GC056 Generalized Muscle Weakness
Generalized muscle weakness is a diffuse reduction in muscle strength affecting multiple muscle groups, resulting from neurological, muscular, metabolic, or systemic disorders that impair the ability to generate normal voluntary force.
Generalized Muscle Weakness: Myasthenia Gravis, Myopathy & Myositis, Neuropathy, Neurophysiology II
This lecture (GC 056) is a cornerstone neuromuscular session that asks you to systematically evaluate a patient presenting with generalized weakness. The "big idea" is anatomical localization: once you know where the lesion is (peripheral nerve vs. neuromuscular junction vs. muscle), the differential diagnosis, investigations, and management flow logically. The lecture also covers the floppy infant syndrome and the principles of clinical neurophysiology (NCS/EMG).
Learning objectives [1]:
- Evaluate a floppy baby clinically.
- Differentiate floppiness with or without weakness to narrow the aetiology.
- Understand the simple classification of neuromuscular diseases (common types).
- Recall the neuroanatomy of peripheral nerves, NMJ, and muscle.
- Understand different entities of neuropathy and principles of neurophysiology tests.
- Learn the classification, pathophysiology, pathogenesis, clinical features, investigations, and differential diagnosis of myasthenia gravis.
- Learn entities of muscle disorders and principles of neurophysiology tests in myopathy.
How the lecture fits clinically and in exams: Generalized weakness is a frequent SAQ/minicase stem. Examiners love asking you to distinguish between neuropathy, NMJ disease, and myopathy using clinical features, then select the correct investigation. Past paper themes include GBS management, MG investigations, DMD presentation, and inflammatory myopathy associations with malignancy.
The critical first step is to determine if the lesion is at the level of the CNS, peripheral nerve, NMJ, or muscle. [1][2]
This is the single most important concept in the lecture. Everything else is a branching tree from this localization.
Why Localization Matters From First Principles
The motor pathway runs: Motor cortex → Corticospinal tract → Anterior horn cell → Peripheral nerve → NMJ → Muscle. A lesion at each level produces a distinct pattern of signs because:
- UMN lesions (cortex/cord) lose inhibitory modulation → hypertonia, hyperreflexia, upgoing plantars
- LMN lesions (anterior horn/peripheral nerve) lose trophic support → wasting, fasciculations, hyporeflexia
- NMJ lesions have intact nerve and muscle architecture but impaired transmission → fatigability without wasting or sensory loss
- Muscle lesions damage the effector → proximal weakness, elevated CK, no sensory involvement
High Yield – The Localization Table
This table is directly from the lecture and senior notes and is the framework examiners use to write question stems. Memorize the discriminating features.
| Feature | CNS Lesion | Peripheral Nerve | NMJ Disease | Muscle Disease |
|---|---|---|---|---|
| Pattern of weakness | Whole limbs; UL extensors, LL flexors | Symmetrical distal | Symmetrical proximal; fatigable | Symmetrical proximal |
| Wasting | Minimal | Early wasting | NO wasting | Variable; pseudohypertrophy possible |
| Tone | ↑ (spastic) | ↓ (flaccid) | Normal | Normal or slightly ↓ |
| Reflexes | Hyperreflexia | Hypo-/areflexia | Preserved (↓ in LEMS) | Variable |
| Sensory loss | Dissociated possible | Non-dissociated, glove-and-stocking | ABSENT | ABSENT |
| Fasciculations | No | Yes | No | Possible (rarely) |
| Gait | Spastic/scissoring | Steppage gait | — | Waddling gait |
| Sphincter | May be involved | Rare | Spared | Spared |
| Key Hx clue | Higher function deficits, bulbar | Pain, autonomic dysfunction | Fluctuating, diurnal variation, ocular/bulbar | Proximal difficulty (stairs, standing), ± myalgia |
| Key Ix | CT/MRI brain, LP | NCS, bloods, LP | RNS, Tensilon test, anti-AChR | CK, EMG, muscle biopsy |
Exam Trap
Do NOT confuse "no sensory loss" in NMJ/muscle disease with "no sensory symptoms." GBS patients often report sensory symptoms (tingling, pain) but the hallmark is motor > sensory deficit. In pure MG or myopathy, there is truly no sensory involvement at all.
