Neurology in Practice THE BARE ESSENTIALS
Neuro-ophthalmology Simon J Hickman
Correspondence to Dr S J Hickman, Consultant Neurologist, Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK;
[email protected]
INTRODUCTION Neuro-ophthalmology deals with visual disorders caused by disease of the nervous system. The principles of diagnosis are the same as in any other branch of neurology; a good history with a directed examination. In addition, a sound knowledge of the anatomy and physiology of the visual sensory and oculomotor systems is essential. Most referrals come from ophthalmologists who either detect an obvious abnormality of the optic nerve, or eye movements, or they cannot explain the visual symptoms from their examination of the eye. Neurologists should have a close working relationship with the ophthalmology department so there are clear pathways for how referrals can be made. Also, it is important to make friends with: Orthoptists: who perform detailed measurements of eye movements, which can be subsequently repeated to assess change. In addition, they can help to correct double vision with prisms and can advise when corrective strabismus surgery may be indicated. Visual field technicians: because a formal visual field assessment can clarify the nature of the presenting problem as well as provide a baseline record to assess progress. Photographers: who can perform retinal photography and retinal imaging. Any optic disc that is thought to be abnormal should be photographed at the fi rst presentation to provide a clear baseline record. Photographs are a lot easier to communicate with than scribbled diagrams in the notes, and can be very useful for any subsequent presentations or case reports. Retinal imaging techniques such as optical coherence tomography (OCT) are widely used by ophthalmologists but are not particularly helpful in making a neuro-ophthalmological diagnosis. However, OCT can measure the thickness of the retinal nerve fibre layer, so providing a quick and cheap marker of axonal integrity in diseases such as multiple sclerosis. Also, OCT may help in differentiating a maculopathy from an optic neuropathy. The principle areas I will discuss are those which generate most referrals to neuro-ophthalmology.
TRANSIENT VISUAL LOSS When taking a history after the symptoms have resolved and there is no visual field loss, it is not
always clear whether a patient is describing monocular symptoms or hemianopia. In hemianopia, the loss is often described as being in the eye with the affected temporal visual field (the larger field). It is important to spend a few minutes trying to fi nd out whether half of faces or other objects appeared to be missing, of if reading was impaired, because this would imply that there was hemianopic rather than monocular visual loss. Purely ocular causes of transient monocular blindness, or blurring, include dry eyes, keratoconus, hyphaema and intermittent angle closure glaucoma. These should be screened out by the ophthalmologists. Optic nerve pathology can cause transient visual symptoms—for example, Uhthoff’s phenomenon (transient visual blurring on getting warm or on exercise)—in a nerve previously affected by optic neuritis, as can the transient visual obscurations of papilloedema. Migraine usually causes positive visual phenomena such as fortification spectra. If these are present, then this may be enough to diagnose migraine and prevent the need for further investigation. Central retinal or branch retinal artery occlusion is the most important cause of transient monocular visual loss and is normally due to emboli. This was previously termed amaurosis fugax. There is often a typical history of a curtain coming down over one eye with vision going to complete darkness in seconds, before returning in a minute or two. Urgent investigation is required to rule out both giant cell arteritis and significant ipsilateral carotid artery stenosis. Transient binocular visual loss is usually due to cortical hypoxia/ischaemia, as in presyncope or vertebrobasilar ischaemia, although it can be due to migraine, papilloedema or hypo-perfusion to both eyes.
OPTIC NEUROPATHIES Optic neuropathies, by defi nition, are diseases of the optic nerve. As with any other disease, they can present with any tempo from suddenly through to chronically. The most important parts of the examination to diagnose an optic neuropathy are testing colour vision (usually with Ishihara plates), the swinging torch (flashlight) test for a relative afferent pupillary defect, and ophthalmoscopy. An abnormality of colour vision with a relative afferent pupillary defect is usually enough to
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Neurology in Practice differentiate a unilateral optic neuropathy from an ocular cause of unilateral visual loss, such as a maculopathy. If there is acute retrobulbar disease of the optic nerve then the optic nerve head will look normal and so colour vision loss with a relative afferent pupillary defect may be the only localising signs to go on. However, the appearance of the optic nerve head can be very helpful in both diagnosing the cause of the optic neuropathy and deciding how long it has been present. Optic atrophy, as shown by a pale optic nerve head, can take up to 6 weeks to appear following the onset of an acute optic neuropathy. Bilateral optic neuropathies may occur simultaneously or sequentially. The onset and progression of symptoms, in conjunction with the signs, helps in elucidating the cause (table 1). Any patient presenting with optic atrophy should have their anterior visual pathways imaged to exclude a compressive lesion such as a meningioma, optic nerve sheath metastasis or aneurysm, unless the diagnosis is suggested by other features—for example, a prior diagnosis of multiple sclerosis (MS) or a family history suggesting an inherited disorder. The gold standard is MRI, including the brain, fat saturated T2 weighted orbital imaging or equivalent, and preand postgadolinium fat saturated T1 weighted orbital imaging.
