How do I approach analyzing a differential diagnosis in a patient?

Systematic Approach to Differential Diagnosis

Begin by generating a comprehensive list of all possible causes organized by pathophysiologic category, then systematically narrow this list through targeted history, examination, and investigations that prioritize life-threatening and treatable conditions first. 1

Step 1: Generate Initial Differential by Category

All possible causes must be considered across seven major categories: idiopathic, autoimmune, degenerative, infectious, malignancy, traumatic, and metabolic etiologies. 1 This categorical framework prevents premature closure and ensures systematic consideration of competing diagnoses. 2

• Document the complete clinical presentation including age, gender, geographical area, functional status, symptom duration, and pattern of involvement before ranking differential diagnoses. 1
• Identify "red flag" features immediately that suggest life-threatening conditions requiring urgent evaluation (e.g., fever at onset, severe respiratory dysfunction, altered consciousness, progressive neurological deficits). 1

Step 2: Prioritize Through Targeted History

Focus history-taking on discriminating features rather than exhaustive questioning. 1

• Recent medical history: infections, trauma, medication changes, substance withdrawal, and psychotropic drug use. 1
• Temporal pattern: acute onset (<24 hours) versus subacute (days to 4 weeks) versus chronic (>4 weeks) progression fundamentally alters differential probability. 1
• Symptom characteristics: morning stiffness duration (>30 minutes suggests inflammatory), improvement versus worsening with activity, presence of constitutional symptoms. 1, 3

Step 3: Perform Discriminating Physical Examination

The physical examination should actively test competing hypotheses rather than serve as routine screening. 1

• Pattern recognition: symmetry versus asymmetry of findings, distribution of joint involvement (large versus small joints), presence of extra-articular manifestations. 1, 3
• Neurological examination specifics: cognitive testing, motor/sensory examination, cranial nerve assessment, reflex testing (areflexia suggests peripheral nerve pathology; hyperreflexia suggests central pathology). 1
• Provocative maneuvers: reproduce symptoms through specific activities or positions to confirm mechanical versus non-mechanical etiology. 4

Step 4: Order Investigations Based on Ranked Differential

Investigations must be hypothesis-driven, not routine screening. 1 The highest probability diagnoses and most dangerous diagnoses guide initial testing.

Essential Baseline Studies

• Inflammatory markers: ESR and CRP at baseline for diagnostic and prognostic purposes, though normal values do not exclude inflammatory conditions. 1, 3
• Complete blood count, comprehensive metabolic panel, blood glucose, electrolytes to identify metabolic and systemic causes. 1, 3
• Autoantibodies when autoimmune disease suspected: RF and ACPA for rheumatoid arthritis (RF: 70% specificity, 60% sensitivity; ACPA: 90% specificity, 60% sensitivity). 1, 3

Imaging Selection

• Plain radiographs of affected areas at baseline for structural pathology and erosive changes. 1, 3
• MRI (preferably with contrast) when CNS pathology, spinal cord compression, or early inflammatory arthritis suspected as it is more sensitive than ultrasound in early stages. 1, 3
• Ultrasound superior to clinical examination for detecting synovitis and structural damage in peripheral joints. 3

Specialized Testing

• CSF analysis when inflammatory, infectious, or demyelinating CNS disease suspected: look for cytoalbuminologic dissociation (elevated protein with normal cell count suggests CIDP), elevated cells (>50×10⁶/L casts doubt on Guillain-Barré syndrome). 1, 5
• Electrodiagnostic studies for peripheral nerve or muscle pathology: distinguish demyelinating from axonal neuropathy, myopathy from neuropathy. 1, 5
• Muscle enzymes (CK, aldolase, AST/ALT, LDH) when myopathy suspected to determine severity and guide treatment intensity. 1, 6

Step 5: Recognize Features That Exclude Diagnoses

Certain findings should prompt immediate reconsideration of the working diagnosis. 1

For Guillain-Barré Syndrome

• Marked persistent asymmetry, bladder/bowel dysfunction at onset, fever at onset, sharp sensory level, hyperreflexia or clonus, extensor plantar responses, continued progression >4 weeks. 1

For Hepatic Encephalopathy

• Significant temporospatial disorientation, anterograde episodic memory impairment, visuoconstructive impairments, speech production abnormalities suggest alternative diagnoses (neurodegenerative disease, Wernicke-Korsakoff syndrome). 1

Step 6: Iterate and Refine

Differential diagnosis is dynamic, not static. 2 Reassess the differential list as new information emerges from investigations or clinical course.

• If initial investigations are unrevealing but clinical suspicion remains high, repeat testing at appropriate intervals (e.g., repeat electrodiagnostic studies 3-8 weeks after onset may reclassify initially equivocal cases). 1
• Document predictors of chronicity or progression that alter prognosis and treatment intensity (disease duration ≥6 weeks, specific autoantibody positivity, radiographic erosions). 1, 3

Critical Pitfalls to Avoid

• Premature closure: failing to consider uncommon diseases in the initial differential leads to missed diagnoses. 2
• Anchoring bias: over-reliance on initial imaging findings (e.g., degenerative changes on cervical spine X-ray) without considering non-mechanical causes. 4
• Failure to recognize non-mechanical pain: when physical examination fails to reproduce symptoms, consider systemic, visceral, or vascular etiologies. 4
• Ignoring temporal patterns: progression beyond expected timeframes (e.g., >4 weeks for Guillain-Barré syndrome) mandates reconsideration of the diagnosis. 1