1. Polyneuropathies
Polyneuropathies present with motor problems (weakness, wasting, fasciculations, hyporeflexia, bulbar/respiratory involvement) AND sensory problems (negative = numbness; positive = pain/paraesthesia). [1]
Classify every polyneuropathy by four axes [1]:
| Axis | Options | Why it matters |
|---|---|---|
| Time course | Acute / Subacute / Chronic / Relapsing | Acute → think GBS, toxin; Chronic → think DM, hereditary, CIDP |
| Distribution | Generalized / Focal | Generalized = polyneuropathy; Focal = mononeuropathy/mononeuritis multiplex (vasculitis) |
| Fibre type | Motor / Sensory / Autonomic / Mixed | Pure motor → GBS, MND; Pure sensory → DM small fibre; Mixed → most common |
| Pathology | Primarily axonal / Demyelinating / Mixed | Axonal = poor prognosis (nerve dies); Demyelinating = potentially treatable (myelin regrows) |
The lecture lists diverse aetiologies [1]:
| Category | Examples |
|---|---|
| Inflammatory demyelinating | GBS, CIDP |
| Infectious/Granulomatous | Leprosy, sarcoidosis, HIV-related, Lyme disease |
| Systemic disease | Diabetes, CRF, vitamin deficiency, paraproteinaemias, CTD, critical illness polyneuropathy |
| Ischaemic | PVD, vasculitis |
| Metabolic | Various inherited metabolic |
| Hereditary | CMT disease, SMA |
| Toxins | Pharmaceuticals (anti-neoplastic, anti-TB, anti-HIV, colchicine, thalidomide, pyridoxine abuse), environmental toxins, alcohol, solvents, heavy metals |
Electrophysiological studies, look for systemic diseases, CSF, nerve biopsy (seldom indicated), genetic tests. [1]
- NCS differentiates axonal (↓ amplitude) from demyelinating (↓ conduction velocity, prolonged distal latency, conduction block).
- Blood tests: Glucose/HbA1c, CBC, L/RFT, TFT, Vit B12/folate, ESR/CRP, serum protein electrophoresis (SPE) — screen for the treatable systemic causes. [2]
- CSF: albuminocytological dissociation in GBS.
- Nerve biopsy: reserved for vasculitis, amyloidosis, granulomatous disease where diagnosis cannot be made otherwise.
1.4 Clinically Important Polyneuropathies (Lecture Deep Dives)
High Yield – GBS Definition
"Rapidly progressive flaccid paralysis, areflexia and raised CSF protein without increase in cells (albuminocytological dissociation)." [1]
Epidemiology & Pathogenesis [1]:
- Incidence: 1–2 per 100,000 per year
- Immune-mediated, inflammatory polyneuropathy
- Antecedent viral/bacterial infection (URTI, GE) in 2/3 of cases — molecular mimicry: antibodies against microbial antigens (e.g., Campylobacter jejuni gangliosides) cross-react with peripheral nerve components
- Onset: subacute over a few days
- Nadir: within 4 weeks (this distinguishes GBS from CIDP, which continues beyond 8 weeks)
Clinical Features [1]:
- Ascending weakness with facial involvement
- Respiratory failure in 30% — this is why FVC monitoring is critical
- Hypo- or areflexia — because demyelination blocks the reflex arc
- Sensory symptoms (tingling, pain) but motor predominates
- Muscle ache
- Autonomic dysfunction in > 2/3 (labile BP, arrhythmias, urinary retention)
Investigations [1]:
- Raised CSF protein without pleocytosis (albuminocytological dissociation) — protein leaks from inflamed nerve roots into CSF, but there are no cells because the process is demyelinating, not infectious
- Electrophysiology: demyelinating pattern (prolonged F-wave latency, conduction block, slowed velocities)
Management [1]:
- General supportive measures:
- Monitor FVC, ABG, BP, ECG, bulbar function — serial FVC is the gold standard for respiratory monitoring; intubate if FVC < 15–20 mL/kg or < 1 L [4]
- Mechanical ventilation for respiratory failure
- General care for immobility (DVT prophylaxis, pressure care, PT)
- Nutritional support (NG tube if dysphagia)
- Treat complications (autonomic instability, infections)
- Specific immunotherapy: Plasma exchange (PLEX) or high-dose IV immunoglobulins (IVIg)
- Both equally effective; IVIg is easier to administer
- Steroids are NOT effective in GBS (a classic exam trap!)
