Progressive degeneration of upper and lower motor neurons producing mixed UMN/LMN signs without sensory involvement.
Also known as: ALS, Lou Gehrig disease, motor neuron disease, MND
Overview
A relentlessly progressive neurodegenerative disease characterized by simultaneous loss of upper motor neurons (corticospinal tract) and lower motor neurons (anterior horn cells and bulbar nuclei). Sensory, autonomic, and oculomotor function are typically spared.
Epidemiology
Incidence ~2 per 100,000 per year; peak onset in the sixth and seventh decades. Male predominance ~1.5:1. ~10% familial (SOD1, C9orf72, FUS, TARDBP); ~90% sporadic. Median survival 3-5 years from symptom onset, although ~10% live >10 years.
Try two board-style Amyotrophic Lateral Sclerosis questions
Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.
Question 1NeurologyMedium
A 50-year-old male has a 6-month history of progressive left arm weakness, left leg spasticity, and dysphagia. Exam shows fasciculations in the left arm and tongue, hyperreflexia in the left leg, and a positive Hoffman sign. Which of the following tests best confirms the suspected diagnosis?
AElectromyography plus nerve conduction studies
BCerebrospinal fluid analysis with cytology
CMRI of the brain and cervical spine
DOpen muscle biopsy with immunohistochemistry
Reveal answer & full explanation
Correct answer: A — Electromyography plus nerve conduction studies
AElectromyography plus nerve conduction studies✓
BCerebrospinal fluid analysis with cytology
CMRI of the brain and cervical spine
DOpen muscle biopsy with immunohistochemistry
Why Electromyography plus nerve conduction studies is correct
Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis based on El Escorial criteria: upper motor neuron (UMN) and lower motor neuron (LMN) signs in multiple regions (bulbar, cervical, thoracic, lumbar), progressive course, no sensory involvement, and no other explanatory diagnosis.
Electromyography (EMG) and nerve conduction studies (NCS) confirm widespread LMN involvement by showing fibrillation potentials, positive sharp waves, and reduced motor unit recruitment across multiple myotomes.
There is no definitive biomarker; ALS is a diagnosis of exclusion.
Why the others are wrong
Cerebrospinal fluid analysis with cytology — CSF studies are used to exclude inflammatory or infectious mimics, not to confirm the LMN denervation that defines ALS (confused-with mimic workup).
MRI of the brain and cervical spine — imaging excludes structural and compressive lesions but does not demonstrate the multilevel LMN denervation needed for diagnosis (rule-out-not-confirm).
Open muscle biopsy with immunohistochemistry — biopsy is reserved for suspected primary myopathy and does not establish a motor neuron disease diagnosis (right-concept-wrong-test).
Additional high-yield points
Median survival is 3-5 years from symptom onset.
Prognostic factors: bulbar onset confers worse prognosis due to aspiration risk; older age at onset and rapid progression are also adverse factors.
Riluzole extends survival by 2-3 months.
Edaravone (IV/oral) reduces functional decline in selected patients.
AMX0035 is a neuroprotective combination with modest benefit.
Tofersen targets the superoxide dismutase 1 (SOD1) mutation and reduces the neurofilament light chain (NfL) biomarker.
Multidisciplinary care is essential.
Question 2NeurologyMedium
A 62-year-old man reports 8 months of progressive right hand clumsiness, frequent cramps, and slurred speech. Examination shows wasting and visible fasciculations of the right forearm and tongue, brisk reflexes throughout, an extensor plantar response, and a spastic dysarthria. Sensation, eye movements, and sphincter function are intact. EMG reveals active denervation with chronic reinnervation in three body regions, and MRI of the brain and spine is unremarkable. He is started on riluzole. Which of the following best explains the findings?
AGlutamate excitotoxicity of motor neurons
BAutoimmune acetylcholine-receptor blockade
CAnti-ganglioside motor conduction block
DImmune-mediated peripheral demyelination
Reveal answer & full explanation
Correct answer: A — Glutamate excitotoxicity of motor neurons
AGlutamate excitotoxicity of motor neurons✓
BAutoimmune acetylcholine-receptor blockade
CAnti-ganglioside motor conduction block
DImmune-mediated peripheral demyelination
Why Glutamate excitotoxicity of motor neurons is correct
The vignette is classic amyotrophic lateral sclerosis: mixed upper motor neuron (hyperreflexia, Babinski, spastic dysarthria) and lower motor neuron (atrophy, fasciculations, tongue involvement) findings in the same regions, with sparing of sensation, eye movements, and sphincters, plus EMG denervation/reinnervation in multiple regions and a normal MRI.
