West Nile Virus Encephalitis Associated with Ocrelizumab for Multiple Sclerosis
Year: 2025
Type: article
Abstract: Dear Editor, West Nile virus (WNV) is the primary cause of domestically acquired arboviral disease in many parts of the world.[1] While most WNV infections are asymptomatic, symptomatic patients typically develop an acute systemic febrile illness. However, <1% of individuals face a potentially lethal condition known as neuroinvasive WNV infection, which includes encephalitis, meningitis, myelitis, and acute flaccid paralysis.[2] Immunosuppressed (IS) individuals may experience a more severe form of the disease than non-IS patients.[3,4] In addition, there has been an increase in reported cases of patients with neuroinvasive WNV who are being treated with ocrelizumab, an anti-CD20 monoclonal antibody used for multiple sclerosis (MS).[5-7] Here, we present a case of encephalitis in an MS patient undergoing treatment with ocrelizumab. A 30-year-old woman arrived at the hospital with subacute and severe symptoms, including fatigue, high fever, and a headache. Within 48 h of developing these symptoms, she experienced slurred speech, walking difficulty, and confusion, leading to her hospitalization. Upon admission, she was partially oriented and cooperative. Her neurological examination revealed exaggerated deep tendon reflexes and bilateral upgoing plantar responses, besides encephalopathy, with no signs of neck stiffness or meningeal irritation. The patient has a history of relapsing-remitting MS and has received anti-CD20 treatment with ocrelizumab every 6 months for the past 2 years. Her most recent ocrelizumab infusion of 600 mg was administered 4 months ago. Her family also reported a travel history to the Maldives 2 weeks ago. Blood test results showed a white blood cell count of 9.33 × 103/uL, lymphocytes – 1.24 × 103/uL, neutrophils – 7.34 × 103/uL, C-reactive protein – 11.67 mg/L, and procalcitonin – 0.05 ng/mL. A multiplex polymerase chain reaction (PCR) test for upper respiratory viruses returned negative results for adenovirus, influenza A and B, coronavirus-2, and respiratory syncytial virus. Serology for HIV, hepatitis B-C, and syphilis was negative. The levels of CD19 and CD20 were 0.1%. The immunoglobulin (Ig) levels (IgA, IgG, IgM) in the patient undergoing ocrelizumab treatment were within the normal range. A brain magnetic resonance imaging (MRI) scan was conducted to evaluate neurological status. The MRI using fluid-attenuated inversion recovery showed high-intensity signal changes consistent with widespread demyelinating lesions, primarily located in the periventricular regions of the supratentorial area [Figure 1a]. Although the current MRI findings indicated an inactive pattern of MS, they did not provide clarity regarding the clinical picture.Figure 1: (a) The magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery showed high-intensity signal changes consistent with widespread demyelinating lesions, primarily located in the periventricular regions of the supratentorial area. (b) A second MRI showed foci of increased signal intensity in the right thalamus. (c) A subsequent MRI revealed regression of the lesion in the thalamusThe cerebrospinal fluid (CSF) analysis revealed an opening pressure of 43 cm water, 260 leukocytes/mm3 with lymphocyte predominance, a glucose concentration of 48 mg/dL, and a protein concentration of 78.8 mg/dL. These findings, along with the patient’s symptoms, led to the initiation of a treatment regimen that includes the antimicrobial agents linezolid, meropenem, and acyclovir. An electroencephalogram showed widespread slow-wave activity, primarily in the frontotemporal regions, with no seizure activity noted during the clinical follow-up. CSF culture showed no bacterial growth. Importantly, tests for herpes simplex virus 1, 2, varicella-zoster virus, and cytomegalovirus were all negative, ruling out these potential causes. A second MRI showed foci of increased signal intensity in the right thalamus [Figure 1b] without contrast enhancement. Although the serum WNV IgM was negative on initial testing, a positive CSF PCR result on the 6th day of clinical follow-up for WNV and the second MRI’s findings effectively confirmed the patient’s diagnosis of WNV encephalitis. The patient did not show any systemic manifestations, including skin rash, ocular issues, or involvement of any organs. She experienced a rapid improvement in her symptoms during the 2nd week of follow-up and fully recovered without any lasting effects. A subsequent MRI revealed regression of the lesion in the thalamus [Figure 1c]. The diagnosis of WNV encephalitis in our patient was indicated by the presence of WNV RNA in the CSF through PCR and increased signal intensity observed in the right thalamus on brain MRI. WNV is a positive-stranded RNA virus that belongs to the Flaviviridae family. The mosquito vectors responsible for WNV transmission are widely distributed across the globe, and the geographic range of WNV transmission and related diseases has continued to expand over 80 years since its initial isolation in Uganda in 1937.