Prognosis [1]:
- Mortality: 2–12%
- 20% permanent disabilities, 10% severe
Exam Trap – GBS vs CIDP
GBS nadir is within 4 weeks and then plateaus/improves. CIDP (Chronic Inflammatory Demyelinating Polyneuropathy) progresses beyond 8 weeks. CIDP responds to steroids; GBS does not.
Charcot-Marie-Tooth (CMT) disease [1]:
- Hereditary condition(s) — the most common inherited neuropathy
- Distal wasting, foot drop, pes cavus
- Slowly progressive
Classification [1]:
| Type | Pathology | Inheritance | Notes |
|---|---|---|---|
| HMSN-I | Demyelinating PN | AD, AR, X-linked | Most common; PMP22 duplication |
| HMSN-II | Axonal PN | AD, AR, X-linked | Later onset, less severe |
| HMSN-III | DSD (Dejerine-Sottas) | Severe infantile | |
| HMSN-IV | Refsum disease | Phytanic acid accumulation | |
| HMSN-V | Axonal + pyramidal signs | ||
| HMSN-VI | With optic atrophy | ||
| HMSN-VII | With retinitis pigmentosa |
Genes: PMP22, MPZ, MFN2, GJB1 etc. [1]
Hereditary motor neuropathies include Spinal Muscular Atrophy (SMA) [1]:
- Gene: SMN1 (Spinraza = nusinersen is an antisense oligonucleotide therapy)
- Other genes: UBA1, DYNC1H1, VAPB
- SMA accounts for 60% of hereditary motor neuropathy cases [1]
"Progressive degeneration of α motor neuron" affecting anterior horn cells AND corticospinal tract. [1]
Key Features [1]:
- ALS / PLS / PMA / PBP / Pseudobulbar palsy — different patterns based on UMN vs LMN predominance
- Sensory involvement: ABSENT — this is the hallmark distinguishing MND from neuropathy
- Incidence: 1 per 100,000/year
- Peak 6th decade, M:F = 3:2
- Familial ~10% (SOD1, C9orf72, TARDBP, FUS)
The name "Amyotrophic Lateral Sclerosis" encodes the pathology [1]:
- "Amyotrophic" = muscle wasting (LMN loss)
- "Lateral Sclerosis" = hardening of lateral columns of spinal cord (UMN corticospinal tract degeneration)
Combined UMN + LMN signs WITHOUT sensory loss = MND until proven otherwise.
Treatment [1]:
- No specific treatment
- Die within 3 years (median survival)
- General nursing care, nutritional support
- Riluzole (modest survival benefit ~2–3 months), Edaravone (uncertain benefit, marked with "?")
- Euthanasia vs long-term ventilation — ethical considerations
Alcohol, solvents, heavy metals, pharmaceuticals (anti-neoplastic agents, anti-microbials for TB and HIV, colchicine, thalidomide, pyridoxine abuse). [1]
Why pyridoxine (vitamin B6)? In excess, it causes a sensory neuropathy through direct neurotoxicity to dorsal root ganglia neurons. This is paradoxical because B6 deficiency also causes neuropathy.
2. Myopathies
Proximal weakness, waddling gait, bulbar/respiratory involvement, tenderness. Sensory and sphincter are SPARED. [1]
Why proximal? The proximal muscles (hip flexors, deltoids) are large and demand high metabolic activity. Myopathic processes (inflammatory, dystrophic, metabolic) preferentially affect these metabolically demanding muscles first.
Waddling gait: Hip abductor weakness → Trendelenburg sign → pelvis drops on the unsupported side during gait → patient compensates by shifting trunk toward the weight-bearing side [4].
Myopathies are classified as inherited or acquired. [1]
| Inherited | Acquired |
|---|---|
| Muscular dystrophies (Dystrophinopathies, FSHD, LGMD) | Inflammatory myopathies (PM, DM, IBM, Necrotising autoimmune myopathy) |
| Metabolic (Mitochondropathies, Glycogenoses, Lipid myopathies) | Complicating systemic diseases (CTD, Endocrinopathies, Sarcoidosis, Critical illness myopathy) |
| Congenital myopathies | Toxic myopathies (statins, steroids) |
| Channelopathies (Myotonic disorders, Periodic paralysis, Malignant hyperthermia) | Rhabdomyolysis |
| Infection-related |
Electrophysiological studies, muscle enzymes (e.g., CK), look for systemic diseases, muscle biopsy, genetic tests. [1]
- CK: The most important screening blood test for myopathy.
