Motor Neuron Disease
Motor Neuron Disease
What Do You Need to Know?
- ALS: combined UMN + LMN disease; male 2:1; mean onset 6th decade; 90–95% sporadic; median survival 3–5 years from symptom onset; spares sensation, extraocular muscles, and sphincters
- El Escorial criteria: definite = UMN + LMN in 3 regions; probable = UMN + LMN in 2 regions; 4 body regions — bulbar, cervical, thoracic, lumbosacral
- Top ALS mimics: multifocal motor neuropathy (anti-GM1, conduction block, treatable with IVIg), cervical spondylotic myelopathy, Kennedy disease, inclusion body myositis
- C9orf72: most common familial ALS gene; hexanucleotide repeat expansion; causes ALS + FTD overlap
- ALS treatments: riluzole (glutamate inhibitor, ~2–3 months survival benefit); tofersen (antisense oligonucleotide for SOD1-ALS, FDA approved 2023); NIV prolongs survival
- SMA: AR, SMN1 gene (5q); Type 1 = Werdnig-Hoffmann (onset <6 months, never sit); 3 disease-modifying therapies now available — nusinersen, risdiplam, onasemnogene abeparvovec
- Kennedy disease (SBMA): X-linked; CAG repeat in androgen receptor; LMN + bulbar weakness + gynecomastia + sensory neuropathy; slowly progressive, much better prognosis than ALS
🚩 Don’t Miss — Test-Day Priorities
- UMN + LMN in same region: hallmark of ALS — hyperreflexia in a weak, atrophic, fasciculating limb is the classic exam clue (El Escorial / Awaji criteria)
- ALS spares: sensation, extraocular muscles, and sphincters (Onuf nucleus S2–S4) — early involvement of any of these = NOT ALS, reconsider diagnosis
- C9orf72 GGGGCC hexanucleotide repeat: MOST COMMON cause of familial ALS and familial FTD; ~50% of ALS-FTD overlap; autosomal dominant
- SOD1 mutations: first ALS gene discovered; tofersen (antisense oligonucleotide) is the first targeted disease-modifying therapy — FDA approved 2023 for SOD1-ALS only
- Riluzole (glutamate antagonist) extends survival ~2–3 months; edaravone (free radical scavenger) modest benefit; AMX0035/Relyvrio withdrawn 2024 after failed phase 3
- Respiratory monitoring: FVC and sniff nasal inspiratory pressure (SNIP/NIF); start NIV (BiPAP) early — prolongs survival and quality of life more than any drug
- Gastrostomy (PEG): place when ≥10% weight loss or FVC drops — before FVC <50% (procedure risk rises sharply below this)
- SMA = SMN1 deletion (5q11.2) in ~95%; SMN2 copy number modifies severity; three disease-modifying therapies — nusinersen (intrathecal ASO), onasemnogene abeparvovec/Zolgensma (AAV9 IV gene therapy, single dose, age <2 yr), risdiplam (oral)
- Kennedy disease (SBMA): X-linked CAG repeat in androgen receptor — bulbar + proximal LMN weakness, perioral/tongue fasciculations, gynecomastia, infertility, mild sensory neuropathy; much better prognosis than ALS
- Hirayama disease: young Asian male, unilateral C7–T1 hand/forearm wasting, “cold paresis,” flexion MRI shows anterior dural detachment with epidural venous engorgement — treat with cervical collar to prevent neck flexion
🔍 Buzzwords & Pathognomonic FindingsClinical · EMG/NCS / imaging · Genetics / treatment
Clinical phenotype
- Hyperreflexia in a weak, atrophic, fasciculating limb → ALS (UMN + LMN in same region)
- Split hand sign (APB + FDI wasting > hypothenar) → ALS
- Pseudobulbar affect — involuntary laughing/crying → Bulbar ALS (treat with dextromethorphan/quinidine, Nuedexta)
- Isolated UMN signs >4 years, no LMN involvement → Primary lateral sclerosis (PLS)
- Isolated LMN, no UMN signs → Progressive muscular atrophy (PMA); flail arm/flail leg variants
- Bulbar + proximal weakness + gynecomastia + infertility + perioral fasciculations → Kennedy disease (SBMA, X-linked AR CAG)
