Pathology B - Peripheral Nervous System (Viterbo, 2016)

Far Eastern University –  Nicanor  Nicanor Reyes Medical Foundation

General Types of Peripheral Nerve Neuropathy

Pathology B  – Peripheral Nervous System

 Axonal Neuropathy

Mirian Viterbo M.D.

Diseases of Peripheral Nerves 

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Two main components of the peripheral nerves are: 

Axons

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Myelin Sheaths made Sheaths made by Schwann cells

Injuries in either of the two result in peripheral neuropathy . 

Axons are the primary target of damage.

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Morphologic hallmark is described as Wallerian degeneration. degeneration.

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Portions of axons distal to point of transection are disconnected from the central neuron and degenerate.

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Distal axons begin to fragment within days of injury and ovoids). disintegrate into spherical structures (myelin (myelin ovoids).

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Regeneration starts at site of transection with formation of growth cone and the outgrowth of new branches from the stump of the proximal axon.

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Axons grow about 1mm per day, guided by BM of Schwann cells New myelin tends to be thinner and shorter than original.

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Somatic motor function  function   is carried out by the motor unit  composed of: 1. Lower motor neuron  – located in anterior horn of the spinal cord or the brainstem. 2. Axon that ravels to a target muscle 3. Neuromuscular junctions 4. Multiple innervated myofibers Somatic sensory function depends function  depends on: 1. Distal nerve endings, may contain specialized structures. 2. Axon that travels to the dorsal root ganglia 3. Proximal axon segment that synapses on neurons of the spinal cord or the brain stem. Autonomic nerve fibers  fibers   outnumber somatic fibers in the PNS, but s/sx related to their involvement are not prominent features. Thin unmyelinated fibers mediate autonomic functions, pain, and temperature sensation, have the slowest conduction speed. Large diameter axons with thick sheaths transmit light touch and motor signals and have fast conduction speed. Schwann cells make cells make only one myelin sheath that wraps around a single axon to make a myelinated segment called internode

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Repair process is only successful only if the two transected ends remain closely approximated.

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Failure of outgrowing axons to find their distal target can produce a  pseudotumor   termed traumatic neuroma  –  a nonneoplastic haphazard whorled proliferation of axonal processes that results in a painful nodule. Electrophysiologic hallmark is a reduction in signal strength owing to the dropout of axons from affected peripheral nerves.

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Demyelinating Nerves 

Schwann cells and myelin sheath are the primary targets.

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Axons are relatively preserved. Individual sheaths degenerate in a random pattern, resulting in discontinuous damage of myelin segments.

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Electrophysiologic hallmark is slowed nerve conduction velocity, reflective of the loss of myelin.

Neuronopathies 

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Internodes are separated by unmyelinated gaps referred to as nodes of Ranvier, Ranvier , which are uniformly spread.

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Most peripheral nerves carry out both motor and sensory functions, thus contain axons of varying diameter.

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Axons are bundled together by 3 connective tissue s:

Destruction of neurons leading to secondary degeneration of axonal processes. Infections like herpes zoster  and   and toxins like  platinum compounds may lead to neuropathies. Since the damage is at the level of cell body, dysfunction is equally likely to affect proximal and distal parts of the body.

Anatomic Patterns of Peripheral Neuropathy 

Mononeuropathies 

Affects a single nerve and result in deficits in a restricted distribution dictated by normal anatomy.

Trauma, entrapment, infections are common causes. Polyneuropathies

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Epineurium – Epineurium – encloses the entire nerve

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Perineurium – Perineurium – multilayer concentric tissue sheath that groups

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subsets of axons into fascicles Endoneurium – Endoneurium – surround individual nerve fibers.

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Involvement of multiple nerves, usually in symmetric fashion.

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Axons are affected in a length dependent fashion, leading to deficits that start in the feet and ascend on progression. Hands show involvement by the time the knee is involved, resulting to a stocking and glove  glove   distribution of sensory deficits.

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Mononeuritis multiplex  

Damage several nerves in a haphazard fashion.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy 

Most common chronic acquired inflammatory peripheral neuropathy, characterized by symmetrical mixed sensorimotor polyneuropathy that persists for 2 months or more.

Vasculitis is a common cause. Polyradiculoneuropathies

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Affect nerve roots as well as peripheral nerves.

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Disease evolves over years, usually with relapses and remissions.

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Diffuse symmetric symptoms in proximal and distal parts.

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Remissions can be achieved with immunosuppressive therapy, plasmapheresis, steroids, and agents against T-/B-cells.

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Time course and response to steroids differentiate them from Guillain-Barre Syndrome.

Specific Peripheral Neuropathies INFLAMMATORY NEUROPATHIES Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)

PATHOGENESIS 

T cells and humoral factors are implicated in inflammation.

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Molecules expressed by Schwann cell-axon junction appear to be the target of the immune response. Complement-fixing IgG and IgM are present on the myelin sheath, deposition of these opsonins lead to recruitment of macrophages that strip the myelin sheath off.

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Recurrent myelination and demyelination leads to formation of onion-blubs – structures with multiple layers of Schwann cells.

Neuropathy Associated with Systemic Autoimmune Disease 

SLE, Sjogren, RA often take form of distal sensory or sensorimotor polyneuropathies.

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May lead to life threatening respiratory paralysis.

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Weakness beginning in the distal limbs that rapidly advances to affect proximal muscles (ascending paralysis).

