Nerves & Neuromuscular Junction
Nerves & Neuromuscular Junction
What Do You Need to Know?
- Nerve structure — endoneurium, perineurium, epineurium; Schwann cells (PNS) vs oligodendrocytes (CNS)
- Fiber classification — Erlanger-Gasser (Aα through C) and Lloyd-Hunt systems; velocity ≈ 6 × diameter
- Action potential — resting membrane potential, Na⁺/K⁺ channels, refractory periods, saltatory conduction
- Synaptic transmission — EPSPs vs IPSPs, temporal vs spatial summation
- NMJ anatomy & physiology — P/Q-type Ca²⁺ channels, SNARE proteins, safety factor
- NMJ disorders — MG (postsynaptic, decrement), LEMS (presynaptic, increment), Botulism (SNARE cleavage)
- Nerve injury — Seddon vs Sunderland classification, Wallerian degeneration timeline
- Channelopathies — hyperkalemic PP (Na⁺ channel, myotonia), hypokalemic PP (Ca²⁺ channel, no myotonia)
🚩 Don’t Miss — Test-Day Priorities
- Conduction velocity ≈ 6 × diameter (µm): Aα 12–22 µm → 70–120 m/s; Aδ 1–5 µm → 5–30 m/s; C 0.4–1.2 µm unmyelinated → 0.5–2 m/s.
- Fiber-by-function: Aα = Ia/Ib + α-motor; Aβ = II touch/pressure; Aγ = fusimotor to muscle spindle; Aδ = III sharp/fast pain + cold; B = preganglionic autonomic (lightly myelinated); C = IV slow pain/warm + postganglionic autonomic.
- Saltatory architecture: Nav1.6 at node — Caspr1 + contactin-1 + NF155 at paranode (axoglial junction) — Kv1.1/1.2 at juxtaparanode. Antibodies vs NF155, NF186, Caspr1, contactin-1 = nodopathies (CIDP variant, poorly IVIG-responsive, treat with rituximab).
- PMP22 dose effect: duplication → CMT1A (uniform demyelination); deletion → HNPP (tomacula, recurrent pressure palsies).
- PNS vs CNS myelin: 1 Schwann cell = 1 internode (PNS, regenerates); 1 oligodendrocyte = up to 50 internodes (CNS, no regeneration).
- Presynaptic NMJ cascade: AP → P/Q-type VGCC (LEMS target) → Ca²⁺ → SNARE (synaptobrevin/VAMP + syntaxin + SNAP-25) zippers → ACh release. SV2A = levetiracetam binding site + BoNT-A receptor.
- Toxin cleavage map: BoNT-A → SNAP-25; BoNT-B/D/F/G → synaptobrevin (VAMP); BoNT-C → syntaxin + SNAP-25; tetanus toxin → synaptobrevin in inhibitory CNS interneurons; α-latrotoxin (black widow) → massive ACh release.
- Postsynaptic clustering: nerve-derived agrin → LRP4 → MuSK → rapsyn → AChR clusters. Antibodies vs any of these = MG variants.
- AChR subunit switch: fetal γ → adult ε postnatally. CHRNE mutations → congenital myasthenia.
- Safety factor: EPP ≫ threshold normally. MG → decrement on 3 Hz RNS. LEMS → ≥60% increment post-exercise / high-frequency RNS (presynaptic facilitation).
- MEPP vs EPP: MEPP = spontaneous single-vesicle quantum (~0.5 mV); EPP = nerve-evoked sum of ~100–200 quanta.
- Succinylcholine red flags: CONTRAINDICATED in malignant hyperthermia, hyperkalemia, denervation injury, severe burns, recent SCI — risk of lethal hyperkalemia from up-regulated extrajunctional AChRs.
- Reversal agents: neostigmine reverses non-depolarizing blockers (roc/vec/atrac/cisatrac); sugammadex encapsulates rocuronium & vecuronium specifically.
- Congenital myasthenia treatment traps: slow-channel → AVOID pyridostigmine, use fluoxetine/quinidine; DOK7 → AVOID pyridostigmine, use ephedrine/salbutamol; fast-channel + RAPSN + ChAT → AChEI helps.
- Ice-pack test: cooling inhibits AChE → ptosis improves ≥2 mm in ocular MG (cheap bedside test).
- Magnesium & NMJ: high Mg²⁺ competes with Ca²⁺ at presynaptic VGCC → reduced ACh release → weakness; avoid IV Mg in MG / eclampsia overlap.