- Young Asian male, unilateral C7–T1 hand wasting, “cold paresis” → Hirayama (monomelic amyotrophy)
- Floppy infant, frog-leg posture, tongue fasciculations, never sits → SMA type I (Werdnig-Hoffmann)
- New weakness/fatigue ≥15 yr after acute polio → Post-polio syndrome
- Pure spastic paraplegia, lower limbs > upper, slowly progressive → Hereditary spastic paraplegia (HSP, SPG4/SPAST AD)
EMG/NCS / imaging
- Active denervation (fibrillations, positive sharp waves) + chronic reinnervation (large polyphasic MUAPs) in 3+ regions → ALS (Awaji criteria)
- Bunina bodies — eosinophilic intraneuronal inclusions in anterior horn cells → ALS (pathognomonic)
- TDP-43 cytoplasmic inclusions → ALS (~97%, except SOD1) and FTD overlap
- Giant motor unit potentials on EMG (massive reinnervation) → Post-polio syndrome / chronic SMA
- Flexion cervical MRI: anterior dural detachment, posterior epidural venous engorgement → Hirayama disease (flexion myelopathy)
- Motor conduction block at non-entrapment sites + anti-GM1 antibodies → Multifocal motor neuropathy (MMN) — key ALS mimic, treat with IVIg
- Corticospinal tract hyperintensity on T2/FLAIR MRI → ALS / PLS (UMN degeneration)
Genetics / treatment / disease-modifying
- C9orf72 GGGGCC hexanucleotide repeat expansion → Most common familial ALS and familial FTD (ALS-FTD overlap)
- SOD1 mutation → First ALS gene discovered; tofersen (antisense oligonucleotide) is FDA-approved targeted therapy
- TARDBP (TDP-43) / FUS mutations → Familial ALS; FUS = young-onset, aggressive course
- SMN1 deletion on 5q11.2 (95%); SMN2 copy number modifies severity → Spinal muscular atrophy (SMA)
- Onasemnogene abeparvovec (Zolgensma) — AAV9 gene therapy, single IV dose, age <2 yr → SMA
- Nusinersen (intrathecal ASO) and risdiplam (oral SMN2 splicing modifier) → SMA (all ages, all types)
- CAG repeat expansion in androgen receptor (AR) gene, X-linked → Kennedy disease (SBMA)
- SPG4/SPAST (spastin, AD) — most common; SPG7 (paraplegin, AR, mitochondrial, adult-onset) → Hereditary spastic paraplegia
- Riluzole (glutamate antagonist) — modest survival benefit; edaravone (free radical scavenger); AMX0035/Relyvrio withdrawn 2024 → ALS
ALS — Overview
Epidemiology & Pathology
| Feature | Details |
|---|---|
| Incidence | ~2 per 100,000/year |
| Male:Female | ~2:1 (sporadic); equal in familial |
| Onset age | Mean ~55–65 years; younger in familial cases |
| Familial | 5–10%; autosomal dominant most common |
| Median survival | 3–5 years (bulbar onset worse; limb onset slightly better) |
| Cause of death | Respiratory failure (diaphragm weakness) |
| Pathology | Anterior horn cell + corticospinal tract degeneration; TDP-43 cytoplasmic inclusions (most cases); Bunina bodies (eosinophilic intraneuronal inclusions, pathognomonic) |
| Spared | Sensation, extraocular muscles (cranial nerves III/IV/VI), sphincters (Onuf nucleus) |
💎 Board Pearl
- Bunina bodies are eosinophilic intraneuronal inclusions pathognomonic for ALS
- TDP-43 inclusions are found in ~97% of ALS cases (except SOD1-mutant ALS) — shared with FTD
- Extraocular muscles and Onuf nucleus (S2–S4, controls sphincters) are characteristically spared — if either is affected early, reconsider diagnosis
ALS — Clinical Features
UMN vs LMN Signs in ALS
| UMN Signs | LMN Signs |
|---|---|
| Spasticity | Weakness / atrophy |
| Hyperreflexia | Fasciculations |
| Babinski sign | Hyporeflexia (in denervated muscles) |
| Hoffman sign | Muscle cramps |
| Clonus | Fibrillations (on EMG) |
| Pseudobulbar affect (emotional lability) | Tongue atrophy / fasciculations |