- 200–1000: most myopathies
- > 1000: inflammatory myopathies, rhabdomyolysis, DMD/BMD [4]
- EMG: Shows polyphasic, low-amplitude, short-duration motor unit potentials (MUAPs) — because fewer muscle fibres per motor unit are functional
- Also: increased insertional activity, fibrillation potentials, complex repetitive discharges (CRD) [1]
- Muscle MRI (fat suppression/STIR): Signal changes from inflammation, edema, or muscle replacement by connective tissue. Guides biopsy site and monitors treatment response. [1]
- Muscle biopsy: Definitive for inflammatory myopathies, dystrophies (immunohistochemistry for dystrophin, sarcoglycans)
3. Muscular Dystrophies (In Detail)
Old definition: (1) Inherited, (2) All symptoms due to muscle weakness, (3) Progressive, (4) No histopathological abnormalities other than degeneration and regeneration. [1]
DMD, BMD, FSHD, LGMD, Myotonic dystrophy. [1]
Phenotypic → Immunohistochemical → Genetic [1]
| Level | Examples |
|---|---|
| Immunohistochemical | Dystrophinopathy, Sarcoglycanopathy, Laminin, Caveolin, Calpain, Dysferlin |
| Genetic inheritance | X-linked (DMD, BMD); AD (LGMD1, FSHD); AR (LGMD2) |
High Yield – DMD vs BMD
Both are X-linked dystrophinopathies caused by mutations in the dystrophin gene (Xp21.2). The critical difference is the reading frame rule:
- DMD: frameshift/nonsense mutation → no or very little dystrophin → severe
- BMD: in-frame deletion → partially functional dystrophin → milder
| Feature | DMD | BMD |
|---|---|---|
| Dystrophin | No or few dystrophin-positive fibres | Partial deficiency |
| Motor milestones | Mild delay | Near-normal |
| Onset of weakness | 3–5 years | Later |
| Wheelchair-bound | By 9–12 years | Continue to ambulate beyond 15 |
| Respiratory failure | By late teens | Later |
| Death | 2nd–3rd decade | Between 40–60 |
| Associated features | Cardiomyopathy, mild mental impairment | Cardiomyopathy |
| Key signs | Gower's sign, pseudohypertrophy of calves, tip-toe gait | Similar but milder |
4. Inflammatory Myopathies (Autoimmune Myopathies)
Inflammatory infiltration (or necrosis) of skeletal muscle, limb-girdle pattern of weakness, occasionally myalgia, can be associated with extra-muscular manifestations. Annual incidence: 5/100,000. [1]
1. Polymyositis, 2. Dermatomyositis, 3. Overlap myositis, 4. Inclusion body myositis, 5. Necrotising autoimmune myopathy. [1]
High Yield – Dermatomyositis
F > M. Subacute or insidiously progressive proximal weakness, sometimes with myalgia. Skin manifestations: heliotrope rash, malar rash, V & shawl rash, Gottron papules, mechanic's hands, periungual erythema, gingival and oral involvement. ILD, polyarthritis. Calcinosis and GI involvement in juvenile cases. [1]
Association with malignancy in 6–45% of cases (breast, lung, pancreas, colon, cervix, NPC). 2 years before, 3 years after diagnosis. [1]
Pathology: Complement-mediated microangiopathy → perimysial and perivascular inflammation (macrophages, B-cells, CD4+ plasmacytoid dendritic cells), perifascicular atrophy, capillary depletion. [1]
Myositis-Specific Antibodies in DM [1]:
| Antibody | Association |
|---|---|
| Anti-TIF-1γ | Neoplasia, dysphagia |
| Anti-NXP-2 | Neoplasia in adults, calcinosis in children |
| Anti-Mi2 | Rapid onset, but LOW risk neoplasia/ILD, good response to immunotherapy |
| Anti-MDA-5 | Amyopathic DM, polyarthritis, SEVERE ILD |
| Anti-SAE | Amyopathic DM, in Asians associated with ILD |
Exam Trap – Anti-MDA-5
Anti-MDA-5 is classically associated with amyopathic DM (minimal/no muscle involvement) but rapidly progressive ILD which can be fatal. Don't assume "no weakness = benign."
