What is the differential diagnosis for this patient?

Differential Diagnosis for This Patient

Critical Initial Considerations Based on Presenting Features

The differential diagnosis must be guided by the temporal pattern of symptom onset, specific joint distribution, presence of systemic symptoms, and key laboratory abnormalities—particularly thrombocytopenia, leukopenia, and fever patterns. 1

Primary Diagnostic Categories to Consider

Tickborne Rickettsial Diseases

• Human Monocytic Ehrlichiosis (HME) should be strongly considered when fever, thrombocytopenia, and leukopenia occur together, particularly with history of tick exposure 1
• Characteristic laboratory findings include WBC count <4.5 x 10⁹ cells/L, platelet count <150 x 10⁹ cells/L, and elevated liver enzymes (AST often >300 U/L) 1
• Rash is uncommon in adults with HME, so its absence does not exclude the diagnosis 1
• Morulae in leukocytes are diagnostic but only observed in 1-20% of cases, making microscopy insensitive 1
• Anaplasmosis (HGA) presents similarly with fever, thrombocytopenia, leukopenia, and changes in mental status 1

Inflammatory Arthritides (If Joint Symptoms Present)

• Rheumatoid arthritis characteristically targets MCPs, PIPs, and wrists with symmetric bilateral involvement 2
• Morning stiffness exceeding 30 minutes strongly supports RA over osteoarthritis 2
• Soft tissue swelling on palpation indicates inflammatory rather than degenerative disease 2
• Psoriatic arthritis can affect MCPs and PIPs but typically presents asymmetrically and often involves DIP joints 2
• Adult-Onset Still's Disease presents with symmetric polyarthritis affecting wrists, knees, ankles, PIPs, and MCPs, accompanied by high-spiking quotidian fevers and salmon-pink evanescent rash 2

Neurologic Causes (If Weakness/Paralysis Present)

• Guillain-Barré syndrome progresses over days to 4 weeks with bilateral paresthesias, weakness, absent/decreased reflexes, and elevated CSF protein 3
• Spinal cord ischemia presents with acute onset paraparesis and sensory changes 3
• Epidural abscess or hematoma presents with localized back pain, fever (in only one-third of abscess cases), radiculopathy, and progressive spinal cord syndromes 3
• Multiple sclerosis presents with multifocal paresthesias affecting different body regions at different times 3, 4

Metabolic/Systemic Disorders

• Glycogen Storage Disease Type I presents with hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia 1
• Elevated transaminases (AST and ALT) are common but typically return to normal with appropriate treatment 1
• Vitamin B12 deficiency causes subacute combined degeneration with both central (myelopathic) and peripheral (neuropathic) manifestations 3

Drug-Induced Syndromes (If Medication History Present)

• Neuroleptic Malignant Syndrome presents with hyperthermia, altered mental status, muscle rigidity, and autonomic instability in patients taking antipsychotics 1
• Hallmark features include lead pipe rigidity, fever up to 41°C or higher, tachycardia, blood pressure instability, and diaphoresis 1
• Leukocytosis (15,000-30,000 cells/mm³) and elevated creatine kinase (≥4 times upper limit of normal) support the diagnosis 1
• Immune checkpoint inhibitor-induced arthritis can present with symmetric polyarthritis resembling RA 2

Essential Diagnostic Approach

History and Physical Examination Priority

• Medical history leads to the final diagnosis in 76% of cases, making it the most critical component 5
• Document temporal pattern: acute onset (hours to days) suggests vascular/inflammatory causes; subacute (weeks) suggests mimics; gradual progression suggests neoplastic/metabolic etiologies 3, 4
• Query tick exposure, recent travel, outdoor activities, pet illness, and sick contacts 1
• Assess for systemic symptoms: fever pattern, rash characteristics, weight loss, malaise, and fatigue 2
• Examine joint distribution: symmetric vs asymmetric involvement, presence of soft tissue swelling vs bony enlargement 2
• Bilateral MCP involvement essentially excludes primary osteoarthritis 2

Critical Laboratory Tests

• Complete blood count to identify thrombocytopenia and leukopenia suggestive of tickborne illness 1
• Liver function tests (AST, ALT) to assess hepatic involvement 1
• Creatine kinase if muscle involvement or NMS suspected 1
• C-reactive protein and ESR for inflammatory markers 1
• Blood cultures if sepsis or endocarditis considered 1
• CSF examination when distinguishing spinal cord infarction from myelitis, or when Guillain-Barré syndrome suspected 3

Imaging Studies

• MRI is the preferred imaging modality for suspected spinal pathology, demyelinating disease, or cord compression 3, 4
• MRI with gadolinium demonstrates plaques of demyelination in MS and characterizes inflammatory lesions 3, 4
• Plain radiographs for joint assessment if inflammatory arthritis suspected 1

Specialized Testing Based on Clinical Suspicion

• PCR for E. chaffeensis and A. phagocytophilum if tickborne illness suspected 1
• Serologic assays for Borrelia burgdorferi, Ehrlichia, and Anaplasma 1
• Rheumatoid factor, anti-CCP, ANA if inflammatory arthritis suspected 1, 2
• Ferritin levels (very high with low glycosylated fraction <20%) if Adult-Onset Still's Disease suspected 2
• Aquaporin-4 IgG antibody testing to exclude neuromyelitis optica spectrum disorders if neurologic symptoms present 4

Common Diagnostic Pitfalls to Avoid

• Do not anchor on referral data from other institutions; treat the patient as if they were presenting for the first time and conduct a thorough interview 6
• Do not dismiss the absence of rash in suspected HME, as rash is uncommon in adults 1
• Do not delay imaging if neurologic symptoms progress, as prompt investigation identifies rare but critical conditions like epidural abscess 3
• Do not diagnose MS on MRI findings alone—at least one clinical event consistent with acute demyelination is required 4
• Avoid satisfaction bias (finding one disease that prevents accurate diagnosis of another coexisting condition) 6
• Do not overlook epidemiological clues: age <10 or >59 years requires more stringent diagnostic criteria for MS 4
• Subacute onset evolving over weeks rather than hours-to-days should raise concern for MS mimics 4

Algorithmic Approach to Narrowing the Differential

1. Determine temporal pattern: Acute (hours-days) → vascular/infectious; Subacute (weeks) → inflammatory/demyelinating; Chronic (months) → metabolic/neoplastic 3, 4

2. Identify key laboratory abnormalities: Thrombocytopenia + leukopenia + fever → tickborne illness 1; Elevated CK + rigidity → NMS or myositis 1; Elevated ferritin → Adult-Onset Still's Disease 2

3. Assess joint distribution if present: Bilateral MCP/PIP → RA or psoriatic arthritis 2; DIP involvement → psoriatic arthritis or hand OA 1, 2

4. Evaluate for systemic features: Quotidian fevers + rash → Adult-Onset Still's Disease 2; Tick exposure + thrombocytopenia → ehrlichiosis/anaplasmosis 1; Antipsychotic use + rigidity → NMS 1

5. Obtain targeted imaging: Neurologic symptoms → MRI spine/brain 3, 4; Joint symptoms → plain radiographs initially 1

6. Pursue confirmatory testing: PCR/serology for suspected infections 1; CSF analysis for neurologic syndromes 3; Autoantibodies for inflammatory arthritis 2