beams that pass through tissue along pathways of a complex intersecting matrix (Fig. 9.1). The cross-sectional area defined by any two intersecting beams is referred to as a pixel and is analogous to a single dot in a newspaper photograph. Because the X-ray beam has a certain thickness,

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9

Fig. 9.1 Simplified diagrammatic representation of computed tomographic scanning matrix. As X-rays pass through tissues, the beam is attenuated by reflection and absorption so that the exiting beam is weaker than the entering beam. The width and thickness of the intersecting beams define the size of the pixel and voxel, which in turn define the image resolution

the area of beam intersection defines a volumetric space, referred to as the voxel. The smaller the pixel size and the thinner the tissue slice are, the smaller will be the volume of the voxel and therefore the higher the resolution of the final image. As the X-ray beams traverse the body, they are weakened or attenuated according to the density of the tissues through which they pass. The degree of attenuation of each intersecting beam emerging from a volume of tissue allows calculation of the average attenuation

value for all the tissues included within the area of intersection of the beams, which is the voxel. This mean attenuation assigned to each voxel is proportional to the density of the tissues with respect to the passage of X-rays. Attenuation values are designated in Hounsfield units, a 2,000-unit scale ranging from −1,000 to +1,000. By convention, the density of air is assigned a value of −1,000, the density of water is 0, and the density of bone is +1,000. The CT image contrast is based on these attenuation values, and the final CT image is seen in variations of gray scale. Tissues with low attenuation and therefore low tissue density (e.g., air) allow more X-rays to pass through and appear black or dark on the final image. Areas of high attenuation, and therefore high tissue density (e.g., bone), block the X-rays and appear white or lighter on the final image. Each tissue type in the orbit usually exhibits a characteristic density on CT (Table 9.1) and pathologic lesions may also show consistent density and homogeneity changes (Table 9.2). For visualization by the human eye, this 2,000-unit scale is collapsed to 64 levels of gray between black and white. Because of this, tissues of different but similar densities may not be distinguishable on standard CT studies. For more specific anatomic detail, the CT image may be manipulated by setting “windows.” The window level refers to the Hounsfield unit on which a narrow range of units is centered. The window range is the inclusive number of Hounsfield units above and below this level that are expanded into the black-to-white scale for final imaging. Soft tissue windows are used to image normal anatomic

Table 9.1. Characteristic densities of normal orbital and periorbital structures on computed tomography Tissue

Tissue window settings

Bone window settings

Air

Black

Black

Blood

Intermediate to dark

Very dark

Bone, cortical

White

Bright

Bone, marrow

White

Intermediate to dark

Calcification

White

Bright

Cortical gray matter

Intermediate

Very dark

CSF

Very dark

Very dark

Fat

Very dark

Very dark

Muscle

Intermediate

Dark

Optic nerve

Intermediate

Dark

Proteinaceous fluid

Intermediate

Dark

Sclera

Intermediate

Dark

Vitreous

Intermediate to dark

Dark

Water

Dark

Dark

White matter

Intermediate

Dark

9.1

Computerized Tomography

127

Table 9.2. Characteristics of common orbital diseases on computed tomography Disease

Diffuse

Well outlined

Enhancement

Density

Cystic

Bone erosion or destruction

Abscess

+

−

−

+

−

−

Adenoid cystic carcinoma

+

+

+

++

−

±

Alveolar soft part sarcoma

−

+

+++

+++

±

±

Amyloidosis

++

+

++

+

−

−

±

−

++

−

−

Basal cell carcinoma

+

+

++

Capillary hemangioma

−

++

+++

Cavernous hemangioma

−

+++

++

++

−

−

Cellulitis

+

+

+

+

±

±

Dermoid cyst

−

+++

−

−

+++

Variable

Epithelial cyst

−

++

−

−

+++

−

Hemangiopericytoma

−

++

+++

+

−

−

Hematic cyst

−

++

−

−

+++

−

Lymphangioma

++

+

+

+

Variable

−

Lymphoma

++

+

+

+

−

−

Metastases

++

+

+

++

−

±

Mucocele

−

+++

−

Variable

+++

+++

Optic nerve glioma

−

+++

+

+

±

−

Optic nerve meningioma

−

+++

+++

+

−

−

Pleomorphic adenoma

−

+++

+

+

+

±

Plexiform neurofibroma

++

−

++

+

−

±

Pseudotumor

++

−

++

+

−

−

Rhabdomyosarcoma

−

+

+

+

−

±

Schwannoma

−

+++

+

+

±

−

Solitary neurofibroma

−

++

++

+

−

−

Thyroid orbitopathy

−

++

+

++

−

−

Varix

+

++

±

Variable

Variable

−

− Low; + mild; ++ moderate; +++ marked

structures such as the eye, muscles, and optic nerve, but details of bone are not seen. Bone window settings give excellent visualization of bony detail, but soft tissue structures fade to low-contrast shades of gray (Fig. 9.2). Iodinated intravenous contrast agents are frequently used to improve contrast by increasing the Hounsfield value of blood vessels or highly vascularized tissues. Such agents may help outline normal anatomy and can more clearly define pathologic processes compared with noncontrasted scans (Fig. 9.3a, b). Early scanners were slow with poor resolution. Moderngeneration CT scanners utilize a spiral or helical technique with multiple detectors or a detector system that rotates continuously around the patient. This allows a continuous series of thin-section, high-resolution images that scan a

volume of tissue rather than individual slices. The data are reformatted automatically to display images as axial slices. Additional reconstructed images can be produced readily in the coronal, sagittal, and oblique planes [20, 23, 25]. Spiral scanning has several advantages. The scan time is much shorter than in conventional CT. Better resolution is achieved in all planes because more closely spaced scans can be obtained. CT angiography is also possible. The multislice CT scanner is an advanced spiral scanner that employs up to eight rows of detectors. This allows much faster data acquisition and larger scanned volumes. For most orbital studies, a standard CT scan should include images in both the axial and coronal planes. Axial images allow the simultaneous view of both orbits, the ethmoid sinuses, the middle cranial fossa, and the

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intraorbital optic nerves, thin 1.5-mm or overlapping 3-mm sections may be useful, but there is a certain sacrifice of low contrast and increased background noise. If bone erosion or remolding is suspected or for the detection of calcification, bone window images should be obtained. Unless contraindicated because of iodine allergy, a contrast series should be included in all orbital scans. Only the rare orbit, such as a posttraumatic one, can adequately be studied with a noncontrasted study alone.

9

Summary for the Clinician ■

Fig. 9.2 Bone window CT scan of a patient with fibrous dysplasia showing fine details in bony structures involving the sphenoid and ethmoid bones on the left side

■

■

temporal fossae. Coronal scanning has proved to be invaluable in evaluating the orbit and skull base. These views give better definition of structures oriented parallel to the axial plane, such as the orbital floor and roof. It also allows more accurate size comparison of structures such as the optic nerve and extraocular muscles. Both views are usually necessary to properly localize any pathology within the various orbital anatomic compartments and to characterize their relationship with other structures [3]. For evaluation of the cavernous sinus, optic canals, and

a

■

■

CT utilizes the passage of X-rays through tissues as the basis for contrast differentiation. Tissues that are similar in their ability to transmit or block X-rays will appear similar on the final CT image and therefore may not be anatomically distinguishable. The attenuation values calculated for each voxel are compressed to only 64 gray levels so that nearly similar tissues will show identical imaging characteristics. Window settings are used to expand small segments of the Hounsfield scale so that tissues can be more readily distinguished. The clinician should use the clinically derived differential diagnosis to help in ordering the most appropriate type of scan and window settings.

b

Fig. 9.3 (a) Axial tissue window contrast-enhanced CT scan showing multiple cavernous hemangiomas that enhance due to increased vascular supply. (b) Noncontrasted axial CT image of a child with a fusiform optic nerve glioma in the left orbit

9.3

9.2 Three-Dimensional Imaging Three-dimensional images combine a series of CT slices into a surface-rendered volume. The most widely used technique is shaded surface display (SSD). Here, threedimensional (3D) volume data are represented in a two-dimensional plane, displaying spatial relationships with visual depth cues. The computer algorithm determines which pixels within the volume data are displayed and how they are spatially related to other pixels in the volume set. In SSD, surfaces are modeled as a number of overlapping polygons, with surface shading added, and a virtual light source is computed for each. More sophisticated programs allow the surface models to be repositioned and manipulated. With surface rendering algorithms, interior structures are not visible (Fig. 9.4). Volume rendering is a technique by which selected surfaces can be defined by a threshold density and overlying tissues can be made semitransparent. Transparency and colors are used to represent specific volumes. This technique allows 3D reconstructions that allow exceptional evaluation of skull anomalies, fractures, and other bony lesions.

Fig. 9.4 Three-dimensional reconstructed CT image of a patient with fibrous dysplasia of the left face and orbit

Magnetic Resonance Imaging

129

9.3 Magnetic Resonance Imaging Magnetic resonance imaging offers several advantages over CT for orbital disease [6]. Because of the low resonance signal generated from bone, soft tissue visualization in the region of the orbital apex, optic canal, and cavernous sinus is not degraded by dense surrounding bone as in CT scans [4, 11, 12]. However, because of the low signal generated by bone and foreign bodies, these structures are not well imaged on MRI. Manipulation of resonance signals from various tissues provides contrast variability and a level of tissue differentiation unobtainable with any CT technique. This is particularly useful for neural tissues such as the optic nerve and brain. Surface coil technology, improvements in signal-to-noise ratios, and techniques for suppressing the high-fat signal on T1-weighted (T1-WI) images have greatly improved visualization of many orbital lesions [14–17]. The major component of the MRI system is the magnet that provides the primary polarizing field. Located within the bore of the magnet are gradient coils that provide the spatial localization information during the imaging process. Within the gradient coils are the radio-frequency (RF) antennae (“coils”), which transmit the RF energy to the tissues and receive the returning resonance signals. The use of smaller surface coils placed immediately over the area of interest increases the signal strength and increases the signal-to-noise ratio. These permit acquisition of the highresolution images of modern scanners. However, such coils are limited in the depth of penetration they can image, and they are associated with some artifact. The generation of a magnetic resonance signal depends on the presence of magnetic isotopes of common elements in biological tissues. The atom most frequently imaged is the ubiquitous hydrogen nucleus, or proton [13]. All protons are normally in a state of axial spin. This spinning charged particle generates a magnetic field, with north and south poles. Under normal conditions, all the nuclei in a given volume of tissue are randomly oriented, but when placed within a strong external magnetic field the individual protons align with the external magnetic direction (Fig. 9.5a). Most of the axes of individual protons lie at various small angles to the external magnetic moment, and they are equally distributed 360° around it. Like spinning tops, these inclined axes wobble, or precess, around the mean magnetic direction (Fig. 9.5a). The rotating axes therefore describe a conical surface with angular momentum determined by the strength of the external magnetic field and by an intrinsic property of the particular type of atomic nucleus. The resultant angular velocity of precession is called the Larmor frequency. When this system is exposed to an external RF pulse at the Larmor frequency, energy is absorbed by the atomic

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9 Modern Concepts in Orbital Imaging

External magnetic field, B0

Z

9

Net longitudinal magnetic moment, Mz = 0%

External magnetic field, B0 y

RF pulse

Mxy

a

X

b

Z

z

c

Net longitudinal magnetic moment, Mz = 100% External magnetic field, B0

External magnetic field, B0

Net longitudinal magnetic moment, Mz = 50%

y

y

d

x

X

Fig. 9.5 (a) Spinning proton nucleus in an external magnetic field showing axial precession. (b–d), Following exposure to an RF pulse at the Larmor frequency, the mean magnetic axis of the spinning protons deflect to a position 90° from the external magnetic orientation; when the RF pulse is removed, they decay back to their original parallel orientation by T1 relaxation

nuclei, and the spinning nuclei move into higher energy levels. The angular orientation of their axes with respect to the external magnetic direction increases, and in so doing they tilt away from the magnetic axis and into a plane perpendicular to it (Fig. 9.5b). In addition, the individual atomic axes group to one side of the external magnetic direction. When the RF signal is turned off, the precessing nuclei return to equilibrium by giving up energy to the environment at the specific Larmor frequency. Return to equilibrium occurs by two simultaneous decay, or relaxation, processes, which are detected as resonance signals.

Mz

T1 relaxation time

Time

9.3.1 The T1 Constant During the T1 relaxation, the nuclear axes realign into an orientation parallel to the external magnetic direction as the spinning protons gradually give up their absorbed energy to the environment [18] (Fig. 9.5c, d). The time

Fig. 9.6 The T1 relaxation or decay is represented as a timedependent asymptotic curve as energy is given up to the environment

required for completion of this process is an exponential rate called the T1 time (Fig. 9.6). It is influenced by the interaction of the proton with other atoms bound to the

9.3

Magnetic Resonance Imaging

131

Table 9.3. Characteristic signal intensities of normal orbital and periorbital structures on magnetic resonance imaging Tissue

T1-WI

T2-WI

Air

Very dark

Very dark

Blood, acute

Dark to intermediate

Dark

Blood, chronic

Dark rim with variable center

Dark rim with variable center

Blood, hyperacute

Intermediate

Intermediate

Blood, subacute

Bright rim

Bright

Bone, cortical

Very dark

Very dark

Bone, marrow

Bright

Intermediate

Cortical gray matter

Dark

Bright

CSF

Very dark

Very bright

Fat

Very bright

Intermediate to dark

Muscle

Dark

Dark

Optic nerve

Dark to intermediate

Intermediate

Proteinaceous fluid

Intermediate to bright

Very bright

Sclera

Dark to intermediate

Intermediate

Vitreous

Dark

Bright

Water

Very dark

Very bright

White matter

Bright

Dark

T1-WI T1 weighted image, T2-WI T2 weighted image

molecular lattice, by temperature, and by viscosity of the tissue. At any specific time following the RF pulse, the total amount of energy given up by the spinning protons depends on the rate at which the T1 relaxation occurs. Tissues with a short T1 constant, such as fat, give up more resonant energy per unit time and therefore appear brighter on the final MR (magnetic resonance) image than tissues with longer T1 constants, such as muscle. This is the basis for contrast intensity, and specific orbital tissues will demonstrate characteristic T1 signal intensities (see Table 9.3).

time, and is influenced by the tiny magnetic fields generated around adjacent spinning nuclei (Fig. 9.8). As with T1 constants, biochemical differences between tissues confer slightly different T2 relaxation times to their protons. At any specific time following the RF pulse, tissues with long T2 constants, such as vitreous, maintain a greater transverse vector component than tissues with short T2 constants, such as muscle. This greater transverse vector produces a higher signal and is therefore brighter on the final MR image.