"Symmetric proximal myositis and the absence of histopathological signs of other myopathies or typical rash of DM." Endomysial mononuclear inflammatory infiltrates. Actually a heterogeneous group; many PM cases are in fact sIBM or OM. True idiopathic PM is rare (or even a controversial entity) — "diagnosis of exclusion." [1]
Commonest autoimmune myopathy in ≥ age 50, M > F. Affects quadriceps, volar forearm muscles, dorsiflexors → axial muscles. Slowly progressive, life expectancy not significantly affected. CK normal or up to 10-fold above ULN. Histology: inflammatory infiltrates (CD8+ T cells, macrophages) invading non-necrotic muscle fibres, rimmed vacuoles, congophilic inclusions (amyloidogenic proteins). Antibody: Anti-cN1A (anti-cytosolic 5'-nucleotidase 1A). Immunotherapy NOT beneficial. [1]
High Yield – IBM vs PM
IBM is the most common inflammatory myopathy in the elderly. Unlike PM, it has asymmetric and distal involvement (quadriceps, finger flexors), does NOT respond to steroids, and has rimmed vacuoles on biopsy. If a patient labeled as "PM" doesn't respond to treatment, reconsider IBM.
Myositis with overlap features (other than rash) and/or "overlap autoantibodies." With other CTDs: Anti-U1RNP (SLE/MCTD-OM), Anti-PM/Scl, Anti-Ku, Anti-U3RNP (SSc-OM). [1]
Anti-synthetase syndrome: Acute myopathy, fever, ILD, polyarthritis, Raynaud's, mechanic's hand. Anti-Jo1 (anti-tRNA-synthetase). Also Anti-PL-7, Anti-PL-12 (amyopathic variant), Anti-OJ, Anti-KS, Anti-EJ, Anti-Zo, Anti-Ha-YRS. [1]
Myositis-autoantibodies (60–80% AIM): immunoprecipitation/immunodot, ELISA/ALBIA. [1] PET scan (malignancies in 20% AIM). [1] EMG: increased insertional activity, fibrillation, CRD, spiky polyphasic MUAP. [1] Muscle MRI (fat suppression or STIR): signal changes in muscle and fascia from inflammation, edema, or muscle replacement by connective tissue. Guides biopsy site and monitors disease activity/treatment response. [1]
5. Neuromuscular Junction (NMJ) Disorders
NMJ disorders present with: Fluctuating weakness, fatigability, extra-ocular muscle manifestation, bulbar/respiratory involvement. Sensory and sphincter are SPARED. [1]
The NMJ is either pre-synaptic or post-synaptic:
| Location | Disease | Mechanism |
|---|---|---|
| Post-synaptic | Myasthenia Gravis | Antibody to AChR |
| Pre-synaptic | LEMS | Antibody to voltage-gated Ca²⁺ channel |
| Pre-synaptic | Botulism | Toxin from Clostridium botulinum → cytotoxic to nerve terminals |
High Yield – MG
Prevalence: 5 per 100,000. Antibody to ACh receptor. Fluctuating weakness with fatigability. Ocular ± generalized involvement. Associated with (1) thymic pathology and (2) other autoimmune diseases. [1]
Why "fatigability"? Anti-AChR antibodies reduce the number of functional AChR at the post-synaptic membrane. With each successive nerve impulse, fewer ACh molecules find available receptors (normal NMJ has a "safety factor" with excess receptors; this is lost in MG). So strength is initially near-normal but declines with repeated use.
