Central Nervous System Involvement in Whipple Disease

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 neur...

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections

“…Depending on the location of the lesions, symptoms can be both central or peripheral and either isolated or multifocal. Symptoms associated with Whipple's disease range from abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia), hypersomnia, coma, ophthalmoplegia, cognitive impairment, frontal lobe syndrome, cerebellar ataxia, or upper motor neuron and extrapyramidal symptoms (127). It has even been suggested that there is a relation between T. whipplei infection and the development of Parkinson's disease (117,128,129), but it is unlikely that there is a causative relation.…”

“…Symptoms like diarrhea, joint pain, and fever usually disappear within a week, while other symptoms may take several weeks to disappear (33,62,102,106). It is difficult to cure patients with late symptoms like eye, heart, and CNS involvement, and these patients tend to have high relapse and mortality rates (33,62,125,127,130). Sometimes patients with early symptoms are also hard to treat, as they seem to suffer from lifetime infection either due to permanent carriage of the bacteria in a niche in the patient where it is difficult for the antibiotics to eradicate the bacteria, the development of resistance against these antibiotics, or by reinfection (41,199).…”

“…Several studies by a French group reported the clinical implications of isolated encephalitis caused by T. whipplei (127,157,158). The most common neurological symptoms are cognitive impairment, ataxia, and supranuclear ophthalmoplegia (157).…”

“…The intracellular concentration of antibiotics should be sufficient and in the case of CNS involvement, the drug must be able to efficiently cross the blood-brain barrier. There is no evidence for different treatment regimens for chronic localized infections and classic Whipple=s disease, and therefore, patients should be treated similarly (103,113,125,127).…”

Movement Disorders in Systemic Diseases

“…Polymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) is confirmatory in patients with isolated CNS-WD. 5 MRI of the brain can show tumorlike or multifocal lesions in the midbrain, thalamus, and temporal lobe, 5 or signal abnormalities in the middle cerebellar peduncle (Fig. 1).…”