Optic neuritis In a typical case of acute unilateral idiopathic optic neuritis, investigations are not required to make the diagnosis. Most patients recover vision well spontaneously. High dose corticosteroid therapy, either orally or intravenously, may be given although this will only speed up visual recovery without affecting the fi nal visual outcome. Any patient with optic neuritis must be followed-up to ensure spontaneous recovery does occur, and that there is not subsequent worsening vision if a short course of corticosteroids is administered. Most patients with optic neuritis will go on to develop MS, and in those circumstances the optic neuritis can be termed MS associated optic neuritis. A proportion, however, will remain clinically
isolated or just go on to have recurrent attacks of idiopathic optic neuritis in the future. There are a few rare causes of atypical optic neuritis, including chronic relapsing infl ammatory optic neuropathy (CRION) and optic neuritis associated with neuromyelitis optica, systemic lupus erythematosus, sarcoidosis and Behçet’s disease. Atypical features for idiopathic optic neuritis are listed in table 2. It is important to recognise that the diagnosis may not always be idiopathic or MS associated optic neuritis because different management may be required to save sight.
MULTIPLE SCLEROSIS Optic neuritis is the initial symptom in about 20% of MS patients and occurs as a relapse at some point of the disease course in about 50% of cases. The presence of MS-like lesions on brain MRI of clinically isolated optic neuritis patients is highly predictive of the subsequent development of MS; about 20–25% go on to develop MS when there are no initial brain lesions, rising to 70–80% in patients with one or more baseline lesions. Oligoclonal bands in the CSF which are unmatched with bands in serum only give additional predictive value when the initial brain imaging is normal. It is worth discussing the risk of developing MS in all patients who present with typical optic neuritis. The choice to investigate further with brain MRI to help predict the likelihood of subsequent MS can then be a joint decision, especially because, at present, in the UK the MS disease modifying drugs are not currently available following the fi rst clinical episode of demyelination. Insurance and employment issues may also be relevant.
VISUAL FIELD DEFECTS Although bilateral visual field defects can occur in bilateral optic neuropathies, the usual presentation to neurologists is with a ‘neurological’ field defect of a pattern suggestive of a lesion in the optic chiasm or retrochiasmal visual pathways. The cause of the visual field defect will usually be obvious from the presentation and from brain imaging. It is important to tell the patients to inform the appropriate driving licence authority because a
Table 1 Presenting features of optic neuropathies Presentation
Typical clinical signs
Sudden onset and non-progressive. May be first noticed on awakening Acute visual loss. Retro-ocular pain. Pain on eye movement (10% painless). Spontaneous recovery Sequential (can be simultaneous) eg, bilateral painless acute visual loss. Maternal inheritance Unilateral or bilateral visual loss. May be acute or chronic Chronic bilateral visual loss. History of alcoholism, poor nutrition or drug/toxin exposure Chronic bilateral visual loss. Family history
Altitudinal visual field defect. Swollen optic disc acutely Arteritic or non-arteritic anterior ischaemic optic neuropathy Central or centro-caecal scotoma. Normal or swollen Optic neuritis. See table 2 for differential diagnosis optic disc Central or centro-caecal scotoma. Swollen optic disc Leber’s hereditary optic neuropathy acutely. Disc capillary telangiectasia acutely Optic atrophy Compression of optic nerve, chiasm or optic tract. Old optic neuritis Central or centro-caecal scotoma. Optic atrophy Tobacco–alcohol amblyopia. Nutritional optic neuropathy. Toxic optic neuropathy Central or centro-caecal scotoma. Optic atrophy Autosomal dominant optic atrophy. Autosomal recessive optic atrophy. Leber’s hereditary optic neuropathy
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Likely diagnoses
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Warning features in the presentation that should prompt further investigation to rule out diagnoses other than idiopathic optic neuritis
Warning feature
Reason
Optic atrophy on presentation without previous history of optic neuritis or MS Severe optic disc oedema with haemorrhage and/or vitreous reaction Macular star Bilateral, simultaneous or rapidly sequential, optic neuritis or chiasmitis Previous history of neoplasia African, Afro-Caribbean, African-American or Asian racial origin
Possible compressive lesion Possible infectious aetiology May have a different inflammatory aetiology such as neuroretinitis Other inflammatory aetiology possible including sarcoidosis, CRION or NMO May be metastasis causing optic nerve compression Other inflammatory aetiology may be more likely than idiopathic optic neuritis, including sarcoidosis, CRION and NMO Unusual severity and lack of recovery may point to a different sort of inflammatory aetiology such as sarcoidosis, CRION or NMO Lack of pain and lack of early recovery points to a possible compressive aetiology Pain in optic neuritis is usually not severe and settles early. Possible infectious or different sort of inflammatory aetiology Optic neuritis usually only progresses for ≤ 2 weeks. Possible infectious, atypical inflammatory or compressive aetiology Optic neuritis usually starts recovering by 3 weeks. Possible infectious, atypical inflammatory or compressive aetiology May be an alternative corticosteroid dependent inflammatory aetiology such as sarcoidosis, CRION or NMO
Loss of vision to no perception of light with no early recovery Painless loss of vision to ≤6/60 with no early recovery Severe or persistent pain for >2 weeks since onset Visual loss progressing for >2 weeks since onset of visual symptoms No recovery >3 weeks after onset of visual symptoms Deterioration of vision after withdrawal of corticosteroids
CRION, chronic relapsing inflammatory optic neuropathy; MS, multiple sclerosis; NMO, neuromyelitis optica.