🔍 Buzzwords & Pathognomonic FindingsNerve fiber types · NMJ structure · Disease / drug
Nerve fiber types / properties
- Aα (Ia/Ib) → muscle spindle primary + GTO afferents + α-motor; 12–22 µm, 70–120 m/s
- Aβ (II) → touch / pressure / vibration; 5–12 µm, 30–70 m/s
- Aγ → fusimotor to intrafusal muscle spindle fibers (sets spindle gain)
- Aδ (III) → fast/sharp pain + cold + crude touch; 1–5 µm, 5–30 m/s; first pain
- B fiber → preganglionic autonomic, lightly myelinated, 3–15 m/s
- C fiber (IV) → slow/burning pain + warmth + postganglionic autonomic; unmyelinated, 0.5–2 m/s; second pain
- Velocity rule → v (m/s) ≈ 6 × diameter (µm) for myelinated fibers
- Saltatory conduction → AP jumps node-to-node at Ranvier nodes (Nav1.6 clustered)
NMJ structure / signaling
- P/Q-type VGCC (Cav2.1) → presynaptic Ca²⁺ influx; LEMS antibody target
- SNARE complex → synaptobrevin (VAMP) + syntaxin + SNAP-25 zipper for vesicle fusion
- SV2A → synaptic vesicle protein; levetiracetam & BoNT-A binding site
- ChAT → acetylcholine synthesis from choline + acetyl-CoA in nerve terminal
- Hemicholinium-3 → blocks high-affinity choline reuptake into terminal
- Vesamicol → blocks VAChT (vesicular ACh transporter) loading
- Nicotinic AChR (adult) → pentamer 2αβδε (fetal γ → adult ε switch postnatally)
- α-bungarotoxin → irreversibly binds α-subunit of nicotinic AChR (krait venom)
- Agrin → LRP4 → MuSK → rapsyn → AChR clustering pathway at end-plate
- AChE in synaptic cleft → hydrolyzes ACh → choline + acetate; ends signal
- MEPP → miniature end-plate potential from single spontaneous vesicle (~0.5 mV)
- EPP → evoked end-plate potential = sum of many quanta; depolarizes > threshold → muscle AP
- Safety factor → ratio of EPP amplitude to threshold; reduced in MG, normal in LEMS at rest
- Caspr1 + contactin-1 + NF155 → paranodal axoglial junction (septate-like)
- Kv1.1 / Kv1.2 → juxtaparanodal K⁺ channels (under the myelin)
- Nav1.6 → node of Ranvier Na⁺ channel cluster
- MAG (myelin-associated glycoprotein) → periaxonal myelin; anti-MAG IgM → distal acquired demyelinating symmetric neuropathy
Disease / drug association
- Decrement on 3 Hz RNS → myasthenia gravis (postsynaptic AChR Ab)
- ≥60% increment post-exercise / 50 Hz RNS → LEMS (P/Q VGCC Ab; small-cell lung cancer)
- Ice-pack test improves ptosis ≥2 mm → ocular myasthenia gravis
- Descending flaccid paralysis + dilated pupils + dry mouth in infant → infant botulism (BoNT cleaves SNAREs)
- BoNT-A cleaves SNAP-25 → botulinum toxin / therapeutic onabotulinumtoxin
- BoNT-B cleaves synaptobrevin (VAMP) → rimabotulinumtoxinB
- Tetanospasmin cleaves synaptobrevin in Renshaw cells → tetanus (loss of glycine/GABA inhibition → spastic paralysis, trismus, opisthotonos)
- α-latrotoxin / massive ACh release → black widow spider envenomation
- PMP22 duplication → CMT1A (uniform demyelinating, onion bulbs)
- PMP22 deletion → HNPP (tomaculous neuropathy, recurrent pressure palsies)
- Anti-NF155 / Caspr1 / contactin-1 / NF186 → autoimmune nodopathies (IVIG-refractory CIDP variant, rituximab-responsive)
- Anti-MuSK MG → bulbar/oculobulbar predominant, poor response to AChEI, rituximab effective
- SLUDGE-M + miosis + fasciculations → cholinergic crisis / organophosphate poisoning (treat atropine + pralidoxime)
- Succinylcholine in burns / SCI / denervation → lethal hyperkalemia (up-regulated extrajunctional AChR)
- Sugammadex → specific encapsulating reversal of rocuronium / vecuronium
- Neostigmine / pyridostigmine → reverse non-depolarizing blockade; first-line symptomatic MG therapy
- Edrophonium (Tensilon) → short-acting AChEI; historic MG diagnostic test