Pathophysiology [4]:
- Anti-AChR Ab (90% of generalized, 50% of ocular MG): T-cell dependent; causes receptor blockade + complement-mediated destruction + accelerated receptor internalization
- Anti-MuSK Ab: more bulbar/respiratory involvement, higher risk of crisis, poorer response to anticholinesterase
- Anti-LRP4 Ab: more ocular involvement
- Thymic pathology: thymic hyperplasia (85% of AChR-Ab+ patients), thymoma (15%)
- Autoimmune diseases (1/3): Graves', Hashimoto's, T1DM, RA, SLE
- Malignancy: SCLC, Hodgkin lymphoma
Types of MG [4]:
- Ocular MG (15%): weakness limited to eyelids and EOMs; 50% seropositive; 50% risk of generalizing within 2 years
- Generalized MG (85%): ocular + bulbar + limb + respiratory; 90% seropositive
- Early: diurnal variation (worse evening), symptom-free periods
- Late: persistent weakness
- Ocular (> 50%): ptosis (uni/bilateral), diplopia, pupil ALWAYS spared
- Bulbar (15%): dysarthria (nasal voice), dysphagia, jaw weakness
- Facial: expressionless, transverse smile ("myasthenic sneer")
- Neck: dropped head syndrome
- Limb: proximal, UL > LL
- Respiratory: SOBOE, orthopnea → respiratory failure (MG crisis)
Osserman Classification [4]:
| Type | Description |
|---|---|
| 1 | Ocular MG only |
| 2A | Mild generalized (limb) |
| 2B | Moderate generalized (bulbar) |
| 3 | Acute fulminating (respiratory, < 6 months) |
| 4 | Late severe ( > 2 years, high mortality) |
- Anti-AChR Ab → confirmatory; if negative, check anti-MuSK/anti-LRP4
- Electrophysiology: Repetitive Nerve Stimulation (RNS) → ≥ 10% decremental response in CMAP amplitude at 3 Hz
- Single-fibre EMG: most sensitive test
- Tensilon (edrophonium) test: short-acting anticholinesterase; if ptosis improves within 30–60 seconds, it's MG. Requires cardiac monitoring (risk of bradycardia). Now largely replaced by ice pack test.
- Ice pack test: apply ice to ptotic eyelid for 2–5 min → cooling improves NMJ transmission (inhibits acetylcholinesterase) → improvement of ptosis
- CT thorax: for thymoma
- TFT ± other autoantibodies
- Supportive: NPO until swallowing test passed; close FVC monitoring (inform if < 1 L or < 15 mL/kg)
- Anti-cholinesterase: Pyridostigmine — inhibits acetylcholinesterase → more ACh available at NMJ
- Thymectomy — especially if thymoma; also beneficial in non-thymomatous generalized MG
- Immunotherapy — steroids (prednisolone), steroid-sparing agents (azathioprine, mycophenolate), IVIg/PLEX for crises
Drugs to AVOID in MG [4]: Aminoglycosides, quinolones, macrolides, metronidazole, β-blockers, CCBs, HCQ, quinine, penicillamine, procainamide, lithium, phenytoin, lidocaine — all can exacerbate NMJ blockade.
Lambert-Eaton Myasthenic Syndrome (LEMS): Ab to voltage-gated Ca²⁺ channel, associated with SCLC. [1]
| Feature | MG | LEMS | Botulism |
|---|---|---|---|
| Fatigability | Worsens with exercise | Improves with exercise | Improves with exercise |
| Muscles | Generalized/ocular | LL >> UL, eyes spared | Eyes > bulbar > limbs |
| Autonomic | Absent | Present (cholinergic) | Present (++) |
| Association | Thymoma | SCLC | GI symptoms |
| Antibody | Anti-AChR | Anti-VGCC | — (toxin) |
Why does LEMS improve with exercise? The antibodies impair Ca²⁺ influx needed for ACh vesicle release. With repeated stimulation, residual Ca²⁺ accumulates in the presynaptic terminal, eventually reaching threshold for vesicle release — hence post-exercise facilitation (and incremental response on RNS at high frequency).
Botulism: Toxins from Clostridium botulinum (food, wound, gut). Cytotoxic to nerve terminals. [1]
6. Floppy Infant Syndrome
- Chromosomal: Trisomy, Prader-Willi, partial deletion/duplication
- Cerebral malformation
- Perinatal distress (HIE)
- Postnatal cerebral injury
- Single gene disorders: Zellweger syndrome, neonatal adrenoleukodystrophy, oculocerebral renal syndrome, acid maltase deficiency
- Spinal cord: Hypoxic-ischaemic myelopathy, trauma, congenital malformation
- Motor neuronopathies: SMA, congenital cervical SMA, infantile neuronal degeneration, neurogenic arthrogryposis, vaccine-associated poliomyelitis
- Polyneuropathies: Congenital hypomyelinating polyneuropathy, Dejerine-Sottas syndrome
- NMJ disorders: Congenital defect of NMJ, neonatal MG (transplacental maternal Ab), infantile botulism
