Central Nervous System Involvement in Whipple Disease

Whipple disease (WD) is a rare multisystemic infection with a protean clinical presentation. The central nervous system (CNS) is involved in 3 situations: CNS involvement in classic WD, CNS relapse in previously treated WD, and isolated CNS infection. We retrospectively analyzed clinical features, diagnostic workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data in 18 patients with WD and CNS infection. Ten men and 8 women were included with a median age at diagnosis of 47 years (range, 30Y56 yr). The median follow-up duration was 6 years (range, 1Y19 yr). As categorized in the 3 subgroups, 11 patients had classic WD with CNS involvement, 4 had an isolated CNS infection, and 3 had a neurologic relapse of previously treated WD. CNS involvement occurred during prolonged trimethoprim-sulfamethoxazole (TMP-SMX) treatment in 1 patient with classic WD. The neurologic symptoms were various and always intermingled, as follows: confusion or coma (17%) related to meningo-encephalitis or status epilepticus; delirium (17%); cognitive impairment (61%) including memory loss and attention defects or typical frontal lobe syndrome; hypersomnia (17%); abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron (44%) or extrapyramidal symptoms (33%); and ophthalmoplegia (17%) in conjunction or not with progressive supranuclear palsy. No specific pattern was correlated with any subgroup. Brain magnetic resonance imaging (MRI) revealed a unique focal lesion (35%), mostly as a tumorlike brain lesion, or multifocal lesions (23%) involving the medial temporal lobe, midbrain, hypothalamus, and thalamus. Periventricular diffuse leukopathy (6%), diffuse cortical atrophy (18%), and pachymeningitis (12%) were observed. The spinal cord was involved in 2 cases. MRI showed ischemic sequelae at diagnosis or during follow-up in 4 patients. Brain MRI was normal despite neurologic symptoms in 3 cases. CSF cytology was normal in 62% of patients, whereas Tropheryma whipplei polymerase chain reaction (PCR) analysis was positive in 92% of cases with tested CSF. Periodic acidYSchiff (PAS)positive cells were identified in cerebral biopsies of 4 patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years (range, 1Y7 yr) with either oral monotherapy (TMP-SMX, doxycycline, third-generation cephalosporins) or a combination of antibiotics that sometimes followed parenteral treatment with beta-lactams and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow-up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Thirteen patients (72%) had stopped treatment for an average time of 4 years (range, 0.7Y14 yr). Four patients had clinical worsening despite antimicrobial therapy; 2 of those died following diffuse encephalitis (n = 1) and lung infection (n = 1). In conclusion, the neurologic manifestations of WD are diverse and may mimic almost any neurologic condition. Brain involvement may occur during or after TMP-SMX treatment. CSF T. whipplei PCR analysis is a major tool for diagnosis and may be positive in the absence of meningitis. Immune reconstitution syndrome may occur in the early months of treatment. Late prognosis may be better than previously reported, as a consequence of earlier diagnosis and a better use of antimicrobial therapy, including hydroxychloroquine and doxycycline combination. (Medicine 2013;92: 324Y330) Abbreviations: CNS = central nervous system, CSF = cerebrospinal fluid, CT = computed tomography, FLAIR = fluid-attenuated inversion recovery, MRI = magnetic resonance imaging, PAS = periodic acidYSchiff, PCR = polymerase chain reaction, TMPSMX = trimethoprim-sulfamethoxazole, WD = Whipple disease. INTRODUCTION Whipple disease (WD) is a rare systemic chronic infection caused by the soil-borne gram-positive bacillus Tropheryma whipplei (T. whipplei). Clinical presentation is typically dominated by gastrointestinal symptoms, weight loss, and joint involvement. The diagnosis of WD involves a combination of pathology and molecular microbiology. T. whipplei-infected macrophages contain sickle-form particles that stain positive with periodic acidYSchiff (PAS). Immunochemistry with specific antibodies against T. whipplei may also be used. Polymerase chain reaction (PCR) analysis can be performed with any body tissue or fluid using broad-range primers for amplification of the 16S ribosomal ribonucleic acid (rRNA) gene or the intergenic region of the 16s-23s rRNA; PCR is followed by sequencing of the amplified product. Fluorescence in situ hybridization in tissue specimens and cultivation of T. whipplei on human fibroblast cell lines may also be performed in specialized laboratories. Central nervous system (CNS) involvement is a classic feature of WD. The neurologic manifestations of the disease are diverse and can mimic almost any neurologic condition. Neurologic manifestations occur in 3 circumstances: CNS relapse of previously treated classic WD (that is, with microscopic lesions in the gastrointestinal tract), neurologic involvement in untreated classic WD, and isolated neurologic symptoms (that is, without histologic evidence of intestinal involvement) due to T. whipplei. 324 www.md-journal.com Medicine & Volume 92, Number 6, November 2013 From the Service deMédecine Interne (CC, KS, TP) and Service de Radiologie (IK), Université Paris Diderot, Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Bichat, Paris; INSERM U699, (KS) Université Paris Diderot, Paris; Centre de Référence National sur les Vascularites Systémiques (XP), Université Paris-Descartes, Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Cochin, Paris; Service de Médecine Interne (DV-D), Universite Lyon-Sud, Lyon; Service de Neurologie (J-LH), Université Poitiers, Poitiers; Service de Neurologie (TDB), Hôpital de Saint-Denis, Saint Denis; Aix Marseille Université (DR), URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France. *Both authors contributed equally to this work. Financial support and conflicts of interest: The authors have no funding or conflicts of interest to disclose. Reprints: Professor Thomas Papo, MD, Department of Internal Medicine, Paris Diderot University, APHP, Bichat Hospital, 46 rue Henri Huchard, 75018, Paris, France (e<mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000010 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. In the current study, we retrospectively analyzed clinical data, brain imaging, cerebrospinal fluid (CSF) analysis, and longterm follow-up in 18 cases of WD with CNS involvement. PATIENTS AND METHODS We included 18 patients with WD who were followed between 1989 and 2007 in the departments of Internal Medicine, Infectious Diseases, Rheumatology, and Neurology in France and Belgium. Six cases have already been published, mostly as single case reports with a short follow-up. All patients had 1) microscopic lesions characteristic of the disease on tissues stained with PAS and/or the presence of T. whipplei DNA, as assessed by positive PCR of tissues or body fluids; and 2) clinical neurologic symptoms or proven meningeal involvement, with or without other manifestations of the disease. We analyzed demographic characteristics, clinical symptoms and signs associated with WD, imaging, diagnostic workup, treatment, and follow-up data. Notably, various PCR assays targeting the 16S bacterial RNA gene and other specific T. whipplei sequences were applied following technical improvements over time. Approval from an institutional review boardwas not required for this human noninterventional study. For ethical considerations, however, patients were informed that data collected in their medical records might be used for research study in accordance with privacy rules and ethical guidelines of the 1975 Declaration of Helsinki.