- 3,4-diaminopyridine (amifampridine) → K⁺ channel blocker → prolongs presynaptic AP → LEMS therapy
- Slow-channel CMS → AVOID pyridostigmine; treat with fluoxetine or quinidine
- DOK7 CMS → AVOID pyridostigmine; treat with ephedrine or salbutamol
- RAPSN / fast-channel / ChAT CMS → AChEI responsive
- COLQ CMS (end-plate AChE deficiency) → AVOID AChEI; treat with ephedrine/salbutamol
- High Mg²⁺ (eclampsia infusion) → blocks presynaptic Ca²⁺ entry → weakness; avoid in MG
- Aminoglycosides, fluoroquinolones, telithromycin → worsen MG (presynaptic Ca²⁺ + postsynaptic AChR effects)
Nerve Structure
Neuron Components
- Soma (cell body) — contains nucleus, Nissl substance (rough ER), site of protein synthesis
- Axon — single process for impulse conduction; axon hillock has lowest threshold for AP generation
- Dendrites — multiple branching processes; receive synaptic input
- Axonal transport:
- Anterograde (soma → terminal): kinesin; fast (200–400 mm/day) for vesicles, slow (1–5 mm/day) for cytoskeletal proteins
- Retrograde (terminal → soma): dynein; carries growth factors, viruses (rabies, herpes)
Peripheral Nerve Connective Tissue Layers
| Layer | Surrounds | Clinical Significance |
|---|---|---|
| Endoneurium | Individual nerve fibers | Must be intact for accurate regeneration; contributes to blood-nerve barrier |
| Perineurium | Fascicles (fiber bundles) | Main component of blood-nerve barrier; provides tensile strength |
| Epineurium | Entire nerve trunk | Contains vasa nervorum; target of surgical repair |
Myelinating Cells
| Feature | PNS — Schwann Cells | CNS — Oligodendrocytes |
|---|---|---|
| Cell-to-axon ratio | 1 Schwann cell : 1 internode | 1 oligodendrocyte : up to 50 internodes |
| Regeneration support | Good — forms bands of Büngner | Poor — inhibitory environment (Nogo, MAG) |
| Diseases | GBS, CIDP, CMT | MS, leukodystrophies |
Board Pearl
The perineurium is the primary barrier of the blood-nerve barrier. It is the structure that must be breached in perineuritis (e.g., leprosy). Schwann cells myelinate one internode each; oligodendrocytes myelinate up to 50 — explaining why CNS demyelination is more devastating.
Nerve Fiber Classification
Erlanger-Gasser Classification
| Fiber Type | Diameter (μm) | Velocity (m/s) | Myelination | Function |
|---|---|---|---|---|
| Aα | 12–20 | 70–120 | Heavy | Motor to skeletal muscle; proprioception (Ia, Ib) |
| Aβ | 5–12 | 30–70 | Heavy | Touch, pressure (type II afferents) |
| Aγ | 3–6 | 15–30 | Medium | Motor to muscle spindle (intrafusal fibers) |
| Aδ | 2–5 | 12–30 | Light | Fast pain, temperature, crude touch (type III) |
| B | 1–3 | 3–15 | Light | Preganglionic autonomic |
| C | 0.5–1.5 | 0.5–2 | Unmyelinated | Slow pain, temperature, postganglionic autonomic (type IV) |
Lloyd-Hunt Classification (Sensory Only)
| Lloyd-Hunt | Erlanger-Gasser Equivalent | Function |
|---|---|---|
| Ia | Aα | Muscle spindle primary endings (stretch) |
| Ib | Aα | Golgi tendon organs (tension) |
| II | Aβ | Muscle spindle secondary endings; touch, pressure |
| III | Aδ | Deep pressure, pain |
| IV | C | Slow pain, temperature |
Key Rule: Velocity ≈ 6 × Diameter
- Large myelinated fibers (Aα) → affected first by compression and ischemia
- Small unmyelinated fibers (C) → affected first by metabolic/toxic neuropathies (e.g., diabetes)
- Local anesthetics → block small fibers first (pain before motor)
Board Pearl
Conduction velocity ≈ 6 × fiber diameter. Compression/ischemia affects large fibers first (proprioception, motor). Metabolic/toxic neuropathies affect small fibers first (pain, temperature, autonomic). This distinction explains why diabetic neuropathy presents with burning pain while carpal tunnel presents with numbness.
