What are the potential neurological causes of bilateral leg and arm weakness in a patient with negative Multiple Sclerosis (MS) testing and mild degenerative disease?

Differential Diagnosis for Bilateral Limb Weakness with Negative MS Testing

Guillain-Barré syndrome (GBS) should be your primary consideration in a patient presenting with bilateral arm and leg weakness when MS has been excluded, particularly if the weakness is progressive, symmetric, and accompanied by diminished reflexes. 1, 2

Key Neurological Conditions to Consider

Guillain-Barré Syndrome (Most Important)

GBS is an acute inflammatory polyradiculoneuropathy that must be at the top of your differential. The diagnostic features include: 1, 2

Required diagnostic features:

• Progressive bilateral weakness of arms and legs (may initially involve only legs) 1
• Absent or decreased tendon reflexes in affected limbs at some point during the clinical course 1

Strongly supportive features to assess:

• Progressive phase lasting days to 4 weeks (usually <2 weeks) 1, 2
• Relative symmetry of symptoms 1
• Recent infection within the past 6 weeks (present in two-thirds of patients) 2
• Bilateral facial palsy or other cranial nerve involvement 1, 2
• Back or limb pain (affects approximately two-thirds of patients early in disease) 1, 2
• Distal paresthesias or sensory loss that may precede or accompany weakness 2

Critical workup for GBS:

• Lumbar puncture showing elevated CSF protein with normal cell count (albumino-cytological dissociation), though normal protein in the first week does not exclude the diagnosis 1, 2
• Electrodiagnostic studies revealing sensorimotor polyradiculoneuropathy with reduced conduction velocities, reduced amplitudes, temporal dispersion, or conduction blocks 1, 2
• Look for the characteristic "sural sparing pattern" (normal sural sensory nerve action potential with abnormal median/ulnar responses) 1, 2

Important caveat: Electrophysiological measurements may be normal when performed within 1 week of symptom onset or in patients with initially proximal weakness, so repeat testing 2-3 weeks later may be necessary. 1

Motor Neuron Disease (ALS)

Amyotrophic lateral sclerosis should be considered, particularly if the patient demonstrates both upper and lower motor neuron signs: 1

Clinical features to assess:

• Hypertonicity and hyperreflexia (upper motor neuron degeneration) 1
• Muscle fasciculations, weakness, and atrophy (lower motor neuron degeneration) 1
• Progressive course without remissions 1

Key diagnostic tests:

• Electromyography and nerve conduction velocity studies are essential for diagnosis 1
• MRI spine without contrast may show abnormal T2 signal in the anterior horns ("snake eyes" appearance), though this finding may only appear later in disease course 1
• MRI head without contrast may show abnormal signal on T2/FLAIR along the corticospinal tracts 1

Spinal Cord Pathology (Myelopathy)

Given the mention of mild degenerative disease, compressive myelopathy from spondylosis or other structural lesions must be excluded: 1

Imaging approach:

• MRI spine without contrast is the optimal initial study for evaluating myelopathy 1
• Look for cord compression, intramedullary signal changes, or stenosis 1
• Intramedullary T2 signal changes represent prognostic factors and can indicate chronic compression 1

Alternative myelopathy etiologies to consider:

• Spinal cord ischemia (requires MRI with and without contrast, plus diffusion-weighted imaging) 1
• Inflammatory myelitis (transverse myelitis, neuromyelitis optica) 1
• Infectious causes (epidural abscess, viral myelitis) 1

Miller Fisher Syndrome Variant

This GBS variant presents with a distinct triad and should be considered if the patient has specific features: 3

Diagnostic triad:

• Ophthalmoplegia (eye movement abnormalities) 3
• Ataxia (coordination and balance difficulties) 3
• Areflexia (reduced or absent deep tendon reflexes) 3

Confirmatory testing:

• Anti-GQ1b antibody testing 3
• Accounts for 5-25% of all GBS cases 3

Features That Should Make You Reconsider GBS

Red flags suggesting alternative diagnoses: 1

• Marked persistent asymmetry of weakness 1
• Bladder or bowel dysfunction at onset or persistent during disease course 1
• Fever at onset 1
• Sharp sensory level indicating spinal cord injury 1
• Hyper-reflexia, clonus, or extensor plantar responses 1
• Continued progression for >4 weeks after symptom onset 1
• Marked CSF pleocytosis (>50 cells/μl) 1

Practical Diagnostic Algorithm

1. Perform detailed neurological examination focusing on:

   • Pattern of weakness (proximal vs. distal, symmetric vs. asymmetric) 1, 2
   • Reflex status (areflexia suggests GBS; hyperreflexia suggests myelopathy or ALS) 1
   • Sensory level (suggests myelopathy) 1
   • Cranial nerve involvement (supports GBS) 1, 2
   • Upper vs. lower motor neuron signs (helps distinguish ALS from GBS) 1

2. Order MRI spine without contrast immediately to exclude structural myelopathy, especially given the mild degenerative disease mentioned 1

3. If MRI spine is unrevealing, proceed with:

   • Lumbar puncture for CSF analysis (protein, cell count) 1, 2
   • Electrodiagnostic studies (EMG/NCS) 1, 2
   • Serum creatine kinase to assess for muscle involvement 2

4. Do not delay treatment if GBS is suspected - treatment with IVIG (0.4 g/kg daily for 5 days) or plasma exchange should begin promptly without waiting for antibody results 2

The prognosis for GBS is generally favorable with full recovery expected in approximately 90% of cases, though recovery may take up to 2 years. 2 In contrast, ALS has a median survival of 3-4 years after symptom onset. 1