What is the approach to master differential diagnosis in a patient with unknown symptoms and past medical history?

Mastering Differential Diagnosis: A Systematic Framework

To master differential diagnosis, you must adopt a structured, system-based approach that begins with establishing a temporal pattern and anatomic localization, followed by applying a two-dimensional diagnostic grid (anatomy × disease type), and then systematically narrowing possibilities through targeted history, examination, and high-yield investigations. 1, 2

Core Diagnostic Framework

Step 1: Establish Timeline and Pattern Recognition

• Document the temporal pattern of symptom onset first, as acute presentations (hours to days) suggest vascular or inflammatory causes, while gradual progression (weeks to months) indicates neoplastic or metabolic etiologies 1
• Age at presentation provides critical diagnostic clues: conditions have characteristic age distributions (e.g., idiopathic pulmonary fibrosis occurs almost exclusively beyond age 50, while primary psychiatric disorders typically onset in late adolescence or early adulthood) 3, 1
• Determine if onset is insidious with progression versus abrupt or fluctuating, as insidious progression suggests neurodegenerative or fibrotic diseases, while abrupt onset points toward vascular events or acute infections 3

Step 2: Apply the Two-Dimensional Diagnostic Grid

Use a systematic grid with anatomy on one axis and disease categories on the other to ensure completeness, particularly when starting out 2:

• Anatomic axis: Identify the organ system or anatomic structure involved (cardiovascular, respiratory, neurological, hepatic, rheumatologic, infectious) 1, 2
• Disease type axis: Apply categories including congenital, metabolic, inflammatory/autoimmune, infectious, neoplastic, vascular, traumatic, and degenerative 2
• This grid prevents premature closure by forcing consideration of all possible disease categories for each anatomic location 4, 2

Step 3: Obtain Targeted History Elements

Focus on specific high-yield historical elements rather than generic comprehensive history 1, 5:

• Travel history with specific countries visited to identify region-specific diseases (malaria in Central/Western Africa, dengue in Eastern/Western Africa) 5
• Occupational and environmental exposures, medication use (including over-the-counter and supplements), and family history of similar conditions or genetic disorders 1
• Relationship to life events, psychosocial stressors, and developmental history to distinguish primary psychiatric from neurodegenerative conditions 3
• Relieving and aggravating factors: effect of hot/cold/sweet foods, prolonged chewing, touching the face, physical activity, posture, stress for facial pain; exertional versus non-exertional for chest pain 3
• Associated symptoms by system: taste changes, salivary flow, nasal/eye/ear symptoms for facial pain; pre-syncopal events, postural changes, fluid intake for syncope 3

Step 4: Perform System-Specific Physical Examination

Target examination findings that localize pathology and narrow the differential 1:

Cardiovascular System

• Measure vital signs during orthostatic maneuvers to detect autonomic dysfunction 3
• Assess for jugular venous distension, hepatojugular reflux, peripheral edema, right ventricular heave, and accentuated pulmonic second sound indicating right heart failure 1

Respiratory System

• Listen for "dry," end-inspiratory, "Velcro" crackles most prevalent in lung bases (present in >80% of interstitial lung disease) 1
• Examine for clubbing (present in 25-50% of idiopathic pulmonary fibrosis) and cyanosis in late disease 1

Neurological System

• Perform complete cognitive, motor, sensory, neurovisual and cranial nerve testing, with asterixis being strongly suggestive of metabolic encephalopathy 1
• Detect abnormalities on physical examination including measuring vital signs during orthostatic maneuvers for syncope evaluation 3

Rheumatologic/Musculoskeletal System

• Examine all joints and skin, palpate muscles of mastication and head/neck muscles for tenderness and trigger points, and assess temporomandibular joint movement including crepitus 3
• Check for symptoms of temporal arteritis such as headache, visual disturbances, or jaw claudication 1

Step 5: Order High-Yield Investigations Strategically

Select investigations based on the probabilistic differential diagnosis, not as a screening battery 3, 1:

Mandatory First-Line Tests

• Complete blood count with differential, inflammatory markers (ESR, CRP), and at least 3 sets of blood cultures before any antibiotics for fever of unknown origin 5
• Natriuretic peptides (BNP >100 pg/mL or NT-proBNP >300 pg/mL if hospitalized or >125 pg/mL if ambulatory) to confirm heart failure diagnosis 1

System-Specific Advanced Testing

• Echocardiography to assess left ventricular ejection fraction, right ventricular function, wall thickness, diastolic function, and estimated pulmonary artery pressures for cardiovascular complaints 1
• MRI with gadolinium for suspected spinal pathology, demonstrating plaques of demyelination in multiple sclerosis and characterizing inflammatory lesions 1
• [18F]FDG PET/CT as the highest-yield advanced diagnostic tool for fever of unknown origin, with 84-86% sensitivity and 56% diagnostic yield (perform within 3 days of starting steroids to avoid false negatives) 5
• CSF examination when distinguishing spinal cord infarction from myelitis, as it shows elevated protein in Guillain-Barré syndrome and lymphocytic pleocytosis in Lyme neuroborreliosis 1

Metabolic Workup

• Thyroid function, vitamin B12, electrolytes (potassium, magnesium, phosphate, calcium) for suspected metabolic causes 1
• Blood ammonia level measurement requires venous blood in EDTA tube, placed immediately on ice, with transport to laboratory at +4°C within 60-90 minutes 1

The Hypothetico-Deductive Approach for Complex Cases

When pattern recognition fails (particularly in fibrotic or atypical presentations), apply this five-step iterative process 3:

1. Form a hypothesis and estimate its likelihood based on prevalence, patient demographics, and clinical presentation 3
2. Decide how certain the diagnosis must be in the context of disease severity, behavior, and consequences if left undiagnosed and untreated 3
3. Reassess the a priori probability and choose an appropriate diagnostic test with adequate sensitivity/specificity for your pretest probability 3
4. Determine the posttest confidence using test properties at your specific institution 3
5. Determine if further testing or treatment is needed according to prognosis and nature of treatment (e.g., antigen avoidance, anti-inflammatory, antifibrotic therapy) 3

Critical Pitfalls to Avoid

• Do not diagnose "fever of unknown origin" prematurely in any setting, and always assume and treat infection when fever cannot be explained by other pathologies to prevent missing treatable infections 5
• Do not delay imaging if delayed recovery after neuraxial block occurs, as prompt investigation is necessary to identify rare cases of epidural abscess or hematoma 1
• Do not attribute all symptoms to a single primary disease, provide inadequate investigation, or delay appropriate imaging in patients with complex presentations 1
• Avoid empiric antibiotics or steroids in stable patients with fever of unknown origin, as they obscure diagnosis and may be harmful if malignancy or certain infections are present 5
• If a disease is not included in differential diagnosis, it is not likely to be diagnosed—therefore, include uncommon as well as common diseases in your initial differential 4
• Do not use high-dose steroids empirically, as they increase hospital-acquired infection risk, hyperglycemia, gastrointestinal bleeding, and delirium without improving mortality, and mask inflammatory findings on subsequent imaging 5

Practical Implementation Strategy

The diagnostic process is iterative and should be revisited as additional data become available 3:

• Patients without a confident diagnosis but in whom a condition is suspected have a provisional diagnosis, underscoring the importance of reviewing the diagnosis at regular intervals 3
• Seek additional expertise or multidisciplinary team consultation to help confirm or reject the working diagnosis when uncertainty persists 3
• Use high or low confidence terminology rather than binary yes/no diagnoses, as this better reflects diagnostic uncertainty and guides management decisions 3
• Computer differential diagnosis generators like Isabel© and DxPlain® can supplement clinical reasoning (mean performance scores 3.45/5.0 on standardized cases), but should not replace systematic clinical thinking 6