Key Clinical Patterns
- Limb onset (~70%): asymmetric distal hand weakness most common → progressive spread to contiguous regions
- Bulbar onset (~25%): dysarthria, dysphagia, tongue fasciculations/atrophy — worse prognosis, median survival ~2 years
- Respiratory onset (~5%): dyspnea, orthopnea without limb weakness initially — worst prognosis
- Split hand sign: APB (abductor pollicis brevis) and FDI (first dorsal interosseous) wasting > hypothenar muscles — relatively specific for ALS
- Split leg sign: anterior compartment (tibialis anterior) weakness > posterior compartment (gastrocnemius)
- Pseudobulbar affect: involuntary laughing/crying; treat with dextromethorphan/quinidine (Nuedexta)
🎯 Clinical Pearl
- Hyperreflexia in a weak, atrophic limb = hallmark of ALS (UMN + LMN in same territory)
- The split hand sign helps distinguish ALS from cervical radiculopathy or carpal tunnel syndrome
- If a patient has sensory loss, eye movement abnormalities, or early sphincter dysfunction — the diagnosis is NOT ALS
El Escorial Diagnostic Criteria
Four Body Regions
- Bulbar: face, mouth, throat (CN V, VII, IX, X, XII)
- Cervical: neck, arm, hand, diaphragm (C1–C8)
- Thoracic: back, abdomen (T1–T12)
- Lumbosacral: back, abdomen (lower), leg, foot (L1–S2)
Diagnostic Categories
| Category | Criteria |
|---|---|
| Definite ALS | UMN + LMN signs in 3 regions (bulbar + 2 spinal, or 3 spinal) |
| Probable ALS | UMN + LMN signs in 2 regions with UMN signs rostral to LMN signs |
| Probable — lab-supported | UMN + LMN in 1 region + EMG evidence of LMN degeneration in ≥2 limbs (from revised El Escorial 1998; deprecated under Awaji) |
| Possible ALS | UMN + LMN in 1 region only, OR UMN signs in ≥2 regions, OR UMN + LMN in 2 regions with LMN rostral to UMN |
Key Diagnostic Studies
| Test | Findings |
|---|---|
| EMG/NCS | Widespread denervation (fibrillations, positive sharp waves) + reinnervation (large MUPs, reduced recruitment) in ≥3 regions; normal sensory NCS; normal motor conduction velocities |
| MRI brain/spine | To exclude mimics (cord compression, MS); may show corticospinal tract T2 signal |
| CK | Mildly elevated (1.5–3× normal) in ~50% |
| Genetic testing | Consider if family history or onset <45 years; C9orf72, SOD1 testing |
💎 Board Pearl
- Normal sensory nerve conduction studies are essential for ALS diagnosis — if sensory amplitudes are reduced, reconsider
- EMG must show active + chronic denervation (fibrillations + large MUPs) in multiple myotomes from different nerve roots and limbs
- The Awaji (Awaji-Shima) criteria allow fasciculation potentials to be equivalent to fibrillations/positive sharp waves → increases EMG sensitivity
Gold Coast Criteria (2020)
- Simplified two-tier framework developed to increase diagnostic sensitivity, particularly earlier in the disease course; now widely used in clinical practice and trials
- Required elements:
- Progressive motor impairment documented by history or repeat clinical assessment, preceded by normal motor function
- UMN + LMN dysfunction in ≥1 body region (with UMN and LMN in the same region) OR LMN dysfunction in ≥2 body regions
- Exclusion of other disease processes by appropriate investigations
- Advantages: eliminates the multiple diagnostic categories of El Escorial/Awaji; higher sensitivity without sacrificing specificity; facilitates earlier trial enrollment
ALS Genetics
Major ALS Genes
| Gene | Chromosome | Inheritance | Key Features |
|---|---|---|---|
| C9orf72 | 9p21 | AD | Most common familial ALS gene (~25–40% of familial, ~7% sporadic); GGGGCC hexanucleotide repeat expansion; causes ALS + FTD overlap; RNA foci + dipeptide repeat proteins |