9.3.3 9.3.2 The T2 Constant Immediately following the RF pulse, the atomic nuclei are grouped on one side of the mean magnetic axis (Fig. 9.7a). As they rotate, they generate an RF signal as they cut across the external magnetic field and thus generate a small alternating current voltage. During the T2 relaxation, the atomic nuclei redistribute themselves evenly 360° around the external magnetic field direction (Fig. 9.7b). As they do so, the strength of this induced signal decreases because of the increasing canceling vectors. The time for complete decay of this signal (i.e., even distribution of magnetic moments) is the T2, or spin–spin relaxation

Creating the MR Image

The signals generated by the T1 relaxation and the T2 decay are measured by RF detectors. They will detect in mass fashion all similar signals at the Larmor frequency, regardless of their specific location within the tissue. Spatial encoding of resonant signals from particular small volumes of tissue is necessary for the creation of a meaningful two-dimensional image. This is achieved by deformation of the external magnetic field using gradient coils, such that the protons in every small volume of examined tissue (voxel) has a unique magnetic field strength and therefore a unique Larmor frequency. The detected Larmor frequency therefore will identify the precise

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9 Modern Concepts in Orbital Imaging

a z

9

Net longitudinal magnetic moment, Mz = 0%

b z

Net longitudinal magnetic moment, Mz = 100%

External magnetic field, B0

External magnetic field, B0

y

y

RF pulse

x

x

Fig. 9.7 (a, b) When exposed to the RF pulse, the proton magnetic moments group to one side of the external magnetic field direction. When the RF signal is removed, the moments redistribute themselves 360° around the external field by T2 relaxation

a

Signal

T2relaxation time

Time

Fig. 9.8 The T2 relaxation is represented as a time-dependent asymptotic curve as energy is given up and the signal decays to zero

location of the signal, and a topographic image can be created. The final MR image is determined by the proton density and by the variations in the T1 and T2 decay constants of specific tissue components. The T1 and T2 resonance signals can be manipulated by application of various pulsed sequences, thus altering the way the signals are collected. The MR image can therefore be weighted in favor of the T1 or the T2 information (Fig. 9.9a, b). In a T1 image, the vitreous is imaged as a dark hypointense signal compared to fat, which shows a bright hyperintense signal. On a T2 scan, the vitreous is typically bright, and the fat is dark (Fig. 9.10a, b). Pathologic lesions in the orbit often show distinctive T1 and T2 imaging characteristics that can help distinguish them from other lesions (Table 9.4) [31]. Gadolinium is a rare earth element with paramagnetic properties. In the presence of an external magnetic

b

Fig. 9.9 (a) Coronal T1 MRI image of a patient with a lymphoma of the medial right orbit; the lesion is isointense to normal muscle. (b) Axial T2 MRI scan of a different patient showing a lateral orbital lymphoma that is homogeneous and slightly hyperintense to muscle

9.3

a

Magnetic Resonance Imaging

133

b

Fig. 9.10 (a) Axial T1-weighted image of a schwannoma in the right orbit that is mildly heterogeneous and hypointense. (b) T2 image of the same patient showing the lesion to be moderately hyperintense Table 9.4. Characteristics of common orbital diseases on magnetic resonance imaging Disease

Compared to fat

Compared to muscle

T1-WI

T2-WI

T1-WI

T2-WI

Gadolinium enhancement

Texture

Abscess

Hypo

Hyper

Hyper

Hyper

−

Hetero

Adenoid cystic carcinoma

Hypo

Iso

Hyper

Hyper

++

Hetero

Alveolar soft part sarcoma

Hypo

Hyper

Iso

Hyper

+++

Hetero

Amyloidosis

Hypo

Hypo

Hypo

Hypo

Capillary hemangioma

Hypo

Hyper

Hyper

Variable

++

Homo/hetero

Cavernous hemangioma

Hypo

Hyper

Iso/hyper

Hyper

+

Homo/hetero

Hetero

Cellulitis

Hypo

Hypo

Iso

Hypo

−

Dermoid cyst

Hypo/iso

Iso/hyper

Hypo

Iso

−

Home/hetero

Epithelial cyst

Hypo

Hypo

Iso

Iso

−

Homo

Fibrous histiocytoma

Hypo

Iso/hyper

Iso

Hypo

++

Hetero

Hemangiopericytoma

Hypo

Hyper

Iso

Hypo

++

Homo

Hematic cyst

Hypo/iso

Variable

Hypo

Iso

−

Homo/hetero

Lymphangioma

Hypo

Hyper

Hyper

Iso

Variable

Homo

Lymphoid neoplasm

Hypo

Iso/hyper

Iso

Iso

+++

Homo Homo

Lymphoma

Hypo

Iso/hyper

Hyper

Iso

++

Metastases

Hypo

Hyper

Iso

Hyper

Variable

Homo/hetero

Mucocele

Hypo/iso

Hyper

Hypo/hyper

Hyper

−

Homo/hetero

Neurofibroma

Hypo

Hyper

Iso

Hyper

Variable

Hetero/homo Hetero

Optic nerve glioma

Iso

Hyper

Iso

Hyper

++

Optic sheath meningioma

Iso

Hypo

Iso

Iso

+++

Hetero

Plexiform neurofibroma

Hypo

Hyper

Hypo

Hyper

++

Hetero/homo

Pseudotumor

Hypo

Hyper

Iso

Hyper

++

Homo/hetero

Rhabdomyosarcoma

Hypo

Hyper

Iso

Hyper

+++

Homo/hetero

Schwannoma

Hypo

Hyper

Iso/hyper

Hypo

−

Hetero

Thyroid orbitopathy

Hypo

Hypo

Iso/hyper

Hyper

+++

Homo

Varix

Hypo

Hyper

Iso

Hypo

+++

Homo

hypo hypointense, hyper hyperintense, iso isointense, homo homogeneous, hetero heterogeneous, + mild, ++ moderate, +++ marked T1-WI T1 weighted image, T2-WI T2 weighted image

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influence, its magnetic moment preferentially aligns with the magnetic field. The magnetic moment of gadolinium is 1,000 times greater than that of a hydrogen nucleus, and its presence in tissues shortens the T1 relaxation time, resulting in a marked increase in signal intensity. In many cases, gadolinium will increase the relative contrast of adjacent tissues, and the degree of enhancement can often be used to help characterize specific pathologic lesions (see Table 9.4). However, this enhancing effect of gadolinium on some tissues may actually result in decreased contrast in the orbit because of the intense signal from adjacent retrobulbar fat on routine T1-weighted sequences, so that the lesion may not be distinguished from normal orbital fat. Various fat suppression techniques are available and should be employed for better visualization of gadolinium-enhanced tissues within the orbital fat. Special techniques can greatly expand the usefulness of MRI in certain circumstances. Time-of-flight MR angiography is based on the phenomenon of flow-related enhancement of spinning protons entering an imaging slice. These “fresh” protons enter unsaturated, thereby giving a higher signal than the surrounding stationary protons. Images can be combined or obtained simultaneously by phase encoding in the slice direction to produce a 3D image of the vessels analogous to a conventional angiogram.

9.4 Imaging of Common Orbital Lesions It is useful to review the typical CT and MRI appearance of some common orbital lesions as a reference for clinical evaluation. It should be kept in mind that many lesions will have similar imaging characteristics, so that definitive diagnosis is usually not possible. Nevertheless, a carefully selected CT or MRI sequence, or a combination of both modalities, will frequently narrow the differential diagnosis to a few more likely possibilities.

9.4.1

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma is the most common primary malignancy of the lacrimal gland, representing about 30% of all epithelial lacrimal gland tumors. It is seen most commonly in the fourth decade of life. The CT usually shows a round-to-oval, heterogeneous mass that is defined to poorly demarcated in the superotemporal orbit. It may extend along the lateral orbital wall, and foci of calcification may be seen. Bone destruction is a frequent finding. On MRI, the T1 image gives a heterogeneous hyperintense signal to muscle that becomes hyperintense to fat on the T2 sequence. Moderate enhancement is seen with gadolinium (Fig. 9.11a, b).

9.4.2 Cavernous Hemangioma

Summary for the Clinician ■

■ ■

■

■

■

MRI is a technique that uses biochemical differences between tissues to create an image of a cross-sectional slice of the body. It relies on resonance signals generated by protons exposed to an external magnetic field. Within this magnetic field, when exposed to a RF pulse these spinning protons change their orientation and clustering as they rotate around the mean magnetic direction. When the RF pulse is removed, the protons return to baseline by relaxation processes while giving up energy to the environment as T1 and T2 resonance signals. These signals can be measured and manipulated to produce an image that can be weighted toward the T1 or the T2 resonance signals. Various tissues show different T1 and T2 relaxation times, and these can be used to maximize the signal strengths and therefore the contrast between these tissues.

The cavernous hemangioma is a benign, noninfiltrative, slowly progressive vascular tumor of large endothelial channels. It presents most commonly in early to middleaged adults from 20 to 60 years of age. On CT scan, these lesions demonstrate a well-defined, rounded, homogeneous tissue density mass. Bone remodeling may be seen with long-standing lesions. Enhancement is mild to moderate owing to generally low vascular flow. The MRI shows a homogeneous isointense signal on T1-weighted images and a high signal on T2WI (Fig. 9.12a, b).

9.4.3

Dermoid Cyst

The dermoid is the most common orbital cystic lesion. It represents a developmental choristoma arising from trapped pouches of ectoderm into bony sutures or from failure of surface ectoderm to separate from the neural tube. They slowly enlarge as they fill with sebum and keratin. The CT appearance is a rounded, well-defined cystic lesion usually in the anterior superotemporal orbit, eyelid, or brow. The center typically shows a low fat density,

9.4 Imaging of Common Orbital Lesions

a

135

b

Fig. 9.11 (a) CT and (b) T1 MRI showing the characteristic imaging findings of adenoid cystic carcinoma of the lacrimal gland

a

b

Fig. 9.12 (a) CT and (b) T1 MRI showing the characteristic imaging findings of cavernous hemangioma

and a fluid–fat level may sometimes be seen. On T1 MRI images, the cyst shows low signal intensity due to water content but may be hyperintense when there is a high fat content. On T2 images, a fluid–fat interface will show an upper lipid layer with low intensity and a lower fluid layer that is hyperintense (Fig. 9.13a, b).

9.4.4

Fibrous Dysplasia

Fibrous dysplasia is a nonhereditary benign developmental fibro-osseous anomaly that represents a

hamartomatous malformation. Bone is replaced with fibrous tissue containing abnormally arranged dysplastic bony trabeculae. Progressive constriction of orbital foramina and canals may cause cranial nerve palsies and visual loss from optic nerve compression. The CT image is best evaluated with bone window settings and shows bone thickening and sclerosis with a typical ground-glass appearance and narrowing of orbital foramina. On MRI, the bone images as homogeneous and hypointense, with less-calcified areas showing foci of more hyperintense signal (Fig. 9.14).

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9 Modern Concepts in Orbital Imaging

a

b

9

Fig. 9.13 (a) CT and (b) T2 MRI showing a dermoid cyst at the right lateral upper eyelid, with (b) also showing a small dermoid cyst at the left lateral brow

hyperintense heterogeneous signal on T1-WI (T1 weighted image) and on the T2-WI (T2 weighted image) blood cysts give a high signal intensity. Serpentine areas of signal void within the mass represent vessels containing flowing blood (Fig. 15a–c).

9.4.6

Fig. 9.14 Bone window CT showing the characteristic imaging findings of fibrous dysplasia

9.4.5 Lymphangioma Lymphangiomas are lesions of abortive vascular elements that arborize among normal structures. They represent hamartomas of venous–lymphatic channels. Although these lesions are hemodynamically isolated from largeflow vessels of the arteriovenous system, they are prone to intrinsic hemorrhage from small vessels. The CT scan shows irregular heterogeneous and poorly defined infiltrates among normal orbital structures. Low-density cystic areas may be present, and higher-density phleboliths may be seen. The MRI image demonstrates a mildly

Lymphoma

The vast majority of orbital lymphomas are of the nonHodgkin variety, mostly low-grade proliferations of small monoclonal B lymphocytes. Lymphomas represent 5–10% of orbital mass lesions and 40–60% of lymphoproliferative disease in the orbit. On CT scan, lymphomas appear as a mass that is diffuse to moderately defined and is homogeneous or less often heterogeneous in texture, isodense to muscle, and typically molded around the globe, the optic nerve, and along the orbital walls. On T1 MRI images, lymphomas are slightly hyperintense with respect to muscle and hypointense to fat. On T2 images, resonance signals are brighter but variable from isointense to moderately hyperintense with respect to both muscle and fat (Fig. 9.16a, b).

9.4.7

Myositis

Myositis is an orbital inflammatory process confined to one or more extraocular muscles. It is related to the group of idiopathic inflammatory pseudotumor syndromes of unknown etiology. The CT image shows diffuse enlargement of one or more extraocular muscles with somewhat

9.4 Imaging of Common Orbital Lesions

a

b

c

Fig. 9.15 (a) CT, (b) T1 MRI, and (c) T2 MRI showing the characteristic imaging findings of lymphangioma

a

b

Fig. 9.16 (a) CT, (b) T1 MRI showing the characteristic imaging findings of a lymphoma

137

138

9 Modern Concepts in Orbital Imaging

a

b

9

Fig. 9.17 (a) CT and (b) T1 fat saturation contrasted MRI showing the characteristic imaging findings of myositis

irregular borders. The density is usually slightly higher than for normal muscle and is homogeneous in texture. On MRI, the involved extraocular muscles are enlarged, and the inflammatory process usually does not involve adjacent orbital fat. On T1-weighted images, the muscle produces an intermediate homogeneous signal that is isointense to normal muscle. On the T2-weighted image the signal is generally isointense to fat (Fig. 9.17a, b).

9.4.8

Optic Nerve Glioma

Optic nerve gliomas are uncommon neoplasms of astrocytic glia located along the visual pathways. They represent 2–4% of all orbital tumors and 66% of primary optic nerve tumors. Gliomas are seen most commonly in

a

children, with a mean age of 9 years at presentation. About 29% of optic gliomas are seen in the setting of neurofibromatosis. On noncontrast CT, the orbital glioma appears as a well-outlined enlargement of the optic nerve that is usually fusiform but may be more rounded or even mulitilobulated. Increased tortuosity or kinking of the nerve is a common finding. Following contrast administration, enhancement is heterogeneous and variable from imperceptible to moderate. On the T1 MRI, gliomas are isointense or slightly hypointense with respect to cortical gray mater. A dilated subarachnoid space filled with cerebral spinal fluid (CSF) may image as a hypointense zone surrounding the tumor. Low-signal hypointense areas within the lesion represent cysts of mucinous degeneration and necrosis. On T2-WI, the signal may be more variable (Fig. 9.18a, b).

b

Fig. 9.18 (a) CT and (b) T1 MRI showing the characteristic imaging findings of optic nerve glioma

9.4 Imaging of Common Orbital Lesions

9.4.9

Pseudotumor

Pseudotumor is a common nonneoplastic, nongranulomatous inflammatory disease of unknown cause. It accounts for about 5% of all orbital lesions. The process ranges from acute to chronic and is not associated with systemic disease. Involvement may be diffuse within the orbital fat but can also involve specific structures such as extraocular muscle, lacrimal gland, posterior sclera, or optic nerve sheath. The CT shows a streaky, irregular, heterogeneous area of increased density with shaggy borders. This lesion typically molds around the globe and along extraocular muscles and insinuates between fascial planes. On MRI, the T1-weighted image gives a heterogeneous, poorly defined signal that is isointense to muscle and hypointense to fat. The T2-weighted image is hypointense or isointense to fat (Fig. 9.19a, b).

a

9.4.10

139

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue mesenchymal tumor and malignancy of the orbit in children. It arises from pleuripotential mesenchymal precursors that normally differentiate into striated muscle. It occurs primarily in children, with a mean age of 8–9 years old, but rarely may be seen in older adults. CT scan shows an irregular, but moderately well-defined, soft tissue density mass. Most tumors occupy the extraconal space, with about half extending into the intraconal compartment. The MRI shows a heterogeneous-to-homogeneous irregular mass that is isointense to slightly hypointense with respect to muscle and hypointense to fat on T1-WI. On T2-weighted sequences, the tumor signal is higher, being hyperintense to both muscle and fat (Fig. 9.20a, b).

b

Fig. 9.19 (a) CT and (b) T1 MRI showing the characteristic imaging findings of orbital pseudotumor

a

b

Fig. 9.20 (a) CT showing the characteristic imaging findings of an orbital rhabdomyosarcoma. (b) T2 MRI of a small rhabdomyosarcoma of the right sphenoid sinus

140 9.5

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9 Modern Concepts in Orbital Imaging

Diffusion MRI (Diffusion-Weighted Imaging)

