A 53-year-old woman with no significant past medical history presented with slowly progressive weakness in the lower extremities, new-onset numbness below the midthoracic area, urinary incontinence, and slurred speech. One year prior to presentation, she experienced left-sided transitory weakness involving the face and extremities. She was evaluated by multiple neurologists and her brain imaging studies were unrevealing. She later developed tremor in the upper extremities and she was suspected to have central tremor or Parkinson's disease. The patient never had fever, chills, or sweating; however, she had lost 30 pounds during the three-month period preceding her presentation.
The patient grew up on a dairy farm and played in silos. She is married; she lives and works in a farm in rural Kansas, where they grow corn and soy. She has no significant travel history. She denied having sick contacts or significant animal exposure. And she had no history of drug use, incarceration, or exposure to tuberculosis.
The patient first presented to an outside hospital. MRI of the brain and spine, as well as lumbar puncture (LP), was obtained. The MRI images showed leptomeningeal enhancement, predominantly linear, involving the basal cisterns, the brainstem, and spinal cord. Cerebrospinal fluid (CSF) analysis showed 4 rbc/mm3, 157 wbc/mm3 (55% lymphocytes, 35% neutrophils, and 10% monocytes), protein 362 mg/dL, and glucose 24 mg/dL. CSF Gram stain showed no organisms and AFB smear was negative. Bacterial culture was negative. CSF studies including cryptococcal antigen, human herpes simplex virus PCR, West Nile virus PCR, Lyme antibodies, M. tuberculosis (TB) PCR, and cytology were all negative. HIV screen, RPR, and QuantiFERON-TB Gold were negative as well. A CT of the chest, abdomen, and pelvis was unremarkable. The patient was treated with antibiotics and steroids and transferred to our hospital 8 days after her initial admission for further evaluation and treatment. At that time, her CSF fungal and mycobacterial cultures were pending.
After transfer to our facility, a second LP was performed, three days after the initial one. CSF analysis revealed 248 wbc/mm3 (77% lymphocytes, 6% neutrophils, and 17% monocytes), protein 340 mg/dL, and glucose 51 mg/dL. Routine bacterial culture was again negative. C-reactive protein and procalcitonin levels were normal. Repeat brain and spine MRI at our facility showed mild improvement of the meningeal enhancement (Figures 1, 2, and 3). Repeat CSF analysis two days later revealed 25 rbc/mm3, 150 wbc/mm3 (61% neutrophils, 23% lymphocytes, and 16% monocytes), glucose 14 mg/dL, and protein 587 mg/dL. The shift from lymphocytes to neutrophils was felt to be due to steroid therapy. The CD4 lymphocyte count was 372 (58.5%), despite treatment with steroids. The work-up at this point focused on ruling out a fungal infection since TB seemed unlikely.
Fungitell was negative. Serum Histoplasma antibody was positive by EIA; however, complement fixation and immunodiffusion assays were negative. Histoplasma urine antigen was 0.68 ng/mL. Blastomyces antibody was negative (immunodiffusion assay). Blastomyces urine antigen was 0.55 ng/dL. Sporothrix antibody was negative. CSF Histoplasma and Blastomyces antibodies were both negative. At this time, fluconazole, which was given initially for empiric antifungal therapy, was changed to liposomal amphotericin B. Repeat Histoplasma urine antigen was 0.71 ng/mL and Blastomyces urine antigen was 0.56 ng/dL. CSF Histoplasma and Blastomyces antigens were both positive, above the limits of quantification.
Last LP, two weeks later, showed further improvement of pleocytosis and protein level (60 wbc: 58% lymphocytes, 33% neutrophils, and 9% monocytes; glucose 54 mg/dL; protein 173 mg/dL). Repeat CSF Histoplasma and Blastomyces antibodies were again negative, while repeat CSF Histoplasma and Blastomyces antigens were both positive, above limits of quantification. Serum Histoplasma antigen was measured as well and came back positive, below limit of quantification (<0.4 ng/dL). Two CSF fungal and mycobacterial cultures done at the outside hospital remained negative. One of two CSF fungal cultures, obtained two days after admission to our facility, eventually grew Histoplasma capsulatum one month later. Four weeks after admission to our facility, the patient was discharged to a long-term acute care hospital to continue treatment. She received 6 weeks of treatment with liposomal amphotericin B followed by oral voriconazole with minimal improvement of her weakness during the first two months of treatment. Patient was lost to follow-up afterwards.