Neuropathy Associated with Vasculitis 

Vasculitis is a non-infectious inflammation of blood vessels.

Histologic features are inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy ).

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1/3 of patients with vasculitis have peripheral nerve involvement Often presents as mononeuritis multiplex ; mononeuropathies and polyneuropathies are also encountered. Patchy axonal degeneration and loss.

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PATHOGENESIS

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Acute-onset immune-mediated demyelinating neuropathy.

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2/3s are preceded by influenza-like illness. Infections with C. jejuni, CMV, EBV, M. pneumoniae   or prior vaccination have association with this disease.

INFECTIOUS NEUROPATHIES Leprosy (Hansen Disease)

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No infectious agent is demonstrated in the affected nerves, and an immunologic reaction is the favored underlying cause.

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T-cell mediated immune response ensues, accompanied by segmental demyelination induced by activated macrophages.

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Circulating antibodies that cross-react with components of the peripheral nerves may also play a role.

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Peripheral nerve is involved in both lepromatous & tuberculoid. Lepromatous Leprosy :  Schwann cells are invaded by M. leprae

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MORPHOLOGY 

Dominant finding is inflammation of peripheral nerves manifested as perivenular and endoneurial infiltration by lymphocytes, macrophages, and plasma cells.

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Segmental demyelination is the most prominent.

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Cytoplasmic processes of macrophages penetrate the BM of Schwann cells, particularly near the nodes of Ranvier, and extend between the lamellae, stripping the myelin sheath from the axon

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Segmental demyelination, remyelination, and loss of both myelinated and unmyelinated axons. Endoneural fibrosis and multilayered thickening occurs Symmetric polyneuropathy most severe in the cool distant extremities and in the face due to lower temperature that favors the bacterial growth. Prominently involves the pain fibers leads to loss of sensation

Large traumatic ulcers may develop since the patient is unaware of the painful stimuli. Tuberculoid Leprosy 

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Most prominent proximally, close to the nerve roots.

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Active-cell mediated immune response to M. leprae.

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Usually manifests as dermal granulomatous inflammation.

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Injures cutaneous nerves, fibrosis of endo- and perineurium.

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More localized nerve involvement.

nodules

containing

CLINICAL FEATURES 

Ascending paralysis and areflexia.

Lyme Disease

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DTRs disappear early in the process.

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Cause neurologic manifestations in 2  and 3  stage of disease.

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Sensory involvement including loss of pain is often present.

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Polyradiculoneuropathy

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Nerve conduction velocity is slowed. CSF : proteins elevated due to inflammation, little/no pleocytosis

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Unilateral/bilateral facial nerve palsies.

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Plasmapheresis and IV Ig appear to be beneficial.

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HIV/AIDS

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Several patterns of peripheral neuropathies that are poorly understood, but appear to be related to immune dysregulation. Early stage – mononeuritis multiplex, demyelinating disorders

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Later stage – distal sensory neuropathy, often painful

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individuals, has protean manifestations (postural hypertension, incomplete emptying of the bladder, sexual dysfunction). 

Diphtheria 

Most commonly in developing world.

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Peripheral nerve results from effect of diphtheria endotoxin.

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Produces an acute peripheral neuropathy associated with prominent bulbar and respiratory muscle dysfunction.

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Varicella-Zoster Virus  Following chickenpox, a latent infection persists with neurons of sensory ganglia.  

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When reactivated, may be transported along sensory nerves. It infects keratinocytes, leading to painful vesicular skin eruption (shingles) in a distribution that follows sensory dermatomes. Most commonly involved: thoracic and trigeminal dermatomes Affected ganglia usually show neuronal death, accompanied by abundant mononuclear inflammatory infiltrates, focal necrosis, and hemorrhage.

METABOLIC, HORMONAL, AND NUTRITIONAL NEUROPATHIES Diabetes

Dysfunction of the autonomic nervous system  affects 20-40% of

Older adults with long history develop asymmetric neuropathies including mononeuropathy , cranial neuropathy , and radiculo plexus neuropathy   (devastating painful acute disorder, presents in the brachial or lumbosacral nerve plexus), Often monophasic may be caused by microvascular disease.

Uremic Neuropathy 

Most individuals with renal failure have peripheral neuropathy.

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Typically distal, symmetric neuropathy.

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May be asymptomatic or have muscle cramps, distal dysesthenia and diminished DTR. Axonal degeneration is the primary event, recovery are common after dialysis.

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Thyroid Dysfunction 

Hypothyroidism  can lead to compression mononeuropathies

such as carpal tunnel syndrome.  

Distal symmetric predominantly sensory polyneuropathy. Hypethyroidism  is associated with a neuropathy resembling Guillain-Barre Syndrome

Vitamin B12 Deficiency

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Most common cause of peripheral nerve neuropathy.

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50% with diabetes overall, and up to 80% of those who had it more than 15 years have clinical evidence of neuropathy.

Results in subacute combined degeneration with damage to long tracts in the spinal cord and also peripheral nerves.

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Both types (1 and 2) are affected. Most common pattern is ascending sensorimotor polyneuropathy .

Other vitamin deficiencies have all been associated with peripheral neuropathies such as: B1, B6, Folate, Vit. E, Cu, and Zn

TOXIC NEUROPATHIES

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distal

symmetric

PATHOGENESIS

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Alcohol, heavy metals, and organic solvents.