Diffusion imaging focuses on the random Brownian micromovements of water molecules inside tissues [28]. Because of these motions, water molecules collide and thereby diffuse through tissues. As they diffuse, they encounter different obstacles, such as cell membranes, proteins, and fibers, which vary according to the specific tissue type. These structures can also be modified by certain pathological conditions, such as intracellular edema, abscess, and tumors. Water diffusion is relatively unrestricted in some tissues, such as cerebral gray matter. However, in other tissues such as white matter and muscle with a fiber structure, or in highly cellular tumors, water diffusion is more restricted. Diffusion-weighted imaging (DWI) therefore provides valuable information on the structure and geometric organization of tissues [30]. In DWI diffusion of extracellular water is the imaging object of interest. Diffusion data provide indirect information about the histological and gross anatomical tissue structure surrounding the water molecules [22, 27]. Diffusion MRI produces in vivo images of biological tissues weighted according to the local microstructural characteristics that influence diffusion. As discussed, in a typical T1-weighted MRI image water molecules in the sample are excited by a strong magnetic field. This causes the protons in these water molecules to precess simultaneously, producing signals that are used to create the image. In T2-weighted images contrast is produced by measuring the loss of coherence or synchrony between the water protons. When water is in an environment where it can move freely (diffuse), relaxation tends to take longer, and this can generate increased contrast between an area of pathology and the surrounding healthy tissue [2] and can be used to image structures that may not be appreciated by conventional MR techniques [34] (Fig. 9.21). Various diffusion-weighted sequences are designed to obtain images with contrast that is influenced by differences in water molecule mobility [5]. This is done by adding multiple diffusion gradients during the preparatory phase of an imaging sequence. The final image will depend on the speed of diffusion and on the direction of diffusion controlled in part by structures that restrict water movement, such as nerve and muscle fibers. The image intensity in each imaged voxel is attenuated (weakened) depending on the strength and direction of the magnetic diffusion gradient as well as on the local microstructure in which the water molecules diffuse. The greater the attenuation at a given position, the more diffusion there is in the direction of the diffusion gradient, and the darker will be the image. Where diffusion is low, as in the optic

Fig. 9.21 Diffusion-weighted MRI scan of a child with an optic nerve glioma showing focal increased water diffusion

nerve, extraocular muscles, or hypercellular tumors, the signal is brighter. To measure the diffusion profile, the MR scan is repeated many times, applying different directions and strengths of the diffusion gradient for each scan. In DWI, three gradient directions are usually applied, which approximately show the trace of the diffusion tensor. The diffusion image is normalized in a variety of ways to yield different types of images based on diffusion signals. They include ADC (apparent diffusion coefficient), Dav (average diffusion constant), and TDC (true diffusion coefficient).

Summary for the Clinician ■

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Diffusion MRI produces an image that is based on the microscopic movement of free water in the extracellular tissue compartment. Water diffusion can be isotropic in some tissues or anisotropic where barriers are present that only allow diffusion in one direction; the latter is seen in white matter due to fiber orientation and in muscles. Pathological processes can alter diffusion characteristics. Diffusion-weighted MRI measures the rate and direction of water diffusion and is used to map nerve fiber patterns and locations of impediments to diffusion, such as hypercellular tumors.

9.6

Diffusion tensor imaging enables the in vivo evaluation of tissue microstructure. It provides data that can help in the diagnosis of microscopic features, such as nerve fiber anomalies in white matter, which may not be visible with standard imaging techniques [38]. DWI has become useful for the detection of tumors, infections, inflammations, trauma, and degenerative diseases. It can distinguish a solid tumor from areas of cystic degeneration and necrosis and between benign and malignant neoplasms because of its ability to distinguish hypercellular from paucicellular tumors.

9.6 Positron Emission Tomography Positron emission tomography is an imaging technique that has become useful in medicine. Unlike the CT, which images the transparency of tissues to the passage of X-rays, PET scanning measures the emission of positrons (photons) from a radiotracer that is injected intravenously [1]. The technique makes use of the concept of positron annihilation. In a PET scan, the patient is injected with the radioactive substance and placed on a table that moves through a circular shaped housing. This housing contains the gamma ray detector array, which has a series of scintillation crystals. Each detector is connected to a photomultiplier tube that converts the gamma rays emitted from the patient to photons of light. The photomultiplier tubes convert and amplify the photons to electrical signals. These signals are then processed by a computer to generate a clinical image. As the table and patient incremen-

a

Positron Emission Tomography

141

tally move forward, the process is repeated, giving a series of thin-slice images of the body. These images are then assembled into a 3D representation [32, 37, 40]. The combined use of PET and CT is proving to be even more valuable by demonstrating metabolic activity along with anatomical detail and localization [36]. The most commonly used positron-emitting nuclides are carbon-11 and fluorine-18. These replace the normal atoms in tissue compounds, and the labeled compounds are taken up by certain tissues. Thus, fluorine-18 replaces fluorine-19 in fluorinated glucose to produce [2-18F]fluoro2-deoxy-D-glucose (FDG). The radioactive atom decays by positron emission. When a positron is emitted by a nucleus, it immediately collides with an electron, and the pair annihilates, converting all the mass energy of the two particles into two gamma rays. The two gamma ray photons possess momentum, and the conservation of momentum requires that they travel in opposite directions. The simultaneous detection of these gamma ray photons in two detectors situated 180° apart in the scanner allows location of the source on a line directly between those two detectors. FDG PET scanning exploits the increased glycolytic activity associated with neoplastic diseases and has proven to be superior to other imaging modalities for some tumors, such as head and neck squamous cell carcinoma and lymphoma [24, 26, 41, 42]. PET scan imaging is of particular value for imaging of the brain (Fig. 9.22a, b). The fluorine isotope 18F-labeled glucose can pass through the blood–brain barrier, where the concentration of the tracer is a measure of the level of metabolic activity at that location in the brain. In the brain and elsewhere in the

b

Fig. 9.22 (a, b) Coronal and axial PET scans showing normal metabolic activity of the brain

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9 Modern Concepts in Orbital Imaging

body, an area of abnormally high activity suggests a fastgrowing malignancy (Fig. 9.23). After treatment of the tumor, the PET scan is useful to show if the lesion has become metabolically inactive or is still consuming glucose, thereby indicating continued activity [21]. PET can also provide images of blood flow or other biochemical functions, depending on the type of molecule that is radioactively tagged. Newer technologies are emerging that will enhance the value of PET scanning in the future [19]. PET scanning so far has shown more limited value for orbital lesions because of the high signal from the adjacent brain and the relatively low resolution of about 7 mm [29, 39]. Single-photon emission computed tomography (SPECT) is a technique similar to PET. However, the

Summary for the Clinician ■

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PET scanning is a modality that images tissues based on the concentration of specific atomic nuclei. Fluoride-labeled glucose is the most commonly used tracer and is concentrated in tissue with high glycolytic activity, such as tumors. The radioactive tracer is selectively taken up by certain tissues and, in the case of glucose, is concentrated in areas of high metabolic activity. Tissues with high metabolic activity image with a bright signal and can localize regions with suspected tumors.

Fig. 9.23 PET scan of a patient with a left orbital malignant melanoma (arrow) extending from an intraocular choroidal primary

radioactive substances used in SPECT are different, such as xenon-133, technetium-99, and iodine-123. These have longer decay times than those used in PET and emit single instead of double gamma rays. SPECT is better in providing information about blood flow and the distribution of radioactive substances in the body.

9.7

Orbital Ultrasound

Orbital ultrasound (echography) has been used for over four decades to augment the clinical evaluation of patients with suspected orbital disease. Ophthalmic ultrasound was first introduced as a diagnostic tool by Mundt and Hughes in 1956. Beginning in the 1960s, Coleman and Bronson popularized the use of B-scan in ophthalmology, and around the same time Ossoinig developed the standardized A-scan instrument for the evaluation of intraocular and orbital disease [35]. These methods of ophthalmic ultrasound offer specific and comprehensive examination techniques for the detection, differentiation, and measurement of orbital and periorbital lesions [7–10, 33].

9.7.1 Physics and Instrumentation Ultrasound is the oscillation of particles at frequencies greater than 20 kHz (20,000 cycles/s). In ophthalmic ultrasound, frequencies generally range from 8 to 10 MHz (1 MHz = 1 million cycles/s). These relatively high frequencies provide short wavelengths that are necessary for the resolution of small orbital structures. The velocity at which ultrasound travels is determined by the physical properties of the media through which it passes. Ultrasound instruments make distance measurements by taking into consideration the velocity of sound in specific media and the time it takes the sound waves to reach a given interface and then return to the probe. Short pulses of sound are emitted from a probe placed on the eye or lids. When the sound beam reaches an acoustic interface between two different tissues, an echo is produced that returns to the probe. Echoes are produced mainly through the phenomenon of scattering or reflection [10]. Scattering occurs at the surfaces of very small acoustic interfaces, such as clumps of tumor cells. Reflection occurs at the surfaces of large acoustic interfaces, like connective tissue septae and large blood vessels. The returned echoes are processed in the instrument for display as either an A-scan or B-scan echogram (Fig. 9.24). The one-dimensional standardized A-scan utilizes a small probe that emits a stationary, nonfocused sound beam at a frequency of 8 MHz. The two-dimensional

9.7

a

Orbital Ultrasound

143

b

Fig. 9.24 (a) Normal A-scan echogram; v vitreous, r retina, c choroid, s double scleral peaks (inner and outer walls), f orbital fat, m extraocular muscle, (b) Normal B-scan echogram; l posterior lens capsule, v vitreous, r retina, f = orbital fat, on optic nerve

B-scan employs a separate, larger probe that emits an oscillating, focused sound beam at a frequency in the range of 10 MHz. Once an orbital mass is detected, the special examination techniques of topographic, quantitative, and kinetic echography are employed for differentiation (Table 9.5). These techniques incorporate the use of B-scan and A-scan as appropriate to ascertain a variety of acoustic data about the lesion.

9.7.1.1

Topographic Echography

B-scan is the primary modality used to evaluate the topographic features of a lesion (location, shape, and extension) and to facilitate 3D thinking. The sound beam is directed through (transocular) or around the eye (paraocular) as appropriate, depending on the location of the lesion. Transocular approaches (transverse, longitudinal, and axial) are employed to display lesions behind the globe, whereas anterior lesions are better imaged with a paraocular approach [10]. The topographic examination serves to display a lesion in relationship to the globe and orbital bone as well as to the extraocular muscles or the optic nerve (Figs. 9.25–9.28).

9.7.1.2

the size and distribution of cell aggregates, the presence of connective tissue septae, large blood vessels, etc.) [10]. The sound beam incidence must be perpendicular to the lesion’s anterior and posterior surfaces. It is primarily carried out with A-scan using the tissue sensitivity gain setting. The amplitude of a lesion’s internal echoes is compared to the vitreous baseline (0% amplitude) and the peaks of the initial echo (100% amplitude). As an example, a cavernous hemangioma shows high reflectivity compared to a lymphangioma or glioma, which generally show low reflectivity. (Figs. 9.25 and 9.26, respectively). In Graves orbitopathy, the separation of muscle fascicles yields a highly reflective irregular pattern (Fig. 9.27). The internal structure of a lesion is classified as either regular (similar texture) or irregular (dissimilar texture). This is done by observing the degree of uniformity in the echoes. Similar internal spike amplitude usually indicates homogeneous texture by histopathology. Conversely, irregular internal structure suggests heterogeneous texture by histopathology. Lesions with regular internal structure are further analyzed for their level of internal reflectivity, which refers to the strength of echoes; these correlate with the fine histologic texture of the lesion. The internal reflectivity is generally classified as low, 0–40%; medium, 40–60%; or high, 80–100%.

Quantitative Echography

Quantitative echography is employed to evaluate the strength of a lesion’s internal echoes (internal structure, internal reflectivity, and sound attenuation). These characteristics correlate with histopathologic features (e.g.,

9.7.1.3

Kinetic Echography

Kinetic echography is the dynamic assessment of motion (consistency and internal vascularity) and is one of the primary advantages of ultrasound in the evaluation of

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Table 9.5. Major ultrasound features of common orbital diseases Disease

9

A-scan

B-scan

Reflectivity

Structure

Attenuation

Shape

Borders

Other

Abscess

Low-medium

Irregular

Weak

Irregular

Poorly defined

±Dense septae

Adenoid cystic carcinoma

Medium-high

Irregular

High

Diffuse-round

Variable

±Bone erosion

Alveolar soft part sarcoma

Low-medium

Irregular

Absent

Well defined

Well defined

Amyloidosis

High

Regular

Weak

Variable

Well defined

Basal cell carcinoma

Medium

Irregular

Absent

Irregular

Poorly defined

Capillary hemangioma

Medium-high

Irregular

Variable

Irregular

Poorly defined

Heterogeneous

Cavernous hemangioma

High

Regular

Moderate

Round-oval

Well defined

±Calcium ±Fluid level

Dermoid cyst

Low-medium

Variable

Variable

Rounded

Well defined

Eosinophilic granuloma

Low-medium

Regular

Weak

Well defined

Well defined

Bone defect

Epithelial cyst

Very low

Regular

Absent

Rounded

Well defined

Compressible

Hemangiopericytoma

Medium

Regular

Medium

Round-oval

Well defined

±Cystic spaces

Hematic cyst

Low

Regular

Weak

Rounded

Well defined

±Fluid level

Lymphangioma

Low

Irregular

Variable

Irregular

Poorly defined

Dense septa

Lymphoma

Low-medium

Regular

Weak

Diffuse

Variable

Metastases

Medium-high

Regular

Variable

Variable

Variable

Mucocele

Low

Regular

Weak

Rounded

Well defined

Bone defect Fusiform

Optic nerve glioma

Low-medium

Regular

Weak

Large nerve

Well defined

Optic nerve meningioma

Medium-high

Irregular

Absent

Large nerve

Well defined

±Calcium

Pleomorphic adenoma

Medium-high

Regular

Moderate

Round-oval

Well defined

±Bone erosion

Plexiform neurofibroma

Medium-high

Irregular

Weak

Irregular

Poorly defined

Pseudotumor

Low-medium

Regular

Weak

Variable

Variable

Rhabdomyosarcoma

Low-medium

Variable

Variable

Variable

Well defined

±Septa

Schwannoma

Low-medium

Regular

Moderate

Oval

Well defined

Solitary neurofibroma

Low-medium

Regular

Variable

Round-oval

Well defined

Thyroid orbitopathy

Medium-high

Irregular

Absent

Large muscle

Well defined

Normal tendon

Varix

Low-medium

Regular

Weak

Tubular

Well defined

+Valsalva

a

±Cystic spaces

b

Fig. 9.25 (a) A-scan of a cavernous hemangioma showing high reflectivity and an irregular internal structure. (b) B-scan of a cavernous hemangioma with a well-defined low echogenic retrobulbar mass

9.7

a

Orbital Ultrasound

145

b

Fig. 9.26 (a) A-scan of a lymphangioma showing low reflective irregular echoes in a chocolate cyst of blood. (b) B-scan of the same patient as in (a); the retrobulbar mass is somewhat irregular with variable reflectivity

a

b

Fig. 9.27 (a) Graves orbitopathy showing a high reflective wide muscle defect within the orbital fat; m muscle belly, s muscle sheath. (b) B-scan echogram of the same patient showing an enlarged extraocular muscle (m) with relatively normal tendon (arrow)

orbital lesions. Consistency (compressibility) can be assessed with A-scan or B-scan. Vascularity (spontaneous motion) indicates blood flow within a lesion. Consistency is evaluated by exerting moderate pressure against the tissue with the probe. A soft lesion will be seen to decrease in size, whereas a hard lesion will remain unchanged. Vascularity can be observed when a lesion contains blood vessels with rapidly flowing blood (e.g., capillary hemangiomas). In lesions with high blood flow, the A-scan may show a fast, flickering motion or pulsations of one or more internal echoes that indicate blood flow.