| SOD1 | 21q22 | AD (most) | ~12–20% of familial ALS (~1–2% of all ALS); first ALS gene discovered (1993); Cu/Zn superoxide dismutase; toxic gain of function; NO TDP-43 inclusions (exception to rule); targetable with tofersen |
| TARDBP | 1p36 | AD | Encodes TDP-43 protein; ~4% familial; TDP-43 is the major pathological protein in most ALS |
| FUS | 16p11 | AD | RNA-binding protein; ~4% familial; younger onset; aggressive course; FUS inclusions (NOT TDP-43) |
| ALS2 (alsin) | 2q33 | AR | Juvenile-onset ALS/PLS; rare; alsin is a GEF involved in endosomal trafficking |
| KIF5A | 12q13 | AD | Kinesin family motor protein; minor cause of familial ALS; allelic with HSP (SPG10) and CMT2 |
| PFN1 | 17p13 | AD | Profilin 1; rare actin-binding protein mutation; minor familial cause |
💎 Board Pearl
- C9orf72 = #1 cause of familial ALS AND familial FTD — the most important ALS gene to know for boards
- SOD1-ALS is the exception: does NOT have TDP-43 pathology — has SOD1 inclusions instead
- SOD1 is on chromosome 21 — same chromosome as Down syndrome (but different gene, APP is on 21 too)
ALS Mimics
Critical Differential Diagnosis
| Condition | Key Distinguishing Features | Why It Matters |
|---|---|---|
| Multifocal motor neuropathy (MMN) | Pure LMN, asymmetric distal upper limb weakness; anti-GM1 antibodies (~50%); conduction block on NCS; no UMN signs | Treatable with IVIg — must not miss |
| Cervical spondylotic myelopathy | UMN legs + LMN arms (at level of compression); sensory findings common; MRI shows cord compression | Can closely mimic ALS; check MRI spine |
| Kennedy disease (SBMA) | X-linked; slow progression; gynecomastia; perioral fasciculations; sensory neuropathy; no UMN signs | CAG repeat test is diagnostic |
| Inclusion body myositis (IBM) | Finger flexor + quadriceps weakness; age >50; CK mildly elevated; rimmed vacuoles on biopsy | Asymmetric weakness can mimic ALS |
| Benign fasciculation syndrome | Fasciculations without weakness, atrophy, or UMN signs; normal EMG (no denervation) | Common; reassurance only |
| Hirayama disease (monomelic amyotrophy) | Young male (Asian predominantly, teens–20s); asymmetric C7–T1 anterior horn cell injury → forearm/hand wasting; neck-flexion cervical MRI shows forward dural displacement + lower cord flattening; self-limiting after 2–5 years; cervical collar in neutral/flexion-restriction is a treatment option | Neck-flexion MRI is the diagnostic test of choice; misdiagnosed as ALS but does not progress like ALS |
🎯 Clinical Pearl
- Conduction block on NCS + pure LMN weakness = think MMN, not ALS — give IVIg, not a death sentence
- If fasciculations are present WITHOUT weakness or denervation on EMG → benign fasciculation syndrome
- Any sensory involvement should prompt reconsideration of ALS diagnosis
ALS Treatment
Disease-Modifying Therapies
| Drug | Mechanism | Key Points |
|---|---|---|
| Riluzole | Glutamate inhibitor (blocks presynaptic glutamate release) | First FDA-approved ALS drug (1995); prolongs survival ~2–3 months; monitor LFTs; oral daily |
| Edaravone (Radicava) | Free radical scavenger | FDA approved (IV 2017, oral 2022); modest benefit in select patients; slows functional decline |
| Tofersen (Qalsody) | Antisense oligonucleotide targeting SOD1 mRNA | FDA approved 2023; intrathecal; only for SOD1-ALS (~2% of all ALS); reduces SOD1 protein + neurofilament light chain |
| AMX0035 / Relyvrio | Sodium phenylbutyrate + taurursodiol (targets mitochondrial & ER stress) | Voluntarily withdrawn from market (2024) after phase 3 PHOENIX trial failed to show benefit |