Figure 1 Humphrey visual field plot in functional visual loss showing a ‘four leaf clover’ pattern with clover leaf overlying on the right. There is a high false negative rate. There is a reduction in the apparent sensitivity of the patient over time from the first four points tested by the machine, which are the apices of the four leaves. The false negative and positive rates give indications of consistency when points are retested.
binocular visual field defect will usually lead to disqualification from driving. The ophthalmology department can be asked to perform a binocular Esterman visual field plot which the UK Driver and Vehicle Licensing Agency (DVLA) can use to determine eligibility to drive. In exceptional circumstances, if it can be demonstrated that the lesion is non-progressive and full adaptation to the deficit has occurred (often in congenital hemianopia), then the DVLA may allow driving after the patient has had a satisfactory practical driving assessment at an approved centre.
FUNCTIONAL VISUAL LOSS Functional visual loss accounts for a high proportion of referrals to neuro-ophthalmology clinics. Presentations can be with monocular or binocular visual loss with the visual impairment ranging from minor blurring through to no perception of light in both eyes. There may be additional
functional disorders elsewhere, both in the nervous system and in other body systems. Functional visual loss should be suspected if there is: ▶ Dissociation between the apparent degree of visual acuity loss and the fi ndings on examination ▶ Functional disability less than expected from the apparent severe visual acuity loss or visual field constriction ▶ An extremely constricted visual field which would not be expected from the rest of the examination ▶ Inconsistency in testing visual fields, including tubular visual fields, to confrontation at different distances (physiologically, the visual fields should be cone shaped). On Humphrey automated perimetry, a four leaf clover pattern may be seen with many false negative errors due to the apparent sensitivity of the patient reducing over time from the fi rst four points tested by the machine. These are at the apices of the four leaves of the clover (figure 1). On Goldmann perimetry, spiralling and crossing of the isopter lines can occur, again due to inconsistency and reduction of apparent sensitivity of vision over time (figure 2). This is not possible physiologically because the isopter lines are akin to contour lines—that is, they should be fi xed and should not cross each other. In functional monocular visual loss: ▶ There will not be the expected relative afferent pupillary defect although this may also be the case in Leber’s hereditary optic neuropathy ▶ Deficits on binocular visual field testing may be seen, despite the area being tested corresponding to the nasal field of the contralateral `good’ eye ▶ If visual acuity is tested using trial lenses and a lens is introduced surreptitiously to make the image from the apparent `good’ eye go out
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Neurology in Practice lead to problems with reading despite preserved single letter visual acuity, or with difficulties in recognising faces. In the examination of a suspected case, cognitive screening tests, such as the Queen Square Screening Test for Cognitive Deficits (the ‘Green Book’) or the Cortical Vision Screening Test can be useful in characterising the nature of the patient’s deficits. Brain imaging may show a responsible lesion or posterior atrophy.
PAPILLOEDEMA/IDIOPATHIC INTRACRANIAL HYPERTENSION
Figure 2 Goldmann visual field plot in functional visual loss showing spiralling and crossing of isopters. The isopter lines are akin to contour lines and show where different sizes and relative intensities of light were first detected by the patient when they were brought in from the periphery. of focus, this may be enough to `improve’ the visual acuity in the `impaired’ eye because the patient is tricked into thinking they are still seeing with their `good’ eye ▶ The patient may still perceive the figures and shapes in stereo acuity charts that require binocular vision. In severe functional binocular visual loss, opticokinetic nystagmus tested with a rotating drum should be detectable although de-focusing may prevent this. There should also be preserved pupillary responses although this will not differentiate functional binocular visual loss from bilateral occipital disease or from a higher order visuoperceptual abnormality. Brain imaging will usually be needed and appropriate follow-up to make sure posterior cortical atrophy is not developing (see below).
HIGHER ORDER VISUAL DISORDERS Visuospatial and/or visuoperceptual abnormalities can occur with degenerative diseases such as posterior cortical atrophy, with tumours, and after strokes in the parieto-occipital lobes, and after hypoxic–ischaemic brain injury. Posterior cortical atrophy can be hard to diagnose in the early stages because the fi rst symptoms are often vague and described as not being able to read or see properly. The ophthalmic examination is often normal or shows only minor abnormalities, such as mild cataract or early macular degeneration, insufficient to explain either the level of vision or the degree of functional impairment. Over time, the symptoms tend to worsen. Visuospatial abnormalities may result in minor road traffic accidents due to failure to judge distances. Visuoperceptual problems may 194
When assessing a patient with papilloedema and suspected raised intracranial pressure (ICP), points to look for are: ▶ Headaches, worst on fi rst awakening and associated with nausea and vomiting ▶ Pulsatile tinnitus ▶ Visual obscurations, often brought on by bending forward or Valsalva manoeuvres ▶ Any focal neurological problems, especially double vision It is crucial to distinguish true papilloedema from pseudo-papilloedema. Small crowded discs or buried optic disc drusen can often make the optic discs appear swollen. When there is not a clear history of raised ICP-like headaches and no clear papilloedema, then it is often more useful to fi rst request an ultrasound scan of the optic nerve heads to look for buried optic disc drusen (figure 3) rather than rush to brain imaging and lumbar puncture. In true papilloedema, as well as optic disc swelling, there is usually capillary dilatation, haemorrhages, cotton wool spots and choroidal folds (figure 4). Differentiation from bilateral optic nerve swelling due to optic nerve disease can usually be made because in papilloedema central visual acuity and colour vision are preserved early on, although, if left untreated, papilloedema can lead to blindness. When there is true papilloedema, brain imaging is required to rule out a space occupying lesion and also intracranial venous sinus obstruction due to thrombosis or extrinsic compression. After that, unless imaging suggests it is not safe, a lumbar puncture (LP) should be performed to measure the opening pressure and assess the CSF constituents. Infections, many types of infl ammation and raised CSF protein, for example, due to a spinal tumour, can all cause raised ICP. The opening pressure must be measured in the lateral decubitus position with the legs stretched out and relaxed. If the LP has been done sitting up, then the patient should be laid down carefully to have the pressure measured. More than one manometer should be at the ready in case the opening pressure is greater than 40 cm of CSF; the normal range in an adult is 10–25 cm CSF. Idiopathic intracranial hypertension (IIH) is mostly seen in obese women of childbearing age, 2011;11:191–200. doi:10.1136/practneurol-2011-000015
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Figure 3 (A) Swollen optic disc (pseudo-papilloedema) due to buried optic disc drusen. (B) B mode ultrasonograph demonstrating the drusen as echogenic material (arrow), still visible in (C) with the gain turned down (arrow).
