What is the differential diagnosis for a patient with bilateral lower‑limb paresthesia?

Differential Diagnosis for Bilateral Lower Limb Paresthesia

The most critical diagnosis to exclude first is Guillain-Barré syndrome (GBS), because it can rapidly progress to respiratory failure requiring mechanical ventilation within hours to days, even when initial symptoms appear mild. 1

Immediate Life-Threatening Considerations

Guillain-Barré Syndrome (GBS)

• GBS presents with progressive bilateral ascending weakness starting in the legs, diminished or absent reflexes, and distal paresthesias that often precede or accompany the weakness. 1, 2
• Recent infection history within 6 weeks is present in approximately two-thirds of patients and serves as a critical diagnostic clue. 1
• Back and limb pain affects approximately two-thirds of patients and often appears as an early symptom before obvious weakness develops. 1
• Approximately 20% of patients develop respiratory failure requiring mechanical ventilation, which can occur rapidly and sometimes without obvious dyspnea. 1
• Immediately assess respiratory function by measuring vital capacity, negative inspiratory force (NIF), and maximum inspiratory/expiratory pressures at presentation. 1
• Apply the "20/30/40 rule": patient is at risk of respiratory failure if vital capacity <20 ml/kg, maximum inspiratory pressure <30 cmH₂O, or maximum expiratory pressure <40 cmH₂O. 1
• Continuously monitor for dysautonomia including blood pressure and heart rate instability, pupillary dysfunction, and bowel/bladder dysfunction. 1

Miller Fisher Syndrome Variant

• This GBS variant accounts for 5-25% of cases and presents with the distinct triad of ophthalmoplegia, ataxia, and areflexia. 1, 3
• Anti-GQ1b antibody testing is confirmatory and positive in up to 90% of cases with this classic triad. 1
• This variant carries a 15-30% risk of respiratory failure, warranting focused respiratory monitoring. 1

Spinal Cord Pathology (Myelopathy)

• Myelopathy from spinal cord compression or intramedullary pathology presents with bilateral weakness accompanied by hyperreflexia, spasticity, and extensor plantar responses. 3
• A sharp sensory level indicates the level of cord involvement and is a key distinguishing feature from peripheral neuropathy. 3
• Bladder/bowel dysfunction appears early in the course of myelopathy, unlike in peripheral neuropathy where it is a late finding. 3
• MRI spine without contrast is the optimal initial study for evaluating myelopathy, looking for cord compression, intramedullary signal changes, or stenosis. 3, 2

Peripheral Neuropathy (Non-GBS)

Diabetic Polyneuropathy

• The most common cause of bilateral lower limb paresthesias in clinical practice, presenting as a "stocking-glove" distribution of sensory symptoms. 4
• Initial laboratory tests should include blood glucose levels and HbA1c to screen for diabetes. 5
• Nerve conduction studies typically show reduced amplitudes and velocities in a length-dependent pattern. 6

Metabolic and Endocrine Neuropathies

• Vitamin B12 deficiency can cause bilateral lower limb paresthesias with or without weakness. 5
• Thyroid dysfunction (both hypo- and hyperthyroidism) can present with peripheral neuropathy. 5
• Basic screening tests should include thyroid function tests, renal and liver function tests, vitamin B12, and immunofixation. 5
• Hypokalemia can present with acute bilateral lower extremity paralysis and paresthesias; an abnormal electrocardiogram (U waves, flattened T waves) immediately points to this diagnosis. 7

Chronic Ischemic Neuropathy

• Chronic and critical limb ischemia causes a predominantly sensory neuropathy with rest pain (58% of patients), numbness (58%), burning (42%), and paresthesias (37%) in the ischemic foot. 8
• The most common asymmetric neurologic signs include hypalgesia (74%), toe weakness (64%), hyperesthesia (63%), and pallanesthesia (53%) in the distal leg. 8
• Sural sensory potentials are reduced or absent, frequently on both sides, with reduced tibial motor amplitudes. 8
• Vascular examination should include palpation of lower extremity pulses (femoral, popliteal, dorsalis pedis, posterior tibial) and auscultation for femoral bruits. 4
• Ankle-brachial index (ABI) measurement is required to confirm peripheral artery disease when pulse abnormalities are detected. 4

Lyme Disease-Associated Peripheral Neuropathy

• Late neurologic Lyme disease typically presents as a mild, diffuse "stocking-glove" peripheral neuropathy with intermittent limb paresthesias. 4
• The most frequent abnormality on neurologic examination is reduced vibratory sensation of the distal lower extremities. 4
• Serum IgG antibody to B. burgdorferi detected by 2-tier approach (ELISA and immunoblot) is expected; absence of antibody should lead to an alternative diagnosis. 4
• Electrophysiologic studies show findings consistent with a mild confluent mononeuritis multiplex. 4

