What is the appropriate management for a patient presenting with headache, fever, and extremity weakness without lymphadenopathy?

Management of Headache, Fever, and Extremity Weakness Without Lymphadenopathy

Immediately initiate empiric doxycycline 100 mg twice daily for presumed tickborne rickettsial disease (TBRD), specifically human monocytic ehrlichiosis (HME) or anaplasmosis, while simultaneously pursuing urgent diagnostic workup to exclude other life-threatening causes. 1

Immediate Empiric Treatment

• Start doxycycline 100 mg orally or IV twice daily immediately without waiting for confirmatory testing, as delay in treatment is the most important factor associated with mortality in TBRD 1
• This triad of fever, headache, and neurologic symptoms (extremity weakness) without lymphadenopathy is highly consistent with ehrlichiosis or anaplasmosis, where CNS manifestations including focal weakness occur in up to 20% of HME cases 1
• Doxycycline is effective against both rickettsial organisms and Borrelia burgdorferi (Lyme disease), making it the optimal empiric choice when distinguishing between these tickborne diseases is difficult 1

Critical Diagnostic Workup

Laboratory evaluation to perform immediately:

• Complete blood count looking for thrombocytopenia and leukopenia (common in ehrlichiosis/anaplasmosis) 1
• Comprehensive metabolic panel to assess for hyponatremia and elevated hepatic transaminases (frequently seen in TBRD) 1
• Blood cultures to exclude bacterial sepsis 1
• Serum for acute rickettsial serologies (IgG/IgM for Ehrlichia chaffeensis and Anaplasma phagocytophilum), though these will be negative early in disease 1

Lumbar puncture is indicated given the combination of headache, fever, and neurologic symptoms:

• CSF analysis typically shows lymphocytic pleocytosis (usually <100 cells/μL) in approximately 50% of HME patients, though neutrophilic pleocytosis can occur early 1
• CSF protein may be moderately elevated (100-200 mg/dL) with normal glucose 1
• Send CSF for Gram stain, culture, HSV PCR, and consider rickettsial PCR if available 1

Neuroimaging with MRI brain with and without contrast is essential:

• MRI is preferred over CT for evaluating CNS infection, encephalitis, and inflammatory processes 1
• Neuroimaging is often normal or shows nonspecific findings in TBRD, but is critical to exclude other serious causes like abscess, tumor, or vascular events 1
• T2 FLAIR sequences are sensitive for vasogenic edema and meningeal enhancement 1

Differential Diagnosis to Exclude

Other tickborne diseases:

• Lyme disease with neurologic involvement (though extremity weakness without lymphadenopathy is less typical) 1
• Rocky Mountain spotted fever (though rash is present in most cases by day 3-5 of illness) 1

CNS infections requiring different management:

• Bacterial meningitis (requires broader antibiotic coverage with ceftriaxone and vancomycin) 1
• Viral encephalitis, particularly HSV (requires acyclovir) 1
• West Nile virus (can cause acute flaccid paralysis with extremity weakness) 1

Inflammatory/autoimmune causes:

• Immune checkpoint inhibitor-related myositis or encephalitis if patient has cancer history (requires high-dose corticosteroids) 1
• Autoimmune encephalitis (may require immunosuppression and IVIG) 1

Bioterrorism agents (if epidemiologically relevant):

• Inhalational anthrax (presents with fever, malaise, and can progress to meningitis) 1
• Plague (bubonic form has lymphadenopathy, but septicemic form may not) 1
• Tularemia (can present with systemic symptoms and weakness) 1

Clinical Pitfalls to Avoid

• Do not wait for serologic confirmation before starting doxycycline, as acute-phase antibodies are typically negative and convalescent titers (obtained 2-4 weeks later) are needed for retrospective diagnosis 1
• Do not assume absence of rash excludes TBRD, as rash may be absent, subtle, or develop later in the course of ehrlichiosis/anaplasmosis 1
• Do not overlook the need for close outpatient follow-up if treating as outpatient, as these diseases can rapidly progress to severe complications including respiratory failure, renal failure, and death 1
• Consider hospitalization for patients with severe weakness, altered mental status, or laboratory evidence of multiorgan involvement 1

Additional Considerations Based on Exposure History

• Obtain detailed history of tick exposure, outdoor activities, geographic location, and season (ehrlichiosis/anaplasmosis peak in spring/summer) 1
• Ask about animal contact (particularly cats for plague, horses/mules for glanders, rodents for tularemia) 1
• If patient works outdoors in wooded areas and removed ticks within past 2 weeks, this strongly supports TBRD diagnosis 1

When to Escalate Treatment

Add acyclovir 10 mg/kg IV every 8 hours if:

• Patient develops seizures or altered mental status suggesting encephalitis 1
• HSV PCR results are pending and clinical suspicion is high 1

Consider adding broader antibacterial coverage (ceftriaxone 2g IV daily + vancomycin) if:

• CSF shows neutrophilic pleocytosis suggesting bacterial meningitis 1
• Patient appears septic with hemodynamic instability 1

Initiate high-dose corticosteroids (methylprednisolone 1g IV daily for 3 days) only if:

• Immune-mediated process is confirmed (myositis with very elevated CK, autoimmune encephalitis) 1
• Do not give steroids empirically for suspected TBRD as this may worsen outcomes 1

Expected Clinical Response

• Patients with ehrlichiosis/anaplasmosis typically defervesce within 24-72 hours of starting appropriate doxycycline therapy 1
• Mental status and neurologic symptoms should normalize over 3-7 days 1
• If no improvement after 48-72 hours of doxycycline, aggressively pursue alternative diagnoses 1