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Medications can cause toxic nerve damage most notorious are chemotherapeutic agents (vinca alkaloids, taxanes, microtubule inhibitors that interfere with axonal transport and cisplatin which may cause neuronopathy )

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Both metabolic and secondary vascular changes are believed to contribute to the damage of neurons and Schwann cells.

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Hyperglycemia causes non-enzymatic glycosylation of proteins, lipids, and nucleic acids, resulting to advanced glycosylation end products (AGEs) that may interfere with normal protein function and active inflammatory signaling. Excess glucose is reduced to sorbitol , which depletes NADPH and increases intracellular osmolality.

NEUROPATHIES ASSOCIATED WITH MALIGNANCY Direct Infiltration or Compression of peripheral nerves 

Common cause of mononeuropathy. Brachial plexopathy  – neoplasms at apex of the lungs

Vascular injuries due to hyperlipidemia causes ischemic damage

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Obturator palsy  – from pelvic malignant neoplasms

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Cranial nerve palsy  – from intracranial tumors or tumors at the base of the skull.

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Meningeal carcinomatosis involving the cauda equine can cause polyradiculopathy involving the lower extremities.

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MORPHOLOGY  Distal Symmetric Sensorimotor Neuropathy , predominant finding is an axonal neuropathy. 

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Reduced number of axons, axonal damaged marked by degenerating myelin sheaths. Endoneurial arterioles show thickening, hyalinization and intense PAS(+) of their walls, and reduplication of basement membrane.

CLINICAL FEATURES  Distal Symmetric Sensorimotor Neuropathy   presents with sensory symptoms (numbness, loss of pain sensation, balance difficulties, and parasthesias/dysesthesias).  Positive Symptoms – Paresthesia/dysesthesias, painful sensation that result from abnormal discharges from the damaged nerves.

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Paraneoplastic Neuropathies 

Can occur anytime, often precede diagnosis of the tumor. Sensorimotor neuronopathy  is the most common form.

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Commonly associated with lung cancer.

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Antibodies that recognize proteins expressed by cancer cells and normal neurons (e.g. anti-Hu antibodies) are often present. Damage appears to be mediated by a CD8+ T cell attack. Patients with anti-CV2 autoantibodies  tend to present with a mixed axonal and demyelinating sensorimotor neuropathy.

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Neuropathies associated with Monoclonal Gammopathies 

Neoplastic B cells may secrete monoclonal Ig or Ig fragments socalled paraproteins that damages nerves. 

IgM may be associated with demyelinating peripheral neuropathy, the pathogenic IgM paraprotein binds to myelinassociated antigens such as myelin associated glycoprotein.

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IgG or IgA paraproteins may also be associated.

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POEMS Syndrome  (Polyneuropathy, Organomegaly, Endocrinopathy,

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Monoclonal Gammopathy, Skin Changes)  – patients often develop

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demyelinating neuropathy associated with deposition of paraproteins between non-compacted myelin lamella. Excess light chain Ig may deposit as amylo id.

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Peripheral nerves are commonly injured by trauma/entrapment  Laceration  –  results from cutting injuries and from sharp fragments of a fractured bone.   Avulsion – may occur when tension is applied, often the limb  Compression Neuropathy   - (Entrapment neuropathy) occurs when a peripheral nerve is chronically subjected to increased pressure, often within an anatomic compartment.

Encoding proteins that regulate mitochondrial function.

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Encoding proteins involved in vesicle and axonal transport

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Encoding heat-shock proteins

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Encoding proteins involved in membrane structure/function

Major classifications of inherited peripheral neuropathies: 1. Hereditary motor and sensory neuropathies (CMT) 2. Hereditary motor neuropathies 3. Hereditary sensory w/ or w/o autonomic neuropathy 4. Other inherited conditions

Hereditary motor and sensory neuropathies or Charcot-MarieTooth Disease (CMT) 

NEUROPATHIES CAUSED BY PHYSICAL FORCES

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By far the most common inherited neuropathies. Distal muscle atrophy, sensory loss, and foot deformities.

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Demyelinating forms of CMT are associated with morphology of demyelination and remyelination (Schwann cell hyperplasia and onion bulb formation)

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More common variants:

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CMT1 

Autosomal dominant, most common subtype. CMT1A  - duplication of a region on chromosome 17 that includes the peripheral myelin protein 22 (PMP22) gene.

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Usually presents in the second decade of life.

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Carpal Tunnel Syndrome

Slowly progressive distal demyelinating motor and sensory neuropathy  CMT1B – mutations in myelin protein zero gene, 9% of cases. CMTX 

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X-linked forms of CMT, CMT1X  is the most common (15%)

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Linked to mutations in the GJB1 gene, encodes for connexin32, a gap junction component of Schwann cells.

CMT2 Autosomal dominant associated with axonal   rather than demyelinating injury.  CMT2A  is the most common subtype (4%), associated with mutations in MFN2 gene required for mitochondrial fusion.  Severe, disease onset is early childhood. 

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Most common entrapment neuropathy, due to compression of the median nerve  at the level of the wrist within the compartment delimited by the transverse carpal ligament .

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Women are more commonly affected, frequently bilateral.

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Associated with edema, pregnancy, inflammatory arthritis, hypothyroidism, amyloidosis, acromegaly, DM, and excessive repetitive motion of the wrist.

