17.3 Neuromuscular Junction & Peripheral Nerve Disorders
Key Takeaways
- Myasthenia gravis is mediated by postsynaptic anti-AChR (85%) or anti-MuSK antibodies, causing fatigable weakness with normal sensation and reflexes; thymic pathology is present in 80% (10–15% thymoma, requiring mandatory contrast CT chest).
- Lambert-Eaton myasthenic syndrome (LEMS) involves presynaptic voltage-gated calcium channel (VGCC) antibodies, strongly linked to small cell lung cancer (50–60%); it presents with proximal weakness, hyporeflexia, and autonomic symptoms that uniquely improve following brief voluntary contraction (post-exercise facilitation).
- Motor neurone disease (ALS) is defined by combined upper motor neurone (spasticity, brisk reflexes, extensor plantars) and lower motor neurone (wasting, fasciculations) signs in the same body territory, with strict sparing of sensation, sphincter function, and external ocular motility; riluzole and non-invasive ventilation prolong survival.
- Guillain-Barré syndrome presents as acute ascending flaccid tetraparesis and areflexia following Campylobacter jejuni infection; CSF demonstrates albuminocytological dissociation, and management mandates serial vital capacity monitoring with prompt IVIG or plasma exchange, while corticosteroids are strictly ineffective.
- Mononeuropathies have clear localising anatomical boundaries: radial nerve lesions at the spiral groove cause wrist drop with preserved triceps; carpal tunnel syndrome affects LOAF thenar muscles with spared thenar eminence sensation; common peroneal nerve injury causes foot drop with preserved foot inversion, distinguishing it from an L5 radiculopathy.
Neuromuscular junction pathology, motor neurone disease, and peripheral neuropathies are cornerstone topics in the MRCP(UK) examination. Candidates must master clinical distinctions between presynaptic and postsynaptic junctional transmission failures, identify mixed upper and lower motor neurone signs, navigate emergency monitoring in neuromuscular respiratory failure, and apply precise neuroanatomical localization to peripheral nerve entrapments.
1. Neuromuscular Junction Disorders: Myasthenia Gravis vs. Lambert-Eaton Syndrome
| Diagnostic Feature | Myasthenia Gravis (MG) | Lambert-Eaton Myasthenic Syndrome (LEMS) |
|---|---|---|
| Primary Antigen & Target | Postsynaptic nicotinic Acetylcholine Receptor (anti-AChR) in 80–85% generalised (50% ocular); Muscle-Specific Kinase (anti-MuSK) in 5–10% | Presynaptic P/Q-type Voltage-Gated Calcium Channels (anti-VGCC) in >90% |
| Pathophysiology | Autoantibody binding causes complement-mediated destruction of junctional folds, cross-linking, and receptor endocytosis, reducing the safety factor of neuromuscular transmission | Antibodies block presynaptic calcium influx during nerve action potential, preventing calcium-dependent exocytosis of acetylcholine vesicles |
| Muscle Weakness Distribution | Ocular symptoms prominent & early (>85%): Asymmetric ptosis, diplopia, Cogan's lid twitch (pupils strictly spared).<br>Bulbar weakness: Dysphagia, nasal regurgitation, dysarthria, "myasthenic snarl".<br>Neck flexion and proximal limb weakness | Proximal lower limb weakness predominant: Difficulty rising from chairs or climbing stairs.<br>Ocular and bulbar symptoms are typically mild, transient, or absent |
| Fatigability vs. Facilitation | Marked fatigability: Weakness worsens with sustained or repetitive exercise and toward evening; improves with rest | Post-tetanic facilitation / Post-exercise potentiation: Muscle strength and deep tendon reflexes transiently improve immediately after 10–15 seconds of maximal voluntary contraction |
| Deep Tendon Reflexes | Normal throughout; easily elicited | Depressed or completely absent at baseline; characteristically augment or reappear immediately following brief exercise |