9.7.2

Extraocular Muscles

Extraocular muscle thickening is a common finding in patients presenting with signs or symptoms of orbital disease. Standardized echography has proven to be an excellent modality for the measurement of extraocular muscle thickness and the differentiation of thyroid dysfunction (Fig. 9.27) from other conditions, such as idiopathic orbital myositis, or tumors. The differentiation of various disorders affecting the extraocular muscles is based primarily on laterality and the topographic

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9 Modern Concepts in Orbital Imaging

a

b

9

Fig. 9.28 (a) A-scan of an optic nerve glioma showing a low reflective widening of the nerve shadow (on). (b) B-scan of an optic nerve glioma; the optic nerve shadow shows low reflectivity with more highly reflective foci of calcification

features of size and location as well as on quantitative properties.

9.7.3

Optic Nerves

Lesions of the optic disc and disorders of the retrobulbar optic nerve are well suited for evaluation with echography. B-scan is the method of choice to evaluate the optic disc and demonstrates gross abnormalities of the retrobulbar optic nerve in the anterior orbit. B-scan can easily demonstrate gross enlargement of the optic nerve just behind the eye as well as heterogeneous echoes such as calcification that may provide important clues to aid in differentiation (Fig. 9.28).

References 1. Abramoff MD (2005) New concepts in orbital imaging. In: Karcioglu ZA (ed) Orbital tumors. Springer, New York, pp 109–110 2. Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329 3. Armington WG, Bilaniuk LT (1988) The radiologic evaluation of the orbit: conal and intraconal lesions. Semin Ultrasound CT MR 9:455–473 4. Atlas SW, Galetta SL (1991) The orbit and visual system. In: Atlas SW (ed) Magnetic resonance imaging of the brain and spine. Raven, New York, pp 709–722 5. Bammer R (2003) Basic principles of diffusion-weighted imaging. Eur J Radiol 45:169–184

6. Bilaniuk LT, Zimmerman RA, Newton TH (1990) Magnetic resonance imaging: orbital pathology. In: Newton TH, Bilaniuk LT (eds) Radiology of the eye and orbit. Raven, New York, Chap 5 7. Byrne SF (1984) Standardized echography in the differentiation of orbital lesions. Surv Ophthalmol 29:226–228 8. Byrne SF (1986) Standardized echography of the eye and orbit. Neuroradiology 28:618–640 9. Byrne SF, Green RL (1992) Ultrasound of the eye and orbit. Mosby Year Book, St. Louis 10. Byrne SF (2000) Introduction to orbital imaging. In: Dutton JJ, Byrne SF, Proia AD (eds) Diagnostic atlas of orbital diseases. Saunders, Philadelphia, pp 19–30 11. Daniels DL, Pech P, Mark L, et al (1985) Magnetic resonance imaging of the cavernous sinus. Am J Radiol 145: 1145–1146 12. Daniels DL, Yu S, Pech P, Haughton VM (1987) Computed tomography and magnetic resonance imaging of the orbital apex. Radiol Clin North Am 25:803–817 13. DeMarco JK, Bilaniuk LT (1990) Magnetic resonance imaging: technical aspects. In: Newton TH, Bilaniuk LT (eds) Radiology of the eye and orbit. Raven, New York, pp 1–14 14. DePotter P, Shields JA, Shields CL (1995) MRI of the eye and orbit. Lippincott, Philadelphia, pp 3–17 15. DePotter, Flanders AE, Shields CL, Shields JA (1993) Magnetic resonance imaging of orbital tumors. Int Ophthalmol Clin 33:163–173 16. Dortzbach RK, Kronish JW, Gentry LR (1985) Magnetic resonance imaging of the orbit. Part I. Physical principles. Ophthal Plast Reconstr Surg 5(3):151–159 17. Dortzbach RK, Kronish JW, Gentry LR (1989) Magnetic resonance imaging of the orbit. Part II. Clinical applications. Ophthal Plast Reconstr Surg 5(3):160–170

References 18. Dutton JJ (2000) Introduction to orbital imaging. In: Dutton JJ, Byrne SF, Proia AD (eds) Diagnostic atlas of orbital diseases. Saunders, Philadelphia, pp 31–41 19. Frangiomi JV (2008) New technologies for human cancer imaging. J Clin Oncol 26:4012–4021 20. Garvey CJ (2002) Computed tomography in clinical practice. BMJ 324:1077–1080 21. Gayed I, Eskandari MF, McLaughlin P, et al (2007) Value of positron emission tomography in staging ocular adnexal lymphomas and evaluating their response to therapy. Ophthal Surg Lasers Imaging 38:319–325 22. Habes C (2004) Basic principles of diffusion tensor MR technology. J Radiol 85:281–286 23. Hu H, He HD, Foley WD, Fox SH (2000) Row helical CT: image quality and volume coverage speed. Radiology 215: 55–62 24. Jabour BA, Choi Y, Hoh CK, et al (1993) Extracranial head and neck PET imaging with 2-[F-18]fluoro-2-deoxy-Dglucose and MR imaging correlation. Radiology 186: 27–35 25. Jones R, Kaplan RT, Lane B, et al (2001) Single versus multi-detector row CT of the brain: quality assessment. Radiology 219:750–755 26. King AD, MA BB, Yau YY, et al (2008) The impact of 18-FFDG PET/CT on assessment of nasopharyngeal carcinoma at diagnosis. Br J Radiol 81:291–298 27. Koh DM, Collins DJ (2007) Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 188:1622–1635 28. Koyama T, Tamai K, Togashi K (2006) Current status of body MRI imaging: fast MR imaging and diffusionweighted imaging. Int J Clin Oncol 11:278–285 29. Lane KA, Bilyk JR (2006) Preliminary study of positron emission tomography in the detection and management of orbital malignancy. Ophthal Plast Reconstr Surg 22: 361–365 30. Le Bihan D (2006) From Brownian motion to mind imaging: diffusion MRI. Bull Acad Natl Med 190:605–627

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31. Mafee MF, Putterman A, Valvassori GE, et al (1987) Orbital space-occupying lesions: role of computed tomography and magnetic resonance imaging. Radiol Clin North Am 25:529–559 32. Mandelkern M, Raines J (2002) Positron emission tomography in cancer research and treatment. Technol Cancer Res Treat 1:423–439 33. Mundt GH, Hughes WF (1956) Ultrasonics in ocular diagnosis. Am J Ophthalmol 41:488–492 34. Nagae-Poetscher LM, Jiang H, Wakana S, et al (2004) High-resolution diffusion imaging of the brain stem at 3 T. AJNR Am J Neuroradiol 25:1325–1330 35. Ossoinig KC (1991) Echographic differentiation of vascular lesions in the orbit. In: Thijssen JM, Verbeek AM (eds) Ultrasonography in ophthalmology. Junk, Dordrecht, p 283 36. Pan T, Mawlawi O (2008) PET/CT in radiation oncology. Med Phys 35:4955–4966 37. Reader AJ (2008) The promise of new PET image reconstruction. Phys Med 24:49–56 38. Rovaris M, Gass A, Bammer R, et al (2005) Diffusion MRI in multiple sclerosis. Neurology 65:1526–1532 39. Spraul CW, Lang GE, Lang GK (2001) Value of positron emission tomography in the diagnosis of malignant ocular tumors. Ophthalmologica 215:163–168 40. Townsend DW (2004) Physical principles and technology of clinical PET imaging. Ann Acad Med Singapore 33: 133–145 41. Valenzuela AA, Allen C, Grimes D, et al (2006) Positron emission tomography in the detection and staging of ocular adnexal lymphoproliferative disease. Ophthalmology 113:2331–2337 42. Wirth A, Seymour JF, Hicks RJ, et al (2002) Fluorine-18 fluorodeoxyglucose positron emission tomography, gallium-67 scintigraphy, and conventional staging for Hodgkin’s disease and non-Hodgkin’s lymphoma. Am J Med 112:262–268

Chapter 10

Management of Periorbital Cellulitis in the 21st Century

10

Michael P. Rabinowitz and Scott M. Goldstein

Core Messages ■ ■

■

Periorbital cellulitis can be a serious infection and must be promptly recognized and treated. Due to vaccines and antibiotic use in the twentieth century, the microbiologic spectrum of bacteria causing infections in the periorbital area in the twenty-first century is different from 10–15 years ago. Methicillin-resistant Staphylococcal aureus (MRSA) infections are now a common entity and are aggressive.

10.1

Introduction

Infection in the periorbital area is an acute problem that must be astutely recognized and treated. Even though these infections have been around for centuries, the spectrum of bacteria involved continues to evolve with the ever-changing landscape of antibiotics and vaccines. These bacterial infections can be superficial in the preseptal tissue, involve the orbital space, or encompass both. They are a common cause for ophthalmic emergency visits and need to be treated promptly. When the orbit is infected, severe sequelae can result, including death, and thus must be managed aggressively. The goal of this chapter is to review the mechanisms and organisms responsible for cellulitis given that the spectrum of bacteria causing cellulitis is constantly in flux. Current treatment regimens based on current bacteria and antibiotic sensitivity are addressed along with the increasing incidence of MRSA and other antibiotic resistance.

10.2 The Infection: Stages, Symptoms, and Effects Most cellulitis involves the preseptal eyelid tissue. Orbital cellulitis represents an acute infection with inflammation

■

■

Clinical examination and computed tomographic (CT) scans are the two important aspects of properly evaluating patients with infections. A combination of medical antibiotic therapy and surgical intervention is often needed to appropriately treat these infections, especially in teenagers and adults.

of orbital contents, often including the pre- and postseptal eyelids [2, 6, 20, 44]. Periorbital cellulitis can be classified into five stages. The first stage is preseptal cellulitis, in which inflammatory edema remains anterior to the orbital septum. The second stage is posterior spread of this inflammation, behind the arcus marginalis, to a true orbital cellulitis (inflammation of the orbital contents without abscess formation). Third, subperiosteal abscesses may form, in which pus collects between the orbit and the periosteum of the involved sinus. The fourth stage is an orbital abscess, and the fifth involves cavernous sinus thrombosis [6, 24]. The course of treatment varies based on several factors, including the stage of the infection, the source of the infection, the health of the patient, and the underlying organism involved. By and large, symptomatology and presentation of cellulitis vary with stage of disease. Therefore, a patient with a swollen eyelid can present a challenge but may be readily diagnosed by careful clinical history, examination, and potentially necessary imaging modalities. Stage 1 disease, or preseptal cellulitis, typically presents as tender erythema of the upper or lower eyelids, with no orbital involvement (Fig. 10.1). Since this inflammation is not restricted by the arcus marginalis, it may spread around the eye to involve both the upper and lower lids as well as the cheek and forehead. The history often includes a

150

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Management of Periorbital Cellulitis in the 21st Century

associated proptosis, limited ocular motility, or visual disturbances [7, 24, 35]. As the stages of orbital cellulitis become more advanced, symptoms worsen, and diplopia, orbital congestion, and inflammation will arise. As the orbital pressure increases, focal abscesses enlarge, and the optic nerve becomes more compromised. Abnormal pupillary reflexes, ophthalmoplegia, impaired color vision, and more severe visual loss may arise. More extensive spread may elicit proptosis, meningismus, altered mental status, headaches, and other signs indicative of cavernous sinus, meningitic, encephalitic, or systemic involvement. These symptoms are fairly specific for advanced orbital cellulitis.

10

Fig. 10.1 Patient with 2 days of progressive swelling and discomfort in the right upper eyelid. Note the eye is white and quiet, and there is normal motility

Summary for the Clinician ■

concurrent sty, recent trauma, or sometimes nothing that the patient can recall. Examination often demonstrates lid pathology with a focal hordeolum or innocuous injury and surrounding edema and erythema that is often tender and warm to the touch. Proptosis, restricted motility, diplopia, vision changes, pupillary defects, or other optic nerve complications will be absent. Orbital cellulitis, however, represents a more severe ophthalmic condition with significant morbidity, including the possibility of blindness from optic nerve compression or invasion and even mortality (Fig. 10.2a, b) [10, 13, 43, 48, 49]. When infection and inflammation extend posterior across the orbital septum, edema of the orbit and associated increased orbital pressure provide for

a

■ ■

■ ■

■ ■

Orbital cellulitis represents an acute infection with inflammation of orbital contents, often including the pre- and postseptal eyelids Periorbital cellulitis can be classified into five stages. The first stage is preseptal cellulitis, in which inflammatory edema remains anterior to the orbital septum. The second stage is posterior spread of this inflammation, behind the arcus marginalis. In the third stage, subperiosteal abscesses may form as pus collects between the orbit and the periosteum of the involved sinus. The fourth stage is an orbital abscess. The fifth involves cavernous sinus thrombosis.

b

Fig. 10.2 (a, b) Patient with 5 days of upper respiratory infection developed sudden swelling and pain of left eye in 24-hr period. Note erythema, edema, proptosis, chemosis, ophthalmoplegia, and nasal discharge. CT scan demonstrates severe left-sided rhinitis, pan sinusitis, and extension of the infection into the medial left orbit. Note the gas in the anterior ethmoids and orbit

10.4 Microbiology

It is good that most patients present with an early stage that will advance, if untreated, to later stages. However, there is no exact correlation between extent of cellulitis and clinical presentation. Further, patients do not necessarily progress stage by stage. Last, lab work is historically ineffective in establishing or aiding a diagnosis [26, 35, 37]. Cultures are positive only 50% of the time, blood cultures are typically negative without underlying bacteremia, and white blood cell counts and c-reactive protein levels are usually unreliable [23, 35]. That stated, any abscess or conjunctival discharge that can potentially be cultured should be.

151

frontal sinuses, pathogens may spread through the thin bony roof or floor, respectively. These progressions are supported by orbital and frontal venous drainage systems, joined by valveless communications.

Summary for the Clinician ■

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Preseptal cellulitis in the periorbital area most commonly arises from superficial skin bacteria invading into the preseptal tissue. Preseptal cellulitis can be caused by dacryocystitis as well. Sinusitis remains the most common cause of orbital cellulitis.

