What are the diagnostic criteria for Amyotrophic Lateral Sclerosis (ALS)?

How ALS is Diagnosed

ALS diagnosis requires demonstrating both upper and lower motor neuron degeneration through clinical examination combined with electromyography (EMG) and nerve conduction studies, while systematically excluding treatable mimics through MRI brain imaging and comprehensive laboratory testing. 1, 2

Clinical Diagnostic Foundation

The diagnosis fundamentally depends on identifying specific motor neuron signs that progressively spread across body regions 1:

Upper Motor Neuron Signs

• Hypertonicity and spasticity in affected limbs 1
• Hyperreflexia (exaggerated deep tendon reflexes) 1
• Pathological reflexes (Babinski sign) 1

Lower Motor Neuron Signs

• Muscle fasciculations (visible twitching under the skin) 1
• Progressive weakness starting focally and spreading 1
• Muscle atrophy (wasting) in affected regions 1

Progressive Pattern

• Symptoms must spread from one body region to others over time, demonstrating the relentless progression characteristic of ALS 1, 3

Mandatory Electrophysiological Testing

EMG and nerve conduction velocity studies are absolutely required for diagnosis, as they detect lower motor neuron degeneration that may not be clinically apparent and distinguish ALS from treatable mimics 1, 2, 4:

• Fibrillation potentials or positive sharp waves at rest indicate active denervation 4
• Fasciculation potentials in resting muscle support the diagnosis 4
• Incomplete interference pattern with abnormal motor unit potentials during contraction 4
• Large macro-motor unit potentials reflecting collateral reinnervation 4
• Evidence of denervation in at least two limbs is typically required 5

The Awaji-shima consensus recommendations have enhanced the diagnostic utility of EMG by giving fasciculation potentials equal weight to fibrillation potentials for detecting lower motor neuron involvement 4.

Neuroimaging to Exclude Mimics

MRI brain without IV contrast is mandatory as the initial imaging study to exclude structural lesions, inflammatory conditions, and other diseases that can present identically to ALS 1, 2:

Supportive MRI Findings in ALS (Not Diagnostic)

• Abnormal T2/FLAIR hyperintensity in corticospinal tracts, particularly the posterior limb of internal capsule and cerebral peduncles 1, 2
• Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging (highly sensitive and specific when present) 1, 2

Spinal MRI Considerations

• May show "snake eyes" appearance (abnormal T2 signal in anterior horns), though this is neither sensitive nor specific and appears late in disease 2
• Consider spine MRI when structural, infectious, or neoplastic etiologies need exclusion 2

Comprehensive Laboratory Exclusion Panel

A systematic laboratory workup is essential because multiple treatable conditions can mimic ALS, and missing these represents catastrophic diagnostic failure 1, 2:

Hematologic and Metabolic

• Complete blood count to exclude infectious/inflammatory conditions 1, 2
• Comprehensive metabolic panel (glucose, electrolytes, kidney and liver function) 1, 2
• Thyroid function tests (hypothyroidism can cause weakness) 1, 2

Nutritional Deficiencies

• Vitamin B12, folate, and vitamin E levels (deficiencies cause motor symptoms) 1, 2

Immunologic Testing

• Serum protein electrophoresis to exclude paraproteinemic neuropathies 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude multifocal motor neuropathy with conduction block 1, 2
• Paraneoplastic antibody panel to exclude cancer-related motor syndromes 1, 2
• Anti-acetylcholine receptor and anti-MuSK antibodies to exclude myasthenia gravis 1, 2

Cerebrospinal Fluid Analysis

CSF examination should be performed when the clinical picture is atypical or to exclude inflammatory/infectious mimics 1, 2:

• Cell count, protein, glucose (protein may be normal or mildly elevated in ALS) 2
• IgG index and oligoclonal bands to exclude multiple sclerosis 1, 2
• Cytology to exclude neoplastic infiltration 1, 2

Critical pitfall: Marked pleocytosis (>50 cells/μL) essentially excludes ALS and demands investigation for alternative diagnoses 1, 2.

Genetic Testing

Consider genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP), particularly when family history is present, as approximately 10% of ALS cases are familial 2.

Dysphagia Screening at Diagnosis

Videofluoroscopy should be performed at diagnosis to detect early dysphagia and silent aspirations, even in patients without bulbar symptoms, as swallowing dysfunction impacts mortality and quality of life 6, 1:

• Structured questionnaires (EAT-10) have 86% sensitivity and 76% specificity for unsafe swallowing 1
• Volume-Viscosity Swallow Test has 92% sensitivity and 80% specificity for detecting dysphagia 1
• Videofluoroscopy detects silent aspirations and guides early nutritional interventions 6, 1

Dysphagia evaluation is critical because aspiration can occur without clinical signs, and early detection allows proactive management to prevent aspiration pneumonia—a major cause of morbidity and mortality 3.

Diagnostic Timeline

Using modern diagnostic criteria emphasizing early EMG findings, diagnosis can be established at a mean of 9.7 months from symptom onset, compared to historical delays of 12+ months 5. However, the diagnosis remains clinical, requiring integration of examination findings, electrophysiology, and systematic exclusion of mimics 7, 8.

Common Diagnostic Pitfalls

• Missing the diagnosis entirely due to lack of familiarity with ALS presentation patterns 7
• Failing to perform EMG in patients with pure upper motor neuron signs, missing subclinical lower motor neuron involvement 4
• Not excluding treatable mimics like multifocal motor neuropathy, which responds to immunotherapy 2
• Overlooking bulbar dysfunction in limb-onset patients, delaying nutritional interventions 6
• Accepting CSF pleocytosis as compatible with ALS, when it should prompt reconsideration 1