Action Potential
Resting Membrane Potential
- Value: approximately −70 mV (range −60 to −90 mV depending on cell type)
- Maintained by: Na⁺/K⁺-ATPase (3 Na⁺ out, 2 K⁺ in) and K⁺ leak channels
- Nernst equation: determines equilibrium potential for each ion (EK ≈ −90 mV, ENa ≈ +60 mV)
- Goldman equation: accounts for permeability of all ions; at rest, membrane is most permeable to K⁺
Phases of the Action Potential
| Phase | Ion Channel Activity | Membrane Potential |
|---|---|---|
| Resting | K⁺ leak channels open; voltage-gated channels closed | −70 mV |
| Depolarization | Voltage-gated Na⁺ channels open (activation gate) | Rises toward +30 mV |
| Repolarization | Na⁺ channels inactivate (h-gate); voltage-gated K⁺ channels open | Falls back toward −70 mV |
| Hyperpolarization | K⁺ channels remain briefly open | Transiently below −70 mV (undershoot) |
Refractory Periods
| Period | Mechanism | Clinical Relevance |
|---|---|---|
| Absolute refractory | Na⁺ channels inactivated (h-gate closed); no stimulus can trigger AP | Ensures unidirectional propagation; limits maximum firing rate |
| Relative refractory | Some Na⁺ channels recovered; K⁺ channels still open; suprathreshold stimulus needed | Can fire but requires stronger stimulus; underlies frequency coding |
Saltatory Conduction & Velocity Factors
- Saltatory conduction: AP jumps node to node (nodes of Ranvier) in myelinated fibers → greatly increases speed
- Nodes of Ranvier: high density of voltage-gated Na⁺ channels
- Paranodal region: K⁺ channels normally covered by myelin; exposed in demyelination → K⁺ leak → conduction failure
- Factors increasing velocity: increased myelination, larger axon diameter, higher temperature
- Factors decreasing velocity: demyelination, cooling (hypothermia), smaller fiber size
Clinical Pearl
Demyelination exposes paranodal K⁺ channels → hyperpolarization → conduction block. This is why 4-aminopyridine (K⁺ channel blocker) can temporarily improve symptoms in MS by prolonging the AP at demyelinated segments.
Synaptic Transmission
Presynaptic & Postsynaptic Components
- Presynaptic terminal: contains synaptic vesicles, mitochondria, voltage-gated Ca²⁺ channels
- Synaptic cleft: 20–40 nm; contains degradative enzymes and extracellular matrix
- Postsynaptic membrane: neurotransmitter receptors (ionotropic and metabotropic), scaffolding proteins
EPSPs vs IPSPs
| Feature | EPSP | IPSP |
|---|---|---|
| Effect | Depolarization (toward threshold) | Hyperpolarization (away from threshold) |
| Ions | Na⁺ influx (or Ca²⁺) | Cl⁻ influx or K⁺ efflux |
| Neurotransmitters | Glutamate, acetylcholine | GABA, glycine |
| Graded? | Yes — not all-or-none | Yes — not all-or-none |
Summation
- Temporal summation: rapid, repeated firing of a single presynaptic neuron → cumulative EPSPs
- Spatial summation: simultaneous input from multiple presynaptic neurons → combined EPSPs at axon hillock
- If summed EPSPs reach threshold at the axon hillock → AP is generated
Neuromuscular Junction
NMJ Anatomy
- Presynaptic terminal: ACh-containing vesicles, P/Q-type voltage-gated Ca²⁺ channels, SNARE complex
- Synaptic cleft: 200–500 Å (20–50 nm); contains acetylcholinesterase (AChE) anchored to basal lamina
- Motor end plate (postsynaptic): junctional folds with nicotinic AChR concentrated at crests; Na⁺ channels at depths of folds
Steps of Normal Transmission
- AP arrives at presynaptic nerve terminal
- P/Q-type voltage-gated Ca²⁺ channels open → Ca²⁺ influx
- Ca²⁺ triggers SNARE-mediated vesicle fusion with presynaptic membrane
- ACh released into synaptic cleft (quantal release — each vesicle = 1 quantum ≈ 5,000–10,000 ACh molecules)
- ACh binds nicotinic AChR (2 ACh molecules per receptor needed)
- Na⁺ influx through receptor → end-plate potential (EPP)
- EPP exceeds threshold → muscle fiber AP → contraction
- AChE rapidly hydrolyzes ACh → choline recycled into nerve terminal
SNARE Proteins
| SNARE Protein | Location | Targeted By |
|---|---|---|
| Synaptobrevin (VAMP) | Vesicle membrane (v-SNARE) | Tetanus toxin; Botulinum toxin B, D, F, G |
| SNAP-25 | Presynaptic membrane (t-SNARE) | Botulinum toxin A, C, E |
| Syntaxin | Presynaptic membrane (t-SNARE) | Botulinum toxin C |
Safety Factor
- Definition: EPP amplitude is normally 3–4× greater than threshold needed for muscle AP
- Ensures reliable transmission even with moderate receptor loss or reduced release
- In MG: reduced AChR → decreased safety factor → transmission failure with repetitive use (fatigable weakness)
- In LEMS: reduced ACh release initially, but Ca²⁺ accumulates with repetitive stimulation → facilitation
Board Pearl
Botulinum toxin type A cleaves SNAP-25; tetanus toxin cleaves synaptobrevin (VAMP). Both block vesicle fusion. Botulism causes flaccid paralysis (blocks release at NMJ). Tetanus causes spastic paralysis (blocks inhibitory interneuron release in the spinal cord — the toxin travels retrograde).