| Autonomic Dysfunction | Absent | Prominent autonomic failure in >80%: Dry mouth (xerostomia), erectile dysfunction, constipation, orthostatic lightheadedness |
| Systemic Associations | Thymic follicular hyperplasia (~65%) (young females); Thymoma (10–15%) (older patients). Contrast-enhanced CT chest is mandatory. Thyroiditis, SLE | Strongly paraneoplastic in 50–60%: Associated with Small Cell Lung Cancer (SCLC); contrast CT/PET thorax is mandatory. Remainder are primary autoimmune |
| Diagnostic Neurophysiology | - Repetitive Nerve Stimulation (2–3 Hz low frequency): Decremental response (>10% drop in CMAP amplitude from 1st to 4th/5th potential)<br>- Single-Fiber EMG (SFEMG): Increased jitter and impulse blocking (gold standard, >95% sensitivity) | - Baseline CMAP amplitude: Markedly reduced<br>- High-frequency RNS (20–50 Hz) or post-exercise: Marked incremental response (>100% to >200% surge in CMAP amplitude) |
| Definitive Management | 1. Symptomatic: Pyridostigmine (oral acetylcholinesterase inhibitor)<br>2. Immunosuppression: Oral prednisolone + azathioprine (check TPMT)<br>3. Thymectomy: Indicated for all thymomas, and non-thymomatous generalised AChR-positive patients aged 18–65 | 1. First-line symptomatic: Amifampridine (3,4-diaminopyridine / 3,4-DAP): Blocks presynaptic K⁺ channels, prolonging action potential and promoting ACh release<br>2. Treat underlying SCLC (produces dramatic neurological remission) |
Myasthenic Crisis & Critical Drug Warnings
- Definition & Monitoring: Life-threatening acute respiratory failure driven by severe diaphragmatic and intercostal weakness. Patients must be monitored in ITU/HDU with serial Forced Vital Capacity (FVC) every 2–4 hours (using the "20/30/40 rule": elective mechanical ventilation is indicated if FVC <15–20 mL/kg, maximum inspiratory pressure <-30 cmH2O, or maximum expiratory pressure <40 cmH2O). Never rely on pulse oximetry alone; hypoxaemia is an exceedingly late sign. Single-breath count <15 indicates critical respiratory compromise.
- Acute Crisis Therapy: Intravenous Immunoglobulin (IVIG 2 g/kg over 2–5 days) OR Plasma Exchange (PLEX, 5 exchanges). High-dose steroids should not be initiated acutely without prior IVIG/PLEX coverage, as corticosteroids can trigger a paradoxical transient deterioration during the first 7–10 days.
- Medications That Exacerbate Myasthenia (Strictly Avoid or Use with Extreme Caution):
- Antibiotics: Aminoglycosides (gentamicin, amikacin—inhibit presynaptic ACh release), Macrolides (erythromycin, clarithromycin), Fluoroquinolones (ciprofloxacin), Telithromycin (black box warning).
- Cardiovascular: Beta-blockers (oral and ophthalmic timolol), Calcium channel blockers, Procainamide, Quinidine.
- Electrolytes & Others: Intravenous Magnesium (potent neuromuscular transmission blocker; can induce immediate respiratory arrest!), D-penicillamine, Chloroquine, Immune Checkpoint Inhibitors (can trigger fulminant necrotising myasthenia).
2. Motor Neurone Disease (Amyotrophic Lateral Sclerosis)
Pathophysiology
- Progressive neurodegeneration selectively affecting Upper Motor Neurones (UMN) in the primary motor cortex (descending corticospinal and corticobulbar tracts) and Lower Motor Neurones (LMN) in the brainstem motor nuclei and spinal cord anterior horn cells.
- Histology demonstrates ubiquitinated cytoplasmic inclusions of TDP-43 in >95% of cases. Familial forms (~10%) involve hexanucleotide repeat expansions in C9orf72 or SOD1 mutations.
Clinical Phenotypes & Hallmarks
- Hallmark Clinical Rule: Simultaneous coexistence of Upper Motor Neurone signs (spasticity, brisk tendon reflexes, positive Hoffman's sign, extensor Babinski plantars, pseudobulbar brisk jaw jerk) AND Lower Motor Neurone signs (muscle wasting, amyotrophy, prominent coarse fasciculations, flaccidity) within the same anatomical territory or limb (e.g. a wasted, fasciculating arm displaying a hyperactive biceps jerk).
