Whipple's disease affecting the central nervous system;
Acquired immune deficiency syndrome
Having shown clinical and radiographic progression despite empiric treatment for Toxoplasma gondii and mycobacteria, the patient was considered for brain biopsy with a view toward distinguishing lymphoma from infection. Magnetic resonance spectroscopy (reported under the MRI reading) suggested features atypical for either lymphoma or abscess, but could not rule out these entities. CSF PCR for T. gondii was negative, as was examination of brain biopsy material for characteristic organisms. Likewise, acid-fast stains of biopsy material, and cultures for mycobacteria, did not suggest infection by this class of organisms. No evidence of CNS fungal infection was found. Likewise, no evidence of lymphoma was found on CSF cytology or brain biopsy. PCR for JC virus was negative, and no viral inclusions were found in biopsy material. Demonstration of periodic acid-Schiff (PAS) positive material in tissue histiocytes, followed by electron microscopy, suggested a diagnosis of CNS Whipple's disease.
Despite a rocky hospital course (characterized by a prolonged ICU admission, a stroke-like episode, and resulting partial seizures), the patient is currently doing very well. Once the organism was identified by electron microscopy, he was started on antibiotic therapy with dramatic resolution of his symptoms. Anti-retroviral therapy was also initiated, as was seizure prophylaxis. The patient is currently living at home with his family, but in all other respects functions independently with little or no residual deficit. As he remains immunocompromised, it was determined that treatment would be continued indefinitely.
Whipple's disease typically presents as a gastrointestinal illness caused by the organism Tropheryma whipplei. The illness is characterized by diarrhea, abdominal cramps, and sometimes frank malabsorption. It was thought that CNS involvement was rare, but many patients without clear neurologic symptoms of Whipple's disease will have evidence of the organism in the CSF by PCR (67%, in one study). CNS symptoms are only reported in 10% to 20% of patients with documented Whipple's disease. These symptoms can include those of oculomotor abnormalities, ataxia, seizures, psychiatric disturbances, parkinsonism, and aseptic meningitis. The protean manifestations of the disease make diagnosis challenging, but two movement disorders are considered to be pathognomonic for CNS Whipple's disease. These are: oculomasticatory myorhythmia (pendular vergence oscillations occurring synchronously with rhythmic mouth and palatal movements) and oculo-facial-skeletal myorhythmia (pendular vergence oscillations occurring synchronously with rhythmic movements of the mouth, face, and body). Unfortunately for the diagnostician, only 20% of cases demonstrate one of these two pathognomonic features.
Surprisingly, gastrointestinal symptoms are not a consistent feature in patients with CNS Whipple's disease, occurring in only 45% of such patients. There are no imaging abnormalities considered to be characteristic of the disease. In the absence of pathognomonic involuntary movements, the diagnosis depends on a high level of suspicion leading to an appropriate diagnostic test (PCR analysis of CSF and/or tissue biopsy demonstrating the characteristic intracellular organisms).
Criteria suggesting a diagnosis of possible CNS Whipple's disease include:
If gastrointestinal disease is prominent, duodenal biopsy is performed. If CNS Whipple's disease is strongly suspected, duodenal biopsy often yields evidence of Trophyrema whipplei by light microscopy, electron microscopy, or PCR, allowing the diagnosis to be substantiated. Brain biopsy or CSF PCR are helpful in substantiating a diagnosis of suspected CNS Whipple's disease. Histopathologically, one sees macrophages containing periodic acid-Schiff (PAS)-positive material. Other intracellular organisms, particularly the atypical mycobacteria, must be distinguished from Trophyrema whipplei. Acid-fast stains of T. whipplei are negative, as was the case in this patient's biopsy material. The characteristic rod-shaped intracellular organism is seen by electron microscopy. PCR amplification of the gene coding for the organism-specific 16S ribosomal RNA may be performed in addition to or instead of histological diagnosis.
Growing recognition that Tropheryma whipplei enters the CNS, even in cases in which CNS symptoms are absent, has affected treatment recommendations. All patients with Whipple's disease are recommended to be treated as though they have CNS involvement, with agents that cross the blood-brain barrier. Current recommendations are for a two-week course of intravenous ceftriaxone, to be followed by one to two years of double-strength oral trimethoprim-sulfamethoxazole. Often, streptomycin or macrolide antibiotics are added to initial treatment regimens. Other regimens have also been suggested, most emphasizing combination antibiotic therapy over a long term. The appropriate duration of treatment is unknown, as is the utility of serial PCR assays of CSF.
Whether a specific predisposition exists for the development of CNS Whipple's disease in immunocompromised patients is unclear. Occasional coexistence of these conditions has been reported (e.g., Albrecht et al., 1997). Also, the enteropathy and systemic manifestations of Whipple's disease may mimic a disorder of immune function (e.g., Maliha et al., 1991).
We thank Drs. Emilie Rouah, Suzanne Powell, and J. Clay Goodman of the Department of Pathology, Baylor College of Medicine, for their assistance with this case.
-- Dennis R. Mosier, M.D., Ph.D.
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