title: Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up.
abstract: 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, 30-56 yr). The median follow-up duration was 6 years (range, 1-19 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 acid-Schiff (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, 1-7 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, 0.7-14 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.
authors.affiliation: From the Service de Médecine Interne (CC, KS, TP) and Service de Radiologie (IK), Université Paris Diderot, Assistance Publique des Hôpitaux de Paris (AP-HP), 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 (AP-HP), Hôpital Cochin, Paris; Service de Médecine Interne (DV-D), Université 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Compain
authors.forename: Karim
authors.initials: K
authors.lastname: Sacre
authors.forename: Xavier
authors.initials: X
authors.lastname: Puéchal
authors.forename: Isabelle
authors.initials: I
authors.lastname: Klein
authors.forename: Denis
authors.initials: D
authors.lastname: Vital-Durand
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Houeto
authors.forename: Thomas
authors.initials: T
authors.lastname: De Broucker
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.forename: Thomas
authors.initials: T
authors.lastname: Papo
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000627:therapeutic use; D002494:Central Nervous System Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000453:epidemiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome; D054851:Tropheryma / Q000187:drug effects / Q000472:pathogenicity; D008061:Whipple Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000453:epidemiology*
chemical_list: D000890:Anti-Infective Agents