Hypoparathyroidism Respiratory failure with carbon dioxide retention ▶ Right heart failure with pulmonary hypertension ▶ Sleep apnoea ▶ Renal failure ▶ Severe iron deficiency anaemia. The major risk in IIH is of blindness due to the retinal ganglion cells at the optic nerve head being damaged by the papilloedema. As the fibres that subserve peripheral vision are damaged fi rst, the degree of damage is best assessed with Goldmann or Octopus perimetry. Humphrey perimetry only assesses the central 24–30° of vision. The enlarged blind spot that is usually present is often due to change in refraction due to the papilloedema pushing the surrounding retina forward and this can also be sufficient to lower the central visual acuity to a degree. The size of the blindspot, though, is not related to prognosis in IIH. Therefore, the degree of peripheral visual field constriction on perimetry gives a better indication of the risk to vision than simply relying on visual acuity or the size of the blind spot. This group of patients often have psychological issues also, and so functional visual loss can occur. As a general rule, visual loss does not occur unless there is papilloedema. Therefore, if there is a lack of correlation between the degree of visual field constriction and the degree of papilloedema, then the visual field plots need to be very carefully assessed for any evidence of functional visual loss (see above and figures 1 and 2) before any surgery is contemplated. There is no clear evidence base for treatment: ▶ Weight loss is the mainstay of treatment and services should be organised to help facilitate this ▶ Acetazolamide, up to 2 g/day, has carbonic anhydrase activity which lowers CSF production; adverse effects such as parasthesiae limit tolerability ▶ ▶
Figure 4 True papilloedema with optic disc swelling, capillary dilatation, haemorrhages, cotton wool spots and choroidal folds. often in the context of recent weight gain. Criteria for diagnosis are: ▶ Symptoms must only reflect those of intracranial hypertension or papilloedema ▶ Signs must only reflect those of intracranial hypertension–for example, sixth cranial nerve lesion ▶ Raised ICP measured in the lateral decubitus position ▶ Normal CSF composition ▶ No hydrocephalus, mass, structural or vascular lesion on brain MRI, or contrast enhanced CT for clinically typical patients, and MRI and MR venography for all others ▶ No other cause of intracranial hypertension identified A careful search needs to be made for a secondary cause for raised ICP, especially if the patient is male or a non-obese female: ▶ Medications such as tetracyclines or vitamin A derivatives ▶ Addison’s disease
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Neurology in Practice Topiramate has weak carbonic anhydrase activity and some benefit in reducing headache ▶ Diuretics such as chlortalidone and furosemide have their proponents. If there is severe vision loss at presentation or progressive vision loss despite conservative treatment, then surgery may be required; optic nerve sheath fenestration, CSF diversion with a shunt or intracranial venous sinus stenting. Again, there is no clear evidence base and the choice usually depends on local availability. Since there is the potential for serious harm from these interventions, and often the need for repeat procedures, it is important to intervene for visual loss and not just for headache, bearing in mind the risk in this group of functional visual loss. Also, patients with IIH are at risk of getting other headache types such as migraine and medication overuse headache. If these are not appropriately managed and the patient is operated on mainly for intractable ▶
Table 3 Common causes of third, fourth and sixth cranial nerve lesions arranged anatomically Brainstem Infarction/haemorrhage *Multiple sclerosis Other central nervous system inflammatory disorders—for example, lupus, sarcoid Tumours—for example, glioma, lymphoma Cavernous malformation *Wernicke’s encephalopathy Trauma Listeria meningoencephalitis Histiocytosis X Subarachnoid space Compression by ectatic or aneurysmal vessel *Subarachnoid haemorrhage *Trauma (most commonly in fourth nerve palsy) *Meningitis (infective, inflammatory or malignant) *Wegener’s granulomatosis *Clivus tumour *Chordoma Cerebellopontine angle tumour expanding medially Trigeminal nerve tumour Intrinsic nerve tumour Neurosurgical complication Petrous apex Infection of the mastoid or tip of the petrous bone (Gradenigo’s syndrome) Petrous tumour Nasopharyngeal carcinoma spreading though the foramen rotundum Thrombosis of the inferior petrosal sinus *Trauma *Raised intracranial pressure or decreased CSF volume (usually sixth nerve palsy) Intrapetrosal internal carotid artery aneurysm Persistent trigeminal artery Dural arteriovenous malformation in the superior petrosal sinus Cavernous sinus and superior orbital fissure Internal carotid artery aneurysm or dissection Cavernous sinus thrombosis Carotid-cavernous fistula: direct and dural Tumours—for example, pituitary adenoma, meningioma, metastasis, nasopharyngeal carcinoma Sphenoid mucocoele Tolosa Hunt syndrome Herpes zoster Intrinsic nerve tumour Orbital, neuromuscular and muscular Orbital tumours and pseudotumour *Myasthenia gravis Uncertain localisation Microvascular occlusion Giant cell arteritis Ophthalmoplegic migraine Toxins and drugs including carbon tetrachloride, ethylene glycol, vincristine
