What is the appropriate workup and treatment for a patient presenting with generalized weakness?

Workup and Management of Generalized Weakness

Initial Clinical Assessment

Begin by distinguishing true muscle weakness (loss of motor power) from generalized fatigue, as this fundamentally changes your diagnostic approach and determines whether neuromuscular evaluation is warranted. 1, 2

Critical History Elements

• Pattern of weakness: Proximal versus distal, symmetric versus asymmetric, ascending versus descending 3, 2
• Temporal profile: Acute (hours to days) versus subacute (weeks) versus chronic (months) 2
• Fatigability: Symptoms worsening with continued activity strongly suggests myasthenia gravis 4
• Associated symptoms:
  • Bulbar involvement (dysphagia, dysarthria, facial weakness) indicates severe disease requiring urgent intervention 3, 4
  • Respiratory symptoms (dyspnea, orthopnea) mandate immediate pulmonary function testing 3, 5
  • Sensory symptoms help distinguish neuropathy from pure myopathy 3
• Medication exposure: Recent initiation of β-blockers, fluoroquinolones, aminoglycosides, macrolides, or IV magnesium can precipitate myasthenic crisis 5, 6, 4

Focused Physical Examination

• Muscle strength testing: Document specific muscle groups affected, particularly proximal versus distal distribution 3
• Deep tendon reflexes: Absent or reduced reflexes suggest Guillain-Barré syndrome 3
• Cranial nerve examination: Ptosis, extraocular movement abnormalities, and facial weakness point toward myasthenia gravis 6
• Pupillary examination: Normal pupils in the setting of ptosis/ophthalmoplegia strongly favor myasthenia gravis over third nerve palsy 6
• Skin examination: Look for dermatomyositis rash (heliotrope rash, Gottron papules) 3

Essential Laboratory Workup

First-Tier Blood Tests (Order Immediately)

• Creatine kinase (CK): Elevated in myositis; if ≥3× upper limit of normal with weakness, initiate corticosteroids 3
• Transaminases (AST, ALT), LDH, aldolase: Can be elevated in muscle inflammation 3
• Troponin and ECG: Essential to evaluate for myocardial involvement, which mandates permanent discontinuation of immune checkpoint inhibitors if present 3
• Inflammatory markers (ESR, CRP): Useful for monitoring disease activity 3
• Acetylcholine receptor (AChR) antibodies: Nearly all patients with generalized myasthenia gravis test positive 6, 4

Second-Tier Tests (Based on Clinical Suspicion)

• Reversible causes screen: Glucose, TSH, B12, folate, HIV 3
• Autoimmune panel: ANA, RF, anti-CCP for rheumatologic conditions 3
• Paraneoplastic antibody panel: Consider if clinical picture suggests myositis or myasthenia gravis 3
• Serum protein electrophoresis: If neuropathy suspected 3

Specialized Diagnostic Studies

When to Order Advanced Testing

• Electromyography (EMG) and nerve conduction studies: Order when diagnosis uncertain or overlap syndromes suspected (e.g., distinguishing myositis from myasthenia gravis) 3
• Single-fiber EMG with jitter studies: Sensitivity >90% for generalized myasthenia gravis 4
• MRI of affected muscles: Consider for grade 2+ myositis when diagnosis uncertain 3
• Muscle biopsy: Reserve for uncertain myositis diagnosis after EMG and MRI 3
• MRI spine with/without contrast: Essential for Guillain-Barré syndrome to rule out compressive lesions and evaluate nerve root enhancement 3
• Lumbar puncture: For suspected Guillain-Barré syndrome; CSF typically shows elevated protein and often elevated WBCs 3

Critical Respiratory Assessment

Perform pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) immediately in any patient with:

• Dysphagia, facial weakness, or respiratory muscle involvement 5, 4
• Suspected myasthenia gravis or Guillain-Barré syndrome, even if symptoms appear mild 5, 4
• Any bulbar symptoms 3, 4

Disease-Specific Management Algorithms

Myasthenia Gravis

For mild disease (MGFA Class 1-2):

• Start pyridostigmine 30 mg orally three times daily, titrate to maximum 120 mg four times daily 5, 6
• Approximately 50% respond adequately to pyridostigmine alone 5, 6
• If inadequate response, add prednisone 0.5-1.5 mg/kg orally daily 5, 6

For severe disease (Grade 3-4, any dysphagia/respiratory involvement):

• Permanently discontinue immune checkpoint inhibitors if applicable 3, 4
• Admit to hospital with ICU-level monitoring capability 3, 4
• Initiate IVIG 2 g/kg over 5 days (0.4 g/kg/day) OR plasmapheresis 3, 5, 4
• Continue corticosteroids (methylprednisolone 2-4 mg/kg/day) 3, 4
• Daily neurologic evaluation and frequent pulmonary function monitoring 3, 4

Myositis

For Grade 1 (mild weakness):

• Continue monitoring; if CK elevated with weakness, treat as Grade 2 3
• Offer acetaminophen or NSAIDs for pain 3

For Grade 2 (moderate weakness, CK ≥3× normal):

• Hold immune checkpoint inhibitors temporarily 3
• Initiate prednisone 0.5-1 mg/kg 3
• Refer to rheumatology or neurology 3
• May require permanent discontinuation if objective findings present (elevated enzymes, abnormal EMG/MRI) 3

For Grade 3-4 (severe weakness, limiting self-care):

• Hold immune checkpoint inhibitors; permanently discontinue if myocardial involvement 3
• Hospitalize for severe weakness 3
• Initiate prednisone 1 mg/kg or methylprednisolone 1-2 mg/kg IV 3
• Consider plasmapheresis or IVIG 3
• Add methotrexate, azathioprine, or mycophenolate mofetil if no improvement after 4-6 weeks 3

Guillain-Barré Syndrome

All grades warrant immediate workup and intervention given risk of respiratory compromise:

• Discontinue immune checkpoint inhibitors 3
• Admit to unit with rapid ICU transfer capability 3
• Start IVIG 0.4 g/kg/day for 5 days (total 2 g/kg) OR plasmapheresis 3
• Consider corticosteroids (methylprednisolone 2-4 mg/kg/day) despite limited evidence in idiopathic GBS, as immune checkpoint inhibitor-related forms may respond 3
• Frequent neurochecks and pulmonary function monitoring 3
• Monitor for autonomic dysfunction 3

Critical Medication Avoidance

Immediately discontinue or avoid these medications in patients with suspected or confirmed myasthenia gravis, as they can precipitate myasthenic crisis:

• β-blockers 5, 6, 4
• IV magnesium 5, 6, 4
• Fluoroquinolones 5, 6, 4
• Aminoglycosides 5, 6, 4
• Macrolide antibiotics 5, 6, 4

Common Pitfalls

• Failing to assess respiratory function early: Any dysphagia, facial weakness, or respiratory symptoms automatically upgrades severity and requires hospital admission 5, 4
• Missing myocardial involvement: Always check troponin and ECG in myositis; cardiac involvement mandates permanent discontinuation of immune checkpoint inhibitors 3
• Confusing fatigue with true weakness: Perform functional muscle testing to confirm actual loss of motor power 1, 7
• Overlooking pupillary examination: Normal pupils with ptosis/ophthalmoplegia strongly favor myasthenia gravis over structural lesions 6
• Delaying specialist consultation: Refer to neurology/rheumatology early for Grade 2+ disease; urgent referral for Grade 3-4 3