Motor Neuron Disease (ALS)

• Amyotrophic lateral sclerosis (ALS) demonstrates both upper and lower motor neuron signs, including hypertonicity, hyperreflexia, muscle fasciculations, weakness, and atrophy. 3, 2
• Progressive course without remissions distinguishes ALS from inflammatory neuropathies. 3, 2
• Electromyography showing widespread denervation is diagnostic, with median survival of 3-4 years after symptom onset. 3, 2

Practical Diagnostic Algorithm

Step 1: Immediate Assessment

• Assess respiratory function immediately in all patients with bilateral lower limb paresthesias and any degree of weakness. 1
• Measure vital capacity, NIF, and maximum inspiratory/expiratory pressures. 1
• Continuously monitor heart rate, blood pressure, and ECG for autonomic dysfunction. 1

Step 2: Detailed Neurological Examination

• Grade muscle strength using Medical Research Council scale in neck, arms, and legs. 1
• Test reflexes systematically: diminished or absent reflexes suggest GBS or peripheral neuropathy, while hyperreflexia suggests myelopathy or ALS. 1, 3, 2
• Assess for sensory level: a sharp sensory level indicates spinal cord pathology. 3, 2
• Examine cranial nerves, particularly for bilateral facial palsy (highly suggestive of GBS). 1
• Test swallowing and coughing ability to identify aspiration risk. 1

Step 3: Initial Laboratory Testing

• Complete blood count, glucose, electrolytes, kidney and liver function tests to exclude metabolic or electrolyte dysfunction. 1, 5
• HbA1c and fasting glucose for diabetes screening. 5
• Vitamin B12 level. 5
• Thyroid function tests. 5
• Serum creatine kinase (CK): elevation suggests muscle involvement. 1
• Immunofixation to screen for paraproteinemia. 5

Step 4: Imaging

• Order MRI spine without contrast immediately if any suspicion of myelopathy (hyperreflexia, sensory level, bladder/bowel dysfunction). 3, 2
• MRI spine with contrast if GBS is suspected to assess for nerve root enhancement. 1

Step 5: Specialized Testing

• Lumbar puncture for CSF analysis: look for albumino-cytological dissociation (elevated protein with normal cell count) in GBS. 1, 2
• Do not exclude GBS if CSF protein is normal during the first week of illness. 1, 2
• Marked CSF pleocytosis should prompt reconsideration of the GBS diagnosis. 1, 2
• Electrodiagnostic studies (nerve conduction studies and EMG) to support diagnosis and classify neuropathy pattern. 1, 2
• Look for "sural sparing pattern" (normal sural sensory nerve action potential with abnormal median/ulnar responses), which is typical for GBS. 1, 2
• Quantitative sensory testing (QST) to assess small fiber function: cold or warm detection thresholds are abnormal in 35.7% of patients with dysesthesias. 6
• Skin biopsy at the dorsum of the foot to measure intraepidermal nerve fiber density (IENFD): decreased IENFD is found in 88.1% of patients with lower limb dysesthesias. 6

Step 6: Specific Antibody Testing

• Serum antiganglioside antibody panel (including GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b) if GBS is suspected. 1
• Anti-GQ1b antibody if ophthalmoplegia or ataxia is present (Miller Fisher syndrome). 1
• Do not delay immunotherapy while awaiting antibody test results if GBS is suspected. 1, 2
• Lyme serology (2-tier testing with ELISA and IgG immunoblot) if endemic area or tick exposure history. 4

Red Flags That Suggest Alternative Diagnoses to GBS

• Marked persistent asymmetry of weakness. 1, 2
• Bladder or bowel dysfunction at onset or persistent during disease course. 1, 2
• Fever at onset. 1, 2
• Sharp sensory level indicating spinal cord injury. 1, 2
• Hyperreflexia, clonus, or extensor plantar responses. 1, 2
• Continued progression for >4 weeks after symptom onset (consider acute-onset CIDP). 1, 2

Common Pitfalls to Avoid

• Do not dismiss GBS based on normal CSF protein in the first week of illness; repeat lumbar puncture after 1-2 weeks if clinical suspicion remains high. 1, 2
• Do not dismiss GBS based on absent sural sparing in the first week; repeat electrodiagnostic studies in 2-3 weeks if clinical suspicion remains high. 1
• Bilateral simultaneous facial weakness is extremely rare in Bell's palsy and should immediately raise suspicion for GBS or other systemic processes. 1
• Nearly all patients with pathological QST have reduced IENFD, indicating a high positive predictive value (93%) of QST in screening for small fiber neuropathy. 6
• In patients with lower limb dysesthesias of unknown origin, non-invasive methods of nerve conduction studies and QST should be used and potentially complemented by skin biopsy. 6