Supportive Care
| Intervention | Indication / Benefit |
|---|---|
| Noninvasive ventilation (BiPAP) | Start when FVC <50% predicted or symptomatic; prolongs survival by months; improves quality of life |
| PEG tube | For dysphagia/weight loss; place before FVC drops below 50% (anesthesia risk) |
| Dextromethorphan/quinidine | Pseudobulbar affect (involuntary laughing/crying) |
| Baclofen / tizanidine | Spasticity management |
| Multidisciplinary ALS clinic | Associated with longer survival and better quality of life |
💎 Board Pearl
- Riluzole is the only oral drug proven to prolong survival in ALS — mechanism = glutamate reduction
- Tofersen is the first gene-targeted ALS therapy — only works for SOD1 mutations; must genotype first
- NIV (BiPAP) is the single most impactful intervention for survival and quality of life in ALS
- FVC (forced vital capacity) is the most important respiratory metric to follow — drives timing of NIV and PEG
ALS Variants
Motor Neuron Disease Spectrum
| Variant | Motor Neuron Involvement | Key Features | Prognosis |
|---|---|---|---|
| Classic ALS | UMN + LMN | Mixed upper and lower motor neuron signs in multiple regions | Median 3–5 years |
| Progressive muscular atrophy (PMA) | Pure LMN | Weakness, atrophy, fasciculations; no UMN signs; ~50% develop UMN signs over time | Slightly better than ALS |
| Primary lateral sclerosis (PLS) | Pure UMN | Spastic paraparesis; no LMN signs for ≥4 years; see dedicated section below | Much better; years to decades |
| Progressive bulbar palsy | UMN + LMN (bulbar predominant) | Dysarthria, dysphagia, tongue atrophy; most develop limb involvement | Worst; median ~2 years |
| Flail arm (Vulpian-Bernhardt) | LMN predominant arms | Bilateral proximal arm weakness/wasting; "man-in-barrel" syndrome | Better; median ~5–7 years |
| Flail leg (pseudopolyneuritic) | LMN predominant legs | Distal leg weakness mimicking neuropathy; bilateral foot drop | Better; median ~5–7 years |
| Hemiplegic ALS (Mills variant) | UMN + LMN | Unilateral progression → eventually bilateral | Variable |
| ALS-FTD | UMN + LMN + cognitive | Behavioral variant FTD most common; strongly linked to C9orf72; ~15% of ALS patients meet FTD criteria | Worse than ALS alone |
💎 Board Pearl
- Up to 50% of ALS patients have some degree of cognitive/behavioral impairment; ~15% meet full FTD criteria
- ALS-FTD overlap = think C9orf72 — most common genetic cause of both diseases
- PMA can convert to ALS over time — many PMA cases show TDP-43 pathology at autopsy identical to ALS
Spinal Muscular Atrophy (SMA)
Overview
- Genetics: autosomal recessive; homozygous deletion/mutation of SMN1 gene on chromosome 5q13
- Pathophysiology: loss of survival motor neuron (SMN) protein → anterior horn cell degeneration
- SMN2 gene: backup copy produces ~10% functional SMN protein; SMN2 copy number inversely correlates with severity (more copies = milder disease)
- Carrier frequency: ~1 in 40–50 — most common AR cause of infant death
- Spared: extraocular muscles, intellect (normal cognition), sensation
SMA Types
| Type | Eponym | Onset | Motor Milestones | SMN2 Copies | Natural History |
|---|---|---|---|---|---|
| Type 0 | — | Prenatal | Never breathe independently | 1 | Death within weeks |
| Type 1 | Werdnig-Hoffmann | <6 months | Never sit | 2 (sometimes 3) | Death by age 2 (without treatment); frog-leg posture, tongue fasciculations, bell-shaped chest, paradoxical breathing |
| Type 2 | — | 6–18 months | Sit but never stand independently | 3 | Survive into 20s–30s; scoliosis, restrictive lung disease; hand tremor (polyminimyoclonus) |