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Symptoms are limited to dysfunction of the median nerve, includes numbness and paresthesias of the tips of thumb and first 2 digits. Other nerves prone to compression include:  Ulnar nerve – at the level of the elbow. 

Peroneal nerve – at the level of the knee

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Radial nerve  –  at the level of the upper arm, occurs from sleeping with arm in awkward position (Saturday night palsy )

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INHERITED PERIPHERAL NEUROPATHIES 

Often present in adults, delayed onset.

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Genes clustered into the following functionally-related groups: 

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Marked by loss of sensation and variable autonomic disturbance

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Loss of pain and temperature sensation is the most common. Typically axonal neuropathies.

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Hereditary Neuropathy with Pressure palsy 

Caused by deletion of gene encoding for PMP22.

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Transient motor and sensory mononeuropathies triggered by compression of individual nerves at sites prone to entrapment.

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Usually resolves within weeks or days.

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Swollen, bulbous myelin sheaths at end of internodes called tomaculi are characteristic morphologic features.

Interdigital nerves – found in the foot at the intermetatarsal

site, common in men, manifests as foot pain, marked by perineural fibrosis (Moron Neuroma).

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Hereditary Neuropathy w/ or w/o autonomic neuropathy

Encoding myelin-associated protein Encoding growth factors and GF receptors

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Familial Amyloid Neuropathies 

Characterized by amyloid deposition within peripheral nerves. Most are due to germline mutations of tranthretin gene.

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Clinical presentation is similar to hereditary sensory/autonomic.

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Peripheral neuropathy accompanying inherited metabolic disorders 

Leukodystrophies, Porphyria, Refsum disease.

Diseases of Neuromuscular Junction

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50% have underlying malignancy, most often neuroendocrine carcinoma of the lungs.

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Patients without cancer have autoimmune diseases such as vitiligo or thyroid disease.

CONGENITAL MYASTHENIC SYNDROMES 

Rare, most have autosomal recessive mode of inheritance.

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Marked by varying degrees of muscle weakness.

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Most common is loss-of-function mutation in the gene encoding for the ε-subunit of AchR.

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Most present in the perinatal period with poor muscle tone, external eye muscle weakness, and breathing difficulties.

DISORDERS CAUSED BY TOXINS Botulism

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Disorders that impair the function of NMJ tend to present with  painless weakness.

ANTIBODY-MEDIATED DISEASES OF NMJ Myasthenia Gravis 

An autoimmune disease that is usually associated with autoantibodies against the acetylcholine receptors (AChR).

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Bimodal age distribution, more common in females in young adults, but more common in males in older adults.

PATHOGENESIS 

85% have autoantibodies against postsynaptic AchR.

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Most of the remaining has antibodies against sarcolemmal protein muscle-specific receptor tyrosine kinase .

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Caused by exposure to neurotoxin called Botox   produced by the anaerobic positive organism Clostridium botulinum.

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These autoantibodies are pathogenic, as they can be passively transferred to animals with serum from affected individuals.

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Acts by blocking the release of Ach from presynaptic neurons. Curare is a common name for muscle relaxants that block AchR resulting in flaccid paralysis.

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Postsynaptic membranes show alteration in morphologic and are depleted of AchR, this limits the ability of the myofibers to respond to Ach. Autoantibodies against muscle-specific RTK interfere with trafficking and clustering of AchR within the sarcolemma. 10% have thymoma, 30% have thymic hyperplasia.  

Marked by appearance of B-cell follicles in the thymus. Both disrupt normal thymic function; it promotes autoimmunity against AchR expressed in thymic myoid cells.

CLINICAL FEATURES  

Present with fluctuating weakness that worsens with exertion. Diplopia and ptosis due to involvement of extraocular muscles.

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Cases with Ab against muscle-specific RTK have more focal muscle involvement.

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Electrophysiologic studies reveal decrement in muscle response with repeated stimulation, a characteristic of this disorder. Acetylcholinesterase inhibitor that increase half-life of Ach are the first line of treatment.

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Lambert-Eaton Myasthenic Syndrome 

Autoimmune disorder caused by antibodies that block Ach release by inhibiting presynaptic calcium channels.

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Rapid repetitive stimulation increases muscle response.

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Present with weakness of their extremities.

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Diseases of Skeletal Muscles 

During embryogenesis, skeletal muscles develop through the fusion of mononucleated precursor cells (myoblasts) into multinucleated myotubes that mature into myofibers.

SKELETAL MUSCLE ATROPHY 

Common feature of any disorder.

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Loss of innervation, disuse, cachexia, old age, and primary myopathies can all produce muscle atrophy.

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Certain patterns suggest underlying etiologies:  Group of atrophic fibers are seen in neurogenic diseases 

Perifascicular atrophy is seen in dermatomyositis

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Type II fiber atrophy with sparing of Type I is seen with prolonged corticosteroid therapy or disuse.

NEUROGENIC ANG MYOPATHIC CHANGES IN SKELETAL MUSCLE 

Damaging myofibers directly (myopathic injury ) or by disrupting muscle innervation (neurogenic injury ).

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Neurogenic injuries lead to fiber type grouping and grouped atrophy, both stem from disruption of innervation.

INFLAMMATORY MYOPATHIES 

Polymyositis and dermatomyositis show typical features of autoimmune inflammatory disease, associated with HLA-DR.