10.3 Etiology Preseptal cellulitis in the periorbital area most commonly arises from superficial skin bacteria invading into the preseptal tissue. Superficial wounds to the periorbital area can result in superficial cellulitis. Commonly, inciting factors include periocular trauma, periocular surgery, insect bites, abscesses, stys, impetigo, spread from associated upper respiratory illness, conjunctivitis, blepharitis, or even tooth abscesses [7, 24]. Some of these wounds will result in focal abscess formation, while others result in a more diffuse cellulitis. Focal abscess can often be treated with simple drainage, especially hordeolums. Once the infection starts to spread along the skin and orbicularis, antibiotic therapy is required. Preseptal cellulitis can be caused by dacryocystitis as well. The location of the lacrimal sac anterior to the orbital septum is largely responsible for its tendency toward preseptal cellulitis, as opposed to orbital infection. Further, the lacrimal sac inserts on the posterior lacrimal crest and is buffered posteriorly by the lacrimal fascia, posterior limb of the medial canthal ligament, and deep heads of the pretarsal and preseptal orbicularis muscles. All of these factors preclude posterior extension of lacrimal sac infection [30]. Sinusitis remains the most common cause of orbital cellulitis [6, 20, 24, 35]. Of orbital infections, 60–80% arise secondary to sinus infections, whereas local periocular trauma, periocular surgery, and orbital/ocular surgery are much less-common etiologies given the anatomic barriers mentioned. Most reports show that ethmoid involvement is the most common sinus of origin, followed by maxillary sinusitis [7, 23, 24, 35]. Antecedent upper respiratory infections are common in these scenarios, and contagions typically spread from the ethmoid sinuses across the lamina papyracea or orbital plate of the ethmoid bone [24]. When originating in the maxillary or

10.4

Microbiology

Certainly, microbial pathogenesis of periorbital infection is dictated by cause as an isolate from a maxillary sinus infection may be different from invasion of the periorbita from superficial local trauma. Further, isolation is difficult as wound cultures are positive in only half of patients [35, 37]. In the late twentieth century, based on positive cultures, Haemophilus influenza (H. flu) had been the most common pathogen responsible for orbital cellulitis prior to the advent of its vaccine [37]. Also, H. flu would commonly progress to subsequent sepsis and central nervous system infection in pediatric cases. Epidemiologic data support this organism’s consistent decline since the beginning of HiB (Haemophilus influenza type B) vaccination in the late 1980s. Currently, the most common bacterial isolates in orbital cellulitis include the Staphylococcus species. Coagulase-negative Staphylococcus and Staphylococcus aureus (S. aureus) are common causes of both preseptal cellulitis and postseptal infection. Pseudomonas species, Streptococcus species, Moraxella catarrhalis, and Ekinella corrodens are all less-common causes of orbital cellulitis, and anaerobic organisms are frequently isolated from adult patients with inflamed sinuses and are generally associated with chronic sinusitis [12, 24, 35, 37]. In our recent study at Wills Eye Institute in Philadelphia, we analyzed 33 consecutive cases of orbital cellulitis between 2005 and 2007 and found similar results. Coagulase-negative Staphylococcus was responsible for 23% of the infections, while Streptococcus species were responsible for 16%. Methicillin-sensitive and methicillinresistant S. aureus (MSSA and MRSA, respectively) each accounted for 13%. Haemophilus influenzae, fungi, and

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other microbes contributed to the remaining cases. As other studies have found, underlying sinusitis was by far the most common cause of orbital cellulitis, accounting for 72% of the infections. Extension from endophthalmitis, preseptal cellulitis, and dacryocystitis accounted for 10%, 6%, and 6% of the cases, respectively. Pathogenesis also varies by age group; Staphylococcus and Streptococcus species inoculate the vast majority of children, especially under the age of 9, whereas those teenagers over 14 years old and adults commonly suffer from polymicrobial, mixed aerobic, and anaerobic infections [26, 35]. Between these age groups lies a transition zone in which infections transition from those caused by a single organism to those as a result of a combination of aerobic and anaerobic bacteria [13, 21, 26, 43].

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The most common bacterial isolates in orbital cellulitis include the Staphylococcus species. Coagulase-negative Staphylococcus and S. aureus are common causes of both preseptal cellulitis and postseptal infection. Pseudomonas species, Streptococcus species, Moraxella catarrhalis, and Ekinella corrodens are all less-common causes of orbital cellulitis.

10.5 Changing Pathogens and Resistance Over the last century, common pathogens in orbital cellulitis have changed. Human activity has played the predominant role in changing the microbiology of infections. From vaccines to antibiotics, there has been a profound change in the organisms responsible for causing human morbidity. Measles, mumps, rubella, smallpox, and chicken pox are many of the scourges no longer readily seen by physicians. As mentioned, H. influenza as of 20 years ago was a prominent, and often devastating, organism involved in a variety of head and neck infections, periorbital cellulitis included. All of these passed to the footnotes of history due to vaccinations. In addition, the introduction of antibiotics has changed the behavior of bacteria as they evolve in the ongoing battle with humankind. The most prevalent problem in the early twenty-first century is MRSA [5, 38, 48]. The changing epidemiology of MRSA in both the hospitalized and community populations mirrors the emergence of penicillin-resistant strains of S. aureus

decades ago. Penicillin was first introduced in 1941, and soon thereafter penicillin resistance among hospitalized patients was being reported. By the end of World War II, most hospital-acquired strains of S. aureus were resistant to penicillin. This is largely attributed to previous first-line treatment with beta-lactam antibiotics in these patient populations [55]. Over several decades, most S. aureus infections in the hospitals first and then later in the community became equally resistant to penicillin [5]. In a similar manner, methicillin was introduced as a treatment for S. aureus in 1961, and in less than 1 year, resistance to methicillin was reported in the hospital setting [38]. Initially, large urban tertiary care centers suffered MRSA rates of 10% or less, while smaller community-based institutions were largely unaffected. Within 25–30 years, over 20% of S. aureus strains in these smaller, nonreferral centers were resistant to methicillin, as were over 40% in larger urban institutions. By 1998, resistance reached 50% in hospital settings, and soon after, rates of resistance in the community-based population quickly rose. Currently, rates of hospital-acquired MRSA are well over 80%, with recent exponential rises in several epidemiologic studies from around the United States. Infections due to community-acquired MRSA (CA-MRSA) have been reported all over the world and have been exponentially growing in incidence [10, 14, 22, 49, 55]. Based on the aforementioned epidemiology of penicillin resistance, the CA-MRSA should exponentially continue to increase over the next decade. Studies between 1995 and 2006 showed CA-MRSA rates increasing from about 20% to about 60% in patients presenting with soft tissue infections [22, 33, 38]. A study found 68% of staphylococcal isolates from periorbital cellulitis were methicillin resistant [23].

10.5.1

CA-MRSA Versus Hospital-Acquired MRSA

The most likely mechanism of methicillin resistance in S. aureus comes secondary to the presence of the mecA gene complex, which transcribes a penicillin-binding protein that has multiple insertion sequences within its targeted DNA fragment [11, 22]. This mechanism accounts for the resistance of hospital-acquired MRSA to many antibiotics. Although it has variations of these genes, CA-MRSA is comparably susceptible to many non-beta-lactam antibiotics and can typically be successfully treated with a variety of available antibiotics, including tetracyclines, vancomycin, clindamycin, and sulfa-based drugs [22, 48, 49]. This

10.5

is largely because fewer S. aureus strains are exposed to broad-spectrum antibiotics in the community, and multiple-drug-resistant strains therefore have less of a survival advantage. The mecA gene translation is thought to vary accordingly. Distinctive strains within the community and hospital groups have been confirmed different in studies using pulsed-field gel electrophoresis. Health care-associated MRSA and CA-MRSA differ in that the former tends to carry mec types I, II, and III, and the latter encodes mec type IV [39, 54]. By far the prominent among these CA-MRSA strains is the USA300 clone. Pathologic examination of the MRSA USA300 clone, a community-acquired strain, shows extensive tissue necrosis due to its Panton– Valentine leukocidin gene held within its mec IV chromosome-containing cassette [5, 17, 29, 36, 38, 48, 49]. This gene encodes an exotoxin that has been shown in vitro to destroy polymorpholeukocytes and macrophages. More recent research elucidated that the USA300 clone virulence may be attributable to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and alpha-toxin and not just the panton valentine leukocidin toxin (PVL) gene [34].

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The introduction of antibiotics has changed the behavior of bacteria as they evolve in the ongoing battle with humankind. The most prevalent problem in the early twentyfirst century is MRSA. Currently, rates of hospital-acquired MRSA are well over 80%. Infections due to CA-MRSA have been reported all over the world and have been exponentially growing in incidence. The most likely mechanism of methicillin resistance in S. aureus comes secondary to the presence of the mecA gene complex, which transcribes a penicillin-binding protein that has multiple insertion sequences within its targeted DNA fragment. This mechanism accounts for the resistance of hospital-acquired MRSA to many antibiotics. Although it has variations of these genes, CA-MRSA is comparably susceptible to many non-beta-lactam antibiotics and can typically be successfully treated with a variety of available antibiotics, including tetracyclines, vancomycin, clindamycin, and sulfa-based drugs.

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While providing a histologic difference between MRSA types, this virulent clone is also blurring the lines between hospital-acquired MRSA and CA-MRSA [39, 48]. There have been reports internationally of its outbreak within health centers. The term community-associated infection may eventually be more appropriate for these MRSA strains. Regardless, despite their differences, both hospital and community strains can progress to severe soft tissue infections, necrotizing infections, systemic illness, osteomyelitis, bacteremia, and death even in healthy adults. Given the past epidemiologic trends regarding the time course of penicillin and methicillin resistance and the aforementioned genetic evolution of MRSA, one would assume the eventual rise of vancomycin-resistant S. aureus (VISA) in the community setting is inevitable. In fact, there is now a growing prevalence of clindamycin resistance as well as hospital-acquired VISA infections [3]. The Centers for Disease Control and Prevention (CDC) has already confirmed a number of cases of VISA-related deaths.

10.5.2

Orbital MRSA

One of the most common bacterial isolates in many ocular infections historically includes the S. aureus species, so one may have predicted that MRSA would emerge as an increasingly common etiology of ophthalmic ailments. To be sure, MRSA has become a more frequently reported cause of lid abscess (Fig. 10.3), dacryocystitis, endophthalmitis, panophthalmitis, and superior ophthalmic vein thrombosis [13, 23, 31]. It has also been isolated as a source of conjunctivitis and keratitis in patients with underlying surface disease, poor overall health, malignancies, and operative interventions, including cataract, LASIK, and retinal surgeries [9, 15, 16, 28, 41, 46, 47, 51, 52].

Fig. 10.3 Young woman with acute onset of focal abscess and preseptal cellulitis that cultured positive for MRSA

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Fig. 10.4 (a, b) Patient who had been plucking her brows and lashes developed severe onset of cellulitis. On opening the lid for drainage, there was diffuse infection of the soft tissue with multiple microabscesses consistent with MRSA

MRSA has also been reported as an increasingly common pathogen in orbital cellulitis [11]. However, little is known about CA-MRSA infections of the eye and orbit [1, 25, 27, 32, 40, 42, 43, 50, 56, 57]. Most of what we know is limited to case reports, and the majority of these CA-MRSA infections involved the USA300 clone. In almost all community-acquired cases described in the current literature, this disease quickly assumes a downhill clinical course. In some cases, even with appropriate antibiotic treatment and surgical debridement, some patients are left with significant morbidity from extensive tissue necrosis, including blindness or the need for enucleation. Our personal experience at the Wills Eye Institute initially was derived from ten consecutive cases of postseptal MRSA identified from March 2006 through February 2008, with more and more cases presenting after the analysis. This initial cohort represents cases seen at several hospitals in the Philadelphia area as well as cases seen in an outpatient office setting. The average age of this initial cohort was 28.9 years, with a bimodal distribution ranging from 6 weeks to 61 years. Patients were diagnosed and monitored with both clinical examination and CT scanning. The younger cohort of patients had focal, superficial abscesses with surrounding cellulitis that were drained and treated with oral antibiotics. These patients all required just one surgical intervention. The exception to this was a 6-weekold infant who was transferred to Children’s Hospital of Philadelphia with a significant orbital cellulitis that appeared to arise from a local wound to the lower eyelid and spread into the subperiosteal space. She required prolonged intravenous antibiotics and two trips to the operating room, but eventually settled without sequelae.

The adult patients had more aggressive infections that spread along tissue planes with multiple microabscesses and a true tissue cellulitis (Fig. 10.4a, b). These more aggressive infections required hospitalization, intravenous antibiotics, and often multiple surgeries to debride the infections. On average, each of these older patients had two surgical debridements to bring the infections under control. Because of the more severe nature of some of these infections, their slow responses to antibiotics, and the inflammatory effects of surgery, steroids were added in three of five adult cases. In these cases, corticosteroids noticeably helped patients improve and recover. Inpatient management included vancomycin in all our patients, typically in conjunction with a second drug. These combinations were always chosen and managed by the infectious disease team, which was invaluable. In addition, most of these patients were sent home with prolonged 2- to 4-week courses of intravenous vancomycin via a peripherally inserted central catheter. All ten patients returned to baseline, although some with residual scarring. Two of the adult patients had residual ptosis, one of which was treated, and the other is still being followed.

10.6

Evaluation of Orbital Cellulitis

The evaluation of orbital cellulitis has evolved over the past several decades. At the heart of this debate is the fact that periorbital cellulitis ranges from a relatively benign condition with no lasting side effects that may be treated with oral antibiotics to a debilitating, progressive infection requiring surgical and intravenous intervention that

10.7

potentially leads to optic nerve dysfunction, central nervous system damage, and even death. Complicating this devastating range of infectious manifestations is the potentially rapid rate of orbital expansion that can occur, leading to the aforementioned consequences. After completing a thorough physical exam, dedicated orbital CT scan is the investigation of choice for preseptal and orbital cellulitis [8, 24]. However, not every patient warrants radiological evaluation. On initial presentation, CT can assess the sinuses and extent of periorbital infection if edema is excessive and the clinician is unsure that the infection is solely preseptal. Patients with clear clinical pictures and no signs of postseptal or optic nerve involvement do not need CT evaluation. On the other hand, patients with worsening clinical presentation, proptosis, ophthalmoplegia, worsening visual acuity, declining color vision, bilateral symptomotology, or signs of central nervous system complications require immediate CT scan, especially if surgery is planned because of orbital compression or if there is no clinical response to treatment after 48 h [8, 24, 43, 53]. The use of CT must be tempered with the knowledge that radiologic improvement will lag behind the clinical picture by a number of days [24]. CT scans are helpful in aiding the initial evaluation of orbital cellulitis, the location of the primary infection, and the risk of spread to surrounding areas. Yet, the clinical examination and follow-up, not CT scans, should drive therapy, and CT scans should not be repeated regularly once obtained. Once orbital cellulitis is diagnosed, the clinical exam and culture results will dictate appropriate management with specific antibiotics and possible surgery. If rapid visual decline occurs on clinical exam, operative intervention will take place well before a follow-up CT scan documents progression. Repeat CT scan may be useful in follow-up to rule out frontal lobe abscesses if the clinical exam dictates.

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MRSA has also been reported as an increasingly common pathogen in orbital cellulitis. The evaluation of orbital cellulitis has evolved over the past several decades. Dedicated orbital CT scan is the investigation of choice for preseptal and orbital cellulitis. The use of CT must be tempered with the knowledge that radiologic improvement will lag behind the clinical picture by a number of days.

