What is the differential diagnosis and management for a patient presenting with ascending weakness, considering potential underlying conditions such as Guillain-Barré syndrome, myasthenia gravis, or spinal cord injuries?

Differential Diagnosis of Ascending Weakness

Guillain-Barré syndrome (GBS) is the most critical diagnosis to consider in ascending weakness, but a systematic approach must exclude spinal cord pathology, metabolic derangements, and neuromuscular junction disorders before confirming the diagnosis. 1

Immediate Life-Threatening Assessment

Assess respiratory function and autonomic stability immediately, as these determine mortality risk and need for ICU-level care. 2

• Measure vital capacity, negative inspiratory force (NIF), and maximum inspiratory/expiratory pressures at presentation 2
• 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 3, 2
• Single breath count ≤19 predicts need for mechanical ventilation 2
• Perform ECG and continuously monitor heart rate and blood pressure for arrhythmias and autonomic instability 2
• Up to 30% of GBS patients develop respiratory failure, which can occur rapidly without obvious dyspnea 2

Key Clinical Features to Distinguish GBS

Features Required for GBS Diagnosis

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

Features That Strongly Support GBS

• Progressive phase lasting days to 4 weeks (usually <2 weeks) 1
• Relative symmetry of symptoms and signs 1
• Relatively mild sensory symptoms (absent in pure motor variant) 1
• Cranial nerve involvement, especially bilateral facial palsy 1
• Autonomic dysfunction 1
• Muscular or radicular back or limb pain 1
• Recent infection history within 6 weeks (present in two-thirds of patients) 2

Red Flags That Cast Doubt on GBS Diagnosis

These features should prompt immediate reconsideration of alternative diagnoses: 1

• Sharp sensory level indicating spinal cord injury 1
• Hyperreflexia or clonus 1
• Extensor plantar responses 1
• Bladder or bowel dysfunction at onset or persistent during disease course 1
• Marked CSF pleocytosis (>50 cells/μl) 1, 2
• Marked, persistent asymmetry of weakness 1
• Fever at onset 1
• Nadir <24 hours 1
• Severe respiratory dysfunction with limited limb weakness at onset 1

Comprehensive Differential Diagnosis by Anatomic Location

Central Nervous System (Spinal Cord)

Obtain MRI of spine with contrast urgently if any red flags are present. 1, 2

• Acute transverse myelitis 1
• Spinal cord compression from trauma, tumor, or abscess 1
• Neuromyelitis optica 1
• Myelin oligodendrocyte glycoprotein antibody-associated disorder 1
• Sarcoidosis or Sjögren syndrome affecting spinal cord 1
• Leptomeningeal metastases or neurolymphomatosis 1

Critical pitfall: GBS can occur following spinal cord trauma, making diagnosis extremely challenging 4, 5. In trauma patients with ascending weakness, consider both spinal cord injury AND GBS, as they can coexist 4, 5.

Central Nervous System (Brainstem)

• Brainstem stroke 1
• Brainstem inflammation or infection (sarcoidosis, Sjögren syndrome) 1
• Brainstem compression 1

Peripheral Nerve/Nerve Root

• Infectious polyradiculitis (Lyme disease, CMV, HIV) 1
• Leptomeningeal malignancy 1

Neuromuscular Junction

Myasthenia gravis can coexist with GBS in the same patient, though rare. 6

• Myasthenia gravis 6
• Botulism
• Lambert-Eaton myasthenic syndrome

Muscle Disorders

• Hypokalaemia 1
• Thyrotoxic hypokalaemic periodic paralysis 1
• Hypomagnesaemia 1
• Hypophosphataemia 1
• Inflammatory myositis 1
• Acute rhabdomyolysis 1
• Drug-induced toxic myopathy (colchicine, chloroquine, statins) 1

Metabolic/Nutritional

• Vitamin B12 deficiency (subacute combined degeneration) 1
• Vitamin B1 deficiency (Wernicke encephalopathy) 1

Other

• Conversion or functional disorder 1

Diagnostic Workup Algorithm

Initial Laboratory Tests

Obtain these immediately to exclude metabolic causes: 2

• Complete blood count 2
• Comprehensive metabolic panel (glucose, electrolytes, kidney function, liver enzymes) 2
• Serum creatine kinase (elevation suggests muscle involvement) 2
• Magnesium, phosphate 1
• Thyroid function tests 2
• Vitamin B12, folate, vitamin B6 2
• HbA1c 2

Cerebrospinal Fluid Analysis

Perform lumbar puncture to look for albumino-cytological dissociation (elevated protein with normal cell count). 1, 3, 2