Dermatomyositis  Systemic autoimmune disease that present with proximal muscle weakness and skin changes. 

Most common inflammatory myopathy in children.

PATHOGENESIS  Immunologic disease in which damage to small blood vessels contribute to muscle injury.  Can be seen as telangiectasia (dilated capillary loops) in the nail folds, eyelids, gums, and drop out of vessels in skeletal muscles. 

Shows deposition of complement MAC (C5b-C9) within capillary.

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Inflammatory signature enriched for genes that are upregulated by Type I interferons is seen In muscle and leukocytes.

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Autoantibodies associated: 

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Anti-Mi2  –  against a helicase implicated in nucleosome remodeling, linked to Gottron papules and heliotrope rash Anti-Jo1  –  against histidyl t-RNA synthetase linked to interstitial lung disease, non-erosive arthritis, skin-rash described as mechanic’s hands Anti-P155/P140  –  against transcription regulators linked to paraneoplastic and juvenile cases of dermatomyositis.

MORPHOLOGY 

Biopsies show infiltrates of mononuclear inflammatory cells.

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Most pronounced in the perimysial connective tissue. Distinctive perifascicular atrophy.

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Following denervation, myofibers undergo atrophy, often have flattened, angulated shape.

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Reinnervation restores fiber size and shape but may make a denervated myofiber part of a different motor unit, may lead to switch in fiber type.

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Motor axons may innervate larger numbers of myofibers leading to enlargement of motor units, each comprised of a single type of muscle fiber, also susceptible to grouped atrophy. Most primary myopathic processes are associated with a distinct set of morphologic changes:  Segmental myofiber degeneration and regeneration  Seen only when part of a myofiber undergoes necrosis  Sarcomeres are removed by myophagocytosis  Fusion of activated satellite cells to damaged myofibers.  Regenerating fibers are rich in RNA, therefore basophilic with enlarged nuclei with prominent nucleoli.  In chronic diseases, muscles show endomysial fibrosis, dropout of myofibers and fatty replacement.  Myofiber hypertrophy   Physiologic adaptation to exercise  Can also be seen in chronic myopathic co nditions.  Cytoplasmic Inclusions

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IHC may identify infiltrate rich CD4+ T-helper cells and deposition of C5b-9 in capillary vessels.

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EM shows tubuloreticular endothelial inclusions.

CLINICAL FEATURES 

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Muscle weakness is slow in onset, symmetric, and often accompanied by myalgias, typically affects proximal muscles first Fine movements controlled by distal muscles are only affected late in the disease.

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Elevation of serum creatine kinase.

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Various rashes, most characteristic are lilac colored discoloration of the upper eyelids (heliotrope rash) associated with periorbital edema and a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules)

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Dysphagia may occur in 1/3 of affected individuals.

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Interstitial lung disease may occur in 10% of patients.

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Cardiac involvement is common, but rarely leads to failure.  Juvenile dermatomyositis – average age of onset is 7 y/o

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 Adult dermatomyositis – onset from 4  to 6  decade of life

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Childhood disease is more likely to be associated with calcinosis and lipodystrophy, overall prognosis is better in children.

Polymyositis 

Adult-onset inflammatory myopathy that shares myalgia and weakness with dermatomyositis, but lacks its cutaneous features

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A diagnosis of exclusion.

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Similar autoantibodies.

PATHOGENESIS  Uncertain, believed to have an immunologic basis. 

CD-8+ cytotoxic T cells are prominent part.

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Vascular injury does not have a major role

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Degenerating necrotic, regenerating, and atrophic myofibers are typically found in a random or patchy distribution.

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Presents most common as acute/chronic proximal weakness May also present with exophthalmic ophthalmoplegia  – swelling of the eyelids, edema of conjunctiva, and diplopia.

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Hypothyroidism can cause cramping or aching of muscles.

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MORPHOLOGY  Mononuclear inflammatory infiltrates are present, usually endomysial in location. 

Thyrotoxic myopathy 

Reflexes may be slowed.  Fiber atrophy, increase number of abnormally localized nuclei, glycogen aggregates, and mucopolysaccharide deposit  Alcohol  

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Binge drinking may produce acute toxic syndrome of rhabdomyolysis, myoglobinuria, and renal failure. Acute myalgias which may be confined or generalized.

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Perifascicular atrophy is absent. 

Inclusion Body Myositis  Disease of late adulthood, affects patients older than 50. 

Most common myopathy in patients older than 65 y ears.

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Slow progressive muscle weakness, most severe in quadriceps and distal upper extremity muscles.

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Dysphagia is common, elevated creatine kinase, autoantibodies are absent, but antibody to cN1A has recently been described.

INHERITED DISEASES OF SKELETAL MUSCLES 

Heart is of importance since its common and life-limiting.

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See Table 27-2, Robbins 9  Ed., Page 1241 for summary 

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MORPHOLOGY 

Features similar to polymyositis: 

Patchy, endomysial mononuclear cells (CD8)

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Increased sarcolemmal expression of MHC I

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Focal invasion of myofibers by inflammatory cells. Admixed degenerating and regenerating myocytes.

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More typical changes or specific for inclusion body myositis: Abnormal cytoplasmic inclusions – rimmed vacuoles

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Tubulofilamentous inclusions in myofibers.

