Case Presentation: A 47-year-old woman with rheumatoid arthritis on methotrexate presented with horizontal diplopia, dysarthria, unsteady gait, and leg weakness. Two days earlier, she went to an urgent care for 3 days of severe frontotemporal headaches and nausea, reporting a tick bite followed by targetoid rash on her inner thigh after hiking in Minnesota 3 weeks prior. She was empirically diagnosed with Lyme disease and treated with oral doxycycline 100mg twice daily. Within 2 days, she developed new neurologic symptoms. On exam, she demonstrated dysarthric speech, horizontal nystagmus, hyperreflexia, ankle clonus, and broad-based, unsteady gait. The rash had resolved. Electrocardiogram showed an incomplete right bundle branch block. Doxycycline 100mg was continued for 21 days total. She also received IV ceftriaxone 2g daily for 4 days due to concern for neuroborreliosis. On hospital day 2, her neurologic symptoms progressed, prompting transfer to the intensive care unit. Cognitive testing showed moderately severe impairment. Lumbar puncture revealed lymphocytic pleocytosis with elevated protein. While extensive infectious and autoimmune workup was in progress, she received 1g IV methylprednisone for 5 days followed by 2 mg/kg IVIG for 3 days with subjective symptom improvement. Infectious testing included: • Bacterial/viral PCR: cerebrospinal fluid (CSF) meningoencephalitis panel negative. • Lyme: Serum and CSF Borrelia burgdorferi antibodies negative. • West Nile virus (WNV): Serum and CSF IgG elevated; serum, CSF IgM, and CSF PCR negative. • St. Louis encephalitis: Serum and CSF IgG weakly positive; serum and CSF IgM negative. • Other arboviruses: Serum and CSF IgG/IgM for California encephalitis and Eastern/Western equine encephalitides negative. • Tick-borne co-infections: PCR for Babesia, Anaplasma, and Ehrlichia species negative. • Powassan virus: Serum IgM positive; CSF PCR negative. Her neurologic syndrome along with positive serum IgM suggested Powassan encephalitis, confirmed by positive Powassan Plaque Reduction Neutralization Test with 1:5120 titer. She was discharged to acute rehabilitation; at follow-up 8 weeks later, she had markedly improved and had minimal residual deficits.
Discussion: It is critical to maintain a broad differential diagnosis in immunosuppressed patients, even when clinical presentation seems straightforward. Recent travel, tick exposure, and reported targetoid rash matched the illness script for Lyme disease, leading to premature closure at initial presentation to care. Our differential diagnosis included other tick-borne illnesses and arboviral infections, particularly given known cross-reactivity within Flaviviridae. Although WNV and St. Louis encephalitis virus IgG were positive, absence of IgM suggested cross-reactivity rather than acute infection. While pre-test probability for Lyme disease was high, other diagnoses (like Powassan encephalitis) could have been considered earlier, given the patient’s immunosuppressed status. Keep in mind that some vectors, such as the Ixodes scapularis tick, can carry several different pathogens and may transmit any of them through their bite.
Conclusions: When evaluating immunocompromised patients for a suspected infectious syndrome, maintain a broad differential, even when presentation appears classic. Interpretation of serologies and other diagnostics in this population requires nuanced analysis.