headaches, then there is a risk that the headaches will recur. Repeated LPs with removal of CSF is controversial. The primary aim of treatment in IIH is to prevent blindness with a secondary related aim to reduce headache. If there is an immediate threat to sight then daily LPs should be performed until surgery can be arranged. Because symptoms can improve without normalisation of ICP, there is not necessarily the need to have an ongoing knowledge of the ICP. LPs to measure the ICP are often traumatic to patients and do not lead to prolonged reduction in ICP. The patients can be adequately assessed on the basis of their ongoing symptoms, visual field plots and optic disc appearance with treatment adjusted accordingly.
DOUBLE VISION The most important part of the assessment here is to work out the cause of the double vision. In the broadest sense the neurological causes are: ▶ Brainstem disease ▶ Third, fourth or sixth cranial nerve palsy ▶ Neuromuscular junction disorder ▶ Orbital myopathy. Two useful questions to help elucidate the cause are: ▶ Is the double vision binocular (ie, only with both eyes open)? In ocular disease, such as cataract, and in functional disorders, there may be monocular diplopia ▶ In which direction of gaze is the separation of images worst?
Brainstem disease There are usually other neurological symptoms and signs that help to localise the lesion, or the clinical syndrome may be classical—for example, internuclear ophthalmoplegia due to a lesion in the medial longitudinal fasciculus (usually but not always due to MS). This is characterised by a slow adducting eye relative to the abducting eye during horizontal saccadic gaze. In addition, there may be limitation of adduction, overshoot nystagmus in the abducting eye and a skew deviation. Brain MRI with fi ne cuts through the posterior fossa is the investigation of choice to investigate brainstem disorders.
Third, fourth or sixth cranial nerve lesions Common causes are listed in table 3. In an older patient with vascular risk factors, the most likely cause is microvascular occlusion of the small arterioles supplying the nerve. Therefore, apart from ruling out giant cell arteritis, these patients may simply be observed rather than extensively and expensively investigated at presentation. About 60% of patients with double vision due to microvascular occlusion recover in 3 months and 80% by 5 months.
*May be bilateral.
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Neurology in Practice If there are no vascular risk factors, typically in a younger patient, there is pain, failure to recover or other cranial nerves involved, then further investigations are required to fi nd an alternative cause: MRI with fi ne cuts through the posterior fossa and cavernous sinus, with the addition of gadolinium, to rule out inflammatory or compressive causes. Further investigations will depend on the presentation and the imaging fi ndings. Third nerve palsies may be pupil sparing or pupil involving: microvascular third nerve palsies are usually pupil sparing. Patients with vascular risk factors and pupil sparing third nerve palsies may simply be observed and only imaged if they fail to recover. A pupil involving third nerve palsy should be urgently investigated for a compressive cause, often a posterior communicating artery aneurysm. The onset is typically painful. A child or young adult presenting with a painful pupil involving third nerve palsy may have ophthalmoplegic migraine. This is rare but needs to be considered. It can cause recurrent attacks of painful diplopia, usually due to oculomotor nerve involvement, although the other nerves subserving eye movements can be affected. During an attack the cisternal part of the affected nerve may show gadolinium enhancement on MRI. Fourth nerve palsies are usually due to head trauma or microvascular occlusion. However, another common cause is breakdown of congenital superior oblique muscle weakness, often around the time of onset of presbyopia. This can be hard to differentiate from an acquired palsy. Review of old photographs may reveal a longstanding head tilt. Also, patients with congenital palsies may have larger ocular deviations, especially in upgaze, and larger vertical fusion amplitudes on orthoptic testing, although neither of these is completely reliable in differentiating a congenital from an acquired trochlear nerve lesion. Sixth nerve palsies may be a false localising sign of raised ICP or low CSF volume. They are a common additional sign in IIH. Normalisation of the ICP in cases with a false localising abducens nerve palsy usually leads to resolution of the diplopia.