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Cytoplasmic inclusions associated with neurodegenerative disorders such as beta-amyloid, TDP-43, and ubiquitin. Endomysial fibrosis and fatty replacement

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Inclusi on body ‘myopathy’  – familial inclusion myopathies linked to chronic myopathic changes and rimmed vacuoles, lacking the inflammation.

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Corticosteroids are first-line for polymyositis & dermatomyositis

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Immunosuppressive drugs are used for steroid-resistant diseases or as steroid-sparing agents.

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Intravenous immunoglobulins, cyclophosphamide, cyclosporine, and rituximab are third-line agents.

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Inclusion body myositis poorly responds to steroids or immunosuppressive therapies.

TOXIC MYOPATHIES 

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Muscle show myopathic changes including vacuolization that predominantly affects type I fibers.

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Aggregates of whorled, lamellar membranous structures.

ICU myopathy or myosin deficient myopathy  

Seen in patients in ICU especially with steroid therapy.

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Relatively selective degradation of sarcomeric myosin filaments producing profound weakness.

Page 7 of 10

Congenital myopathies  – present in infancy with muscle defects that tend to be static or to even improve over time, often associated with distinct structural abnormalities of the muscle. Muscular dystrophies  – progressive muscle damage that comes to attention after infancy, except congenital muscular dystrophy , includes two important groups:  Conditions with defects in ECM surrounding myofibers  Exemplified by Ullrich Congenital Dystrophy (UCMD) and merosin deficiency.  In UCMD, causative mutation involve one of three collagen VI alpha genes. In merosin, the gene encoding for it is disrupted.  UCMD  –  proximal contractures, distal hyperextensibility, and hypotonia, morphologic hallmark is mismatched expression of normally co-localized matrix proteins  perlecan and collagen VI.  Conditions with abnormalities in receptors for ECM  Disrupt the post-translational modification of alphadystroglycan by O-linked glycosylation.  Alpha-dystroglycan is important for CNS and eye devt. 

Muscular Dystrophies 

Common progressive muscle damage that typically manifests itself between childhood and adulthood.

 X-linked Muscular Dystrophy with Dystropin Mutation 

Duchenne and Becker Muscular Dystrophy 

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Most common muscular dystrophies are X-linked and stem from mutations that disrupt the function of a large structural protein called dystrophin.

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Duchenne muscular dystrophy  – most common early onset form

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Becker muscular dystrophy  – second common dystrophinopathy characterized by later onset and milder phenotype.

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Present with isolated cardiomyopathy, asymptomatic elevation in creatine kinase, myalgias and cramps.

Statins  are the leading culprits; myopathy is the most common

complication of statins. Chloroquine  and Hydroxychloroquine  interfere with lysosomal function and cause drug-induced lysosomal storage myopathy.  Slowly progressive muscle weakness.

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PATHOGENESIS 

Both are caused by loss-of-function mutations in the dystrophin gene on the X-chromosome, it is a key component of the dystrophin glycoprotein complex (DCG).

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Creatine kinase falls as dse progress & muscle mass is lost.

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Current treatment consists of primary supportive care.

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Definitive therapy requires restoration of dystrophin levels.

Myotonic Dystrophy 

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Serves as a link of the cytoskeletons inside to the outside. Amino terminus of dytrophin binds actin filaments, while the carboxy terminus binds beta-dystroglycan.

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Provides mechanical stability to the myofiber and its cell membrane during muscle contraction.

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Defects in the complex may lead to small membrane tears that permit calcium influx triggering myofiber degeneration. Carboxy terminus also interacts with nitric oxide synthase. Duchenne muscular dystrophy  –  associated with deletions or frame shift mutations that result in total absence of dystrophin. Becker muscular dystrophy  – permit the synthesis of a truncated version of dystrophin, which retains some function

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Autosomal dominant multisystem disorder associated with skeletal muscle weakness, cataracts, endocrinopathy, and cardiomyopathy. Myotonia  – a sustained involuntary contraction of muscles, is a key feature of this disease.

PATHOGENESIS  Caused by expansion of CTG repeats in the 3’-noncoding region of the myotonic dystrophy protein kinase (DMPK) gene.  Skeletal muscle phenotype stems from a toxic gain-of-function mutation caused by the triple repeat expansion. 

CUG-repeats transcript appear to bind and sequester a protein called muscleblind-like1  which has an important role in RNA splicing, the protein inhibits the muscleblind-like1 function.

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RNA splicing defect causes missplicing including the transcript of CCL1 a chloride channel. Deficiency of CCL1 is believed to be the cause of myotonia.

Emery-Dreifuss Muscular Dystrophy 

MORPHOLOGY  Changes in the two are similar but differ in degree.

EMD is caused by mutations in genes that encode nuclear lamina proteins, marked by a triad of: 1. Slowly progressive humeroperoneal weakness 2. Cardiomyopathy associated with conduction defects 3. Early contractures of Achilles tendon, spine, and elbows X-linked (EDM1) and autosomal form (EDM2) are caused by mutations in the genes encoding emerin and laminin A/C, respectively, both localize to the inner face of nuclear membrane

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Marked by chronic muscle damage that outplaces repair. Ongoing damage in form of segmental myofiber degeneration and regeneration with an atrophic myofibers.

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Fascicular architecture is preserved at this stage of disease.

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Usually no inflammation, but with myophagocytosis. Muscle tissue is replaced by collagen and fat cells ( fatty replacement or fatty infiltration).