| Type 3 | Kugelberg-Welander | >18 months | Walk independently (may lose later) | 3–4 | Near-normal lifespan; proximal > distal weakness; Gower sign |
| Type 4 | — | Adult (>21 years) | Walk throughout life | 4–8 | Normal lifespan; mild proximal weakness |
SMA Treatments
| Drug | Mechanism | Route | Key Points |
|---|---|---|---|
| Nusinersen (Spinraza) | Antisense oligonucleotide; modifies SMN2 splicing to produce more functional SMN protein | Intrathecal (q4 months after loading) | FDA approved 2016; first SMA therapy; approved for all types/ages |
| Onasemnogene abeparvovec (Zolgensma) | AAV9 gene therapy; delivers functional SMN1 gene | Single IV infusion | FDA approved 2019; for age <2 years; one-time treatment; monitor for hepatotoxicity (elevated transaminases); thrombotic microangiopathy risk |
| Risdiplam (Evrysdi) | Small molecule SMN2 splicing modifier | Oral (daily) | FDA approved 2020 (originally ≥2 months; expanded 2022 to include newborns); all types; convenient oral administration |
💎 Board Pearl
- SMA Type 1 (Werdnig-Hoffmann): "never sit" — floppy infant with tongue fasciculations, areflexia, alert eyes, normal intellect
- SMN2 copy number is the most important prognostic factor and determines disease severity
- Pre-symptomatic treatment yields the best outcomes — newborn screening programs now detect SMA before symptoms appear
- Zolgensma is a one-time gene replacement therapy — delivers SMN1 via AAV9 vector; must be given before age 2
- All 3 SMA therapies target the SMN protein pathway but through different mechanisms (antisense, gene replacement, small molecule splicing modifier)
Kennedy Disease (SBMA)
Key Features
| Feature | Details |
|---|---|
| Genetics | X-linked recessive; CAG trinucleotide repeat expansion in androgen receptor gene (Xq11–12); ≥38 repeats pathogenic |
| Onset | Age 30–50 (typically after age 40); only males affected (females are carriers) |
| Motor features | Progressive proximal limb + bulbar weakness; perioral/chin fasciculations (characteristic); tongue atrophy; hand tremor |
| Endocrine | Gynecomastia (hallmark); testicular atrophy; reduced fertility; diabetes mellitus |
| Sensory | Sensory neuropathy present (reduced vibration, absent sensory NCS) — distinguishes from ALS |
| CK | Often significantly elevated (can be >10× normal) |
| EMG | Widespread denervation + reinnervation; reduced sensory nerve action potentials |
| Prognosis | Slowly progressive; near-normal lifespan; much better than ALS |
| Treatment | No disease-modifying therapy; supportive care; androgen-reduction trials inconclusive |
🎯 Clinical Pearl
- Kennedy disease triad for boards: X-linked male + bulbar/proximal weakness + gynecomastia = SBMA until proven otherwise
- Key distinguisher from ALS: sensory neuropathy + no UMN signs + very slow progression
- Perioral fasciculations (chin quivering) are characteristic of Kennedy disease but rare in ALS
Primary Lateral Sclerosis (PLS)
Key Features
| Feature | Details |
|---|---|
| Definition | Pure UMN motor neuron disease; <5% of all MND |
| Onset | Mean ~50 years; insidious progressive spastic paraparesis |
| Diagnostic criteria | Diagnosis of exclusion; must follow for ≥4 years without LMN signs developing (Pringle original criteria: ≥3 years; Gordon/Turner consensus criteria: ≥4 years) |
| Exam | Spasticity, hyperreflexia, Babinski; NO atrophy, fasciculations, or denervation |
| EMG | Normal (no fibrillations or denervation) — if EMG abnormal, reclassify as ALS/PMA |
| Prognosis | Much better than ALS; survival measured in years to decades |
| Caveat | ~20% eventually develop LMN signs → reclassified as UMN-dominant ALS |
