Peripheral Nervous System and Muscle Diseases

Key questions

1. Q1What are the three connective tissue layers of a peripheral nerve?

   Epineurium binds all the fascicles together and carries blood vessels; perineurium (concentric flattened cells + collagen) wraps each fascicle and forms the blood–nerve barrier; endoneurium surrounds individual axons and their Schwann cells, with collagen, fibroblasts and capillaries.
2. Q2How are myelinated and unmyelinated axons arranged?

   Each myelinated axon has its own Schwann cell per internode; myelin thickness scales with axon diameter. Several small unmyelinated axons (<1 µm) invaginate into the surface of a single Schwann cell (Remak bundle).
3. Q3How do they look on stains and EM?

   Osmium/toluidine blue: myelin = black ring around a pale axon. EM: dark concentric myelin lamellae around a pale axoplasm; unmyelinated axons are tiny pale profiles in Schwann cell cytoplasm.
4. Q4Which nerve is biopsied, and why?

   The sural nerve — purely sensory, so removing a segment leaves only a small patch of numbness on the lateral foot.
5. Q5What does normal skeletal muscle look like in cross section?

   Polygonal fibers of similar size packed in fascicles (perimysium around fascicles, endomysium around fibers, epimysium around the muscle), with nuclei at the periphery and almost no connective tissue between fibers.
6. Q6What is a motor unit and why does it matter?

   One anterior horn cell + its axon + all the muscle fibers it innervates (hundreds). All fibers of a unit are the same fiber type and are scattered randomly → the normal "checkerboard" of type 1 and type 2 fibers. The nerve decides the fiber type.
7. Q7How do type 1 and type 2 fibers differ?

   Type 1: red, slow-twitch, sustained/postural, oxidative, many mitochondria, lipid-rich, glycogen-poor. Type 2: white, fast-twitch, sudden power, glycolytic, few mitochondria, glycogen-rich. ATPase pH 9.4: type 1 light, type 2 dark; pH 4.3: type 1 dark, type 2 light; NADH-TR darkest in type 1.
8. Q8What is the sarcomere?

   Z line to Z line: thin actin filaments anchored at Z lines overlap thick myosin (A band); troponin/tropomyosin sit in the actin grooves; the dystrophin complex links actin to the sarcolemma and extracellular matrix.

Key questions

1. Q9What are the three big categories of skeletal muscle disease?

   Myopathic (intrinsic muscle disease: dystrophies, congenital, metabolic/mitochondrial, toxic/drug), inflammatory (immune-mediated) and neuropathic/neurogenic (changes due to loss of the motor neuron or axon).
2. Q10What does a dystrophic biopsy show?

   Marked variation in fiber size and shape (rounded atrophic and hypertrophic fibers), internalized nuclei, degenerating/necrotic and regenerating (small, basophilic) fibers, increased endomysial fibrosis and, late, replacement by fat — with little or no inflammation.
3. Q11What is Duchenne muscular dystrophy?

   X-linked (Xp21) dystrophin mutation — frameshift/deletion → no functional dystrophin; ~1/3 new mutations, 2/3 inherited from carrier mothers. Boys: weakness by age 5, Gowers maneuver, calf pseudohypertrophy, markedly ↑ CK, wheelchair by 10–12, death in early 20s from cardiomyopathy or respiratory failure.
4. Q12How is DMD confirmed, and how does Becker differ?

   Immunostaining shows absent dystrophin (C-terminal, N-terminal and rod antibodies) in DMD, weak/patchy in Becker; Western blot shows no band (DMD) or a band of abnormal size/amount (Becker); gene sequencing. Becker = in-frame mutation, milder, later, less common.
5. Q13Which other proteins cause dystrophies?

   Sarcoglycans and caveolin → autosomal limb-girdle muscular dystrophies; α2-laminin (merosin) → a congenital muscular dystrophy. Also Emery-Dreifuss, facioscapulohumeral and oculopharyngeal dystrophies. Most are now diagnosed by clinical exam + genetics rather than biopsy.
6. Q14What is myotonic dystrophy?

   Autosomal dominant repeat-expansion disease — DM1: CTG trinucleotide expansion in DMPK on chromosome 19 (anticipation); DM2: CCTG tetranucleotide expansion in ZNF9 (CNBP) on chromosome 3, milder. Myotonia (can't relax grip), distal and facial weakness, cataracts, frontal balding, testicular atrophy, cardiac arrhythmias; congenital DM1 with learning disability. Biopsy: many internal (central) nuclei, ring fibers, type 1 atrophy.
7. Q15What is nemaline (rod) myopathy?

   A congenital myopathy: floppy infant with hypotonia and weakness (face, neck, respiratory). Rod-shaped purple inclusions in the cytoplasm on trichrome; EM shows Z-band–density rods. Genes: ACTA1 (skeletal actin, usually dominant/de novo) and nebulin (NEB, recessive), rarely tropomyosins, troponin T, cofilin.
8. Q16What marks mitochondrial myopathies?