NMJ Disorders
Major NMJ Disorders — Comparison
| Feature | Myasthenia Gravis | Lambert-Eaton | Botulism |
|---|---|---|---|
| Site | Postsynaptic | Presynaptic | Presynaptic |
| Target | Nicotinic AChR | P/Q-type VGCC | SNARE proteins |
| Antibodies | AChR (~80–85% generalized), MuSK (5–10%), LRP4 (1–3%) | VGCC (P/Q-type) | None (toxin-mediated) |
| Weakness pattern | Ocular → bulbar → proximal limbs; fatigable | Proximal legs > arms; improves transiently with use | Descending: cranial nerves → limbs → respiratory |
| Reflexes | Normal | Reduced/absent (improve post-exercise) | Reduced/absent |
| Autonomic | Spared | Prominent (dry mouth, constipation, impotence) | Prominent (dilated pupils, dry mouth, ileus) |
| RNS (2–3 Hz) | Decrement >10% | Low baseline CMAP; may decrement | Low baseline CMAP; may decrement |
| Post-exercise / high-freq RNS | Brief repair of decrement | Increment ≥60% (modern AANEM); >100% is the classic older/high-specificity threshold | Small increment (20–40%) |
| Association | Thymoma (10–15%), thymic hyperplasia | Small cell lung cancer (50–60%) | Contaminated food, wounds, infant honey |
Myasthenia Gravis — Key Details
- AChR antibodies (~80–85% generalized): complement-mediated destruction of postsynaptic membrane
- MuSK antibodies (5–10%): bulbar-predominant, muscle atrophy, AChE-I resistant (poor response to pyridostigmine)
- LRP4 antibodies (1–3%): rare, generally milder phenotype
- Drugs that worsen MG: Aminoglycosides, fluoroquinolones (esp ciprofloxacin), macrolides (telithromycin = boxed warning), magnesium (IV), beta-blockers (esp parenteral), procainamide, quinidine, quinine, lithium, neuromuscular blockers, D-penicillamine (induces MG), immune checkpoint inhibitors (PD-1/PD-L1 — triad MG + myositis + myocarditis), statins (rare).
- Myasthenic crisis: Intubate when FVC <20 mL/kg, NIF |<30| cmH2O, or MEP <40 cmH2O (20/30/40 rule). Treat with IVIG or plasmapheresis; hold AChE-I in crisis.