[1,8] As animal models of WNV infection have provided valuable insights into how the virus affects humans, it has become clear that innate and adaptive immune responses are vital players in defending against WNV.[1,9] The innate immune response is crucial for controlling WNV replication, limiting virus-induced pathology, and preparing the immune system for protective responses involving humoral (B cell) and cell-mediated (which includes CD8+ T cells, CD4+ T cells, and regulatory T cells) immunity against WNV infection.[10] Adaptive immune responses help to control viral replication in peripheral organs, reduce viremia, restrict tissue tropism, prevent neuroinvasion, manage viral replication and spread within the central nervous system, and inhibit neuronal invasion.[1,11] On that basis, it appears that individuals with IS are significantly more susceptible to severe WNV infections, potentially leading to neuroinvasive disease forms, which include encephalitis, meningitis, myelitis, and acute flaccid paralysis. Among neuroinvasive disease cases, encephalitis is the most common clinical manifestation in more than %50 cases, followed by meningitis.[3,4] Previous studies have shown a link between WNV and rituximab, another anti-CD20 therapy used in lymphoma and transplant patients.[12,13] However, recent observations suggest an increase in WNV cases associated with ocrelizumab, an anti-CD20 therapy for MS that was approved in 2017.[5-7] Although this trend has been reported in a few cases, it highlights the importance of humoral immunity in eliminating WNV infection. In the case of our patient, analogous to findings documented in some of the cases in the literature, no serological antibody response was observed at the diagnostic timeline.[5,6] The diagnosis was subsequently confirmed through the application of CSF PCR testing, highlighting the conduct of PCR testing for accurate and on-time diagnosis in patients undergoing treatment with anti-CD20 therapies. In our case, the patient experienced a self-limiting condition while receiving broad antibiotic therapy aimed at treating encephalitis-causing agents. Our patient’s clinical course was notably less severe than that observed in other patients documented in the literature. The patient fully recovered without any long-term neurological deficits, cognitive impairment, or insomnia. Furthermore, in our patient, WNV infection did not correlate with any clinical or imaging evidence of new disease activity related to MS during or shortly after the infection. Given that the patient’s complaints began 8 days after returning from the Maldives, the prodromal phase suggests potential exposure either in Istanbul, Türkiye, or the Maldives. It is also important to note that the most recent neuroinvasive WNV infection associated with ocrelizumab occurred in a patient with a travel history to Türkiye. This case revealed a genomic sequence compatible with genetic lineage 1, the prevalent WNV lineage in Türkiye.[5] At present, there is no specific antiviral treatment or vaccine for WNV disease in humans. The evidence regarding the potential benefits of immunomodulators and antiviral medications – such as intravenous immune globulins, interferon, ribavirin, and corticosteroids – is limited, mainly consisting of case series or individual case reports.[14] In conclusion, diagnosing WNV requires a heightened level of suspicion for patients undergoing immunosuppressive therapies, particularly those presenting with encephalopathy during mosquito-active seasons. Treatments involving anti-CD20 therapies may increase the risk of developing neuroinvasive disease. Author contributions Serkan Demir: Corresponding author, guarantor, definition of intellectual content. Ipek Güngör Doğan: Literature search, manuscript preparation. Ayhan Oztürk: Manuscript editing, manuscript review. Gülgün Dilek Arman: Manuscript editing, manuscript review. Sevki Sahin: Manuscript editing, manuscript review. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4411744710