PLS Differential Diagnosis
| Condition | How to Distinguish |
|---|---|
| Hereditary spastic paraplegia | Family history; genetic testing; typically younger onset |
| Multiple sclerosis | MRI brain/spine lesions; CSF OCBs; relapsing course |
| Vitamin B12 deficiency | Sensory findings; low B12/elevated methylmalonic acid; dorsal column involvement |
| HTLV-1 myelopathy (HAM/TSP) | Endemic areas; HTLV-1 serology; bladder involvement early |
| Adrenoleukodystrophy | Young males (X-linked); very long chain fatty acids elevated; MRI white matter changes |
| Copper deficiency myelopathy | History of gastric surgery or zinc excess; low serum copper/ceruloplasmin |
💎 Board Pearl
- PLS requires ≥4 years of pure UMN disease to diagnose — any LMN sign before this = probable ALS
- Normal EMG is required for PLS diagnosis — denervation changes on EMG exclude the diagnosis
- Must rule out structural (cord compression), inflammatory (MS), metabolic (B12, copper), and infectious (HTLV-1) causes first
Postpolio Syndrome
Key Features
| Feature | Details |
|---|---|
| Timing | New symptoms 15–40 years after acute poliomyelitis (mean ~35 years) |
| Pathophysiology | Surviving motor neurons that reinnervated denervated muscle fibers via collateral sprouting become exhausted over time → progressive loss of enlarged motor units |
| Symptoms | New progressive weakness, fatigue, muscle atrophy, pain; affects previously affected AND previously unaffected muscles |
| EMG | Giant motor unit potentials (MUPs) from prior reinnervation; may show new active denervation (fibrillations) |
| Diagnosis | Clinical — prior polio history + new weakness after stable period + exclusion of other causes |
| Treatment | Supportive only; energy conservation; assistive devices; avoid overexertion; no proven pharmacotherapy |
| Key distinction | NOT a reactivation of poliovirus; NOT contagious; slowly progressive (not rapidly fatal like ALS) |
💎 Board Pearl
- Giant MUPs on EMG = collateral reinnervation from prior polio — pathognomonic finding in postpolio syndrome
- Postpolio syndrome is NOT due to viral reactivation — it reflects motor unit exhaustion from decades of compensatory overwork
- Board question setup: patient with childhood polio → decades of stability → new progressive weakness + giant MUPs on EMG
Hereditary Spastic Paraplegia (HSP)
Overview
- Definition: heterogeneous group of inherited disorders characterized by progressive lower-extremity spasticity and weakness from corticospinal tract degeneration; >80 genetic loci (SPG1–SPG80+) identified
- Pure HSP: spastic paraparesis (legs > arms), hyperreflexia, Babinski, mild urinary urgency, mild dorsal-column sensory loss
- Complicated HSP: spastic paraparesis PLUS additional features — cognitive impairment, ataxia, neuropathy, optic atrophy, thin corpus callosum, retinopathy, ichthyosis
- Onset: wide range (childhood to late adulthood); AD forms typically later, AR forms earlier
Major HSP Genes
| Gene (locus) | Protein | Inheritance | Key Features |
|---|---|---|---|
| SPG4 | Spastin | AD | Most common AD HSP (~40% of AD cases); typically pure HSP; microtubule-severing ATPase; adult onset most common |
| SPG3A | Atlastin-1 | AD | Second most common AD HSP; childhood onset; pure form; GTPase involved in ER morphology |
| SPG7 | Paraplegin | AR | Most common AR HSP; mitochondrial m-AAA protease; often complicated (cerebellar ataxia, optic atrophy) |
| SPG11 | Spatacsin | AR | Most common complicated AR HSP; thin corpus callosum, cognitive impairment, peripheral neuropathy; juvenile onset |