Myasthenia Gravis — Diagnosis
- Ice pack test — improves ptosis in ocular MG; sensitivity ~80%
- AChR-binding antibody (~80–85% generalized), MuSK Ab (5–10%, bulbar predominant, atrophy, AChE-I resistant), LRP4 Ab (1–3%)
- Striational antibodies — thymoma marker
- RNS slow (2–3 Hz): >10% decrement
- Single-fiber EMG (SFEMG): most sensitive (>95%) — increased jitter and blocking
- CT chest for thymoma
Myasthenia Gravis — Treatment (Modern)
- Symptomatic: pyridostigmine
- Immunosuppression: prednisone (transient worsening — start low, go slow), azathioprine (AZA), mycophenolate mofetil (MMF), cyclosporine, tacrolimus, methotrexate
- Biologics:
- Rituximab (especially MuSK-MG preferred)
- Eculizumab (Soliris) / Ravulizumab (Ultomiris) — anti-C5; meningococcal vaccination required
- Efgartigimod (Vyvgart IV / Vyvgart Hytrulo SC) / Rozanolixizumab (Rystiggo SC) — FcRn inhibitors
- Zilucoplan (Zilbrysq SC daily) — C5 peptide inhibitor (FDA 2023)
- Thymectomy: AChR+ generalized MG <60 yo (MGTX trial — improved outcomes)
- Crisis: IVIG, PLEX; hold AChE-I in crisis
Cholinergic Crisis
- SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis
- Miosis, fasciculations, weakness
- Treatment: atropine + supportive care; hold AChE-I
- Distinguish from myasthenic crisis: cholinergic crisis has miosis, SLUDGE, fasciculations; myasthenic crisis has mydriasis or normal pupils and no SLUDGE
Transient Neonatal Myasthenia
- Transplacental AChR Ab from MG mother
- ~10–20% of MG mothers' infants affected
- Resolves within weeks to months
Lambert-Eaton Myasthenic Syndrome (LEMS) — Treatment
- 3,4-diaminopyridine (amifampridine/Firdapse FDA 2018) — first-line symptomatic
- Pyridostigmine — adjunct
- IVIG / PLEX for severe disease
- Treat underlying SCLC
- Surveillance CT chest q3–6 mo × 2 yr if no cancer at baseline (Titulaer/DELTA-P)
Botulism — Subtypes & Treatment
- Foodborne — canned / improperly preserved foods
- Wound — IVDU (black tar heroin)
- Infant (<1 yr) — honey ingestion; constipation often first sign
- Inhalational — bioterrorism
- Iatrogenic — cosmetic injection
- Treatment: Equine heptavalent antitoxin for adult foodborne / wound botulism; BIG-IV (BabyBIG) for infant botulism (do NOT use equine antitoxin in infants — hypersensitivity); supportive ventilation
- AVOID aminoglycosides in infant botulism — worsen NMJ blockade
Tick Paralysis (Presynaptic NMJ Differential)
- Toxin from female Dermacentor tick
- Ascending flaccid paralysis (mimics GBS)
- Resolves with tick removal within hours
- Preserved sensation; NCS normal early
Organophosphate Poisoning (Synaptic-Cleft NMJ Disorder)
- Irreversible AChE inhibition → SLUDGE, miosis, fasciculations, weakness, respiratory failure
- Treatment: atropine (muscarinic) + pralidoxime (2-PAM — reactivates AChE before aging)
- Aging time is agent-dependent (sarin ~5 hr)
Postsynaptic Molecular Pathway
- Motor neuron-released agrin → binds LRP4 → activates MuSK (via Dok-7) → clusters AChR (anchored by rapsyn)
- Disruptions of this pathway underlie: MuSK-MG, LRP4-MG, Dok-7 CMS, rapsyn CMS
Fetal vs Adult Nicotinic AChR
- Adult NMJ: (α1)2β1δε
- Fetal / immature / denervated: (α1)2β1δγ (γ→ε perinatal switch)
- Anti-fetal AChR Ab → arthrogryposis multiplex congenita
Miniature Endplate Potentials (MEPPs)
- Spontaneous single-vesicle release at NMJ produces miniature endplate potentials (MEPPs) of fixed quantal size
- MEPPs sum to endplate potentials (EPPs) with nerve stimulus — basis of quantal theory of neurotransmission (Katz)
Congenital Myasthenic Syndromes
- Genetic (not autoimmune) — no antibodies; no response to immunotherapy
- Presynaptic: ChAT deficiency (choline acetyltransferase)
- Synaptic: AChE deficiency (endplate acetylcholinesterase)
- Postsynaptic: AChR subunit mutations (most common — slow-channel and fast-channel syndromes)
- Treatment varies by subtype: pyridostigmine for most; fluoxetine or quinidine for slow-channel CMS
Board Pearl
Do not give pyridostigmine to patients with AChE deficiency CMS or slow-channel CMS — it will worsen symptoms. Do not give immunotherapy for congenital myasthenic syndromes (they are not autoimmune).
Board Pearl
MG fatigues (gets worse with use); LEMS facilitates (gets better with use). Both cause proximal weakness. LEMS has prominent autonomic symptoms; MG does not. Always screen LEMS patients for small cell lung cancer. LEMS hallmark: low baseline CMAP with post-exercise / high-rate stim increment ≥60% (modern AANEM threshold); >100% is the classic older / high-specificity teaching threshold.
