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PNS 2023 - Key Points Summary

PART 1: Peripheral Nerve Disorders

Basic Structure (How Nerves Work)

• Every nerve has two main parts: axons (carry signals) and myelin sheaths (insulation, made by Schwann cells)
• Thicker myelin = faster signal conduction
• Touch travels through thick, fast nerves; Temperature/pain travels through thin, slow nerves
• Nerves are bundled into fascicles, surrounded by perineurial cells (a protective barrier)

Two Types of Nerve Damage

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Important Peripheral Neuropathies

• Distal symmetric sensorimotor type is most common - causes numbness and tingling, sensory > motor
• Caused by high blood sugar damage (glycosylation end products, oxidative stress, microvessel changes)
• Other forms: autonomic neuropathy (low BP on standing, bladder/bowel issues) and lumbosacral radiculopathy (leg pain + weakness)
• Best treatment: strict blood sugar control

• Rapid ascending weakness (legs first, moves up)
• Autoimmune - body attacks nerve sheaths after infection (Campylobacter, EBV, CMV, HIV, Zika, COVID-19)
• Most damage in nerve roots and proximal nerves
• Treatment: plasmapheresis, IV immunoglobulin, ventilatory support
• Most patients recover

• Like GBS but slow and chronic (lasts >2 months)
• Both motor and sensory - weakness, numbness, tingling
• Seen with paraproteinemias, lymphoma, HIV

• Toxic: alcohol, chemotherapy drugs (taxanes, platinum) - longest nerves affected first
• Vasculitis: painful, patchy, asymmetric nerve damage
• Charcot-Marie-Tooth disease: most common inherited neuropathy; slowly progressive; gene mutations in myelin proteins
• Amyloid neuropathy: amyloid deposits in nerves → weakness, numbness, autonomic problems
  • Treatment: chemo/stem cell transplant (light chain type); liver transplant or gene therapy (transthyretin type)
• Idiopathic (30-40%): no cause found; elderly; treat symptoms with antiepileptics, antidepressants

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PART 2: Neuromuscular Junction (NMJ) Disorders

How NMJ Works (Simple)

• Nerve impulse → calcium enters → acetylcholine (ACh) released → binds muscle receptor → muscle contracts

• Autoimmune - antibodies attack ACh receptors (85%) or MuSK protein
• Bimodal: young women (20s-30s) and older men (60s-70s)
• Common association: thymic hyperplasia (60-70%) or thymoma (10-15%)
• Symptoms: drooping eyelids (ptosis), double vision (diplopia) - extraocular muscles affected first
• Antibody types:
  • Binding → complement activation, destroys receptor
  • Blocking → prevents ACh binding
  • Modulating → receptor internalization (thymoma-related)
• Nerve stimulation test: response decreases with repetition
• Treatment: cholinesterase inhibitors, steroids, immunosuppressants, plasmapheresis, thymectomy

• Antibodies attack presynaptic calcium channels → less ACh released
• Weakness improves with repeated use (opposite to MG!)
• 2/3 cases = paraneoplastic (small cell lung cancer)
• Treatment: potassium channel blockers
• Worse prognosis than MG due to underlying cancer

• Congenital myasthenic syndromes: gene mutations, mimic MG/Lambert-Eaton
• Tetanus toxin (C. tetani): blocks inhibitory neurons → sustained spasms
• Botulinum toxin (C. botulinum): blocks ACh release → flaccid paralysis (also used as Botox for wrinkles)

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PART 3: Skeletal Muscle Disorders

Muscle Basics

• Two fiber types: Type I (slow, endurance) and Type II (fast, strength)
• Normally arranged in a checkerboard pattern
• Disuse and steroid excess → type II fiber atrophy (proximal muscles)

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Muscular Dystrophies (Inherited)

• X-linked recessive; caused by dystrophin gene mutations
• Dystrophin connects muscle fiber skeleton to outer membrane - without it, membranes tear during contraction → calcium floods in → muscle degeneration
• DMD: no dystrophin; incidence 1:3500 males; wheelchair by teens, fatal by early adulthood
• BMD: partial dystrophin; milder, slower
• Signs: calf pseudohypertrophy (muscle replaced by fat), high creatine kinase, pelvic girdle weakness first
• Cognitive impairment possible in DMD
• Both cause cardiomyopathy
• Mean age of death in DMD: 25-30 years (respiratory failure or heart failure)

• Autosomal dominant; trinucleotide repeat expansion (CTG repeats in DMPK gene; normal <37, affected >45)
• Cardinal feature: myotonia (can't relax muscles after contraction, e.g., after a handshake)
• Also causes: arrhythmias, cataracts, baldness, endocrine problems, testicular atrophy

• Affects trunk and proximal limbs
• Multiple gene mutations (dystrophin-complex proteins, caveolin, cytoskeletal proteins)

• Mutations in nuclear structural proteins (emerin or lamin A/C)
• Progressive weakness + elbow/ankle contractures + severe cardiac disease (arrhythmias, sudden death in up to 40%)

• Autosomal dominant; caused by abnormal DUX4 gene expression
• Facial and shoulder weakness by age 20; usually normal life expectancy

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Channel & Metabolic Myopathies

• Hypokalemic periodic paralysis: most common; calcium channel mutation; attacks triggered by rest after exercise or carbs
• Hyperkalemic periodic paralysis: sodium channel mutation
• Malignant hyperthermia: ryanodine receptor (RYR1) mutation; triggered by anesthesia (halogenated agents, succinylcholine) → muscle spasms, high fever, life-threatening
• Mitochondrial myopathies: maternal inheritance; proximal weakness + eye muscle paralysis; "ragged red fibers" on biopsy
• McArdle disease: myophosphorylase deficiency → can't use glycogen → cramping and myoglobinuria with exercise
• Pompe disease: acid alpha-glucosidase deficiency → glycogen buildup; enzyme replacement therapy available

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Inflammatory Myopathies

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Toxic Myopathies

• Thyrotoxicosis: proximal weakness, may be the first sign
• Steroid myopathy: proximal weakness, normal CK, type 2 fiber atrophy on biopsy
• Alcohol (binge drinking): rhabdomyolysis → can cause acute renal failure from myoglobinuria
• Statin myopathy (most common drug cause): direct toxicity OR immune-mediated (anti-HMG-CoA reductase antibodies)