Motor Neuron Disease
Motor Neuron Disease
What You'll Learn
- 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
HighYield Pearls
- 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antagonist) extends survival ~2–3 months; edaravone (free radical scavenger) modest benefit; AMX0035/Relyvrio withdrawn 2024 after failed phase 3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
🔍 Quick ReferenceClinical · 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
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