Neuromuscular junction disorders The typical signs of myasthenia gravis when it affects the eyes include: ▶ Fatiguing ptosis on one or both sides ▶ Cogan’s lid twitch sign (transient apparent eyelid retraction on refi xation from downwards to straight ahead) ▶ Variable diplopia due to single or multiple extraocular muscle weaknesses ▶ Fatiguing of eye movements ▶ Fast saccadic eye movements, even when there are restricted eye movements due to extraocular muscle weakness ▶ Improvement in ptosis after applying an ice pack to the closed eye for 2 min
Orbicularis oculi weakness may also be present. Anti-acetylcholine receptor antibodies are positive in only about 50% of ocular myasthenia cases, with anti-muscle specific kinase antibodies in an additional small percentage (the muscle specific kinase positive cases usually have other muscle groups affected, such as bulbar muscles). Single fibre electromyography of orbicularis oculi may show abnormal jitter but is often normal in purely ocular myasthenia. An edrophonium (Tensilon) test may be useful if there is marked eye movement restriction or ptosis although false negative and false positive responses can occur. The differential diagnosis of ocular myasthenia gravis includes: ▶ Levator aponeurosis dehiscence (so-called senile ptosis) ▶ Third, fourth or sixth cranial nerve palsy—for example, due to orbital or intracranial space occupying lesion ▶ Chronic progressive external ophthalmoplegia ▶ Oculopharyngeal muscular dystrophy ▶ Myotonic dystrophy ▶ Botulism. Brain imaging should be considered in seronegative cases because compressive lesions—for example in the orbit—can occasionally mimic ocular myasthenia gravis. If the symptoms are relatively mild then it may be best to simply follow the patient up without treatment because myasthenic symptoms can vary over time and may resolve spontaneously. ▶
Orbital myopathies Orbital myopathies may affect all or only specific extraocular muscles. The inherited myopathies such as chronic progressive external ophthalmoplegia generally do not cause double vision even though there is usually marked restriction of eye movements. The presence of slow saccades will help in the differentiation from ocular myasthenia gravis. Thyroid eye disease is a relatively common cause of double vision, usually with other typical features, such as proptosis, chemosis, lid lag and lid retraction. The inferior rectus is the most commonly affected muscle. Vertical diplopia results, with particular restriction of upgaze. The affected extraocular muscles are enlarged on imaging and anti-thyroid stimulating hormone receptor antibodies are usually present. As patients can have more than one autoimmune condition, it is not unusual for patients to have ocular myasthenia gravis as well.
PTOSIS The causes are listed in table 4. Most cases are due to a mechanical cause. Asking a patient whether the ptosis gets worse towards the end of the day will not reliably differentiate myasthenia gravis from a mechanical cause because everyone will
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Neurology in Practice report a degree of increased eyelid drooping with tiredness.
NYSTAGMUS Nystagmus is the rhythmical and repetitive oscillation of the eyes, either in the primary ‘straight ahead’ position only and/or on eccentric gaze (gaze evoked nystagmus). The abnormal eye movement may be an equal ‘to and fro’ motion which is pendular nystagmus or it may have a slow drift phase followed by a corrective quick phase (saccade) which is jerk nystagmus. Acquired nystagmus is not usually symptomatic although occasionally patients complain of oscillopsia (ie, the nystagmus causes illusory movement of the environment). People with congenital nystagmus do not complain of oscillopsia but the nystagmus may be sufficient to reduce visual acuity by reducing the time an object is refracted onto the fovea. The direction of nystagmus is described by the direction of the fast phase and the direction of gaze, if it is gaze specific. The fast phase may be horizontal, vertical or torsional and have variable amplitude and speed. Unless there is an obvious cause such as peripheral vestibular disease (eg, Ménière’s), a toxic cause (eg, alcohol) or drug adverse effect (eg, carbamazepine), then brain MRI with fi ne cuts through the posterior fossa will usually be required to elucidate the cause. Common causes of nystagmus are listed in table 5.
Vestibular nystagmus This occurs when there is an imbalance between the two vestibular end organs (semicircular canals). It usually has a torsional component. The amplitude of vestibular nystagmus increases when gaze is directed towards the fast phase (away from the damaged canal) and decreases with gaze in the opposite direction (Alexander’s law). Vestibular nystagmus is subdivided into: ▶ First degree—only during gaze in the direction of the fast phase ▶ Second degree—present in primary gaze but increases in the direction of the fast phase
Table 4
Common causes of ptosis
Mechanical Levator aponeurosis dehiscence (so-called senile ptosis) Dermatochalasis Orbital, lid and lacrimal gland tumours Neurological Third nerve palsy Miller Fisher syndrome Horner’s syndrome Neuromuscular junction Myasthenia gravis Botulism (including iatrogenic from botulinum toxin injections) Myopathies Myotonic dystrophy Chronic progressive external ophthalmoplegia Trauma
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Third degree—present in all directions of gaze but greatest in the direction of the fast phase. Peripheral vestibular nystagmus is typically diminished when the patient lies with the intact ear down, and is often exacerbated with the affected ear down. Both this and central vestibular nystagmus (from a lesion in the vestibular pathways in the brain) may vary with head position and head movement, typically during a Dix– Hallpike manoeuvre, but in peripheral vestibular nystagmus there is usually a short latent period after the change in posture before the nystagmus develops and the effect tends to fatigue with repeated testing. There is no latency before onset of central vestibular nystagmus with change in posture, and the effect does not fatigue. ▶
Gaze evoked nystagmus Gaze holding requires the neural integrators in the medulla for horizontal gaze (the medial vestibular nuclei and the adjacent nucleus prepositus hypoglossi) and in the midbrain for vertical gaze (the interstitial nucleus of Cajal). The neural integrators connect to the cerebellar flocculus and paraflocculus (tonsils). Horizontal gaze evoked nystagmus is a binocular symmetrical horizontal jerk nystagmus in eccentric gaze. It is caused by a deficient eye position signal in the neural integrator network leading to drift away from the position of gaze and fast correction back. It may be caused by floccular and parafloccular lesions but it is also often seen as an adverse effect of medications such as carbamazepine.
