What is the diagnosis and management plan for a patient presenting with symptoms suggestive of amyotrophic lateral sclerosis (ALS)?

Amyotrophic Lateral Sclerosis (ALS): Clinical Features, Differential Diagnosis, and Management

Clinical Presentation

ALS presents with a combination of upper motor neuron signs (hypertonicity, hyperreflexia, spasticity) and lower motor neuron signs (muscle fasciculations, weakness, atrophy) with progressive spread through different body regions over time. 1, 2

Key Clinical Features to Identify:

Upper Motor Neuron Signs:

• Hyperreflexia and spasticity
• Increased muscle tone
• Pathological reflexes (Babinski sign) 1, 2

Lower Motor Neuron Signs:

• Muscle fasciculations (visible twitching)
• Progressive muscle weakness
• Muscle atrophy and wasting 1, 2

Bulbar Involvement:

• Approximately 80% of patients with bulbar-onset ALS develop dysarthria (speech difficulty) and dysphagia (swallowing difficulty) 1
• Progressive difficulty with articulation and tongue movements 3

Pattern of Progression:

• Typically focal onset with subsequent spread to different body regions
• Progressive and relentless course without remissions 3, 4
• Painless progressive weakness is characteristic 5

Diagnostic Workup

Essential Electrodiagnostic Testing:

Electromyography (EMG) and nerve conduction studies are mandatory cornerstone tests for diagnosing ALS, detecting lower motor neuron degeneration and distinguishing ALS from mimicking conditions. 1, 2

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. 3, 1, 2

Supportive MRI findings (not diagnostic but suggestive):

• Abnormal T2/FLAIR signal in corticospinal tracts, particularly in posterior limb of internal capsule and cerebral peduncles 3, 2
• Abnormal hypointensity in precentral gyrus on T2*-weighted or susceptibility-weighted imaging (highly sensitive and specific) 3, 2
• "Snake eyes" appearance in spinal cord anterior horns on T2/STIR sequences (late finding, not specific) 3

MRI spine without IV contrast may be appropriate to exclude structural, infectious, or neoplastic etiologies mimicking motor neuron disease. 3, 1, 2

Comprehensive Laboratory Panel:

A comprehensive metabolic and immunologic workup is essential to exclude treatable conditions that present with similar symptoms. 1, 2

Required blood tests:

• Complete blood count (CBC) to evaluate for infectious or inflammatory conditions 1, 2
• Comprehensive metabolic panel including glucose, electrolytes, kidney and liver function 1, 2
• Thyroid function tests to rule out thyroid disorders causing weakness 1, 2
• Vitamin B12, folate, and vitamin E levels to exclude nutritional deficiencies 1, 2
• 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 cell count, protein, glucose, IgG index, oligoclonal bands, and cytology to exclude infectious, inflammatory, or neoplastic causes. 1, 2

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

Genetic Testing:

Consider genetic testing for ALS-associated genes (C9orf72, SOD1, FUS, TARDBP), especially in cases with family history. 1 The C9orf72 repeat expansion is the most common known genetic cause, seen in approximately 40% of familial cases and 10% of sporadic cases 5, 4

Dysphagia Evaluation:

Screening for dysphagia should be performed at diagnosis and every 3 months during follow-up, even in patients without bulbar symptoms. 1, 2

Screening tools:

• EAT-10 questionnaire (86% sensitivity, 76% specificity for unsafe swallowing) 1, 2
• Volume-Viscosity Swallow Test (V-VST) (92% sensitivity, 80% specificity for detecting dysphagia) 1, 2
• Videofluoroscopy at diagnosis to detect early signs of dysphagia and silent aspirations 3, 1, 2

Differential Diagnosis

Primary Mimics to Exclude:

Multifocal Motor Neuropathy:

• Pure lower motor neuron involvement without upper motor neuron signs
• Asymmetric weakness with conduction block on nerve conduction studies
• Responds to immunotherapy (unlike ALS) 6

Cervical Spondylotic Myelopathy:

• Upper motor neuron signs may predominate
• Sensory level and sphincter dysfunction (rare in ALS)
• MRI spine shows cord compression 6

Myasthenia Gravis:

• Fatigable weakness without fasciculations
• Ocular involvement common (rare in ALS)
• Positive acetylcholine receptor or MuSK antibodies 1, 2

Kennedy Disease (Spinal and Bulbar Muscular Atrophy):

• X-linked, affects only males
• Gynecomastia and sensory involvement
• Genetic testing for androgen receptor gene mutation 6

Inclusion Body Myositis:

• Slowly progressive weakness
• Elevated creatine kinase
• Muscle biopsy diagnostic 6

Paraneoplastic Syndromes:

• Associated with underlying malignancy
• Positive paraneoplastic antibodies 1, 2, 6

Important clinical distinction: Prominent early sensory symptoms with minimal motor involvement should prompt consideration of alternative diagnoses such as Guillain-Barré syndrome variants or other peripheral neuropathies 7

Management Plan

Disease-Modifying Therapy:

Riluzole 50 mg twice daily is FDA-approved and modestly prolongs survival by approximately 60-90 days. 8 Two pivotal trials demonstrated increased time to tracheostomy or death, with differences reaching statistical significance by Wilcoxon test (p=0.05) 8

Edaravone (free radical scavenger) is the second FDA-approved medication with modest benefits. 5, 9

Nutritional Management:

In ALS patients with muscular fatigue and prolonged meals, fractionate and enrich meals with energy-dense foods; if weight loss progresses, initiate oral nutritional supplementation. 3

In ALS patients with moderate dysphagia, provide dietetic counseling to adapt texture of solids and liquids to facilitate swallowing and avoid aspiration. 3 Instrumental swallowing studies (videofluoroscopy or FEES) can guide the safety and efficacy of texture-modified diets 3

Dysphagia-Specific Interventions:

In ALS patients with moderate dysphagia, recommend postural maneuvers such as chin-tuck posture to protect the airway during swallowing. 3

Consider gastrostomy for patients with severe dysphagia to maintain nutrition and prolong life. 10

Respiratory Support:

Ventilatory support for those with respiratory insufficiency may help extend life. 10 Respiratory failure due to respiratory muscle weakness is the most common cause of death 1

Multidisciplinary Care:

Multidisciplinary care may help extend life and maintain quality of life. 10 Regular follow-up with swallowing evaluations every 3 months is recommended to monitor dysphagia progression 1

Early referral to palliative services is recommended to establish relationships with staff and address end-of-life issues before communication becomes limited. 1

Caregiver Support:

Support for caregivers is crucial, as they often experience significant burden. 1

Prognosis

Mean survival is 3-5 years after symptom onset, with only 5-10% of patients living longer than 10 years. 1, 10, 5 The range of survival extends from a few months to decades for approximately 5% of patients 10

Common Pitfalls to Avoid:

• Do not delay EMG/NCV studies – these are mandatory for diagnosis and cannot be replaced by imaging alone 1, 2
• Do not assume normal MRI excludes ALS – MRI is primarily used to exclude mimics, not to diagnose ALS 3
• Do not overlook dysphagia screening – silent aspiration can occur even without reported swallowing symptoms 1, 2
• Do not miss treatable mimics – multifocal motor neuropathy and myasthenia gravis respond to immunotherapy 6
• Do not wait for severe respiratory symptoms – proactive respiratory monitoring and early intervention improve outcomes 10