Nerve Injury Classification
Seddon vs Sunderland Classification
| Seddon | Sunderland Grade | Structure Injured | Pathology | Recovery |
|---|---|---|---|---|
| Neurapraxia | I | Myelin only | Local demyelination; axon intact | Complete; weeks to 3 months |
| Axonotmesis | II | Axon (endoneurium intact) | Wallerian degeneration distally | Good; 1 mm/day |
| III | Axon + endoneurium | Wallerian degeneration; intrafascicular scarring | Variable; misdirected regeneration | |
| IV | Axon + endoneurium + perineurium | Only epineurium intact | Poor without surgery | |
| Neurotmesis | V | Complete nerve transection | Total disruption | None without surgical repair |
Wallerian Degeneration Timeline
- 0–48 hours: axon and myelin begin to degenerate distal to injury
- 3–5 days: Schwann cells proliferate, macrophages infiltrate to phagocytose debris
- 7–10 days: Wallerian degeneration complete; NCS shows absent/reduced distal CMAP and SNAP
- 2–3 weeks: fibrillations and positive sharp waves appear in proximal muscles on EMG
- 4–5 weeks: fibrillations appear in distal muscles
- Schwann cells form bands of Büngner to guide axonal regrowth
Recovery Patterns
- Regeneration rate: ∼1 mm/day (∼1 inch/month)
- Neurapraxia: full recovery in weeks to 3 months; no fibrillations on EMG
- Axonotmesis: recovery depends on distance from target; motor end plates degenerate by 12–18 months — sets time limit
- Signs of reinnervation: advancing Tinel sign, nascent (small, polyphasic) motor unit potentials on EMG
- Younger age, proximal injury, short distance to target → better prognosis
Board Pearl
Neurapraxia = conduction block without Wallerian degeneration. No fibrillations on EMG, full recovery expected. Axonotmesis shows fibrillations at 2–5 weeks. Key timing: NCS changes at 7–10 days; proximal fibs at 2–3 weeks; distal fibs at 4–5 weeks. Regeneration rate is 1 mm/day.
Channelopathies
Sodium Channelopathies (SCN4A — Nav1.4)
| Disorder | Mechanism | Clinical Features | Triggers |
|---|---|---|---|
| Hyperkalemic Periodic Paralysis | Gain of function → prolonged Na⁺ channel opening → persistent depolarization | Episodic weakness (minutes to hours); myotonia common | High K⁺, fasting, rest after exercise, cold |
| Paramyotonia Congenita | Impaired fast inactivation | Paradoxical myotonia (worsens with activity); cold-induced stiffness then weakness | Cold, exercise |
| Sodium Channel Myotonia | Delayed Na⁺ channel inactivation | Myotonia without paralysis; K⁺-aggravated | K⁺ loading |
Calcium Channelopathies
| Disorder | Gene / Channel | Mechanism | Clinical Features |
|---|---|---|---|
| Hypokalemic Periodic Paralysis | CACNA1S (Cav1.1) — 70%; SCN4A — 10% | Loss of function → reduced excitability during low K⁺ | Episodic weakness (hours to days); NO myotonia; carbs and rest trigger attacks |
| Absence Epilepsy (Childhood) | CACNA1A / CACNA1H (T-type Ca²⁺ channels) | Abnormal thalamocortical oscillation via low-threshold T-type Ca²⁺ channels | Staring spells with 3 Hz spike-and-wave on EEG; treated with ethosuximide (blocks T-type channels) |
| Malignant Hyperthermia | RYR1 (ryanodine receptor) | Uncontrolled Ca²⁺ release from sarcoplasmic reticulum | Triggered by volatile anesthetics/succinylcholine; rigidity, hyperthermia, rhabdomyolysis; treat with dantrolene |
Potassium Channelopathies
- Episodic Ataxia Type 1 (EA1): KCNA1 (Kv1.1) mutations → brief episodes of ataxia with myokymia; responds to carbamazepine
- Benign Familial Neonatal Seizures: KCNQ2/KCNQ3 → reduced M-current → seizures in first week of life; self-limited
- Andersen-Tawil Syndrome: KCNJ2 (Kir2.1) → periodic paralysis + cardiac arrhythmias (prolonged QT) + dysmorphic features
Periodic Paralysis Comparison
| Feature | Hypokalemic PP | Hyperkalemic PP |
|---|---|---|
| Channel | CACNA1S (Ca²⁺) or SCN4A (Na⁺) | SCN4A (Na⁺) |
| K⁺ during attack | Low (<3.5 mEq/L) | High or normal |
| Triggers | Carbs, rest after exercise, insulin, stress | Fasting, rest after exercise, cold, K⁺ load |
| Myotonia | Absent | Often present (clinical or EMG) |
| Attack duration | Hours to days | Minutes to hours (shorter) |
| Acute treatment | K⁺ replacement | Carbohydrate load, inhaled β-agonist, calcium gluconate |
| Prophylaxis | Acetazolamide, K⁺-sparing diuretics | Acetazolamide or dichlorphenamide |
Clinical Pearl
Thyrotoxic periodic paralysis mimics hypokalemic PP but is acquired (not inherited). It is most common in Asian males. Treat the hyperthyroidism; avoid high-dose IV K⁺ (risk of rebound hyperkalemia as K⁺ re-enters cells).