Medical Treatment of Orbital Cellulitis

10.7

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Medical Treatment of Orbital Cellulitis

Medical therapy of periorbital cellulitis obviously requires the use of antibiotics, but which one is the typical question. Preseptal infection is typically treated with oral antibiotics. Orbital infections require immediate intravenous antibiotic therapy, targeting the most likely pathogens. In the early twenty-first century, broad-spectrum antibiotics that cover gram-positive organisms, including MRSA, are the best place to start for preseptal infections. Choices of oral antibiotics may include doxycycline, trimethoprimsulfamethoxazole, clindamycin, or fluoroquiolones. In orbital cellulitis, anaerobes will potentially be involved, in addition to gram-positive cocci and MRSA. In these typically polymicrobial infections, the use of two agents with broad coverage is often required until culture results are obtained. Intravenous antibiotic choices would include vancomycin, clindamycin, ampicillin sulbactam, second- or third-generation cephalosporins, aminoglycosides, and fluoroquinolones. Transition to oral antibiotics may occur once improvement is documented and sustained [4, 45, 53]. Interestingly, data showed that oral ciprofloxacin and clindamycin may be equally effective and safe as initial intravenous therapy for advanced cases [4]. This is not standard of care, however. Targeting specific pathogens initially may be difficult as most studies agreed that routine local culture or blood cultures are typically negative and thus unhelpful. The yield is quite low on all pathogenic studies. Further, what data do exist in favor of culture are often biased; historically, the treatment-refractory and most severe cases are those that have been cultured surgically, yielding poorly universal data pointing toward highly aggressive polymicrobial etiologies of infection [37]. If surgery is performed and microbiology obtained, antibiotics can be changed pending sensitivities. If specimens are not obtained, clinical suspicion and broadspectrum antibiotics geared toward the aforementioned common pathogens remain the gold standard. Further, one must remember the changing spectrum of orbital cellulitis pathogens and the currently growing level of resistance. If suspicion for MRSA is high or broad-spectrum treatment ineffective, appropriate therapy must be redirected. Fortunately, there are still multiple antibiotics that work against CA-MRSA. These include sulfonamides such as trimethoprim-sulfamethoxazole, quinolones, aminoglycosides, tetracyclines, clindamycin, and rifampin; all offer potential aid in curing the infection. Clindamycin or trimethoprim-sulfamethoxazole should be used in children with MRSA as fluoroquinolones and tetracyclines cannot be utilized in this age group. Vancomycin,

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linezolid, and amikacin are effective as well, although usually reserved for aggressive infections and multiresistant hospital-acquired MRSA [17, 49, 55]. Many infectious disease doctors rightfully worry about Clostridium difficile from prolonged clindamycin use. This should be taken into consideration when prescribing antibiotics, especially since drug-resistant C. difficile is now being reported. In addition, more clindamycin-resistant cases of MRSA continue to occur, and it is becoming less of a first-line agent. Nasal decongestants used in the short term will open sinus passages and may augment antibiotic treatment by reducing sinus swelling and improving drainage [24]. Also, the use of corticosteroids in the setting of infection is certainly controversial [58]. Many otolaryngologists manage acute sinusitis with the combination of antibiotics and steroids since steroids diminish the mucosal edema that prevents the sinuses from opening and draining. This is true even in cases that have secondary orbital cellulitis. No doubt, the orbit is a small space, and its

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Preseptal infection is typically treated with oral antibiotics. Orbital infections require immediate intravenous antibiotic therapy. Choices of oral antibiotics may include doxycycline, trimethoprim-sulfamethoxazole, clindamycin, or fluoroquiolones. In orbital cellulitis, anaerobes will potentially be involved in addition to gram-positive cocci and MRSA. The use of two agents with broad coverage is often required until culture results are obtained. Intravenous antibiotic choices include vancomycin, clindamycin, ampicillin sulbactam, second- or third-generation cephalosporins, aminoglycosides, and fluoroquinolones. Transition to oral antibiotics may occur once improvement is documented and sustained. Nasal decongestants used in the short term will open sinus passages and may augment antibiotic treatment by reducing sinus swelling and improving drainage. Many otolaryngologists manage acute sinusitis with the combination of antibiotics and steroids since steroids diminish the mucosal edema that prevents the sinuses from opening and draining.

structures are at risk for compression during an acute process like orbital cellulitis. If bactericidal antibiotics are utilized to destroy the bacteria, then reducing the inflammation within the orbit may reduce the risk for a compartment syndrome. In our anecdotal experience, steroids do seem to help these patients and are typically started with antibiotic therapy if significant swelling and compression are present.

10.8 Surgical Treatment of Orbital Cellulitis While the advent of CT in the evaluation of orbital cellulitis has become critical for diagnostic purposes, debates regarding antibiotic regimen, use of corticosteroids, and surgical drainage have persisted ever since. Management is therefore another point of contention within the recent literature. Fundamentally, when progressing and extending below the periosteum, orbital cellulitis subsists in a largely avascular area with relatively decreased mucosal blood flow. This, coupled with the fact that increasing age usually coincides with mixed infections and microbial synergy, may augment antibiotic resistance [21]. Thus, intravenous antibiotics that are effective against orbital pathogens in vitro may be ineffective in the clinical treatment of advanced orbital cellulitis. Management of orbital cellulitis may therefore be quite difficult. Treatment regimens and management styles have, and often remain, largely driven by individual experiences and physician preferences. Many doctors treat with only antibiotics, having positive personal experiences with such regimens. These physicians are often of the mindset that surgery may seed adjacent areas and reserve such invasive interventions for antibiotic-refractory cases as a result [53]. Further, some reports have shown that early drainage actually prolongs hospitalization. Contradicting this, other cases portend that early surgical intervention may shorten hospital courses; to wait too long for surgical drainage may lead to infection that does not sterilize even with abscess drainage [21]. Harris revolutionized this argument in 1994 by making age a large factor in the management of orbital cellulitis [21]. His review confirmed the tendency to culture-negative or single-isolate infections in children younger than 9 years that responded to antibiotic therapy alone. Ten of his 12 patients younger than 9 years old required no surgical intervention; the remaining 2 cleared their infection promptly after intervention. Four of the 16 patients between 9 and 14 years of age cleared without drainage, while a different 25% in this transitional age range had refractory and multiorganism infections. Polymicrobial illnesses were the norm in the nine adults,

10.8 Surgical Treatment of Orbital Cellulitis

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Fig. 10.5 (a, b) This gentleman presented 12 h after trying to rinse a foreign body out of his right eye; he had severe orbital cellulitis, decreased vision, and ophthalmoplegia. CT scan revealed an atypical lateral orbital infection; thus, he was started on antibiotics and taken to the operating room. There was no abscess, just diffuse soft tissue infection and a superior fornix conjunctival abscess. MRI obtained a few days later (as he was not improving) demonstrated lateral orbital cellulitis and infection of the lateral rectus muscle. His final cultures were positive for MRSA

and on average they had five different bacteria isolated from each culture. Experience gleaned from these studies divided need for surgical intervention into emergent, urgent, and expectant groups. Keep in mind that most cases of orbital cellulitis arise primarily from acute sinusitis. Thus, sinus surgery is the key component in the surgical treatment of orbital cellulitis arising from the sinus infection. As a result, otolaryngology involvement up front is a very important part of managing these patients. Emergency drainage was deemed appropriate for cases of optic nerve or retinal compromise secondary to induced mass effect. This is true for all ages. Urgent drainage is described in this review as drainage within 24 h of presentation. Categorized therein are large subperiosteal abscesses and abscesses that have extended away from the sinuses of origin or atypical infections not arising from the sinus (Fig. 10.5a,b). Frontal sinusitis should be urgently drained for pathogen identification and evaluation as central nervous system penetration of the infection is more likely and can be quite devastating. Also, since virtually all patients older than 14 years will have a complex, polymicrobial infection, these infections should be drained more urgently as antibiotics are less likely to be effective. Patients younger than 9 years may be observed, given the predilection toward simple infections in this population and the typical response to antibiotics alone. Expectant management may also be used for patients with no visual compromise, small medial subperiosteal abscesses and effusions, and cases with no frontal sinus or intracranial involvement. However, while hospitalized and on intravenous antibiotics, these patients must be clinically monitored on a regular basis for progression

and development of an afferent pupillary defect, visual decline, fevers that do not defervesce within 36 h, or 3 days without clinical improvement. In a more recent publication, Harris further summarized criteria necessary for the initiation of nonsurgical intervention [18]. The following needed to be absent: age of 9 years or older, frontal sinusitis, nonmedial or large subperiosteal abscess, gas within abscess on CT or other suspicion of anaerobic infection, recurrence after prior surgical intervention, radiologic evidence of chronic sinusitis, acute optic nerve or retinal compromise, or dental etiology of infection predisposing to anaerobic infiltration. Importantly, it was noted that clinical judgment is of utmost importance in all cases. Patients even without these signs may warrant surgery if clinically deteriorating, so these patients should have clinical exams regularly. Conversely, even patients with these signs may be treated medically if clinically stable. Most studies agreed that surgery is warranted in the circumstances mentioned. However, several more recent studies supported that surgical drainage is justified in all abscesses obvious on CT scan, regardless of patient age or clinical presentation [24]. Still, other reports in the twentyfirst century argued that immediate intravenous antibiotics are the treatment of choice for subperiosteal abscesses as well as retrobulbar loculations [4, 45, 53]. Certain pediatric textbooks written in the last 10–12 years argue those very facts, some of which entertain immediate surgical drainage and watch-and-wait protocols in the same chapter [53]. It seems that the only universal rule within the current literature is that the decision to treat must rest on the physician’s opinion, clinical judgment, and knowledge of the potential course of orbital cellulitis.

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Intravenous antibiotics effective against orbital pathogens in vitro may be ineffective in the clinical treatment of advanced orbital cellulitis. Harris confirmed the tendency toward culturenegative or single-isolate infections in children younger than 9 years that responded to antibiotic therapy alone. Experience gleaned from these studies has classified the need for surgical intervention into emergent, urgent, and expectant groups. Emergency drainage was deemed appropriate for cases of optic nerve or retinal compromise secondary to induced mass effect. Virtually all patients older than 14 years will have a complex, polymicrobial infection, which should be drained more urgently as antibiotics are less likely to be effective. Patients younger than 9 years can usually be observed given the predilection to simple infections in this population and the typical response to antibiotics alone. For observation, the following need to be absent: age of 9 years or older, frontal sinusitis, nonmedial or large subperiosteal abscess, gas within abscess on CT or other suspicion of anaerobic infection, recurrence after prior surgical intervention, radiologic evidence of chronic sinusitis, acute optic nerve or retinal compromise, or dental etiology of infection predisposing to anaerobic infiltration. The only universal rule in the current literature is that the decision to intervene surgically must rest on the physician’s opinion, clinical judgment, and knowledge of the potential course of orbital cellulitis.

result, cellulitis may arise from several days to over 20 years after initial orbital injury. In addition, orbital decompression is a common procedure, representing a controlled fracture of the sinus, and has a very low incidence of postoperative orbital infection. Further, sinuses are protected by lymphocytes, interferons, and alkaline mucus that circulates every 10 min. Logically, sinusitis in these fracture patients has been associated with the development of subsequent orbital cellulitis, albeit rarely, especially in the early healing phases weeks to months after the injury. The role for prophylactic antibiotics has never been established. The potential orbital cellulitis following fracture should hold no clinical importance in patients not suffering from sinusitis. Given the very low incidence of cellulitis attributable to blowout fractures, the prolonged healing of sinus mucosa compared to the short nature of antibiotic treatment, the possibility of a long lag period between injury and orbital cellulitis, and previous case reports showing no obvious benefit from the prophylaxis of orbital cellulitis following blowout fracture, physicians should consider not prescribing antibiotics for orbital fractures. The practice thereof may be unnecessarily costly, time consuming, and potentially harmful to the patients in this era of antibiotic resistance. Patients with active sinus disease at the time of their fracture should still be treated with oral antibiotics, even though studies show they do not always prevent infection.

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10.9 Prevention of Orbital Cellulitis After Orbital Fracture Orbital cellulitis is a rare side effect of an orbital fracture [2]. When cellulitis does result from orbital blowout fracture, one mechanism is thought to be the formation of anatomical communications between the fractured sinuses and orbit [19]. However, the sinus is a sterile space. These new anatomical communications between the orbit and sinus exist for the life of the patient. As a

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It is important to consider MRSA as a cause of infection when choosing appropriate antibiotic therapy. CT scan of the orbit and sinus is a very helpful tool when determining the best course of treatment. Antibiotics are most effective as single therapy in young children, whereas antibiotics and surgery are more often needed in teenagers and adults. MRSA infections of the orbit require aggressive management with appropriate antibiotics and early surgery when indicated. Atypical infections like orbital cellulitis not arising from the sinus or infections that potentially may spread to adjacent areas (like frontal sinusitis with orbital involvement and possible intracranial spread) should be treated surgically in a more urgent matter.

References

References 1. Anari S, Karagama YG, Fulton B, Wilson JA (2005 Jan) Neonatal disseminated methicillin-resistant Staphylococcus aureus presenting as orbital cellulitis. J Laryngol Otol 119(1):64–67 2. Ben Simon GJ, Bush S, Selva D, McNab AA (2005 Nov) Orbital cellulitis: a rare complication after orbital blowout fracture. Ophthalmology 112:2030–2034 3. Braun L, Craft D, Williams R, et al (2005) Increasing clindamycin resistance among methicillin-resistant Staphylococcus aureus in 57 northeast United States military treatment facilities. Pediatr Infect Dis J 24:622–626 4. Cannon PS, Keag DM, Radford R (2008 Feb 29) Our experience using primary oral antibiotics in the management of orbital cellulitis in a tertiary referral centre. Eye (Epub ahead of print) 5. Chambers HR (2001) The changing epidemiology of Staphylococcus aureus? Emerging Infect Dis 7(2):178–182 6. Chandler JR, Langenbrunner DJ, Stevens ER (1970) The pathogenesis of orbital complications in acute sinusitis. Laryngoscope 80:1414–1428 7. Chaudhry IA, Shamsi FA, Elzaridi E, Al-Rashed W, Al-Amri A, Arat YO (2008) Inpatient preseptal cellulitis: experience from a tertiary eye care centre. Br J Ophthalmol 92(10):1337–1341 8. Ho CF, Huang YC, Wang CJ, et al (2007) Clinical analysis of computed tomography-staged orbital cellulitis in children. J Microbiol Immunol Infect 40 9. Chiang RK, Rapuano CJ (2002) Recurrent methicillinresistant Staphylococcus aureus wound ulcer after clearcornea cataract surgery. CLAO J 28:109–110 10. Connell B, Kamal Z, McNab AA (2001) Fulminant orbital cellulitis with complete loss of vision. Clin Exp Ophthalmol 29:260–261 11. Deurenberg RH, Stobberingh EE (2009 Mar) The molecular evolution of hospital- and community-associated methicillin-resistant Staphylococcus aureus. Curr Mol Med 9(2):100–115 12. Devrim I, Kanra G, Kara A, et al (2008 May–Jun) Preseptal and orbital cellulitis: 15-year experience with sulbactam ampicillin treatment. Turk J Pediatr 50(3):214–218 13. Dhariwal DK, Kittur MA, Farrier JN, Sugar AW, Aird DW, Laws DE (2003) Post-traumatic orbital cellulitis. Br J Oral Maxillofacial Surg 41:21–28 14. Diep BA, Chambers HF, Graber CJ, et al (2008) Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann Intern Med 148(4):249–257 15. Donnenfeld ED, O’Brien TP, Solomon R, et al (2003) Infectious keratitis after photorefractive keratectomy. Ophthalmology 110:743–747

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16. Forster W, Becker K, Hungermann D, Busse H (2002) Methicillin-resistant Staphylococcus aureus keratitis after excimer laser photorefractive keratectomy. J Cataract Refract Surg 28:722–724 17. Frazee BW, Lynn J, Charlebois ED, Lambert L, Lowery D, Perdreau-Remington F (2005) High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med 45:311–320 18. Garcia GH, Harris GJ (2000) Criteria for nonsurgical management of subperiosteal abscess of orbit: analysis of outcomes 1988–1998. Ophthalmol 107:1454–1456 19. Goldfarb MS, Hoffman DS, Rosenberg S (1987) Orbital cellulitis and orbital fractures. Ann Ophthalmol 19:97–99 20. Goodyear PWA, Firth AL, Strachan DR, Dudley M (2004) Periorbital swelling: the important distinction between allergy and infection. Emerg Med J 21:240–242 21. Harris GJ (1994) Subperiosteal abscess of the orbit. Age as a factor in the bacteriology and response to treatment. Ophthalmology 101(3):585–595 22. Herold BC, Immergluck LC, Maranan MC, et al (1998) Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 279:593–598 23. Ho CF, Huang YC, Wang CJ, et al (2007) Clinical analysis of computed tomography-staged orbital cellulitis in children. J Microbiol Immunol Infect 40:518–524 24. Howe L, Jones NS (2004) Guidelines for the management of periorbital cellulitis/abscess. Clin Otolaryngol 29:725–728 25. Ingraham HJ, Ryan ME, Burns JT, Shuhart D, Tenedios G, Malone W, et al (1995 Aug) Streptococcal preseptal cellulitis complicated by the toxic Streptococcus syndrome. Ophthalmology 102(8):1223–1226 26. Jakobiec FA, Bilyk JR, Font RL (1990) Orbit. In: Spencer WH (ed) Ophthalmic pathology, Vol 4, 4th ed. Saunders, Philadelphia, pp. 2861–2872 27. Kannoth S, Iyer R, Thomas SV, Furtado SV, Rajesh BJ, Kesavadas C, et al (2007 May 15) Intracranial infectious aneurysm: presentation, management and outcome. J Neurol Sci 256(1–2):3–9. (Epub 23 Mar 2007) 28. Kato T, Hayasaka S (1998) Methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulasenegative staphylococci from conjunctivas of preoperative patients. Jpn J Ophthalmol 42:461–465 29. Kazakova SV, Hageman JC, Matava M, et al (2005) A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med 352:468–475 30. Kikkawa DO, Heinz GW, Martin RT (2002) Orbital cellulitis and abscess secondary to dacryocystitis. Arch Ophthalmol 120:1096–1099 31. Kotlus BS, Rodgers IR, Udell IJ (2005) Dacryocystitis caused by community-onset methicillin-resistant Staphylococcus aureus. Ophthal Plast Reconstr Surg 25:371–375

