What is the diagnosis and differential diagnosis for an adult presenting with progressive focal weakness and combined upper‑motor‑neuron and lower‑motor‑neuron signs?

Diagnosis and Differential of Amyotrophic Lateral Sclerosis (ALS)

Diagnostic Criteria

ALS is diagnosed by demonstrating combined upper and lower motor neuron degeneration with progressive focal weakness, hyperreflexia, muscle atrophy, fasciculations, and preserved sensation—typically presenting in the sixth to seventh decade with rapid bilateral progression over weeks. 1

Core Clinical Features

Upper Motor Neuron Signs:

• Spasticity with velocity-dependent increased muscle tone 2, 3
• Hyperreflexia manifesting as brisk or exaggerated deep tendon reflexes 2, 3
• Extensor plantar responses (Babinski sign) 2, 3
• Clonus showing rhythmic muscle contractions with sudden stretch 2, 3

Lower Motor Neuron Signs:

• Fasciculations—the most characteristic sign, appearing as spontaneous motor unit discharges 2, 3
• Flaccid paralysis with progressive muscle weakness 2, 3
• Muscle atrophy due to denervation 2, 3
• Hyporeflexia or areflexia in affected regions 2, 3

Preserved Functions:

• Sensation remains intact throughout disease course 1, 4
• Oculomotor function is spared 5
• Autonomic function is preserved 5

Mandatory Diagnostic Workup

Electrodiagnostic Studies

Electromyography and nerve conduction studies are mandatory for confirming the diagnosis. 2, 3

• EMG must demonstrate widespread denervation (fibrillation potentials, positive sharp waves, fasciculations) together with chronic reinnervation (large polyphasic motor units) across multiple body regions 1, 2
• Nerve conduction studies show normal sensory responses but may reveal reduced motor amplitudes in advanced disease 1, 2
• Do not rely on clinical examination alone—electrodiagnostic confirmation is essential 3

Neuroimaging Protocol

Brain and spine MRI without contrast is first-line imaging to exclude structural mimics. 1, 2, 3

• T2/FLAIR hyperintensity along corticospinal tracts, especially in the posterior limb of internal capsule and cerebral peduncles, is the most frequent MRI finding 1, 2, 3
• T2*-weighted or susceptibility-weighted imaging showing hypointensity in the precentral gyrus provides high sensitivity and specificity 1
• Spinal MRI may reveal T2 hyperintensity in anterior horn cells ("snake-eyes" appearance), though this appears late and lacks specificity 1, 2, 3

Laboratory Exclusion Panel

A systematic work-up to exclude ALS mimics must include: 1

• Vitamin B12 level
• Thyroid function tests (TSH)
• Serum protein electrophoresis
• Anti-GM1 antibodies
• HIV serology
• Lyme serology
• Creatine kinase (CK) when lower motor neuron weakness is present 2, 3

Genetic Testing

• Test for familial ALS genes (SOD1, C9orf72, TARDBP, FUS) when family history exists or presentation occurs before age 50, recognizing that 85–90% of cases are sporadic 1

Critical Differential Diagnoses

Red Flags That Exclude ALS

Areflexia or hyporeflexia throughout examination:

• Strongly favors Guillain-Barré syndrome over ALS 1
• Guillain-Barré also presents with autonomic symptoms (dry mouth, postural dizziness, bladder dysfunction) absent in ALS 1

Sensory level or sensory loss:

• Indicates spinal cord pathology (compression, myelopathy) rather than motor neuron disease 1

Early bladder dysfunction:

• More consistent with cord compression or cauda equina syndrome 1

Marked asymmetry of weakness:

• Raises consideration of stroke, focal structural lesions, or corticobasal degeneration 1

Muscle pain with markedly elevated CK (>10× normal):

• Suggests inflammatory myopathy (dermatomyositis, polymyositis) which typically presents with normal or reduced reflexes 1

Mimics Requiring Specific Exclusion

Inflammatory Myopathies:

• Present with symmetric proximal weakness, normal or reduced reflexes, muscle pain, and CK elevation >10× normal 1
• Absence of hyperreflexia and presence of pain distinguish these from ALS 1

Structural Spinal Lesions:

• Cervical spondylotic myelopathy can produce combined upper and lower motor neuron signs but typically includes sensory findings and bladder dysfunction 1

Multifocal Motor Neuropathy:

• Presents with pure lower motor neuron findings, conduction block on nerve studies, and elevated anti-GM1 antibodies 1

Management Framework

Disease-Modifying Therapy

• Initiate riluzole 50 mg twice daily at diagnosis, which modestly prolongs survival by 2–3 months 1

Multidisciplinary Care Structure

Establish coordinated care involving neurology, pulmonology, nutrition, physical therapy, occupational therapy, speech-language pathology, and palliative services—this approach improves both survival and quality of life. 1, 2, 3

Respiratory Management

• Start non-invasive ventilation (BiPAP) when forced vital capacity falls below 50% of predicted or when nocturnal hypoventilation symptoms appear 1, 2, 3

Nutritional Support

• Place percutaneous endoscopic gastrostomy when safe oral intake is compromised 1

Medication Safety

Avoid medications that impair neuromuscular transmission: 1

• Aminoglycosides
• Fluoroquinolones
• Macrolides
• β-blockers
• Intravenous magnesium

Infection Vigilance

• Maintain high suspicion for pneumonia and respiratory infections, as patients with motor neuron disease face very high risk for respiratory failure 2, 3

Prognosis

• Median survival after symptom onset is 3–4 years 1
• Approximately 5% of patients survive for decades 1
• First-year mortality ranges from 3–10%, most commonly from respiratory failure 1

Important Clinical Pitfall

Rare cases of reversible motor neuron syndrome clinically identical to ALS have been reported with spontaneous recovery beginning approximately one year after onset. 6 While exceedingly uncommon, this underscores the importance of rigorous exclusion of mimics and consideration of immunological etiologies when atypical features are present, such as elevated IgE or low-titer anti-GM1 antibodies 6.