Downbeat nystagmus This is usually present in the primary position and increases on lateral gaze and on downgaze. It can occur with lesions of the vestibulo-cerebellum (eg, flocculus, paraflocculus, nodulus and uvula) and medulla. It is characteristically seen in cervico-medullary junction disorders although up to 40% of cases are idiopathic.
Table 5
Some common causes of nystagmus
Congenital Latent/manifest latent Idiopathic infantile Spasmus mutans Albinism Low vision Acquired ‘neurological’ causes Multiple sclerosis Brainstem/cerebellar stroke Brainstem/cerebellar tumours Paraneoplastic syndromes Infections—for example, brainstem encephalitis Degenerative—for example, primary cerebellar degeneration Chiari malformation Toxic—for example, organophosphate poisoning, antiepileptic drug toxicity Nutritional—for example, Wernicke’s encephalopathy Acquired peripheral causes Ménière’s disease ’Labyrinthitis’
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Neurology in Practice Upbeat nystagmus This is usually worse on upgaze but unlike downbeat nystagmus it does not typically increase on lateral gaze. It is thought to be due to damage of the ventral brainstem tegmental pathways (eg, superior vestibular nuclei input to the superior rectus and inferior oblique subnuclei of the oculomotor nuclei) although, unlike downbeat nystagmus, there is not one clear anatomical location associated with it.
Management There is no licensed treatment for nystagmus but medications to consider include clonazepam, gabapentin, baclofen and memantine if there is troublesome oscillopsia. If there is a null point (direction of gaze where nystagmus is at its least) then prisms or strabismus surgery may be helpful.
PUPILLARY ABNORMALITIES The diagnostic features of the common pupillary abnormalities are summarised in table 6. The parasympathetic (constrictor) innervation of the iris sphincter muscle comes from the Edinger–Westphal nucleus in the midbrain, part of the oculomotor nucleus complex. The fibres run along the surface of the oculomotor nerve, hence their susceptibility to injury from compression, for example, from a posterior communicating artery aneurysm or uncal herniation. The fibres synapse in the ciliary ganglion in the orbit, and the postganglionic fibres supply both the iris sphincter and the ciliary muscle. In Adie’s pupil there is idiopathic damage to the parasympathetic fibres with typical reinnervation over time. Since 97% of the parasympathetic fibres innervate the ciliary muscle, aberrant reinnervation of the iris sphincter by ciliary muscle nerve fibres can lead to an exaggerated near response of the pupil, hence a tonically contracted pupil on accommodation with slow redilatation on gaze into the distance. Reinnervation of the pupil is usually incomplete, leading to an irregular pupil with vermiform movements when viewed through a slit lamp. The Holmes–Adie syndrome is when there is additional generalised areflexia. Denervation supersensitivity can be demonstrated with a weak muscarinic agonist such as 0.1% pilocarpine which will constrict an Adie’s pupil but not a normal or atropinised pupil. Pilocarpine will not, however, reliably differentiate an Adie’s pupil from a compressive third nerve lesion.
An atropinised pupil may be an adverse effect of ipratropium bromide nebulisers, or following hand contamination from hyoscine patches or topical anticholinergic creams for hyperhidrosis. It is therefore worth taking a full drug history, bearing in mind that the patient with the dilated pupil may be a carer for the user of the anticholinergic agent. The sympathetic (dilator) innervation of the iris dilator muscle arises from the hypothalamus. The fi rst order neurons descend through the brainstem and upper spinal cord to terminate in the ciliospinal centre at C8–T1. The preganglionic fibres leave the spinal cord via the T1 ventral root and synapse in the superior cervical ganglion. The postganglionic fibres ascend with the internal carotid artery and enter the orbit through the superior orbital fi ssure. The cardinal signs of Horner’s syndrome are listed in table 6. It may be confi rmed by application of 4–10% cocaine eye drops which inhibit the active reuptake of norepinephrine at the sympathetic neuro-effector junction. In a normal subject, this will lead to accumulation of norepinephrine and dilatation of the pupil whereas in Horner’s syndrome cocaine has little or no effect on pupil size. As cocaine is difficult to get hold of, 0.5–1.0% apraclonidine has become increasingly popular. At low concentration it is a weak α1-adrenoceptor agonist and administration to the eye will lead to dilatation of a Horner’s pupil due to denervation supersensitivity. Hydroxyamphetamine, which is an indirectly acting sympathomimetic, will differentiate a pre- from a postganglionic sympathetic lesion. Pupillary dilatation occurs in a preganglionic lesion because the postganglionic fibres will be intact. In an acute isolated Horner’s syndrome it is important to consider carotid artery dissection. Other causes, which usually have other localising features are: ▶ Pancoast tumour at the lung apex, or head and neck tumour ▶ Birth trauma ▶ Cluster headache ▶ Lateral medullary syndrome ▶ Idiopathic. It is often worth asking for old photographs to see if the Horner’s syndrome is longstanding. In many cases it is idiopathic, and if it can be demonstrated that it is longstanding, then further investigation may not be needed. In a congenital