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32. Kronish JW, Johnson TE, Gilberg SM, Corrent GF, McLeish WM, Scott KR (1996 Sep) Orbital infections in patients with human immunodeficiency virus infection. Ophthalmology 103(9):1483–1492 33. Layton MC, Hierholzer WJ, Jr, Patterson JE (1995) The evolving epidemiology of methicillin-resistant Staphylococcus aureus at a university hospital. Infect Control Hosp Epidemiol 16:12–17 34. Li M, Diep BA, Villaruz AE, Braughton KR, Jiang X, DeLeo FR, Chambers HF, Lu Y, Otto M (2009) Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci USA 106(14):5883–5888 35. Liu IT, Kao SC, Wang AG, et al (2006) Preseptal and orbital cellulitis: a 10-year review of hospitalized patients. J Chin Med Assoc 69(9):415–422 36. McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC (2003) Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 41:5113–5120 37. McKinley SH, Yen MT, Miller AM, et al (2007) Microbiology of pediatric orbital Ccllulitis. Am J Opthalmol 144: 497–501 38. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, et al (2006; Aug) Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med 355:666–674 39. Moroney SM, Heller LC, Arbuckle J, Talavera M, Widen RH (2007) Staphylococcal cassette chromosome mec and Panton–Valentine leukocidin characterization of methicillin-resistant Staphylococcus aureus clones. J Clin Microbiol 45(3):1019–1021 40. Orekoya AM, McMoli TE (1987 Mar) Morbidity and mortality from orbital cellulitis. East Afr Med J 64(3):190–193 41. Oshima Y, Ohji M, Inoue Y, et al (1999) Scleral buckling: methicillin-resistant Staphylococcus aureus infections after scleral buckling procedures for retinal detachments associated with atopic dermatitis. Ophthalmol 106:142–147 42. Oshitari K, Hirakata A, Okada AA, Hida T, Oda H, Miki D, et al (2003 Oct) Vitrectomy for endophthalmitis after cataract surgery [in Japanese]. Nippon Ganka Gakkai Zasshi 107(10):590–596. 43. Osmoti AE, Ogbedo E (2007 Mar) Ophthalmic mortality in a tertiary centre in Nigeria. Niger Postgrad Med J 14(1): 54–56 44. Paterson AW, Barnard NA, Irvine GH (1994) Naso-orbital fracture leading to orbital cellulitis and visual loss as a complication of chronic sinusitis. Br J Oral Maxillofacial Surg 30:80–82

45. Pereira KD, Mitchell RB, Younis RT, Lazar RH (1997) Management of medial subperiosteal abscess of the orbit in children—a 5 year experience. Int J Pediatr Otorhinol 38:247–254 46. Rubinfeld RS, Negvesky GJ (2001) Methicillin-resistant Staphylococcus aureus ulcerative keratitis after laser in situ keratomilieusis. J Cataract Refract Surg 27:1523–1525 47. Rudd JC, Morshifar M (2001) Methicillin-resistant Staphylococcus aureus keratitis after laser in situ keratomileusis. J Cataract Refract Surg 27:471–473 48. Rutar T, Chambers HF, Crawford JB, Perdreau-Remington F, Zwick OM, Karr M, et al (2006) Ophthalmic manifestations of infections caused by the USA300 clone of community-associated methicillin-resistant Staphylococcus aureus. Ophthalmology 113(8):1455–1462 49. Rutar T, Zwick OM, Cockerham KP, Horton JC (2005) Bilateral blindness from orbital cellulitis caused by community-acquired methicillin-resistant Staphylococcus aureus. Am J Ophthalmol 140(4):740–742 50. Shanmuganathan VA, Armstrong M, Buller A, Tullo AB (2005) External ocular infections due to methicillin-resistant Staphylococcus aureus (MRSA). Eye 19:284–291 51. Solomon R, Donnenfeld ED, Perry HD, Biser S (2003) Bilateral methicillin-resistant Staphylococcus aureus keratitis in a medical resident following an uneventful bilateral photorefractive keratectomy. Eye Contact Lens 29:187–189 52. Sotozono C, Inagaki K, Fujita A, et al (2002) Methicillinresistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis infections in the cornea. Cornea 21:S94–S101 53. Starkey CR, Steele RW (2001 Oct) Medical management of orbital cellulitis. Pediatr Infect Dis J 20(10):1002–1005 54. Strandén AM, Frei R, Adler H, Flückiger U, Widmer AF (2009) Emergence of SCCmec Type IV as the most common type of methicillin-resistant Staphylococcus aureus in a university hospital. Infection 37(1):44–48 55. Tacconelli E, De Angelis G, Cataldo MA, Pozzi E, Cauda R (2008) Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis. J Antimicrob Chemother 61:26–38 56. Uy HS, Tuano PM (2007 Mar) Preseptal and orbital cellulitis in a developing country. Orbit 26(1):33–37 57. Walker JC, Sandhu A, Pietris G (2002 Apr) Septic superior ophthalmic vein thrombosis. Clin Exp Ophthalmol 30(2): 144–146 58. Yen MT, Yen KG (2005 Sep) Effect of corticosteroids in the acute management of pediatric orbital cellulitis with subperiosteal abscess. Opthal Plast Reconstr Surg 21(5):363–6; discussion 366–367

Chapter 11

Current Concepts in the Management of Infantile Hemangiomas: Steroids, Beta-Blockers, or Surgery

11

François Codère and Julie Powell

Core Messages ■ ■

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The term infantile hemangioma (IH) is now preferred to capillary hemangioma. IHs are the most common benign tumors in early childhood and are the most common tumors of the eyelids and orbit in the first years of life. They are characterized by three main phases: ● A nascent phase ● A proliferative phase ● An involutional phase Large segmental hemangiomas of the face should be investigated for the possibility of PHACE (Posterior fossa brain malformations, large facial Hemangioma, Arterial lesions, Cardiac anomalies/aortic coarctation, and Eye abnormalities) syndrome. Early ophthalmological evaluation and follow-up of all periocular hemangiomas over 1 cm in diameter are indicated because of the high risk of amblyopia.

11.1 11.1.1

Clinical Picture Clinical Phases

Infantile hemangiomas, or IHs, are the most common benign tumor in early childhood, are present in up to 10% of infants by age 1, and are seen more frequently in females than males as well as in premature infants. More recently, the term infantile hemangioma has been favored over capillary hemangiomas. In 50% of neonates, a premonitory mark may be evident at birth. This nascent phase is followed by rapid growth over the next few weeks, up to 6–9 months. Subsequent to this proliferative phase, the hemangioma stabilizes and slowly regresses over a period of 5–12 years. Complete involution occurs in 75–90% of cases by the age of 7–9.

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Doppler ultrasonography and magnetic resonance imaging (MRI) are the best tools to confirm the suspected diagnosis, and biopsy is seldom necessary. Intraorbital location of the IH carries more risks of ocular complications. Treatment should be initiated early in the proliferative phase to prevent complications. Uncomplicated lesions can often be observed. Systemic corticosteroids are the gold standard of treatment for complicated lesions. Intralesional injections of steroids can lead to complications and should be used cautiously. More recently, the use of propranolol has shown very promising results in rapidly growing large lesions and has had minimal side effects. Surgery is reserved in most cases for persistent anatomic changes at the end of the involutional phase.

11.1.2 Etiology, Histology, and Classification The etiology of capillary hemangiomas is not known precisely. Different theories have been suggested and reviewed [39]. An intrinsic defect in endothelial cells, caused by a genetic mutation of the endothelial cell or its progenitor, is supported by the identification of several families with an autosomal dominant trait linked to chromosome 5q31–33 and by the hypothesis that hemangiomas are clonal in nature. This theory does not explain the common sporadic IH and appears unlikely for segmental IH. A placental hypothesis has gained popularity because of reports of increased incidence of IH associated with chorionic villus sampling (but not with amniocentesis), by release of placental cells into the circulation that might embolize to fetal vascular sites; this theory is

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further supported by the demonstration that IH endothelium and placental vessels share expression of several surface markers (Glucon transporter 1 (GLUT1), merosin, Lewis Y, FcyRII) that are not found in other vascular tumors or malformations [39]. Evidence suggests that hypoxia has a possible role in the pathophysiology of IH via hypoxia-inducible factor 1a (HIF-1a), a major regulator of cellular response to hypoxia. Histologically, in the proliferative phase, IHs are composed of lobules of plump, dividing endothelial cells lining blood-filled vascular spaces; in the involutional phase, deposition of fibrofatty tissue occurs with resultant fibrosis and eventual involution. GLUT1, a glucose transporter also expressed by placental vessels and other blood–tissue barriers such as brain and retina but not normal skin, has been identified as a specific marker for all stages of IH and can be useful in differentiating IHs from other vascular tumors or malformations [34–36]. Periocular hemangiomas can be categorized according to their clinical appearance and their anatomic position. The reddish, classic superficial “strawberry lesion” or superficial IH involves the superficial dermis. Darker blue or purplish lesions correspond to a subcutaneous location, while deeper lesions without overlying skin color changes represent lesions located in the orbit often causing proptosis [7, 22, 40]. IHs can also be differentiated into focal versus segmental hemangiomas: A focal tumorlike IH appears to arise from a localized point, whereas segmental lesions are plaquelike and cover a territory corresponding to developmental segments [21]. Large segmental facial hemangiomas may well be the skin manifestation of PHACE syndrome, which is characterized by posterior fossa brain malformations, large facial hemangioma, arterial lesions, cardiac anomalies/aortic coarctation, and eye abnormalities [17]. When sternal or other ventral developmental defects are present, it is referred to as PHACES syndrome. This represents a spectrum of associated anomalies [31], with 70% of affected infants having only one extracutaneous manifestation. It is important to suspect this condition as it is associated with a high incidence of arterial and structural central nervous system anomalies with potential secondary neurologic sequelae. These patients are at risk for progression of their neurovascular disease and should be investigated accordingly [17, 30]. Investigation for large segmental facial IHs should include MRI and magnetic resonance angiography (MRA) of the brain, echocardiogram, and ophthalmologic examination. Ocular anomalies, distinct from the visual complications of the hemangioma, associated with PHACE syndrome are microphthalmia, optic nerve hypoplasia, persistent fetal vasculature, and morning glory disc anomaly.

11.1.3

Differential Diagnosis of Infantile Hemangioma

The IHs are vascular tumors characterized by a typical history of proliferative and involutional phases. Vascular malformations, such as a capillary malformation or portwine stain, tend to remain stable and grow along with the growth of the child. Deeper orbital IHs without the characteristic superficial changes can be confused with other orbital lesions of childhood. Orbital lymphangiomas often have a history of acute increase in size due to intralesional hemorrhage, followed by complete or partial resolution over a period of days to months; recurrence of the bleeding can lead to multiple episodes of swelling, sometimes resulting in fibrosis and involution. Plexiform neurofibromas, if involving the superficial tissues, do not have the coloration changes typical of hemangiomas, and their progression, which can be rapid in childhood, is not followed by a phase of involution. Usually, other manifestations of neurofibromatosis are present. Rhabdomyosarcoma is another lesion that has a tendency for rapid growth. It usually occurs later in childhood, with an average age of 7–8 years, but has to be ruled out when the color changes typical of hemangiomas cannot

Differential diagnosis of hemangioma of infancy Other vascular anomalies and tumors Capillary malformation Venous malformation Lymphatic malformation Arteriovenous malformation Non involuting congenital hemangioma (NICH) Rapidly involuting congenital hemangioma (RICH) Lobular capillary hemangioma (pyogenic granuloma) Tufted angioma Spindle cell hemangioendothelioma Kaposiform hemangioendothelioma Fibrosarcoma Rhabdomyosarcoma Myofibromatosis (including hemangiopericytoma) Nasal glioma Encephalocele Lipoblastoma Dermatofibrosarcoma protuberans (and giant cell fibroblastoma) Neurofibroma Modified from Frieden IJ, Enjolras O, Esterly NB. Vascular birthmarks and other abnormalities of blood vessels and lymphatics. In: Schachner LA, Hansen RC (eds) Pediatric dermatology, 3rd ed. Churchill Livingstone, London (in press). With permission

11.3

be seen. The diagnosis of hemangioma can best be confirmed by MRI with gadolinium contrast and Doppler ultrasound. But, in rare instances, when the diagnosis of a malignancy cannot be ruled out by imaging or when clinical evolution is atypical, a biopsy becomes mandatory [9].

Summary for the Clinician ■

■ ■

Knowing the three phases of the natural history of IH will help in the diagnosis and management. Large segmental IHs may point toward the diagnosis of PHACE(S) syndrome. In deep lesions, diagnosis must be confirmed either by imaging or more rarely by biopsy to rule out other potentially lethal lesions.

Investigation

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range of 6/12 to 6/30 were caused by anisometropia or strabismus [42]. In another study, strabismus was present in 15% of cases with eyelid or orbital lesions, but when large lesions part of PHACES syndrome were present, the strabismus incidence was much higher (71%). Visual loss can also be secondary to optic nerve involvement either by direct compression or by ischemic changes due to compression of the optic nerve supply. In rare cases, exposure and scarring of the corneal surface can also cause visual impairment and contribute to refractory amblyopia. Ulcerations are rare in the periocular areas; they typically occur in the proliferative phase and are more common in areas of mechanical trauma. They can be painful and may become infected. Some degree of scarring occurs when they heal [8].

Summary for the Clinician ■

11.2

Amblyopia is the most important risk for the patient with IH.

