Systematic Approach to Differential Diagnosis by Body System
The differential diagnosis process must begin with a thorough medical history that includes symptoms suggesting systemic disorders, occupational and environmental exposures, medication use, and family history, followed by a focused physical examination to identify the anatomic site of pathology before considering etiologic causes. 1
Core Diagnostic Framework
Initial Clinical Assessment
Document the temporal pattern of symptom onset, as acute presentations (hours to days) suggest vascular or inflammatory causes, while gradual progression (weeks to months) indicates neoplastic or metabolic etiologies 2
Age at presentation provides critical diagnostic clues: idiopathic pulmonary fibrosis occurs almost exclusively beyond age 50 years, sarcoidosis predominantly affects young to middle-aged adults, and lymphangioleiomyomatosis occurs primarily in premenopausal women 1
Identify red flag symptoms requiring immediate action: fever suggests infection or malignancy rather than primary musculoskeletal disease; sharp sensory level indicates spinal cord injury requiring emergent imaging; bladder/bowel dysfunction suggests cauda equina syndrome or spinal cord compression 1, 2
System-Specific Diagnostic Approach
Cardiovascular System
Dyspnea and cough indicate left ventricular dysfunction causing pulmonary venous hypertension and pulmonary edema, while bipedal edema reflects elevated right atrial pressure and systemic venous congestion 3
Physical examination findings of S3 gallop, jugular venous distension, and hepatomegaly indicate ventricular dysfunction, elevated right-sided pressures, and advanced right-sided heart failure, respectively 3
Measure 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, though levels may be lower in HFpEF compared to HFrEF, especially with obesity 3, 4
Echocardiography is essential to assess left ventricular ejection fraction, right ventricular function, left ventricular wall thickness, diastolic function parameters, and estimated pulmonary artery pressures 3, 4
Respiratory System
Crackles detected on chest auscultation in more than 80% of patients are typically "dry," end-inspiratory, and "Velcro" in quality, most prevalent in lung bases, with progression extending toward upper lung zones 1
Clubbing is noted in 25 to 50% of patients with idiopathic pulmonary fibrosis, while cyanosis, cor pulmonale, accentuated pulmonic second sound, right ventricular heave, and peripheral edema appear in late disease phases 1
Interstitial lung disease would present with dry cough, crackles on pulmonary exam, and hypoxemia, which helps distinguish it from cardiac causes of dyspnea 4
Neurological System
Complete neurological examination must include cognitive, motor, sensory, neurovisual and cranial nerve testing, with asterixis (included in grade 2 West-Haven score) being strongly suggestive of metabolic encephalopathy 1
For paraparesis, document whether upper motor neuron signs (hyperreflexia, clonus, Babinski sign) are present, as these indicate spinal cord or brain lesions rather than peripheral nerve pathology 2
MRI with gadolinium is the preferred imaging modality for suspected spinal pathology, demonstrating plaques of demyelination in multiple sclerosis and characterizing inflammatory lesions 2
Multiple sclerosis presents with multifocal paresthesias affecting different body regions at different times, with MRI showing periventricular white matter lesions that are sharply demarcated, round or flame-shaped, may enhance with gadolinium, typically spare U-fibers initially, and involve the corpus callosum 2
Guillain-Barré syndrome progresses over days to 4 weeks with bilateral paresthesias, weakness, absent/decreased reflexes, elevated CSF protein without pleocytosis, and electrodiagnostic evidence of neuropathy 2
Hepatic System
Jaundice suggests hepatic congestion from elevated right-sided pressures causing congestive hepatopathy (cardiac cirrhosis) 3
Liver function tests, including elevated transaminases and bilirubin, confirm hepatic congestion and distinguish it from primary liver disease 3
Any initial evaluation of a neurological disorder in a cirrhotic patient should include clinical and paraclinical work-up to exclude differential or associated diagnosis, with blood tests and brain imaging (preferably MRI) being essential 1
Rheumatologic/Musculoskeletal System
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin is required, checking for symptoms of temporal arteritis such as headache, visual disturbances, or jaw claudication, with urgent ophthalmology referral if present as permanent visual loss can occur within days 1
Check ANA, RF, anti-CCP, CK to evaluate differential diagnosis of myositis, and inflammatory markers (ESR and CRP) 1
Severe weakness with or without pain limiting self-care activities requires holding immune checkpoint inhibitors, hospitalization for severe weakness limiting mobility, respiratory compromise, dysphagia, or rhabdomyolysis, and urgent referral to rheumatologist and/or neurologist 1
Infectious Disease Considerations
Recent medical history must specify infections, trauma, withdrawal and psychotropic drugs 1
For suspected tickborne rickettsial diseases, epidemiologic clues (season, tick bite history, travel, outdoor activities, exposure to pets or other animals) prove useful, though early consideration and empiric treatment is critical as diagnostic tests are usually not helpful during initial illness stages 1
Leukopenia or thrombocytopenia in a patient with Lyme disease should raise clinical suspicion for possible coinfection with Anaplasma phagocytophilum 1
Essential Laboratory Evaluation by Clinical Scenario
For Suspected Vascular Causes
- Complete blood count, chemistry panel, prothrombin time, activated partial thromboplastin time are recommended 2
For Inflammatory/Infectious Causes
- CSF examination is essential when distinguishing spinal cord infarction from myelitis, as CSF analysis differentiates these conditions, shows elevated protein in Guillain-Barré syndrome, and demonstrates lymphocytic pleocytosis in Lyme neuroborreliosis 2
For Metabolic Causes
Thyroid function, vitamin B12, electrolytes (potassium, magnesium, phosphate, calcium) are recommended 2
Blood ammonia level measurement requires venous blood sampling in a fasting patient, avoiding venous stasis, collecting blood in EDTA-containing tube, placing immediately on ice, with fastest possible transport to laboratory at +4°C (maximum 60-90 minutes) 1
For Cardiac Causes
- Common blood tests include blood electrolytes, blood glucose, blood calcium, cell blood count, hemostasis, inflammatory proteins, blood urea and creatinine 1
Critical Pitfalls to Avoid
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, even though many patients will have no pathology found 2
Do not attribute all symptoms to primary liver disease, provide inadequate diuresis, ignore right ventricular function, or delay echocardiography in patients with suspected biventricular heart failure 3
ACE inhibitor-induced cough should be considered in the differential diagnosis of cough, as persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation 5
Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (with or without nausea or vomiting), diagnosed by abdominal CT scan or ultrasound, with symptoms resolving after stopping the ACE inhibitor 5
Special care must be taken in patients younger than 10 or older than 59 years, those with progressive onset, and those with atypical presentations 2
For cases of overt hepatic encephalopathy recurrence, only blood tests are systematically recommended for differential diagnosis, though initial evaluation requires both blood tests and brain imaging 1