- Myopathies: Central core disease, congenital fibre-type disproportion, X-linked myotubular myopathy
| Central Hypotonia | Peripheral Hypotonia |
|---|---|
| CT/MRI brain | NCS |
| TFT | CK level |
| Metabolic screen | EMG |
| Karyotype/genetic review | Muscle biopsy |
| TORCH screen | Genetic study (SMN1, CTG repeats) |
7. Clinical Neurophysiology
Three main modalities: (1) Nerve Conduction Studies (NCS), (2) Needle Electromyography (EMG), (3) Special techniques for NMJ conduction. [1]
Electrodiagnostic (EDx) studies provide objective, quantitative, reproducible, non-invasive assessment of PNS function. [1]
- Exclude/confirm peripheral neuropathy, myopathy
- Distinguish neuropathy from myopathy
- Define aetiology of neuropathy (demyelinating vs axonal)
- Define aetiology of myopathy
- Cervical myelopathy
- Diagnose focal/multifocal neuropathies
- Assess severity and monitor progress
- Monitor treatment response
- Prognosis after nerve trauma + guide intervention
- EMG-guided botulinum toxin therapy
| Test | What it measures | Key findings in neuropathy | Key findings in myopathy |
|---|---|---|---|
| NCS (Motor + Sensory) | Large fibre conduction: amplitude, velocity, latency | Axonal: ↓ amplitude, normal velocity; Demyelinating: ↓ velocity, prolonged latency, conduction block | Usually normal (the nerve is fine) |
| EMG | Bioelectric activity of muscles at rest and during contraction | Denervation potentials (fibrillation, positive sharp waves); large, polyphasic MUAPs (reinnervation) | Increased insertional activity, fibrillation, CRD, small spiky polyphasic MUAPs |
| RNS | NMJ transmission (3 Hz and 50 Hz) | Normal | Normal; MG: ≥ 10% decrement at 3 Hz; LEMS: increment at 50 Hz |
8. Integration with Related Conditions
The lecture lists channelopathies under inherited myopathies. Key exam-relevant points from supporting notes [7][8]:
- Primary hypoK PP: AD inheritance (CACNA1S), triggered by CHO load, exercise (after delay), β2-agonists
- Thyrotoxic PP: Mainly in Orientals, male predominance (25% vs 0.8% in Caucasians), occurs during hyperthyroidism, presents with hypokalemia and motor weakness, spares respiratory muscles usually, spontaneous recovery after K⁺ correction and treating thyrotoxicosis
- HyperK PP: AD (SCN4A), triggered by exercise, fasting, cold
- MG
- Botulism
- GBS
- Transverse myelitis
- Secondary hypokalemic PP (thyrotoxic, hyperaldosteronism, RTA type I/II)
1. SAQ: A 35-year-old man presents with ascending weakness over 5 days following a diarrheal illness. Reflexes are absent. What is the most likely diagnosis? Outline the key investigations and management.
Markscheme: GBS (Guillain-Barré syndrome). Ix: CSF (raised protein, no pleocytosis), NCS (demyelinating pattern), serial FVC. Mx: IVIg or PLEX (not steroids), monitor FVC/ABG/BP/ECG, ventilatory support if FVC < 15-20 mL/kg, DVT prophylaxis, nutritional support.
2. SAQ: Describe three clinical features that distinguish NMJ disease from myopathy.
Markscheme: (1) Fatigability with diurnal variation in NMJ vs constant weakness in myopathy; (2) No wasting in NMJ vs wasting/pseudohypertrophy in myopathy; (3) Fluctuating findings with preserved reflexes in NMJ vs non-fluctuating with variable reflexes in myopathy; (4) Ocular involvement prominent in MG but uncommon in most myopathies.
3. MCQ Discriminator: Which antibody in dermatomyositis is most strongly associated with malignancy?
Answer: Anti-TIF-1γ (also anti-NXP-2 in adults). Anti-Mi2 has LOW malignancy risk. Anti-MDA-5 is associated with amyopathic DM and severe ILD, not primarily malignancy.
4. Minicase: A 5-year-old boy with progressive proximal weakness, calf pseudohypertrophy, and elevated CK > 10,000. What is the diagnosis and the inheritance pattern?
Answer: Duchenne muscular dystrophy. X-linked recessive. Mutation in dystrophin gene (Xp21.2). Confirm with genetic testing; immunohistochemistry shows absent/minimal dystrophin.
5. SAQ: Compare and contrast MG and LEMS.
Markscheme: MG = post-synaptic (anti-AChR), worsens with exercise, ocular involvement prominent, associated with thymoma. LEMS = pre-synaptic (anti-VGCC), improves with exercise, LL predominant with eyes spared, associated with SCLC, autonomic dysfunction present.