   Ragged red fibers — subsarcolemmal clumps of abnormal mitochondria that stain red on modified Gomori trichrome; EM shows "parking-lot" paracrystalline inclusions. Maternal inheritance (mtDNA) with heteroplasmy; lactic acidosis; exercise intolerance.
9. Q17Which mitochondrial syndromes should you recognize?

   MELAS (childhood–young adult: stroke-like episodes, migraine-type headaches, seizures, lactic acidosis, PEO, hearing loss, diabetes, short stature); MERRF (myoclonus, seizures, ataxia, weakness, hearing loss, short stature, ragged red fibers); Kearns-Sayre (onset <20: PEO, pigmentary "salt-and-pepper" retinopathy, heart block, ataxia); Leigh syndrome (infancy: ataxia, seizures, developmental delay, abnormal breathing, bulbar weakness).

Key questions

1. Q18What defines an inflammatory myopathy on biopsy?

   Fiber necrosis and regeneration with inflammation — perivascular, perimysial or endomysial. The location of the inflammation and the pattern of atrophy separate the types (dystrophies lack this inflammation).
2. Q19What is polymyositis?

   Adults (>18), F:M 2:1; symmetric proximal weakness; CK up to 50×. Endomysial CD8+ cytotoxic T cells surround and invade non-necrotic fibers; necrotic/regenerating fibers scattered throughout the fascicle. T-cell mediated.
3. Q20What is dermatomyositis?

   Any age — peaks in childhood (5–15) and adults (45–65), F:M 2:1; symmetric proximal weakness with rash (heliotrope eyelids, Gottron papules, shawl sign, nailfold changes); CK normal to 50×; association with underlying malignancy in adults. Perifascicular atrophy with perivascular/perimysial B cells and CD4+ T cells — an antibody/complement-mediated microvascular disease.
4. Q21What is inclusion body myositis?

   Older adults (usually men >50), slowly progressive, often asymmetric weakness of distal and proximal muscles — finger flexors, wrist flexors, ankle dorsiflexors (foot drop) and quadriceps; steroid-resistant. Rimmed vacuoles with tubulofilamentous inclusions (cytoplasm and nucleus), endomysial inflammation invading fibers.
5. Q22What is statin myopathy?

   Myalgia and weakness with mild–moderate CK elevation, occasionally rhabdomyolysis; stop the statin and use another lipid-lowering drug. (Rare: anti-HMGCR necrotizing autoimmune myopathy that persists after stopping.)
6. Q23What happens to muscle after denervation?

   Stage 1: normal. Stage 2 (acute): scattered small angular atrophic fibers (esterase-positive, dark). Stage 3: surviving axons sprout and reinnervate orphaned fibers, converting them to their own type → fiber-type grouping (checkerboard lost). Stage 4: if that large unit dies too → grouped atrophy of same-type fibers.
7. Q24What is spinal muscular atrophy?

   Loss of anterior horn motor neurons from SMN1 mutation (chromosome 5q, autosomal recessive). Severe type I: floppy baby with severe hypotonia, limb and axial weakness, poor head control, weak cry and suck, respiratory failure, tongue fasciculations. Biopsy: large groups of atrophic fibers with a few hypertrophic (still-innervated) fibers.
8. Q25What are the indications for a muscle biopsy?

   Symptoms of muscle disease — weakness, hypotonia, cramps or pain on exercise, fatigue (after excluding myasthenia) — very high CK, a myopathic EMG, a systemic disorder that can involve muscle (inflammatory disease, vasculitis, sarcoidosis, amyloidosis, mitochondrial disease), or family history. Not needed when EMG or genetics diagnose it (myasthenia gravis, Lambert-Eaton, myotonias, periodic paralysis, most pediatric dystrophies). After rhabdomyolysis, wait 1 month.
9. Q26Which muscle should be biopsied?

   One that is recently involved, partially weak or tender — not the side where EMG needles went (artifact) and not a severely weak muscle (end-stage fat and fibrosis only).
10. Q27Can any neuron reinnervate muscle?

    Only peripheral nerve axons sprout and reinnervate; neurons of the brain and spinal cord cannot regenerate.

Key questions

1. Q28What are the principal causes of peripheral neuropathy?

   Hereditary (Charcot-Marie-Tooth), immune (Guillain-Barré, CIDP), vasculitis, amyloid, systemic illness (diabetes, uremia, sarcoidosis, hypothyroidism, acromegaly), paraneoplastic, infection (leprosy, Lyme, HIV, zoster), nutritional/alcohol (B1, B6, B12), compression/trauma/radiation, toxins (lead, gold) and drugs (amiodarone, cisplatin, disulfiram, metronidazole, thalidomide, taxanes, isoniazid, vincristine).
2. Q29What are the basic patterns of nerve injury?

   Axonal degeneration (most common, ~80%), segmental demyelination, both (e.g., vasculitic infarcts), primary vascular pathology, amyloid deposition, and end-stage fiber loss with fibrosis.
3. Q30What does axonal degeneration look like?