• Critical pitfall: CSF protein is normal in 30-50% of patients in the first week and 10-30% in the second week 1
• Do not dismiss GBS based on normal CSF protein early in disease course 1, 2
• Marked pleocytosis (>50 cells/μl) suggests alternative diagnoses such as leptomeningeal malignancy or infectious polyradiculitis 1
• Mild pleocytosis (10-50 cells/μl) is compatible with GBS but should prompt consideration of infectious causes 1
• Also analyze for cell count, cytology, glucose, viral/bacterial cultures 2

Electrodiagnostic Studies

Obtain nerve conduction studies and EMG to support diagnosis and classify neuropathy pattern. 1, 2

• Look for sensorimotor polyradiculoneuropathy with reduced conduction velocities, reduced amplitudes, temporal dispersion, or conduction blocks 1, 2
• "Sural sparing pattern" (normal sural sensory nerve action potential with abnormal median/ulnar responses) is typical for GBS 1, 2
• Critical pitfall: Electrophysiology may be normal when performed within 1 week of symptom onset or in patients with initially proximal weakness 1
• Repeat studies 2-3 weeks later if initial studies are normal but clinical suspicion remains high 1

Imaging

MRI of spine with and without contrast is essential to rule out compressive lesions and spinal cord pathology. 1, 3, 2

• MRI is not routine for GBS diagnosis but critical for excluding differential diagnoses 1
• Nerve root enhancement on gadolinium-enhanced MRI is a nonspecific but sensitive feature of GBS 1
• Particularly important in trauma patients where spinal cord injury and GBS can coexist 4, 5

Additional Testing

• Serum antiganglioside antibody tests for GBS subtypes (anti-GQ1b for Miller Fisher variant) 3, 2
• Pulmonary function testing (vital capacity, NIF) 3, 2

Management Approach

Immediate Actions

Do not wait for antibody test results or complete diagnostic workup before starting treatment if GBS is strongly suspected. 2

• Admit to inpatient unit with capability for rapid ICU transfer for Grade 3-4 disease (severe weakness limiting self-care, dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms) 2
• Obtain neurology consultation for all suspected GBS cases 3, 2
• Grade muscle strength using Medical Research Council scale in neck, arms, and legs 2
• Assess swallowing and coughing ability to identify aspiration risk 2

First-Line Immunotherapy

Initiate treatment in patients unable to walk unaided within 2-4 weeks of symptom onset. 3, 2

• Intravenous immunoglobulin (IVIg) 0.4 g/kg/day for 5 consecutive days (total dose 2 g/kg) 3, 2
• OR plasma exchange 200-250 ml/kg over 4-5 sessions 3, 2
• Both treatments are equally effective 3, 2
• Corticosteroids alone are NOT recommended for idiopathic GBS 3, 2

Treatment Response Expectations

• Approximately 40% of patients do not improve in the first 4 weeks following treatment—this does not necessarily mean treatment failed 3, 2
• Treatment-related fluctuations occur in 6-10% of patients within 2 months after initial improvement 3, 2
• Consider repeating full course of IVIg or plasma exchange for treatment-related fluctuations 2
• Consider changing diagnosis to acute-onset CIDP if progression continues after 8 weeks or if patient has three or more treatment-related fluctuations 2

Supportive Care

• Serial pulmonary function assessment with vital capacity and NIF measurements 2
• Monitor for autonomic dysfunction (blood pressure/heart rate instability, pupillary dysfunction, bowel/bladder dysfunction) 3, 2
• Use gabapentinoids (gabapentin, pregabalin) or duloxetine for neuropathic pain 2
• Standard preventive measures for pressure ulcers, hospital-acquired infections, and deep vein thrombosis 3, 2
• Avoid medications that worsen neuromuscular transmission: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolides 2

Psychological Support

• Recognize that patients with GBS, even those with complete paralysis, usually have intact consciousness, vision, and hearing 2
• Screen for anxiety, depression, and hallucinations, which are frequent complications 3, 2
• Be mindful of bedside conversations and explain procedures to reduce anxiety 2

Prognosis

• 80% of patients regain independent walking ability at 6 months 2
• Recovery can continue for more than 3 years, with improvement possible even more than 5 years after onset 2
• Mortality is 3-10%, primarily from cardiovascular and respiratory complications 2
• Two-thirds of deaths occur during the recovery phase due to cardiovascular and respiratory dysfunction 3
• Advanced age and severe disease at onset are risk factors for poor outcome 2

Special Considerations

Atypical Presentations

While ascending weakness is classic, GBS can present with descending paralysis or upper extremity-predominant weakness in 10% of cases. 2, 7

• Muscle weakness starts in the arms in 10% of patients 2
• Rare descending paralysis pattern has been reported 7
• Bilateral facial palsy can be the presenting feature before limb weakness develops 2

Coexistence with Other Conditions

• GBS can occur following traumatic bone injuries, including spinal cord trauma 8, 4, 5
• GBS can coexist with myasthenia gravis in the same patient, though rare 6
• In trauma patients with ascending weakness, maintain high suspicion for both spinal cord injury AND GBS 4, 5