Histoplasmosis is one of the most prevalent endemic mycosis in the United States. Patients with a previous history of histoplasmosis have a risk of reinfection in the future. Individuals with impaired immunity and those who have massive re-exposure to H. capsulatum, their defenses against this organism can be overwhelmed and diseases can recur. We present a unique case of reactivation disseminated histoplasmosis in an immunocompetent patient. We present a case of a 75-year-old male who presented to the ER on two separate occasions for stroke-like symptoms with progressive falls, impaired speech, hand tremor, confusion and generalized weakness. CT of the head without contrast on both occasions showed chronic atrophy and microvascular changes but no acute abnormalities. MRI could not be performed due to pacemaker incompatibility. EKG showed paced rhythm. The only abnormal lab was a creatinine level of 1.6. Neurology was consulted and they ordered an EEG and lumbar puncture during his second hospitalization. EEG showed generalized slowing, suggestive of diffuse brain dysfunction. Lumbar puncture showed WBC: 103, protein: 172, lymphocytes: 88%, neutrophils: 11%, monocytes: 1%. Following the lumbar puncture, Infectious Disease was consulted. On further investigation, it was discovered that the patient was previously treated for oral histoplasmosis with itraconazole for three months. Cerebrospinal fluid (CSF) was positive for histoplasmosis antigen titer 1:64. Serology was positive for histoplasmosis antibody complement fixation titer of 1:32. The patient was treated with liposomal amphotericin B for six weeks. With treatment, his serology titers continued to improve. The patient was discharged home on itraconazole 200 mg for lifetime, due to his previous history of oral histoplasmosis. On his three-month follow-up, his serology titer was <1:8. Histoplasmosis should be considered in the differential diagnosis of patients who present with chronic meningitis, cerebral vascular accident, focal brain or spinal cord lesions, and encephalitis.

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