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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

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
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
Possible ALS	UMN + LMN in 1 region only, OR UMN signs in ≥2 regions, OR LMN signs rostral to UMN signs

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 criteria allow fasciculation potentials to be equivalent to fibrillations/positive sharp waves → increases EMG sensitivity

ALS Genetics

Major ALS Genes

Gene	Chromosome	Inheritance	Key Features
C9orf72	9p21	AD	Most common familial ALS gene (~40% familial, ~7% sporadic); GGGGCC hexanucleotide repeat expansion; causes ALS + FTD overlap; RNA foci + dipeptide repeat proteins
SOD1	21q22	AD (most)	~20% of familial 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)

💎 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	Young male; asymmetric hand/forearm atrophy; cervical flexion myelopathy; self-limiting	Neck flexion MRI shows dural detachment

🎯 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 2017; IV or oral formulation; 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	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; approved for age ≥2 months; 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
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

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