Ocular Complications

The most frequent ocular complications associated with IHs are related to amblyopia. Amblyopia is most often secondary to astigmatism but can also be due to strabismus or occlusion of the pupil. Risk factors for development of amblyopia are dependent on size and location. In a study of 129 patients by Schwartz et al., lesions measuring less than 1 cm in its greatest diameter were not associated with amblyopia, while lesions of more than 1 cm induced amblyopia in 40 of 75 patients (53%). Fourteen of 18 patients (78%) with large diffuse lesions had amblyopia [12, 35]. Location of the lesion also plays a significant role. In a study looking at the location of IHs, palpebral lesions induced amblyopia or astigmatism in 13 of 32 patients (40%). When the lesion was orbital with or without intraconal involvement, these findings were present in 27 of 31 patients (87%) [12]. The depth of the lesion also appears to be related to the length of the growth phase, with deeper lesion having a more prolonged period of growth. Lesions involving the lid, nasal location, involvement of the lid margin, or presence of a ptosis appear to have a higher incidence of amblyopia [40]. Hemangiomas can also cause strabismus either by a mass effect causing misalignment of the eye or by direct involvement of the extraocular muscles causing anomalies in the movement of the involved eye. In a series of 51 cases of hemangiomas of the eyelids, the most common complications were amblyopia (43%) and strabismus (33%). It was felt that milder forms of amblyopia in the

11.3

Investigation

When a periocular lesion is present and a threat for interference with visual development is suspected, periodic ocular examinations are performed. Measures include visual acuity assessment, evaluation of lid fissures and movement, ocular alignment, and eye movements. Refraction with cycloplegia is performed. The lesion is measured, and photographs are taken for future comparison. Initially, the ophthalmologic evaluation is repeated every 3–6 weeks. Imaging is needed in cases of deep hemangiomas with normal overlying skin, cases of clinically atypical soft tissue masses, when the evaluation of extension of obvious hemangiomas is necessary, in cases of alarming hemangiomas, and for guiding therapy. Doppler ultrasonography is often the first modality used to delineate and characterize vascular lesions. Its main advantages are its flexibility, availability, cost, and ability to be repeated frequently over time [11]. Dubois and Garel defined the Doppler characteristics of hemangiomas as showing a variable echogenicity mass with increased color flow (Fig. 11.1). The lesion displays high vessel density (>5 vessels/ cm2) with a high Doppler shift (>2 kHz) and low resistance. Typically, there is little or no evidence of arteriovenous shunting (i.e., most veins within the lesion remain monophasic) [11]. From a previous study, they showed,

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11

Fig. 11.1 Doppler ultrasound showing high vessel density and high peak arterial Doppler shift characteristic of infantile hemangioma

Fig. 11.3 After gadolinium injection on T1, the lesion is enhanced and shows intraorbital involvement nasally Fig. 11.2 Child with nasal infantile hemangioma and moderate astigmatism

by using the two criteria of high vessel density and high peak arterial Doppler shift for the diagnosis of hemangioma, a sensitivity of 84%, specificity of 98%, and positive predictive value of 97% and negative predictive value of 82% of the Doppler examination [13]. During the involution phase, the lesion will show regression in size and number of vessels, although the remaining vessels will show a persistence of the high systolic flow. On computed tomographic (CT) scan, proliferative hemangiomas present a lobular pattern of homogeneous masses. They show intense and persistent enhancement with infusion. When undergoing involution, they lose this intense staining and appear as heterogeneous masses with fibrofatty changes. CT scan is a modality of imaging that is used sparingly in infants to limit unnecessary exposure to radiation. On MRI, hemangiomas are typically of intermediate signal intensity on T1-weighted sequences and increased signal intensity on T2-weighted sequences. The presence of

flow voids within and around the soft tissue mass is an important feature on MRI. Increased signal intensity on both T1- and T2-weighted sequences correlates with hemorrhage or fatty deposition histologically [3, 11] (Fig. 11.1–11.3).

11.3.1 Angiography Angiography is indicated in cases of heart failure resistant to medical treatment (e.g., secondary to hepatic involvement) and in cases of the Kasabach–Merritt syndrome for endovascular treatment. It is almost never used in periocular hemangioma of infancy except in rare instances where a vascular malformation is suspected [12].

Summary for the Clinician ■ ■

Doppler ultrasound is the first imaging modality for IH. MRI is used for larger or deeper lesions.

11.4 Management

11.4 Management 11.4.1 Active Nonintervention In many uncomplicated lesions, observation without treatment is the preferred approach, but careful ocular monitoring is recommended with serial ophthalmologic assessments and repeated assessment of lid position, evaluation of ocular alignment for potential strabismus, and especially cycloplegic refraction to document potential development of anisometropia. Deciding to observe the natural evolution of the lesion instead of intervening has been referred to as “active nonintervention” by Bruckner and Frieden in opposition to benign neglect [7, 32]. This is reserved for small IHs for which the proliferative phase suggests a limited lesion. Parental support and precise explanations concerning the natural evolution of the condition and its most likely outcome will greatly help the family to cope with the transient but initially progressive lesion of their child. In periocular lesions, frequent monitoring of the visual status and early management of anisometropia or amblyopia are done even if the lesion does not need specific measures for controlling its size or growth. To help guide that decision not to intervene, the natural history of hemangiomas of infancy is very instructive: The most important part of the growth of a specific lesion is completed at 3–6 months in most lesions. Exception to this are segmental lesions and the deeper lesions, which tend to have a late proliferative phase with a peak around 5 months and a persistence of proliferation at a slower rate for a longer period thereafter compared to the superficial lesions. Despite these differences, almost all the lesions have reached their full size by 9 months [10]. Careful screening for amblyopia is performed. If no ocular complications are encountered, observation for eventual involution is indicated. When amblyopia is detected, a regimen of occlusion of the normal eye is started. Results are best when treatment is started early, and in some cases atropine penalization of the normal eye may be sufficient when the amblyopia is mild [9]. When anisometropia is present, corrective glasses are prescribed if the induced cylinder is more than 1 diopter. For lesions for which the amblyopia can be kept under check, the decision to treat or not should be based on the probability of complete regression without irreversible anatomic sequelae. Often, in a newborn with a freshly appeared lesion it is difficult to predict the growth pattern of a specific lesion. Repeated frequent exams will help to get a feel for the growth potential of a specific lesion. The surface involved at presentation may also be

165

an indicator of the potential for growth, especially if the lesion appears to involve a large segmental facial area with its association to PHACE syndrome. These large segmental hemangiomas involve a region of skin corresponding to a derivation from the embryologic mesenchymal prominences [7].

11.4.2 Indications for Treatment Modern management of these patients is often done by teams of physicians that include a neuroradiologist or interventional radiologist, a pediatric dermatologist, a pediatric ophthalomologist, and often a pediatric plastic and oculoplastic surgeon. The extent of the lesion, its position and size, as well as the phase of development will be key elements to decide if specific treatment is necessary.

Risk factor

Associated risk

Periorbital lesion

Astigmatism

Retrobulbar

Anisometropia Visual axis blockage

Large segmental

PHACE syndrome

Rapidly growing

Optic nerve involvement Severe globe distortion Ulceration

When treatment is indicated, the goal is to stop the growth of the lesion or to induce early involution. However, the clinical response of the hemangioma to treatment, even if it is spectacular, should not reassure the team of the outcome of vision. Continuous monitoring of the visual status with repeated cycloplegic refractions and assessment of the presence of strabismus or amblyopia should be performed. Occlusive therapy of the normal seeing eye is continued and depends on the response of the visual deficit independently of the involution of the hemangioma (Fig. 11.2).

Summary for the Clinician ■

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Knowing the risk factors for visual complications will help the clinician in management decisions. Active screening and treatment of amblyopia is important in all phases of an IH.

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Modalities of Treatment

11.5.1 Steroids

11

11.5.1.1 Topical Steroids Application of a potent topical steroid (0.05% clobetasol propionate cream) has been shown to stabilize or shrink small superficial lesions [18]. It has been used instead of intralesional injection in lesions involving the visual axis. It is felt to cause a somewhat slow regression of the lesion, and the improvement in anisometropia is limited [7, 9, 18].

observed within 1–2 weeks of treatment. Medication is maintained at this dose for 4–6 weeks, then gradually tapered according to the clinical evolution. Rapid discontinuation of the drug can be followed by rebound growth; treatment usually has to be maintained until the end of the proliferative phase, which often means several months of treatment. Oral corticosteroids are not effective past the proliferative phase. Side effects of corticosteroids are well known and include cushinoid appearance, irritability, gastrointestinal disturbances, hypertension, transient growth delay, and potential adrenal suppression [20]. There is some concern about possible neurologic complications, especially in premature infants [23–25].

11.5.1.2 Intralesional Corticosteroid Injection Kushner first reported on intralesional injections of a mixture of 40 mg/ml Kenalog mixed with 6 mg/ml Celestone. The response is usually rapid, occurring in less than 2 weeks and with continuous regression for up to 2 months. Injection could be repeated. Many of these lesions were of small size, for which observation and specific management of the anisometropia and amblyopia are often achieved successfully. But, a study by Weiss and Kelly showed that astigmatism induced by the hemangioma could be reduced by 63% after corticosteroid injections [43]. More recently, this modality of treatment has lost popularity. Complications are significant and can be serious. When larger lesions are treated or in small infants, adrenal suppression can occur and has been documented. Eyelid necrosis has been seen, and one of us has seen such a case with secondary scarring. In other instances, atrophy of the soft tissue along the lymphatic channels draining the area of injection has been reported, as well as skin depigmentation in the area of treatment. Some of these side effects can be reversible. Most worrisome have been the reports of embolization of the central retinal artery with secondary occlusion while injecting an IH. We are aware of another unreported case in our institution, and sporadic similar cases have been reported after eyelid injection and even intranasal injections [14, 41, 44, 46].

11.5.1.3

11.5.2 Interferon-Alfa Interferon-alfa, a potent angiogenesis inhibitor, has been shown to be effective in treating complicated IHs and was quite popular in the early 1990s [15, 38]. Effective doses are 1–3 million U/m2 given by daily subcutaneous injections. Initial enthusiasm was dampened by the observation of serious neurotoxicity in the form of spastic diplegia, occurring in up to 20% of infants treated in some series [4].This complication can be reversible if detected early and medication stopped. Currently, interferon-alfa use is restricted to potentially life-threatening or severe function-threatening IHs nonresponsive to systemic corticosteroids. This treatment should only be given by experienced physicians and requires close follow-up, especially regular neurologic evaluations to detect possible neurotoxicity at an early stage (Figs. 11.4 and 11.5).

Oral Corticosteroids

Oral corticotherapy is considered the “gold standard” in the treatment of complicated IH [6–8]. Usually, oral prednisone or prednisolone is initiated at a dose of 2–3 mg/kg/ day, given as a single daily morning dose. A positive response to treatment is either shrinkage or cessation of growth of an actively proliferating lesion. This is usually

Fig. 11.4 Toddler with rapidly growing infantile hemangioma progressing despite systemic steroids

11.5 Modalities of Treatment

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useful in the treatment of ulcerated IHs when topical therapies have failed. PDL is also effective for the residual telangiectasia and erythema of an involuted IH.

11.5.5

Embolization

The vascular tree of the periocular area, especially in toddlers, does not yield itself to selective embolization, especially when large lesions with complex vascularization are present. Smaller localized lesions that could theoretically be treated that way are better handled with modalities that are simpler and less complication prone. Complications from embolization procedures include risk of blindness from optic nerve or retinal vasculature thrombosis [9].

11.5.6 Fig. 11.5 Lesion of same child showing rapid regression after interferon-alfa

11.5.3 Vincristine Vincristine is another second-line option for large, endangering, corticosteroid-resistant IHs and appears to present less neurotoxicity than interferon-alfa [16, 37]. It has gained popularity after reports of its effectiveness in the treatment of other vascular tumors associated with Kasabach–Merritt phenomenon. Again, this medication requires a collaborative approach, usually with a hematooncologist. One of the drawbacks is the necessity of a central venous line because of the highly caustic nature of this medication. Studies are ongoing to determine its precise role in this setting.

11.5.4

Laser

The use of pulsed-dye laser (PDL) in the treatment of proliferating IH is controversial [5, 26]; it can be considered in very superficial lesions because the depth of penetration of PDL is less than 2 mm. This treatment, even if performed early, does not prevent the potential development of an associated deeper component in many cases [2]; it can also induce ulceration or make it worse, resulting in permanent scarring [45]. Paradoxically, it can be

Surgery

Surgical resection has been advocated by many authors. Lesions amenable to surgery are lesions that are usually localized in a preseptal fashion or situated anterior in the orbit and that do not involve the skin to avoid scarring and necrosis of the skin. Indications for surgery are lesions unresponsive to medical therapy, including, in some publications, intralesional injection of steroid. Surgical interventions have been advocated early by some authors to allow regression of the astigmatism [1, 19, 29]. Complications occurred in four cases of ten patients; complications consisted of wound infection, need for additional surgery in two cases, and entropion with trichiasis in one [29]. Surgery certainly has a role to play in the late correction of a partially regressed lesion after or late in the involution phase when the lesion has undergone fatty changes. Often, superficial lid changes with loss of its natural elasticity may warrant surgery to correct a persistent cosmetic blemish. New modalities of treatment, including the use of beta-blockers, may reduce the need for surgery in the proliferative phase while still avoiding the complications associated with prolonged use of steroids or with intralesional injections. Many surgeons will intervene to correct residual changes late in the involution phase except in very specific cases. Early surgical excision can reasonably be considered in small, pedunculated hemangiomas that would likely result in significant cosmetic defect after natural involution. Circular excision with purse-string closure is a technique that results in smaller scars than the traditional lenticular excision [33]. Excision of any disfiguring residual lesion before starting school is desirable when possible to avoid psychological sequelae.

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A new treatment option has been proposed in the form of the nonselective beta-blocker propranolol [27]. This was discovered fortuitously, initially in corticosteroid-failure patients. The initial report of 11 infants with severe or disfiguring IH treated with propranolol at 2 mg/kg/day showed impressive results with minimal side effects. In all patients, 24 h after the initiation of treatment, a change in the color of the lesion was observed along with softening of the mass. In five cases for which ultrasonography was done, an objective regression of the lesion was observed. Improvement leading to flattening of the lesion was noted with continued treatment. Since this was published, many centers have started using this medication with various protocols, often initiating treatment in a hospital setting to monitor vital signs; in the outpatient setting, beginning medication at a lower dose (i.e., 0.5 mg/kg/day) and gradually increasing up to 2 mg/kg/day with close monitoring of blood pressure and pulse is another option. The optimal dosage and frequency of administration of propranolol for IH is still not well established, and additional studies

are necessary before this medication can be recommended on a widespread basis. At this time, this is still an off-label use. Contraindications include bronchospasm/asthma, congestive heart failure, bradycardia, or hypotension. Hypoglycemia can occur, especially in the very young infant. There is concern that propranolol, because of its vasoconstrictive effect, could provoke complications in the setting of cerebrovascular anomalies in patients with PHACE syndrome; it is thus recommended to obtain an MRA in infants with facial segmental IHs to evaluate the cerebral arteries before considering this treatment option. Propranolol, however, appears to be an extremely promising new treatment option with a better safety profile than interferon-alfa or vincristine and potentially might become the first-line treatment for complicated IHs. As with other systemic treatments for IHs, a multidisciplinary approach is optimal. The mechanism of action of propranolol in IHs is not well understood but may include vasoconstriction, explaining the very rapid color change and softening of the IH after initiating treatment; propranolol has also been shown to decrease the expression of VEGF and bFGF genes in vitro as well as to trigger apoptosis of capillary endothelial cells [28] (Figs. 11.6–11.11).

Fig. 11.6 Photograph of a toddler with continued growth of an IH despite systemic corticosteroids

Fig. 11.7 Necrosis of portion of the involved ear occurred despite initiation of steroids

11.5.7 Beta-Blockers: A New Promising Modality of Treatment

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11.5 Modalities of Treatment

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Fig. 11.10 Large, rapidly growing IH involving the lower lid and the cheek causing visual axis blockage

Fig. 11.8 Marked regression of the lesion 6 weeks after initiation of propranolol at a dosage of 2 mg/kg/day

Fig. 11.11 Marked change in color, flattening, and softening of the lesion 3 weeks after initiation of propranolol, allowing for clearing of the visual axis. No other treatment was used in this patient

Summary for the Clinician ■ ■ ■ ■

■

Fig. 11.9 Further regression of the abnormal vessels is seen at 10 weeks after initiation of the treatment. Gradual tapering of steroids was initiated 4 weeks after the initiation of propranolol

Systemic steroids are the gold standard for large IHs for which systemic treatment is necessary. Interferon-alfa is used only in severe selected cases because of its potential for severe side effects. Intralesional injection should be used cautiously. Surgery is indicated mainly in localized lesions or to correct anatomical defects in the involutional phase. Propranolol offers a new and promising modality of treatment with potentially fewer systemic complications than the available alternatives.

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References

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