   Wallerian-type breakdown: the axon and its myelin fragment into myelin ovoids and debris cleared by macrophages; EM shows swollen axons full of degenerating organelles and dense bodies; later, loss of fibers and regenerating clusters. Nerve conduction: ↓ amplitude, near-normal velocity.
4. Q31What does segmental demyelination look like?

   Macrophages strip myelin from internodes while the axon survives (bare axons); remyelinated segments are thin and short. Repeated cycles → Schwann cell layers wrap the axon = onion bulbs. Nerve conduction: ↓ velocity, conduction block.
5. Q32What is Guillain-Barré syndrome?

   Acute, life-threatening immune-mediated demyelinating radiculoneuropathy (AIDP): weakness starting distally that rapidly ascends ("ascending paralysis"), areflexia, possible respiratory failure. Two-thirds follow a flu-like or GI illness — Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae; antibodies and lymphocytes (molecular mimicry), not the organism, cause damage. Inflammation and demyelination of roots and nerves; CSF albuminocytologic dissociation. Rarely biopsied.
6. Q33What is CIDP?

   Chronic inflammatory demyelinating polyradiculoneuropathy: subacute/chronic (>8 weeks), often symmetric, sensory and motor. Biopsy: demyelination/remyelination, onion bulbs, variable myelin thickness and short internodes. No infectious trigger identified; responds to steroids/IVIG.
7. Q34What does diabetic neuropathy look like?

   Affects most diabetics: symmetric distal sensory or sensorimotor ("stocking-glove") neuropathy, autonomic neuropathy, or focal/multifocal (mononeuropathy, CN III). Mechanism: microvascular ischemia (diabetic vasculopathy) + glycation/AGEs and polyol pathway. Biopsy: loss of small and large myelinated fibers, thinly myelinated regenerating fibers, thickened hyalinized endoneurial arterioles.
8. Q35What happens in herpes zoster?

   VZV lies latent in sensory (dorsal root and cranial nerve) ganglia after chickenpox; declining cell-mediated immunity → reactivation → painful vesicular rash in one dermatome. Ganglia show neuronal destruction and loss with abundant mononuclear inflammation; intranuclear inclusions are usually not found.
9. Q36How does leprosy affect nerves?

   Mycobacterium leprae invades Schwann cells in cool peripheral nerves → sensory loss, thickened nerves and injury to numb extremities. Tuberculoid: granulomas destroy nerves, few bacilli. Lepromatous: many acid-fast bacilli in Schwann cells and macrophages with segmental demyelination.
10. Q37How does tetanus act on nerves?

    Clostridium tetani spores enter a wound → tetanospasmin travels retrogradely to the spinal cord and blocks release of inhibitory transmitters (glycine, GABA) from Renshaw cells → spastic paralysis, trismus, opisthotonus. Supportive care, tetanus immune globulin, and prevention by immunization.
11. Q38When is a nerve biopsy indicated?

    When the cause stays unclear after clinical, electrodiagnostic and lab work-up — especially suspected vasculitis, amyloid, sarcoid, leprosy, or an atypical inflammatory neuropathy.
12. Q39What else about tetanus toxin?

    Tetanospasmin binds gangliosides at motor nerve terminals, then travels retrogradely to the spinal cord. Mortality remains high — vaccination is the key prevention.

Key questions

1. Q40When is a muscle biopsy indicated?

   Symptoms/signs of muscle disease (weakness, hypotonia, exercise cramps or discomfort, fatigue once myasthenia is excluded), very high or high CK, myopathic EMG, a systemic disorder that may involve muscle (inflammatory disease, vasculitis, sarcoidosis, amyloidosis, mitochondrial disease), or family history of neuromuscular disease.
2. Q41When is a muscle biopsy NOT the best test?

   When electrodiagnostics or genetics make the diagnosis: myasthenia gravis, Lambert-Eaton, myotonias, periodic paralysis and most pediatric dystrophies. Also wait about a month after rhabdomyolysis.
3. Q42How do you choose the muscle?

   Recently involved, mildly/partially weak or tender muscle; avoid the side needled for EMG and avoid severely weak (end-stage) muscle.
4. Q43What studies are done on a muscle biopsy?

   Frozen-section histology and enzyme histochemistry (H&E, Gomori trichrome, ATPase, NADH-TR, esterase), immunohistochemistry (dystrophin, sarcoglycans, MHC-I, inflammatory cell subsets), electron microscopy, Western blot and molecular studies.
5. Q44When is a nerve biopsy indicated?

   An unexplained, often asymmetric or multifocal neuropathy where the result changes treatment — suspected vasculitis, amyloid, sarcoidosis, leprosy or atypical inflammatory neuropathy. Usually the sural nerve (sensory), often with a muscle biopsy.
6. Q45Why is genetics changing biopsy practice?

   Many dystrophies and hereditary neuropathies are now diagnosed from blood or saliva genetic panels; biopsies are reserved for less obvious cases, with close communication among neurologist, surgeon, geneticist and neuropathologist.