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Primary Neuro-Whipple is a rare entity that might be fatal if not promptly diagnosed.
Primary Neuro-Whipple diagnosis is challenging given its heterogeneous presentation.
Rhombencephalitis is a unique presentation of Neuro-Whipple disease.
Clinicians should be aware about atypical presentation of primary Neuro-Whipple.
Primary Whipple disease of the Central Nervous System is a rare entity whose outcome might be fatal if not promptly diagnosed and treated. Few cases are reported in the literature with heterogeneous clinical and radiological presentations which often make the diagnosis extremely challenging.
We report a case of primary Whipple disease of the Central Nervous System presenting with rhombencephalitis in a female patient in immunosuppressive treatment for rheumatoid arthritis. We describe the management of our patient and discuss the features of this rare clinical entity.
Central Nervous System (CNS) involvement during Whipple’s disease (CNS-WD) can complicate the classic form, or less frequently, present as a primary localization, in particular in immunocompromised patients (
). Primary CNS-WD is a clinical challenge, representing a life-threatening but treatable condition. Herein, we report on an immunocompromised patient who developed primary CNS-WD presenting as rhombencephalitis, with the aim of facilitating prompt diagnosis of this rare disease.
The patient was a 76-year-old woman admitted to our Neurology ward because of subacute onset of diplopia, vertigo, postural instability and headache. She had a 9-year history of rheumatoid arthritis in treatment with methotrexate and low-dose steroids (prednisone 2.5 mg) and reported penicillin allergy.
On admission, neurological examination revealed bilateral ptosis, diplopia in all gaze positions and right dysmetria. Blood tests showed 11520 leukocytes/mm3 with normal C-Reactive Protein (CRP). Brain angio-CT scan was normal.
Soon after admission the patient experienced rapid consciousness deterioration with cranial nerve deficits and ataxic paresis of the right upper limb. Lumbar puncture showed crystal clear cerebrospinal fluid (CSF) with moderate mononuclear pleocytosis (52 cells/mm3), mildly elevated proteins (106 mg/dl) and normal glucose. Molecular amplification for viruses (EBV-DNA, HSV1/2-DNA, CMV-DNA, VZV-DNA, HHV6-DNA, Enterovirus-RNA, Polyomavirus-JC-DNA PCR), M. tuberculosis and Toxoplasma on CSF as well as CSF culture resulted negative. Despite negative microbiological results on CSF, due to increasing leukocytes (15610/mm3) and CRP (8 mg/dL), meropenem (2 g q8h) was started. On the same day in which antibiotics were started, signs of brainstem involvement with tachycardia, tachypnoea, miosis and ataxic quadriplegia appeared, requiring mechanical ventilation in the Intensive Care Unit (ICU). During the ICU stay, brain MRI was performed, showing multiple contrast-enhancing lesions involving the pons, medulla and cerebellum, suggestive for rhombencephalitis. Similar lesions involved the cervical spinal cord and the right trigeminal nerve (see Figure 1).
Considering the radiological findings, linezolid and cotrimoxazole were introduced to empirically cover Nocardia and Toxoplasma. However, toxoplasma serology resulted negative, as well as HIV test. Total-body CT scan also resulted normal.
During wide-spectrum antibiotic therapy, the patient experienced progressive improvement of the consciousness level allowing ICU discharge after few days. Clinical improvement was confirmed by a brain MRI performed after 2 weeks of antimicrobial treatment revealing a reduction of the brainstem lesions.
CSF analysis performed after 1 month of antibiotic treatment confirmed the general improvement (18 cells/mm3; proteins 57 mg/dL): this time, CSF was sent for further analysis including Tropheryma whipplei-PCR, which resulted positive (genotype 2A).
After this finding, antimicrobial therapy was de-escalated by continuing oral cotrimoxazole only (160/800 mg q12 h) and the patient was discharged overall in good clinical condition, although still affected by diplopia in horizontal gaze, right seventh nerve cranial deficit and ataxic hemiparesis. After a 6-month rehabilitation course, esophagogastroduodenoscopy was performed, showing negative Periodic Acid Schiff (PAS) staining and T. whipplei-PCR on multiple duodenal biopsies. Furthermore, a 6-month follow-up brain MRI showed complete resolution of cerebral lesions, while a 12-month follow-up lumbar puncture revealed normal CSF with negative T. whipplei-PCR.
During antibiotic treatment the patient experienced complete resolution of ocular and cranial nerve disorders, while mild hemiparesis persisted as long-term sequela. Cotrimoxazole was continued for 18 months and due to rheumatoid arthritis reactivation, steroids and methotrexate were subsequently reintroduced. The patient is currently 16 months post-antibiotics suspension in overall discrete clinical conditions; nonetheless, follow-up is still ongoing in order to monitor for possible relapses.
Very few cases of primary CNS-WD confirmed by histological or microbiological examination with consensual negative gastrointestinal specimens are reported in the literature (
). Ocular movement disturbance, including oculomasticatory myorhythmia or oculo-facio-skeletal myorhythmia associated with progressive supranuclear ophthalmoplegia, are considered pathognomonic of CNS-WD although rarely reported (
Our patient presented with some of the typical symptoms of CNS-WD including ocular movementsdeficits and ataxia, while brainstem involvement is quite uncommon. Listeria is the most common cause of infectious rhombencephalitis, followed by Enterovirus-71 (
). In our patient, the positivity of the anti-citrullinated peptide/protein antibodies (anti-CCP) and the previous benefit of steroids on arthralgias made the diagnosis of rheumatoid arthritis likely even before excluding a systemic disease by endoscopy.
The delay in performing the duodenal biopsies is certainly a limitation of our case report since the intestinal abnormalities might have improved during antibiotic course. However, studies demonstrate how even after successful eradication of T. whipplei, the PAS-positive material in macrophages of duodenal lamina propria can persist for several years; moreover, the endoscopic lesions are likely to last longer than 6 months in more than 80% of cases (
). The association of doxycycline with hydroxychloroquine represents a valid alternative option. Given her allergy to penicillin, our patient was initially treated with meropenem and afterwards with cotrimoxazole to empirically cover toxoplasma. Hence, she luckily received an appropriate scheme for CNS-WD even before the diagnosis was made, allowing clinical improvement.
The duration of treatment for classic WD is usually one year, and follow-up duodenal biopsies are warranted to monitor treatment response (
The clinical improvement observed in our patient, together with the complete resolution of radiological signs at 6-month follow up MRI and the negativity of T.whipplei PCR on 1-year follow up CSF, led us to discontinue cotrimoxazole after 18 months. However, given the reintroduction of immunosuppressive treatment for rheumatoid arthritis, the patient is being closely monitored for potential relapse.
Isolated CNS-WD is a clinical challenge and should be considered in the differential diagnosis in unusual cases of encephalitis. Awareness among clinicians should be raised in order to help prompt diagnosis and optimal treatment.
As the exact treatment duration of CNS-WD has not been established, patients should be closely followed in case of antibiotics discontinuation in order to monitor for potential relapse, especially in case of coexisting immunosuppression.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient.
No funding was receiving for writing this paper.
Conflict of interest
The authors declare that there is no conflict of interest regarding this publication.
Quiles Granado A.M.
Clinical and neuropathological variability in clinically isolated central nervous system Whipple’s disease.