6. SAQ: A 60-year-old man has slowly progressive weakness of quadriceps and finger flexors, CK mildly elevated. Biopsy shows rimmed vacuoles. What is the diagnosis and will immunotherapy help?
Answer: Inclusion body myositis (IBM). Immunotherapy is NOT beneficial. Anti-cN1A antibody. Most common inflammatory myopathy in > 50 years. Distinguish from PM by asymmetric/distal distribution, rimmed vacuoles, and treatment resistance.
7. Viva: How do you evaluate a floppy infant?
Markscheme: Differentiate central vs peripheral hypotonia. Central: preserved/increased reflexes, no significant limb weakness, more truncal, look for cerebral causes (CT/MRI brain, karyotype, metabolic screen). Peripheral: hyporeflexia, significant weakness, limb involvement — investigate with NCS, CK, EMG, muscle biopsy, genetic testing (SMN1 for SMA).
High Yield Summary
- Localize first: CNS vs Peripheral nerve vs NMJ vs Muscle — the rest follows.
- Polyneuropathies: Classify by time course, distribution, fibre type, axonal vs demyelinating. GBS = acute ascending paralysis + areflexia + albuminocytological dissociation → IVIg/PLEX (NOT steroids). Monitor FVC.
- MG: Post-synaptic anti-AChR Ab → fluctuating fatigable weakness, ocular/bulbar predominant, NO sensory loss, NO wasting. Ix: anti-AChR, RNS (≥ 10% decrement), CT thorax. Rx: pyridostigmine, thymectomy, immunotherapy.
- LEMS: Pre-synaptic anti-VGCC → improves with exercise, associated with SCLC, autonomic features.
- DMD: X-linked, absent dystrophin, onset 3–5 y, wheelchair by 9–12 y, CK massively elevated, Gower's sign, calf pseudohypertrophy.
- Inflammatory myopathies: DM has skin signs + malignancy risk (Anti-TIF-1γ); PM is a diagnosis of exclusion; IBM is commonest in elderly, treatment-resistant, rimmed vacuoles.
- Floppy infant: Central (no weakness, hyperreflexia, cerebral causes) vs Peripheral (weakness, hyporeflexia, SMA/NMJ/myopathy).
- NCS/EMG: NCS for nerve pathology (axonal vs demyelinating); EMG for muscle pathology; RNS for NMJ.
- MND: Combined UMN + LMN signs WITHOUT sensory loss. Fatal within 3 years. Riluzole offers modest benefit.
- Always consider: Electrolyte disorders (hypo/hyperK), thyrotoxic PP, and drugs as reversible causes of generalized weakness.
Active Recall - Generalized Muscle Weakness
[1] Lecture slides: GC 056. Generalized muscle weakness.pdf (all pages) [2] Senior notes: Ryan Ho Neurology.pdf (p. 178 – Approach to Generalized Weakness) [3] Senior notes: Ryan Ho Neurology.pdf (p. 67 – Motor Weakness, Types of motor deficit table) [4] Senior notes: Maksim Medicine Notes.pdf (p. 272–276 – NMJ disorders, Myopathy) [5] Senior notes: Ryan Ho Neurology.pdf (p. 192–194 – Muscular Dystrophies, Channelopathies) [6] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 132–134 – Approach to Floppy Infant, Generalized Weakness) [7] Senior notes: Ryan Ho Neurology.pdf (p. 193–194 – Ion Channelopathies, Periodic Paralysis) [8] Senior notes: Block A - I am losing weight and sweating all the time.pdf (p. 34 – Thyrotoxic periodic paralysis) [9] Senior notes: Ryan Ho Urogenital.pdf (p. 25 – Hypokalemia clinical features) [10] Senior notes: Ryan Ho Urogenital.pdf (p. 28 – Hyperkalemia clinical features) [11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1655 – DDx of generalized weakness)
GC054 Frailty In The Older People
Frailty is a multidimensional syndrome of decreased physiological reserve and increased vulnerability to stressors in older adults, resulting in heightened risk of falls, disability, hospitalization, and mortality.
GC057 Glomerular And Tubulo-interstitial Diseases And Acute Kidney Injury
Glomerular and tubulo-interstitial diseases encompass inflammatory, immune-mediated, or toxic disorders affecting the glomeruli or renal interstitium and tubules, which, along with acute kidney injury, result in a rapid or progressive decline in kidney filtration, concentration, and excretory functions.