- Preserved Systems (Crucial Rule-Outs for Mimics):
- Sensory examination is completely normal (no sensory loss, no paraesthesias).
- Sphincter function is preserved (bowel and bladder control intact; sparing of Onuf's nucleus in S2–S4).
- External ocular motility is preserved (sparing of CN III, IV, VI nuclei).
- Major Disease Variants:
- Amyotrophic Lateral Sclerosis (ALS, ~70%): Classical presentation with mixed UMN and LMN signs in the limbs.
- Progressive Bulbar Palsy (~20%): Bulbar onset featuring dysarthria, dysphagia, tongue wasting, tongue fasciculations, and spastic dysarthria ("hot potato" speech).
- Progressive Muscular Atrophy (PMA, ~5%): Predominantly lower motor neurone limb deficits.
- Primary Lateral Sclerosis (PLS, ~2%): Pure upper motor neurone spastic tetraparesis.
Diagnostic & Multidisciplinary Management
- Electromyography (EMG): Shows widespread active denervation (fibrillation potentials, positive sharp waves) and chronic reinnervation (large-amplitude, polyphasic motor unit potentials) in >= 2 body regions (cervical, thoracic, lumbosacral, bulbar). Neuroimaging (MRI brain and whole spine) is mandatory to exclude cervical spondylotic myelopathy, multiple sclerosis, or spinal dural fistulas.
- Disease-Modifying Therapy: Riluzole (50 mg twice daily; inhibits presynaptic glutamate release and blocks NMDA receptors). Extends tracheostomy-free survival by 2–3 months. Requires baseline and regular monitoring of FBC and liver transaminases (risk of transaminitis and neutropenia).
- Symptom & Supportive Interventions (Highest Impact on Quality of Life and Survival):
- Non-Invasive Ventilation (NIV / BiPAP): Prolongs survival by 7–12 months and dramatically enhances quality of life; indicated when FVC <80% predicted, nocturnal hypoventilation, or orthopnoea.
- Enteral Feeding: Radiologically inserted gastrostomy (RIG) or percutaneous endoscopic gastrostomy (PEG), ideally placed before FVC falls below 50%.
- Sialorrhoea: Oral glycopyrronium or transdermal hyoscine patch; botulinum toxin injection to parotid/submandibular glands for refractory cases.
- Spasticity: Baclofen or tizanidine; cramps treated with quinine sulphate.
3. Guillain-Barré Syndrome (GBS) & Variants
Pathogenesis & Molecular Mimicry
- Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) triggered by an antecedent infection 1–3 weeks prior.
- Classical trigger: Campylobacter jejuni enteritis (in ~30%, associated with anti-GM1/GD1a antibodies and severe axonal variants: AMAN/AMSAN). Other triggers: CMV, EBV, Mycoplasma pneumoniae, Hepatitis E, and Zika virus.
- Pathogenic mechanism: Lipooligosaccharides on the bacterial coat exhibit molecular mimicry with human peripheral nerve gangliosides, triggering cross-reactive autoantibodies that fix complement, dismantle the myelin sheath, and damage nodal axolemma.
Clinical Presentation
- Ascending Symmetrical Flaccid Weakness: Starts in distal lower extremities, advancing rapidly over days to thighs, trunk, upper limbs, and cranial nerves (bilateral lower motor neuron facial weakness / facial diplegia in ~50%).
- Areflexia / Hyporeflexia: Widespread, early loss of deep tendon reflexes.
- Sensory Symptoms: Distal paresthesias in a glove-and-stocking distribution; objective sensory loss is characteristically mild compared to profound motor weakness.
- Autonomic Instability (in ~65%): Sinus tachycardia, severe bradyarrhythmias, paroxysmal hypertension, orthostatic hypotension, cardiac conduction blocks, and paralytic ileus.
- Neuromuscular Respiratory Failure: Develops in 25–30% of patients; mandates serial bedside monitoring of Forced Vital Capacity (FVC) every 4–6 hours. Intubation is indicated when FVC <15–20 mL/kg.
Diagnostic Investigations & Management
- Lumbar Puncture: Albuminocytological Dissociation—markedly elevated CSF protein concentration (>1.0 g/L, often >2–3 g/L) with a completely normal CSF white cell count (<5–10 cells/μL). Protein elevation may be absent during the first 7 days, peaking at 2–4 weeks.