ALS results from selective motor neuron degeneration driven by converging mechanisms — TDP-43 cytoplasmic aggregation, glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, and impaired protein/RNA homeostasis. Excess synaptic glutamate causes excessive calcium influx and motor neuron death.
Riluzole, a glutamate antagonist that reduces presynaptic glutamate release, is first-line precisely because it targets this excitotoxic pathway and confers a modest survival benefit.
Why the others are wrong
Autoimmune acetylcholine-receptor blockade — this is the mechanism of myasthenia gravis, which causes fatigable, ocular-predominant weakness without UMN signs, atrophy, or fasciculations; ophthalmoplegia and fatigability would point away from ALS.
Immune-mediated peripheral demyelination — describes CIDP/Guillain-Barre-type processes, which produce sensory loss and areflexia rather than the brisk reflexes, fasciculations, and preserved sensation seen here.
Anti-ganglioside motor conduction block — this underlies multifocal motor neuropathy (anti-GM1 antibodies, conduction block on NCS), a pure lower motor neuron, IVIG-responsive mimic; it cannot explain the upper motor neuron signs (Babinski, spasticity) present in this patient.
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Family history of ALS or frontotemporal dementia (especially C9orf72 hexanucleotide repeat expansion)
Smoking (modest)
Military service (associations reported but mechanism unclear)
Pathophysiology
Selective degeneration of motor neurons driven by multiple converging mechanisms: TDP-43 cytoplasmic aggregation, glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, impaired protein homeostasis, neuroinflammation, and disturbed RNA processing. C9orf72 GGGGCC repeat expansion is the most common genetic cause and overlaps with frontotemporal dementia.
Clinical presentation
Symptoms
Limb-onset (~70%): asymmetric weakness, foot drop, hand clumsiness, muscle wasting
Spinal muscular atrophy (adult-onset) — Pure LMN, more slowly progressive, SMN1 deletion
Kennedy disease (spinobulbar muscular atrophy) — X-linked, bulbar and proximal weakness with gynecomastia, infertility, perioral fasciculations; CAG repeat in AR gene
Lyme, HIV, syphilis, lead, heavy metals, hyperthyroidism — Reversible mimics — screen routinely to avoid missing a treatable cause
Diagnostic workup
Diagnostic criteria
Gold Coast criteria (2020): progressive motor impairment + UMN and LMN dysfunction in ≥1 body region OR LMN dysfunction in ≥2 body regions + exclusion of mimics. EMG demonstrates active denervation (fibrillations, positive sharp waves) and chronic reinnervation (large motor unit potentials) in multiple body regions.
Labs
CK (mildly elevated in many), TSH, B12, HIV, RPR, Lyme serologies
SPEP/immunofixation to exclude paraproteinemia-related neuropathy
Anti-GM1 antibodies if MMN suspected
Genetic testing (SOD1, C9orf72, FUS, TARDBP) particularly with family history or before tofersen consideration
Imaging
MRI brain and full spine to exclude structural mimics (compression, demyelination, syrinx)
Diagnostic algorithm
flowchart TD
A[Progressive painless<br/>weakness in adult] --> B[Exam: UMN + LMN<br/>signs, no sensory loss]
B --> C[MRI brain/spine<br/>+ labs to exclude mimics]
C --> D[EMG/NCS:<br/>denervation in<br/>multiple regions]
D --> E{Gold Coast<br/>criteria met?}
E -->|Yes| F[ALS diagnosis]
E -->|No| G[Re-evaluate;<br/>consider mimics]
F --> H[Multidisciplinary clinic<br/>+ riluzole ± edaravone<br/>± tofersen if SOD1]
H --> I[Serial FVC,<br/>BiPAP, PEG,<br/>palliative care]
ALS diagnostic and longitudinal management pathway.
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