What is the diagnostic approach for Amyotrophic Lateral Sclerosis (ALS)?

Diagnostic Approach for Amyotrophic Lateral Sclerosis (ALS)

ALS diagnosis requires demonstrating both upper and lower motor neuron degeneration with progressive spread, confirmed by electromyography and nerve conduction studies, while systematically excluding treatable mimics through neuroimaging and comprehensive laboratory testing. 1, 2

Core Diagnostic Requirements

The diagnosis rests on three pillars that must all be present:

• Clinical evidence of both upper motor neuron (UMN) and lower motor neuron (LMN) degeneration - UMN signs include hypertonicity, hyperreflexia, and spasticity; LMN signs include muscle fasciculations, weakness, and atrophy 1
• Progressive spread of symptoms through different body regions over time - this temporal evolution is essential for diagnosis 1
• Exclusion of other treatable conditions that can mimic ALS through systematic testing 1, 2

Mandatory Electrophysiological Testing

EMG and nerve conduction velocity studies are the cornerstone diagnostic tests and are mandatory for diagnosing ALS - these detect lower motor neuron degeneration and distinguish ALS from other conditions 1, 3. The electrophysiological features should follow Awaji-shima consensus recommendations applied to the revised El Escorial Criteria 4.

Key EMG findings include:

• Fibrillation potentials or positive sharp wave potentials at rest - these are required evidence of LMN involvement 5
• Fasciculation potentials in resting muscle 1
• Incomplete interference pattern with abnormal motor unit potentials 4
• Large macro-motor unit potentials reflecting collateral nerve sprouting 4

Essential Neuroimaging

MRI brain without IV contrast is the initial imaging study of choice to exclude structural lesions, inflammatory conditions, and other diseases that mimic ALS 1, 3. While not diagnostic, supportive MRI findings in ALS include:

• Abnormal T2/FLAIR signal in corticospinal tracts, particularly in the posterior limb of internal capsule and cerebral peduncles 1, 3
• Abnormal hypointensity in precentral gyrus on T2-weighted or susceptibility-weighted imaging* - this finding is highly sensitive and specific 1, 3

MRI of the spine without IV contrast may be appropriate in certain cases to exclude structural, infectious, or neoplastic etiologies 2, 3.

Comprehensive Laboratory Workup to Exclude Mimics

A metabolic and immunologic workup is essential to rule out treatable conditions 1. The following tests are recommended:

Basic metabolic panel:

• Complete blood count 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 1, 2, 3

Immunologic testing:

• Serum protein electrophoresis to rule out paraproteinemic neuropathies 1, 2, 3
• Anti-ganglioside antibodies (GM1, GD1a, GD1b) to exclude immune-mediated motor neuropathies 1, 2, 3
• Paraneoplastic antibody panel to exclude paraneoplastic syndromes 1, 2, 3
• Anti-acetylcholine receptor and anti-MuSK antibodies to rule out myasthenia gravis 1, 2, 3

Cerebrospinal Fluid Analysis

CSF examination should include cell count, protein, glucose, IgG index, oligoclonal bands, and cytology to exclude infectious, inflammatory, or neoplastic causes 1, 2, 3.

Critical pitfall: Marked pleocytosis (>50 cells/μL) suggests an alternative diagnosis and should prompt reconsideration of ALS 1, 3. CSF protein may be normal or mildly elevated in ALS 3.

Genetic Testing Considerations

Genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP) should be considered, especially in cases with family history 2, 3. This is particularly important given that ALS forms a clinical continuum with frontotemporal dementia, with overlapping genetics and pathology 6.

Dysphagia Evaluation at Diagnosis

Screening for dysphagia should be performed at diagnosis, even in patients without bulbar symptoms 1:

• Structured questionnaires (EAT-10) have 86% sensitivity and 76% specificity for identifying unsafe swallowing 1, 2
• Volume-Viscosity Swallow Test (V-VST) has 92% sensitivity and 80% specificity for detecting dysphagia 1, 2
• Videofluoroscopy should be performed at diagnosis to detect early signs of dysphagia and silent aspirations 1, 2

This is critical because approximately 80% of patients with bulbar-onset ALS develop dysarthria and dysphagia 2.

Timeline and Diagnostic Accuracy

Using revised diagnostic criteria that require LMN involvement in at least two limbs and UMN involvement in at least one region (bulbar, cervical, or lumbosacral), diagnosis can be made at a mean time of 9.7 months from symptom onset 5. This represents an improvement over the traditional 12-month diagnostic delay 5.

Common pitfall: ALS is a heterogeneous disorder that may present in multiple ways, making diagnosis challenging 6. A systematic approach is required, starting with assessment of motor symptoms and signs, then evaluating for cognitive/behavioral changes within the FTD spectrum, and finally determining if the cause is genetic 6.