- Nerve Conduction Studies (NCS): Hallmark signs of demyelination: marked prolongation of distal motor latencies, reduction in conduction velocities, conduction block, temporal dispersion, and prolonged or absent F-waves.
- First-Line Immunotherapy: Intravenous Immunoglobulin (IVIG 0.4 g/kg/day for 5 days) OR Plasma Exchange (PLEX, 5 sessions over 10–14 days). Both have equivalent clinical efficacy; combining them yields no additional benefit.
- CRITICAL MRCP RULE: Corticosteroids (oral prednisolone or IV methylprednisolone) are completely INEFFECTIVE in Guillain-Barré syndrome; clinical trials show no benefit and potential prolongation of disability.
Miller Fisher Syndrome (MFS)
- Classical clinical triad: 1. Ophthalmoplegia (diplopia, bilateral external ocular motility restriction); 2. Ataxia (severe sensory/cerebellar-like gait unsteadiness out of proportion to limb weakness); 3. Areflexia.
- Strongly associated with serum anti-GQ1b ganglioside antibodies (>90% seropositivity); GQ1b is highly concentrated on cranial nerves III, IV, and VI and neuromuscular spindles.
- Excellent clinical prognosis with prompt response to IVIG.
4. Common Peripheral Nerve Entrapments & Mononeuropathies
| Nerve & Root Levels | Vulnerable Anatomical Site | Characteristic Motor Deficit & Deformity | Specific Sensory Loss Territory | Hallmark Clinical Signs & Diagnostic Differentiation |
|---|---|---|---|---|
| Radial Nerve<br>(C5–T1, Posterior cord) | Spiral groove of the humerus ("Saturday night palsy", humerus shaft fracture, improper crutch use) | Weakness of wrist extension ("wrist drop"), finger extension at MCP joints, and brachioradialis.<br>Triceps extension is SPARED in spiral groove lesions (triceps branch arises higher in the axilla) | Dorsal aspect of the first web space (anatomical snuffbox) and dorsolateral hand | Preserved forearm pronation and wrist flexion differentiates from central lesions. Normal sensation over the arm if lesion is at spiral groove |
| Median Nerve<br>(C6–T1, Medial & lateral cords) | Carpal tunnel at the wrist (beneath the flexor retinaculum); linked to pregnancy, hypothyroidism, RA, acromegaly, obesity, diabetes | Wasting and weakness of thenar muscles (LOAF):<br>- Lateral 2 lumbricals<br>- Opponens pollicis<br>- Abductor pollicis brevis (most sensitive test: weak thumb abduction perpendicular to palm)<br>- Flexor pollicis brevis | Paresthesias and numbness over palmar aspects of digits 1, 2, 3, and lateral half of digit 4.<br>Sensory sparing over thenar eminence (palmar cutaneous branch passes superficial to flexor retinaculum!) | - Tinel's sign: Tapping over carpal tunnel elicits paresthesias<br>- Phalen's sign: Forced wrist flexion for 60s reproduces symptoms<br>- Flick sign: Hand shaking relieves nocturnal pain<br>Rx: Neutral wrist splints, steroid injection, surgical release |
| Ulnar Nerve<br>(C8–T1, Medial cord) | Cubital tunnel at the elbow (retrocondylar groove behind medial epicondyle); Guyon's canal at wrist | Wasting and weakness of hypothenar muscles, all interossei (dorsal "DAB" abduct, palmar "PAD" adduct), medial 2 lumbricals, and adductor pollicis.<br>"Claw hand" (hyperextension at MCP, flexion at IP of 4th/5th digits; ulnar paradox: clawing is worse in wrist lesions than elbow lesions) | Palmar and dorsal surfaces of digit 5 and medial half of digit 4 (hypothenar border) | Froment's Sign: Grasping a sheet of paper between thumb and index finger against resistance forces compensatory hyperflexion of the thumb interphalangeal joint via the median-innervated flexor pollicis longus (due to weak adductor pollicis). Wasting of the first dorsal interosseous |
| Common Peroneal (Fibular)<br>(L4–S1, from Sciatic nerve) | Fibula head / neck (fibula fracture, tight cast, prolonged leg-crossing, prolonged kneeling/squatting, bedbound) | Foot drop: Weakness of ankle dorsiflexion (tibialis anterior) and foot eversion (peroneus longus/brevis). Causes a high-stepping slapping gait | Sensory loss over the anterolateral lower leg and entire dorsum of the foot (including the first web space) | CRITICAL DISTINCTION FROM L5 RADICULOPATHY:<br>- In Common Peroneal Nerve lesion: Foot inversion is completely INTACT (innervated by Tibialis Posterior via the Tibial nerve).<br>- In L5 Radiculopathy: Both foot dorsiflexion AND foot inversion are weak, and hip abduction (gluteus medius) is weak! Ankle jerk (S1) is preserved in both |