Board Pearl
HypoKPP = no myotonia; HyperKPP = myotonia common. Both worsen with rest after exercise. Acetazolamide (carbonic anhydrase inhibitor) is prophylactic for both types. Absence seizures involve T-type Ca²⁺ channels — treat with ethosuximide. Malignant hyperthermia = RYR1 mutation; treat with dantrolene immediately.
Quick Reference
High-Yield Summary Table
| Topic | Key Fact | Board Buzzword |
|---|---|---|
| Nerve layers | Endo → Peri → Epi (inside out) | Perineurium = blood-nerve barrier |
| Myelination | Schwann cell = 1:1; oligodendrocyte = 1:50 | Bands of Büngner (regeneration) |
| Fiber velocity | Velocity ≈ 6 × diameter | Aα fastest; C slowest |
| Resting potential | −70 mV; maintained by Na⁺/K⁺-ATPase | K⁺ leak channels set resting potential |
| Saltatory conduction | AP jumps between nodes of Ranvier | Paranodal K⁺ exposed in demyelination |
| NMJ transmission | P/Q Ca²⁺ channels → SNARE fusion → ACh release | Safety factor = 3–4× threshold |
| MG | Postsynaptic AChR Ab; fatigable; decrement on RNS | Thymoma, ptosis, bulbar weakness |
| LEMS | Presynaptic VGCC Ab; facilitates; increment ≥60% (modern AANEM); >100% is the classic older/high-specificity threshold | SCLC, dry mouth, proximal legs |
| Botulism | SNAP-25 cleavage; descending paralysis | Dilated pupils, autonomic, infant honey |
| Neurapraxia | Demyelination only; conduction block; no fibs | Full recovery, Sunderland I |
| Axonotmesis | Axon loss; Wallerian degeneration; fibs at 2–5 wk | 1 mm/day regeneration |
| HyperKPP | SCN4A gain of function; myotonia + weakness | Fasting, cold, K⁺ triggers |
| HypoKPP | CACNA1S; NO myotonia; carbs trigger | Hours-long attacks; K⁺ replacement |
| Absence seizures | T-type Ca²⁺ channels; thalamocortical | 3 Hz spike-and-wave; ethosuximide |
Clinical Pearl
For any patient with acute weakness: (1) check respiratory function (FVC) before anything else, (2) distinguish UMN from LMN, and (3) if NMJ disorder suspected, check RNS pattern — decrement alone suggests MG; low CMAP with large increment suggests LEMS or botulism.
Board Pearl
Never give succinylcholine to patients with known or suspected hyperkalemic periodic paralysis, malignant hyperthermia susceptibility, or denervation injuries — risk of fatal hyperkalemia or MH crisis. Avoid aminoglycosides, magnesium, and fluoroquinolones in myasthenia gravis — may precipitate crisis.
References
- Kandel ER, Schwartz JH, Jessell TM, et al. Principles of Neural Science. 6th ed. McGraw-Hill; 2021.
- Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. 4th ed. Elsevier; 2021.
- Aminoff MJ, Josephson SA. Aminoff’s Neurology and General Medicine. 6th ed. Academic Press; 2021.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Engel AG. Congenital myasthenic syndromes in 2018. Curr Neurol Neurosci Rep. 2018;18(8):46.
- Statland JM, Bhatt T. Channelopathies: Episodic and electrical diseases of the nervous system. In: Daroff RB, et al., eds. Bradley and Daroff’s Neurology in Clinical Practice. 8th ed. Elsevier; 2022.
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