What is the differential diagnosis for an adult patient with generalized body weakness, considering their demographic, medical history, and presenting symptoms?

Differential Diagnosis for Generalized Body Weakness

The differential diagnosis for generalized body weakness must be systematically organized by anatomical localization within the motor pathway—from brain to muscle—with immediate priority given to life-threatening neuromuscular causes that can progress to respiratory failure within hours to days. 1, 2

Immediate Life-Threatening Considerations

Guillain-Barré syndrome (GBS) is the most critical diagnosis to exclude first because it can rapidly progress to respiratory failure and autonomic instability, requiring ICU-level care. 3, 4 Key features include:

• Progressive bilateral ascending weakness starting in legs and moving to arms, typically reaching maximum disability within 2 weeks 4
• Diminished or absent reflexes in affected limbs (areflexia is a hallmark) 4, 5
• Recent infection history within 6 weeks (present in two-thirds of patients) 4
• Bilateral facial palsy is the most common cranial nerve finding due to the facial nerve's extensive myelin coverage and long intracranial course 4
• Back and limb pain often precedes weakness (affects two-thirds of patients) 4

Red flags that argue against GBS: marked persistent asymmetry, bladder dysfunction at onset, fever at onset, sharp sensory level, hyperreflexia with clonus, or progression beyond 4 weeks 5

Systematic Anatomical Approach to Weakness

Upper Motor Neuron (Brain/Spinal Cord)

Myelopathy from spinal cord compression or intramedullary pathology presents with:

• Bilateral weakness with hyperreflexia, spasticity, and extensor plantar responses 5
• Sharp sensory level indicating the level of cord involvement 5
• Bladder/bowel dysfunction early in the course 5
• MRI spine without contrast is the optimal initial study 5

Lower Motor Neuron (Anterior Horn Cell/Nerve Root)

Amyotrophic lateral sclerosis (ALS) demonstrates:

• Both upper and lower motor neuron signs (hyperreflexia with fasciculations and atrophy) 5
• Progressive course without remissions and median survival of 3-4 years 5
• Electromyography showing widespread denervation is diagnostic 5

Peripheral Nerve

ICU-acquired weakness (ICUAW) is common in critically ill patients, particularly those with:

• Severe sepsis as a major risk factor 3
• Prolonged mechanical ventilation or difficulty with ventilator liberation 3
• Profound symmetric weakness developing during critical illness 3

Neuromuscular Junction

Myasthenia gravis presents with:

• Fluctuating weakness that worsens with repetitive activity 6
• Cranial motor dysfunction (ptosis, diplopia, bulbar weakness) without sensory deficits 6
• Rapid response to edrophonium (2 mg IV) is diagnostic 6
• Antiacetylcholine receptor antibodies confirm diagnosis 6

Botulism causes:

• Descending paralysis (opposite pattern from GBS) 6
• Cranial nerve involvement first (diplopia, dysphagia, dysarthria) 6
• Gastric atony and autonomic dysfunction 6
• History of contaminated food (home-canned products) 6

Muscle (Myopathy)

Inflammatory myopathies (dermatomyositis/polymyositis) feature:

• Proximal muscle weakness (difficulty rising from chair, climbing stairs) 6
• Elevated CK-MM with myopathic EMG changes 6
• Heliotrope rash in dermatomyositis 6
• Muscle biopsy shows lymphocytic infiltration 6

Glycogen storage disease type III presents with:

• Hepatomegaly with hypoglycemia in children 3
• Elevated CK, AST, and ALT levels 3
• Proximal and distal muscle weakness (unlike Pompe disease which spares distal muscles) 3
• Profound ketosis after overnight fast 3

Late-onset Pompe disease (GSD II) demonstrates:

• Truncal and proximal weakness affecting lower more than upper limbs 3
• Diaphragm weakness causing respiratory distress (key distinguishing feature) 3
• Absence of hepatomegaly or hypoglycemia 3

Metabolic/Electrolyte Disorders

Hypokalemic periodic paralysis causes:

• Acute onset weakness triggered by high carbohydrate meals or immobility 6
• Serum potassium typically <2.5 mEq/L 6
• Rapid reversal with potassium replacement (20 mEq over 2 hours) 6
• Associated with thyrotoxicosis in Asian males 6

Miller Fisher Syndrome Variant

This GBS variant accounts for 5-25% of cases and presents with a distinct triad: 4, 7

• Ophthalmoplegia (external eye muscle paralysis) 7
• Ataxia (unsteady gait and coordination problems) 7
• Areflexia (absent deep tendon reflexes) 7
• Anti-GQ1b antibody is confirmatory 5

Critical Initial Workup Algorithm

Step 1: Assess for respiratory compromise immediately 3, 4

• Measure vital capacity, negative inspiratory force, and maximum inspiratory/expiratory pressures 3
• Apply "20/30/40 rule": risk of respiratory failure if vital capacity <20 ml/kg, maximum inspiratory pressure <30 cmH₂O, or maximum expiratory pressure <40 cmH₂O 4
• Single breath count ≤19 predicts need for mechanical ventilation 4

Step 2: Detailed neurological examination 5, 1

• Pattern of weakness: proximal vs. distal, symmetric vs. asymmetric, ascending vs. descending 1
• Reflex status: hyperreflexia (upper motor neuron) vs. hyporeflexia/areflexia (lower motor neuron/peripheral nerve) 5
• Sensory examination: presence of sensory level suggests myelopathy 5
• Cranial nerve involvement: facial weakness, ophthalmoplegia, bulbar dysfunction 4, 5

Step 3: Initial laboratory tests 4

• Complete blood count, glucose, electrolytes (especially potassium), kidney and liver function 4
• Serum creatine kinase (CK): elevated suggests muscle involvement 4
• Thyroid function tests (thyrotoxicosis can cause weakness) 6

Step 4: Imaging and specialized testing 5

• MRI spine without contrast if any suspicion of myelopathy 5
• Lumbar puncture for CSF analysis: albumino-cytological dissociation (elevated protein with normal cell count) supports GBS, though protein may be normal in first week 4
• Electrodiagnostic studies (nerve conduction studies and EMG) to classify neuropathy pattern 4, 5

Common Pitfalls to Avoid

• Do not dismiss GBS based on normal CSF protein in the first week of symptoms 4
• Do not wait for antibody test results before starting treatment if GBS is suspected 4
• Bilateral simultaneous facial weakness is extremely rare in Bell's palsy and should immediately raise suspicion for GBS 4
• Most cases of generalized weakness in hospitalized patients are not due to primary neurologic diseases but rather metabolic, toxic, or critical illness-related causes 8
• Recognize that patients with complete paralysis from GBS usually have intact consciousness, vision, and hearing—be mindful of bedside conversations 4