What are the possible causes of subacute ascending weakness with normal cerebrospinal fluid (CSF) protein results?

Etiology of Subacute Ascending Weakness with Normal CSF Protein

Guillain-Barré syndrome (GBS) remains the primary diagnosis to consider, as normal CSF protein does not exclude this condition, particularly when evaluated early in the disease course or in patients with mild or slowly progressive symptoms. 1

Primary Differential Diagnosis

Guillain-Barré Syndrome (Most Likely)

• Normal CSF protein occurs in early GBS (within the first week of symptom onset) and does not rule out the diagnosis 1
• The classic finding of elevated CSF protein with normal cell count (albuminocytologic dissociation) may not yet be present when lumbar puncture is performed early 1
• GBS typically presents with progressive bilateral ascending weakness, decreased or absent reflexes, and progression over days to 4 weeks 1
• Repeat lumbar puncture 2-3 weeks later often demonstrates the characteristic protein elevation if initial CSF was normal 1
• Electrodiagnostic studies may also be normal early in the disease course, requiring repeat testing 1

Myasthenia Gravis

• CSF parameters including protein are typically normal in myasthenia gravis, which is a key distinguishing feature 2
• Presents with fluctuating weakness that worsens with activity, often involving cranial nerves (ptosis, diplopia, bulbar symptoms) 1
• Diagnosis requires neuromuscular junction testing with repetitive stimulation and/or single-fiber EMG, plus acetylcholine receptor or MuSK antibodies 1
• The presence of normal CSF in a patient with neuromuscular weakness and cranial nerve findings supports myasthenia gravis over GBS 2

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

• While CIDP classically shows elevated CSF protein, 6% of CIDP patients can present with pleocytosis (≥10 cells/µL), and some may have normal or near-normal protein levels 3
• CIDP with subacute onset (mimicking GBS) may show normal CSF protein initially, particularly in younger patients 3, 4
• Distinguished from GBS by progression beyond 4 weeks and relapsing-remitting or progressive course 1

Critical Diagnostic Workup

Immediate Evaluation Required

• Neurology consultation is mandatory given the potential for rapid progression to respiratory compromise 1
• MRI of spine with contrast to rule out compressive lesions and evaluate for nerve root enhancement/thickening 1
• Electrodiagnostic studies including nerve conduction studies and EMG, though these may be normal early in GBS 1
• Pulmonary function testing (negative inspiratory force/vital capacity) to assess respiratory muscle involvement 1
• Serum antiganglioside antibodies (anti-GM1, anti-GQ1b for Miller Fisher variant) 1

Repeat CSF Analysis Considerations

• If initial CSF protein is normal but GBS is strongly suspected clinically, repeat lumbar puncture in 1-2 weeks 1
• Check CSF cell count carefully: >50 cells/µL casts significant doubt on GBS diagnosis and suggests alternative inflammatory or infectious etiology 1
• Mild pleocytosis (10-50 cells/µL) can occur in CIDP, especially with subacute onset 3

Important Clinical Pitfalls

Age-Related CSF Protein Variations

• CSF protein reference ranges are age-dependent: older patients, males, and those with diabetes have higher baseline CSF protein levels 4, 5
• Using fixed reference values (e.g., >45 mg/dL) may miss blood-CSF barrier dysfunction in younger patients, particularly females 4
• Consider albumin quotient (QAlb) rather than total CSF protein in younger patients to avoid false-negative results 4

Features That Argue Against GBS

• Marked persistent asymmetry of weakness 1
• Bladder/bowel dysfunction at onset or persistent during disease course 1
• Fever at onset 1
• Sharp sensory level suggesting spinal cord pathology 1
• Hyperreflexia, clonus, or extensor plantar responses 1
• Progression to nadir in <24 hours or continued progression >4 weeks 1

Alternative Diagnoses to Exclude

• Spinal cord compression or transverse myelitis: requires urgent MRI spine with contrast 1
• Immune checkpoint inhibitor-related neuropathy: if patient has cancer history and recent immunotherapy 1
• Neuromyelitis optica or other demyelinating diseases: consider if atypical features present 1
• Lyme disease with cranial neuropathy: can present with CSF pleocytosis even without meningeal symptoms 6

Management Approach

Monitoring Strategy

• Admit all patients with ascending weakness given risk of respiratory failure 1
• Frequent neurologic assessments and pulmonary function monitoring 1
• Monitor for autonomic dysfunction (arrhythmias, blood pressure instability) 1

Treatment Considerations

• For GBS: IVIG (0.4 g/kg/day for 5 days) or plasmapheresis are first-line treatments 1
• Corticosteroids are not typically recommended for idiopathic GBS, but may be considered for immune checkpoint inhibitor-related cases 1
• Do not delay treatment while awaiting repeat CSF studies if clinical suspicion for GBS is high and patient is deteriorating 1