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IHC for dystrophin show absence of normal sarcolemmal staining pattern in Duchenne muscular dystrophy   and reduced staining in Becker muscular dystrophy .

Fascioscapulohumeral Dystrophy

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CLINICAL FEATURES  Boys with Duchenne muscular dystrophy are normal at birth. 

Walking is often delayed.

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First indications are clumsiness & inability to keep up with peers

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Begins in the pelvic girdle then extends to the shoulder girdle.

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Enlargement of muscle of lower leg associated with weakness termed pseudohypertrophy , is often present.

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Mean age for wheel-chair dependence is 9.5 years old.

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Develops joint contractures, scoliosis, worsening respiratory reserve and sleep hypoventilation.

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Dystrophin deficiency in cardiac muscle leads to development of cardiomyopathy   and arrhythmias, particularly in older patients. May produce mental retardation.

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Mean age of death is 25-30 years of age, due to respiratory insufficiency, pulmonary infection, or heart failure.

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These proteins help maintain the shape and mechanical stability of the nucleus during muscle contraction.

Characteristic pattern involvement that includes prominent weakness of facial muscles and muscles of shoulder girdle.

PATHOGENESIS  Involves overexpression of gene called DUX4 that is located in a region of subteleomeric repeats on long arm of chromosome 4. 

The disease is confined to those who also inherit creatin SNPs at positions immediately 3’ of the DUX4 coding sequence.

Limb-Girdle Muscular Dystrophy 

Heterogeneous group of at least 6 autosomal dominant and 15 autosomal recessive entities.

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All forms are characterized by muscle weakness, preferentially involves proximal muscle groups.

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Implicated genes encoding for: Structural components (sarcoglycans) of the dystrophin glycoprotein complex

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In Becker muscular dystrophy  presents in later childhood, adolescence or adult life, more slowly progressive.

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Enzymes responsible for glycosylation of α-dystroglycan, a component of the dystrophin glycoprotein complex

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Diagnosis based on history, PE, and laboratory studies.

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Proteins associated with Z-disks of sarcomere Proteins involved in vesicle trafficking and cell signaling.

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Genes that stand alone, like protein calpain3 and lamini n A/C

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Serum creatine kinase markedly elevated during 1  decade.

Page 8 of 10

Diseases of Lipid of Glycogen Metabolism 

Tends to produce 2 general patterns of muscle dysfunction: 

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Some become symptomatic only when exercising or fasting, which may produce severe muscle cramping and pain. Some have extensive muscle necrosis (rhabdomyolysis)

Spinal Muscular Atrophy and the Differential Diagnosis of a Hypotonic Infant 

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Carnitine Palmitoyltransferase II deficiency

Spinal muscular atrophy is a neuropathic disorder in which loss of motor neurons lead to muscle weakness and atrophy. Infants may present with generalized hypotonia (floppy infant) Differential diagnosis:  Primary diseases of skeletal muscle

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Most common disorder of lipid metabolism.

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Abnormalities of the brain

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Causes episodic muscle damage with exercise or fasting.

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Neuronopathies

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Defect impairs the transport of FFA into the mi tochondria.

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Autosomal recessive, caused by loss-of-function mutations in SMN1  gene, function is uncertain, but SMN1 deficiency has dramatic effect on motor neuron survival.

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Resulting denervation may lead to characteristic morphologic change consist of large zones of severely atrophic myofibers mixed with scattered normal sized or hypertrophied fibers.

Myophosphorylase deficiency (McArdle disease) 

More common glycogen storage diseases affecting muscles.

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Results in episodic muscle damage with exercise.

 Acid Maltase deficiency 

Impaired lysosomal conversion of glycogen to glucose.

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Glycogen accumulation within the lysosomes.

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Severe deficiency results in generalized glycogenosis of infancy, Pompe disease.

Mitochondrial Myopathies 

Complex systemic conditions that involve many organ systems.

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May appear to impair the ability of mitochondria to produce ATP

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Tends to affect skeletal muscle and other tissues with high ATP requirements (cardiac and nerve muscles). Skeletal involvement   can manifest as weakness, elevation of serum creatine kinase, or rhabdomyolysis. Chronic progressive external ophthalmoplegia  is a common feature, may be in isolation or as part of multisystem disease.

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MORPHOLOGY

Ion Channel Myopathies (Channelopathies) 

Mutations affecting the function of ion channel proteins.

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Most are autosomal dominant with variable penetrance. May present with epilepsy, migraine, movement disorders with cerebellar dysfunction, peripheral nerve or muscle disease.

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Disorders associated with hypotonia can be sub-classified based on whether patient have hyperkalemic, hypokalemic, or normokalemic periodic paralysis.

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Mutated genes associated with muscle dysfunction: KCNJ2  – affect K+ channel, causes Andersen-Twail syndrome ,  autosomal, associated with periodic paralysis, heart arrhythmias, and skeletal abrnomalities.  

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Most consistent change is abnormal aggregates of mitochondria seen in the subsarcolemmal area of affected fiber producing an appearance referred as ragged red fibers.

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SCN4A – affect Na+ channel, myotonia to periodic paralysis CACNA1S  – missense mutation, a subunit of muscle calcium channel, most common cause of hypokalemic paralysis. CLC1 – mutations in Cl channels, cause myotonia congenita RYR1  –  disrupts function of ryanodine receptors, linked to congenital myopathy and malignant hyperthermia.