A 62-year-old man with a 40-pack-year smoking history is evaluated for a 5-month history of progressive difficulty climbing stairs and rising from low armchairs. Over the last 2 months, he has also experienced a persistently dry mouth and progressive erectile dysfunction. On physical examination, cranial nerve testing is completely normal, with no ptosis or diplopia. Motor examination reveals proximal muscle weakness of the pelvic girdle and thighs (Medical Research Council grade 3/5 in hip flexors and quadriceps). Initial testing of deep tendon reflexes reveals completely absent knee and ankle jerks. However, immediately after the patient is asked to perform 15 seconds of sustained, maximal voluntary contraction of his quadriceps against resistance, re-testing demonstrates prompt Medical Research Council grade 5/5 muscle power and easily elicitable 2+ knee jerk reflexes. Sensation is normal. A contrast-enhanced CT scan of the thorax reveals a 2.8 cm hilar mass and mediastinal lymphadenopathy. Which of the following is the primary pathophysiological mechanism underlying this patient's neuromuscular weakness?
A 59-year-old carpenter presents with a 6-month history of progressive weakness in his right hand, difficulty gripping tools, and a painless right foot drop that causes him to trip over carpets. More recently, he has noted slurring of his speech and unintentional weight loss of 5 kg. On examination, cranial nerve testing reveals marked fasciculations and wasting of the tongue, accompanied by a brisk, exaggerated jaw jerk. In the upper limbs, there is prominent wasting of the right first dorsal interosseous and thenar muscles with visible fasciculations, yet the right biceps and brachioradialis reflexes are brisk (3+) with a positive Hoffman's sign. In the lower limbs, there is severe weakness of right ankle dorsiflexion (MRC grade 2/5) with muscle wasting of the anterior tibialis, but the right knee and ankle jerks are markedly brisk with an extensor (Babinski) right plantar response. Sensory examination to light touch, pinprick, vibration, and proprioception is completely normal across all four extremities. Sphincter control is fully preserved, and ocular motility is normal. Electromyography (EMG) reveals active denervation with fibrillation potentials and chronic reinnervation in the tongue, cervical, and lumbosacral segments. What is the most definitive diagnosis?
A 28-year-old man presents to the emergency department with a 4-day history of tingling in his toes and rapidly progressive weakness in both legs, making it impossible for him to walk unassisted. Ten days prior to symptom onset, he experienced a 3-day self-limiting episode of fever, crampy abdominal pain, and bloody diarrhoea while travelling. On physical examination, he is alert and orientated. Cranial nerve assessment reveals mild bilateral lower motor neuron facial weakness (facial diplegia). Motor examination demonstrates symmetrical flaccid quadriparesis, with muscle power graded Medical Research Council 2/5 in the lower extremities and 3/5 in the upper extremities. All deep tendon reflexes (biceps, triceps, supinator, knee, and ankle jerks) are completely absent. Sensory testing reveals mild stocking-gaze hypaesthesia to pinprick over both feet, but proprioception and vibration are intact. Bedside spirometry demonstrates a forced vital capacity (FVC) of 1.4 L (18 mL/kg of body weight, predicted 4.2 L). Lumbar puncture is performed, and CSF analysis reveals: Opening pressure 16 cmH2O, White blood cell count 3 cells/μL (<5), Protein 1.84 g/L (0.15–0.45), Glucose 3.8 mmol/L (serum 5.6). What is the most appropriate disease-modifying treatment for this condition?