Table 6 Diagnostic features of the common pupillary abnormalities Physiological anisocoria
Third nerve palsy
Clinical features
Anisocoria. Pupils react to light and accommodation. Difference in pupil size is the same in all light levels
Pharmacological testing of affected pupil
Smaller pupil: Cocaine: dilatation. Apraclonidine: no dilatation Larger pupil: 0.1% Pilocarpine: no constriction
Fixed dilated pupil. Anisocoria. Irregular pupils. No or Other features of a poor response to light. Tonic response to accommodation. third nerve palsy Vermiform movements on slit lamp 0.1% Pilocarpine: 0.1% Pilocarpine: constriction constriction may occur
Adie’s pupil
Horner’s syndrome
Atropinised pupil
Fixed dilated pupil Partial ptosis. Miosis Anhydrosis. Enophthalmos. Difference in pupil size increases in dim light Cocaine: no dilatation. Apraclonidine: 0.1% Pilocarpine: dilatation. Hydroxyamphetamine: no constriction dilatation with a preganglionic lesion
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It is important to differentiate transient hemianopic visual loss from transient monocular visual loss. Assess patients carefully who are suspected of having acute optic neuritis to make sure there are no atypical features that might point to an alternative diagnosis. When there is bilateral visual loss it is important to advise the patient to inform the appropriate driver licensing authority. If there is dissociation between the clinical signs and the degree of visual impairment, then suspect functional visual loss. However, if there are unusual and progressive visuospatial and visuoperceptual abnormalities, then consider posterior cortical atrophy. Make sure there is true papilloedema before embarking on investigations in patients presenting with headache. Many cases of double vision are due to microvascular occlusion; in an older patient with vascular risk factors, observation is all that is necessary, at first. Many cases of ptosis are benign and mechanical in nature; everyone’s eyelids get heavy towards the end of the day. It is not always easy to localise the cause of nystagmus clinically. If there is not an obvious cause such as drug toxicity, then imaging will often be required. It is usually possible to diagnose pupillary abnormalities on clinical grounds although this can be backed up with pharmacological testing.
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The Neuro-Ophthalmology Virtual Education Library (NOVEL) website. http:// library.med.utah.edu/NOVEL/ (accessed 5 Apr 2011). The Canadian Neuro-Ophthalmology Group website. http://www. neuroophthalmology.ca/index.html (accessed 5 Apr 2011). Miller NR, Newman NJ, eds. Walsh and Hoyt’s clinical neuro-ophthalmology, 6th edition. Philadelphia: Lippincott Williams & Wilkins, 2004. Leigh RJ, Zee DS. The neurology of eye movements, 4th edition. Oxford: Oxford University Press, 2006. Purvin VA, Kawasaki A. Common neuro-ophthalmic pitfalls: Case-based teaching. Cambridge: Cambridge University Press, 2009. Drivers medical group. At a glance guide to the current medical standards of fitness to drive. Swansea: DVLA, 2010. Warrington EK. The Queen Square Screening Test for Cognitive Deficits. London: Institute of Neurology, 1989. James-Galton M, Plant GT, Warrington EK. The Cortical Vision Screening Test (CORVIST). London: Thames Valley Test Company, 2001.
Horner’s syndrome there may be heterochromia iridis. Otherwise, intracranial lesions, cavernous sinus disease and carotid artery dissection can be ruled out by MRI of the head and fat suppressed MRI of the neck. Further neck and upper chest imaging with MRI or CT should be considered in appropriate cases to rule out a tumour. A unilateral small pupil may also be seen in physiological anisocoria which can cause some confusion if there is coexistent ptosis. Assessing the clinical features and response to pharmacological testing will enable differentiation from Horner’s syndrome. Bilaterally small pupils can be seen in old age, opiate use, coma and in tertiary syphilis (Argyll– Robertson pupils which react to accommodation but not to light—that is, they show light-near dissociation). Light-near dissociation is also seen in Adie’s pupil, as described above, and in Parinaud’s syndrome due to a lesion in the dorsal midbrain.
CONCLUSIONS Neuro-ophthalmological disorders may occur as pure disorders within the visual system or as manifestations of more generalised neurological conditions. Instead of relying on the tendon hammer and tuning fork, most neuro-ophthalmological diagnoses require the use of a Snellen chart, Ishihara plates, a red hatpin, a bright torch and an ophthalmoscope or slit lamp. These can then be backed up with orthoptic or visual field assessment followed by careful deduction and the judicious use of investigations. It is probably not a coincidence that Conan Doyle trained as an ophthalmologist although apparently when he set up a practice in Upper Wimpole Street, London, not a single patient crossed his threshold. This did, though, give him plenty of time to write and led him to abandon his medical career for full time writing. Acknowledgements This article was reviewed by Richard Metcalfe, Glasgow. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
2011;11:191–200. doi:10.1136/practneurol-2011-000015