On EM, morphologically abnormal mitochondria are seen.

Peripheral Nerve Sheath Tumors CLINICAL FEATURES  Single point mutations in the mitochondrial leucine tRNA gene may have isolated chronic progressive external opthalmoplegia.  Severe phenotype may have mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. 

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Deletions in mtDNA may lead to isolated ophthalmoplegia or Kearns-Sayre syndrome  –  ophthalmoplegia, pigmentarty degeneration of the retina, and complete heart block. Myoclonic epilepsy with ragged fiber and Leber hereditary optic neuropathy are other examples.

Page 9 of 10

Malignant or benign, majority are composed of cells that show evidence of Schwann cell differentiation  Three common types: schwannoma, neurofibroma and malignant  peripheral nerve sheath tumor (MPNST) 

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Abrupt transition between central and peripheral myelination that occurs as nerves extend out fro m the brain

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Arise within the dura & distal course of the peripheral nerves

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Familial Tumor Syndromes (NF1, NF2, schwannomatosis)

Schwannomas 

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Diffuse neurofibroma  – similar to LCN but with different growth pattern, infiltrating the dermis and SQ connective tissue, entrapping fat and appendage structures producing plaque-like appearance  Large, focal collections of pseudo Meissner corpuscles or tactile-like bodies

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Plexiform neurofibroma  –  grow within and expand nerve fascicles, entrapping axons

Benign tumors that exhibit Schwann cell differentiation and arise directly from peripheral nerves Component of NF2  – loss of expression of the NF2 gene product, merlin, is a consistent finding in schwannomas

Morphology

Well-circumscribed, encapsulated masses that abut the associated nerve without invading it Firm, gray masses, comprised of an admixture of dense and loose areas referred to as Antoni A (Hypercellular)  and B (Hypocellular), respectively

Malignant Peripheral Nerve Sheath Tumors (MPNST)

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Verocay Bodies – the regions of palisading nuclear material

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Characterized by presence of a spindled elongated nucleus with a wavy or buckled shape

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EM: basement membrane deposits encasing single cells and collagen fibers

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Silver stains or Immunostains: axons are largely excluded from the tumor, although trapped in the capsule

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Degenerative changes: nuclear pleormorphism, xanthomatous change, vascular hyalinization, cystic change, necrosis and mitotic activity

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“Bag of worms” appearance of expanded nerve fascicles

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“Shredded carrot” appearance of collagen bundles

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85% are high grade tumors 50% in NF1 patients – plexiform transformation

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Sporadic are de novo

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Larger peripheral nerves in the chest, abdomen, pelvis, neck or limb-girdle

Morphology 

Poorly defined mass that infiltrate along the axis of the parent nerve and invade adjacent soft tissues

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Typical cases show fasciculated arrangement of spindle cells “Marble-ized”   due to variations in cellularity: mitoses, necrosis and anaplasia are common. “Divergent differentiation” –  presence of focal areas that exhibit other lines of differentiation (glandular, cartilaginous, osseous or rhabdomyoblastic)

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Clinical Features 

Local compression of involved nerve or adjacent structures

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Most often in the cerebellopontine angle, attached to the vestibular branch of the eight nerve  (acoustic neuroma)  – tinnitus and hearing loss

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Sensory nerves like branches of trigeminal and dorsal roots may also be involved Surgical removal is curative

Neurofibromatosis Type 1 and 2 Neurofibromatosis Type 1

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AD systemic disease associated with neoplastic and nonneoplastic manifestations

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Neoplastic lesions may be: neurofibromas, MPNTS, gliomas of the optic nerve, glial, hamartomatous lesions, pheochromocytomas

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Mental retardation, seizures, skeletal defects pigmented nodules of the iris (Lisch nodules) and cutaneous hyperpigmented macules (cafe au lait spots)

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Distribution is attributable to mosaicism Loss of function of NF1 gene encoding for neurofibromin

Neurofibromas 

Benign nerve sheath tumors that are more heterogeneous in composition than schwannomas

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Neoplastic Schwann cells are admixed with perineural-like cells, fibroblasts, mast cells and CD34+ spindle cells Sporadic or NF1 associated

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Different types:  Superficial cutaneous neurofibromas – present as pedunculated nodules, isolated: sporadic; multiple: NF1  Diffuse neurofibromas – large plaque-like elevation of skin, NF1

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Plexiform neurofibromas – deep or superficial in nerve roots or

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Neurofibromatosis Type II

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Show complete loss of neurofibromin (NF1 gene product)

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Plexiform and dermal neurofibromas arise from different neural crest derived precursor cells

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Transformation to MPNST is seen in plexiform neurofibromas

Morphology 

Localized Cutaneous Neurofibroma  – small, well-delineated, unencapsulated nodular lesions arising in the dermis and SQ fat.

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Low cellularity with entrapped adnexal structures at the edge of the lesion. Stroma contains loose collagen

Page 10 of 10

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AD disorder resulting in a range of tumors (bilateral 8   nerve schwannomas, multiple meningiomas, gliomas and ependymomas of the spinal cord)

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Schwannosis, meningioangiomatosis and glial hamartia are the non-neoplastic lesions

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Less common than NF1 Loss of function in NF2 encoding for merlin a cytoskeletal protein

large nerves, NF1 Pathogenesis

Triton tumor  – rhabdomyoblastic morphology

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