Cerebral Whipple's disease.
Even if they were scanty, the presence of PAS-positive, diastase-resistant material in macrophages suggested to explore the possibility of cerebral Whipple's disease. PCR for Tropheryma whipplei (T. whipplei) DNA was carried out following a previously reported procedure (3) on cerebral biopsy specimens, both on frozen material and on tissue obtained from histological sections from formalin-fixed, paraffin-embedded blocks. The PCR was positive for T. whipplei DNA both on frozen specimen and on material obtained from histological sections (Figure 3, lanes 1-4: present case; lane 1: frozen tissue; lane 2: frozen tissue diluted 1:10; lane 3: fixed tissue; lane 4: fixed tissue diluted 1:10; 5: buffer; 6: negative control; 7: positive control). In the latter, the positivity was fainter and detectable only after 10-fold dilution.
CLINICAL HISTORY (additional information)
After the biopsy the general conditions of the patient worsened, for diarrhea and anemia. A test for Clostridium difficile was positive. The patient was transferred to a general medical ward and Vancomicyn was started with improvement of the diarrhea. An esophagogastroduodenoscopy was performed with a duodenal biopsy which was normal. PCR for T. whipplei DNA in intestinal specimens was negative. When the diagnosis of cerebral Whipple's disease could be established, sulfametoxazol + trimetoprim was changed to cefriaxone. Despite this the neurological conditions of the patient worsened, he became less reactive, myoclonic jerks became continuous and were not improved by infusion of levetiracetam or midazolam. An EEG showed low amplitude generalized slowing in the delta range but there was no correlation with the jerks. Forty days after the biopsy, the patient was transferred to a long-term care facility near home. At discharge he was in a state of coma with occasional grimacing or eye opening when stimulated, he had severe tetraparesis and persistent jerks of his right face and right arm. He died a month later in a condition of generalized wasting. Autopsy was not performed.
Whipple's disease is a rare, chronic inflammatory, multi-systemic disease caused by the Gram-positive, ubiquitous, environmental bacterium T. whipplei, large numbers of which accumulate within macrophages in the affected tissues. The disorder present with prominent and frequent but not invariable gastrointestinal involvement (4). T. whipplei cannot be cultured by traditional methods, so the diagnosis is based on typical histological lesions and identification of the causative organism that can be achieved by PCR (3).
Neurologic signs of Whipple disease are protean and isolated neurologic symptoms due to T. whipplei without histologic evidence of intestinal involvement rarely occur and present further complexity (1,7).
Our patient had a purely neurological presentation and involvement restricted to the central nervous system indicated by non contributory medical history in particular without any diarrhea or weight loss before the onset of neurological symptoms and confirmed by histology and PCR analysis of intestinal biopsy.
The patient who we presented emphasizes the importance of cerebral biopsy and the need to consider Whipple disease in cases with atypical subacute meningoencephalitis even in the absence of gastrointestinal involvement. Actually, the diagnosis should be considered incidental since PAS stain was carried out with the aim to rule out PAS positive neuronal inclusions as some neurons showed the presence of nuclei displaced at the periphery of the perikaryon. Following the detection of PAS positive macrophages infiltrates in the leptomeninges, even if sparse and scarce, Whipple disease was suspected and specific PCR was performed with positive results.
Brain MRI showed multiple cerebral ischemic lesions that occur in characteristic locations, at the junction of the distal fields of two main arterial territories, like watershed infarcts. Our patient therefore represents a rare case of cerebral Whipple disease presenting with stroke-like symptoms (6), and a unique case with border-zone infarcts. The pathogenesis of this type of cerebral infarctions remains debated, probably precipitated by a hemodynamic impairment associated to a microembolic etiology (2). Isolated cortical border-zone infarcts, as in this case report, may be embolic in nature. Microemboli from the heart or from atherosclerotic plaques or from fibrotic artery may propagate preferentially to cortical border zones, which have lower perfusion than other areas and, thus, a scarce ability to wash out these emboli (5). It is noteworthy that in Whipple disease endocarditis is reported and could have represented a source of microemboli (4).
Contributed by Giorgio Giaccone, Francesco Carella, Carlo Parravicini, Erika Longhi, Luisa Chiapparini, Mario Savoiardo, Nicola Montano, Michela Morbin, Alberto Albanese, Fabrizio Tagliavini