| SPG2 | PLP1 (proteolipid protein 1) | X-linked | Allelic with Pelizaeus-Merzbacher disease; complicated HSP |
Diagnosis & Management
- Diagnosis: clinical pattern + family history + MRI (rule out structural/inflammatory causes) + targeted genetic testing or HSP panel
- Key DDx: PLS (no family history, later onset), MS, B12/copper deficiency, HTLV-1, adrenoleukodystrophy, dopa-responsive dystonia
- Treatment: symptomatic only — baclofen, tizanidine, botulinum toxin for spasticity; physical therapy; assistive devices; treat urinary symptoms
💎 Board Pearl
- SPG4 (spastin) = most common AD HSP; SPG7 (paraplegin) = most common AR HSP
- SPG11 + thin corpus callosum + cognitive impairment = classic complicated AR HSP picture
- HSP vs PLS: HSP has family history + earlier onset; PLS is sporadic and adult-onset
West Nile Virus Poliomyelitis
Key Features
| Feature | Details |
|---|---|
| Pathogen | West Nile virus (flavivirus); mosquito-borne (Culex spp.); reservoir = birds; summer/early fall in endemic areas (continental US, especially central/western) |
| Clinical syndrome | Acute flaccid paralysis — rapid-onset, asymmetric, often monomelic; may follow a febrile/meningoencephalitic prodrome; respiratory failure if diaphragm/intercostals involved |
| Mechanism | Direct viral injury to anterior horn cells (poliomyelitis-like); sensation typically preserved (pure LMN syndrome) |
| CSF | Lymphocytic pleocytosis (early may be neutrophil-predominant); elevated protein; normal glucose; WNV IgM in CSF is diagnostic |
| MRI | T2/STIR hyperintensity in anterior horns of spinal cord (“snake-eye” pattern on axial); may show brainstem/thalamic involvement in encephalitic cases |
| EMG/NCS | Reduced motor amplitudes; normal sensory studies; widespread denervation in affected myotomes |
| Treatment | Supportive only — no approved antiviral; ventilatory support; rehabilitation; recovery often incomplete |
| Key DDx | Guillain-Barré (areflexia + ascending symmetric weakness + albuminocytologic dissociation), enterovirus EV-D68/A71, acute flaccid myelitis (children), poliovirus |
💎 Board Pearl
- Summer + mosquito exposure + asymmetric flaccid paralysis + CSF pleocytosis = West Nile poliomyelitis
- Anterior horn T2 hyperintensity on cord MRI ("snake-eye" pattern) supports the diagnosis
- Distinguish from GBS: WNV is asymmetric, LMN-only, with CSF pleocytosis; GBS is symmetric/ascending with albuminocytologic dissociation
High-Yield Comparison: Motor Neuron Diseases
MND Comparison Table
| Disease | Inheritance | Motor Neuron | Distinguishing Feature | Prognosis |
|---|---|---|---|---|
| ALS | Sporadic (90%) / AD | UMN + LMN | Hyperreflexia + atrophy in same limb | 3–5 years |
| PMA | Sporadic | Pure LMN | No UMN signs; may convert to ALS | ~5 years |
| PLS | Sporadic | Pure UMN | Normal EMG; ≥4 years pure UMN | Years–decades |
| SMA | AR (SMN1) | Pure LMN | Infant/child; tongue fasciculations; spared intellect | Type-dependent |
| Kennedy disease | X-linked (CAG) | LMN + sensory | Gynecomastia; perioral fasciculations; sensory neuropathy | Near-normal lifespan |
| Postpolio | Acquired | LMN | Prior polio history; giant MUPs; decades later | Slowly progressive |
💎 Board Pearl
- UMN + LMN = ALS; pure LMN = PMA or SMA; pure UMN = PLS; LMN + gynecomastia = Kennedy
- Treatable MND mimics: MMN (IVIg), cervical myelopathy (surgery), B12 deficiency (supplementation) — always exclude before diagnosing ALS
- Three SMA therapies: nusinersen (intrathecal antisense), risdiplam (oral splicing modifier), Zolgensma (IV gene therapy) — all target SMN protein production
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