What is the diagnostic approach for a patient suspected of having Amyotrophic Lateral Sclerosis (ALS)?

Diagnosing Amyotrophic Lateral Sclerosis (ALS)

The diagnosis of ALS requires demonstrating both upper and lower motor neuron degeneration with progressive spread of symptoms, confirmed by electromyography (EMG) and nerve conduction studies, while systematically excluding other treatable conditions through MRI brain imaging and comprehensive laboratory testing. 1, 2

Core Diagnostic Requirements

The diagnosis rests on three essential elements that must all be present 1, 2:

• Upper motor neuron signs: Hypertonicity, hyperreflexia, and spasticity 2
• Lower motor neuron signs: Muscle fasciculations, weakness, and atrophy 2
• Progressive spread: Symptoms must demonstrate progression through different body regions over time 2

Clinical Presentation Patterns

ALS typically presents in one of two forms 3:

• Limb-onset (spinal): Progressive weakness beginning in distal limbs, most common presentation 4
• Bulbar-onset: Dysarthria and dysphagia affecting approximately 80% of these patients, with shorter life expectancy than limb-onset 1, 3

Mandatory Electrophysiological Testing

EMG and nerve conduction velocity (NCV) studies are the cornerstone diagnostic tests and must be performed in all suspected cases. 1, 2, 5

These studies accomplish several critical objectives:

• Detect lower motor neuron degeneration showing denervation and reinnervation patterns in multiple body regions 2, 5
• Identify characteristic EMG abnormalities: Fibrillation potentials, positive sharp waves, fasciculation potentials at rest, incomplete interference pattern, and abnormal motor unit potentials 5
• Distinguish ALS from other conditions that can mimic the disease 1, 2

Neuroimaging to Exclude Mimics

MRI brain without IV contrast is the initial imaging study of choice and should be performed in all cases. 1, 2, 3

Key imaging findings include:

• Primary purpose: Exclude structural lesions, inflammatory conditions, tumors, and other diseases that mimic ALS 2
• Supportive (but not diagnostic) findings: Abnormal T2/FLAIR signal in corticospinal tracts, particularly in posterior limb of internal capsule and cerebral peduncles 2, 3
• Highly specific finding: Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging 2

MRI spine without IV contrast may be appropriate in certain cases to exclude structural, infectious, or neoplastic etiologies 1

Comprehensive Laboratory Exclusion Panel

A systematic laboratory workup is essential to exclude treatable conditions that present similarly 1, 2:

Hematologic and Metabolic Testing

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Blood chemistry profile including glucose, electrolytes, kidney function, and liver enzymes 1, 2
• Thyroid function tests to rule out thyroid disorders causing weakness 1, 2

Nutritional Deficiencies

• Vitamin B12, folate, and vitamin E levels to exclude deficiencies that can cause motor symptoms 1, 2

Immunologic Testing

• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 2
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1, 2
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1, 2
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1, 2

Cerebrospinal Fluid Analysis

CSF examination should include 1, 2:

• Cell count, protein, glucose to exclude infectious or inflammatory causes 1, 2
• IgG index and oligoclonal bands to assess for inflammatory processes 1, 2
• Cytology to exclude neoplastic causes 1, 2

Critical caveat: Marked pleocytosis (>50 cells/μL) suggests an alternative diagnosis and should prompt reconsideration of ALS 2

Genetic Testing Considerations

Consider genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP), especially in cases with family history. 1

Approximately 10% of ALS cases are related to genetic variants 6

Dysphagia Screening at Diagnosis

Screening for dysphagia should be performed at diagnosis and every 3 months during follow-up, even in patients without bulbar symptoms. 2, 3

Screening Tools

• EAT-10 questionnaire: 86% sensitivity, 76% specificity for identifying unsafe swallowing 1, 2
• Volume-Viscosity Swallow Test (V-VST): 92% sensitivity, 80% specificity for detecting dysphagia 1, 2

Instrumental Evaluation

Videofluoroscopy should be performed at diagnosis to detect early signs of dysphagia and silent aspirations, even in asymptomatic patients. 1, 2, 3

Common Diagnostic Pitfalls

Several factors contribute to diagnostic delays averaging 10-16 months 6:

• Heterogeneous presentation: ALS can begin in any body segment (bulbar, cervical, thoracic, or lumbosacral) 4
• Lack of physician knowledge: Many physicians, including neurologists, miss the diagnosis due to unfamiliarity with ALS 7
• Failure to include ALS in differential diagnosis: Correct diagnosis requires considering ALS when evaluating progressive weakness 7
• Restricted presentations: Must differentiate from progressive bulbar palsy (pure bulbar), progressive muscular atrophy (pure lower motor neuron), and primary lateral sclerosis (pure upper motor neuron) 7

Diagnostic Algorithm Summary

1. Clinical evaluation demonstrating both upper and lower motor neuron signs with progressive spread 1, 2
2. EMG and nerve conduction studies to confirm lower motor neuron involvement and exclude mimics 1, 2
3. MRI brain without contrast to exclude structural and inflammatory conditions 1, 2
4. Comprehensive laboratory panel to systematically exclude treatable conditions 1, 2
5. CSF analysis when inflammatory or infectious causes remain in differential 1, 2
6. Dysphagia screening with EAT-10, V-VST, and videofluoroscopy at diagnosis 1, 2
7. Genetic testing when family history present or early-onset disease 1