In a 68-year-old man with a 4‑week symmetric proximal weakness of the arms and legs, no pain or sensory loss, normal sensation, hyperreflexia, and no bladder or autonomic symptoms, what is the most likely diagnosis?

Amyotrophic Lateral Sclerosis (ALS)

The most likely diagnosis in this 68-year-old man with symmetric proximal weakness, hyperreflexia, and no sensory loss is amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease characterized by combined upper and lower motor neuron degeneration. 1

Clinical Reasoning

Key Diagnostic Features Present

• Symmetric proximal muscle weakness affecting both arms and legs over 4 weeks indicates progressive motor neuron involvement without the asymmetry typical of stroke or focal lesions 1, 2
• Hyperreflexia is the critical finding that distinguishes this from peripheral neuropathies like Guillain-Barré syndrome, which characteristically presents with areflexia or hyporeflexia 3, 4
• Absence of sensory loss excludes spinal cord compression, peripheral neuropathy, and most radiculopathies 1, 2
• No autonomic symptoms (dry mouth, postural dizziness, bladder dysfunction) argues strongly against Guillain-Barré syndrome and multiple system atrophy 1, 3

Why ALS Fits Best

ALS is a progressive neurodegenerative disorder characterized by degeneration of both upper and lower motor neurons in the brain and spinal cord along the corticospinal tracts 1. The clinical presentation typically includes:

• Hypertonicity and hyperreflexia reflecting upper motor neuron degeneration 1
• Muscle weakness and atrophy reflecting lower motor neuron degeneration 1, 5
• Progressive bilateral weakness developing over weeks to months 6
• Preserved sensation as sensory neurons are not affected 1, 2

The 4-week timeframe of progressive weakness in a 68-year-old man falls within the typical presentation window for ALS, which usually manifests in the sixth or seventh decade 1, 5.

Critical Differential Diagnoses to Exclude

Guillain-Barré Syndrome (Excluded)

• GBS presents with ascending weakness and areflexia/hyporeflexia, not hyperreflexia 3, 4
• The presence of hyperreflexia in this patient definitively excludes GBS as the primary diagnosis 3, 4
• GBS typically includes autonomic dysfunction (blood pressure instability, bladder issues) in many cases, which this patient lacks 3

Inflammatory Myopathy (Less Likely)

• Dermatomyositis and polymyositis cause symmetric proximal weakness but typically present with normal or diminished reflexes, not hyperreflexia 1, 2
• Muscle pain is common in inflammatory myopathies but absent in this patient 1, 2
• Elevated creatine kinase levels (often >10× normal) would be expected in myositis 1, 2

Spinal Cord Compression (Excluded)

• Would present with a sensory level, which is absent here 4
• Bladder/bowel dysfunction typically occurs early in cord compression, not present in this case 4
• Hyperreflexia would be expected below the lesion, but the symmetric distribution without sensory findings makes this unlikely 4

Diagnostic Workup Required

Electrodiagnostic Studies (Essential)

• Electromyography will demonstrate widespread denervation (fibrillation potentials, positive sharp waves) together with chronic reinnervation (large polyphasic motor units) across multiple body regions 2
• Nerve conduction studies will reveal normal sensory responses but may show reduced motor amplitudes in advanced disease 2
• These findings confirm both upper and lower motor neuron involvement characteristic of ALS 1, 5

Neuroimaging

• MRI of the brain and spine without contrast is the appropriate initial imaging to exclude structural lesions, tumors, or compressive pathology that can mimic motor neuron disease 1, 2
• The most common MRI finding in ALS brain imaging is abnormal T2/FLAIR signal in the corticospinal tracts, most frequently in the posterior limb of the internal capsule and cerebral peduncles 1
• T2*-weighted or susceptibility-weighted imaging showing hypointensity in the precentral gyrus is highly sensitive and specific for ALS 1
• Spinal MRI may show abnormal T2 signal in the anterior horns ("snake eyes" appearance) corresponding to lower motor neuron disease, though this is often normal early in the disease 1

Laboratory Exclusion Panel

• Systematic workup to exclude ALS mimics should include vitamin B12, thyroid function (TSH), serum protein electrophoresis, anti-GM1 antibodies, HIV, and Lyme serology 2
• Serum creatine kinase may be mildly elevated in ALS but is typically much lower than in inflammatory myopathies 2

Genetic Testing

• Genetic testing for familial ALS genes (SOD1, C9orf72, TARDBP, FUS) is advised when there is family history or early-onset presentation, though 85-90% of cases are sporadic 1, 2

Common Diagnostic Pitfalls

Do Not Dismiss ALS Based On:

• Absence of fasciculations on initial examination—these may not be prominent early in disease 5, 6
• Symmetric presentation—while ALS often begins asymmetrically, symmetric proximal weakness can occur 6, 7
• Relatively rapid 4-week progression—ALS can progress at varying rates, and some patients deteriorate quickly 8, 9

Red Flags That Would Change the Diagnosis:

• Areflexia or hyporeflexia would strongly suggest Guillain-Barré syndrome instead 3, 4
• Sensory level or sensory loss would indicate spinal cord pathology 4
• Bladder dysfunction at onset would suggest cord compression or cauda equina syndrome rather than ALS 1, 4
• Marked asymmetry would raise consideration of stroke, focal lesions, or corticobasal degeneration 1

Management Priorities

Immediate Actions

• Multidisciplinary care involving neurology, pulmonology, nutrition, physical and occupational therapy, and palliative services is essential for optimal outcomes 2
• Initiate riluzole 50 mg twice daily at diagnosis, which modestly prolongs survival by 2-3 months 2

Monitoring and Support

• Assess respiratory function with forced vital capacity measurements; non-invasive ventilation (BiPAP) should be started when FVC falls below 50% of predicted 2
• Nutritional support with percutaneous endoscopic gastrostomy is indicated when safe oral intake is compromised 2

Medications to Avoid

• Avoid drugs that impair neuromuscular transmission: aminoglycosides, fluoroquinolones, macrolides, β-blockers, and intravenous magnesium, as they may exacerbate weakness 3, 2

Prognosis

• The median survival is 3-4 years after symptom onset, though approximately 5% of patients survive for decades 1, 8
• Mortality is 3-10% in the first year, primarily from respiratory failure and complications 3
• The diagnosis carries a grim prognosis, and early multidisciplinary involvement improves quality of life even when survival cannot be significantly extended 8, 9