Case Report Reveals Rare EBV-Driven Complication of Long-Term Mycophenolate Use in AQP4+ NMOSD

A newly published case report detailed a 75-year-old woman with longstanding aquaporin-4-antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) who developed subacute cognitive decline, gait imbalance, and multifocal brain lesions ultimately attributed to Epstein-Barr virus (EBV)–positive, CNS-restricted iatrogenic immunodeficiency-associated lymphoproliferative disorder after more than 2 decades of oral immunosuppression.¹

For neurologists managing patients with NMOSD on long-term mycophenolate, distinguishing a true relapse from a CNS lymphoproliferative disorder can be challenging but there are key clinical and radiographic clues to watch for, according to senior author Eoin P. Flanagan, MB, BCh.

“Brain involvement at an unusual age or worsening beyond 4 weeks. Also, from an MRI perspective multifocal enhancing lesions or persistently enhancing lesions could suggest a lymphoproliferative disorder. NMOSD attacks tend to effect the optic nerve, spinal cord or area postrema,” Flanagan, professor of neurology and chief of the Division of Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic, told NeurologyLive^®.

Study Overview

The report described a woman diagnosed with AQP4+ NMOSD at age 55 after a prior optic neuritis event and later confirmatory seropositive testing prompted by her identical twin sister's own NMOSD diagnosis. She was maintained on mycophenolate mofetil for 11 years without complication before a breakthrough thoracic myelitis attack led clinicians to consider switching her to a newer attack-prevention therapy. While awaiting insurance approval for an alternative agent, she developed subacute cognitive complaints, leg weakness, gait imbalance, and somnolence progressing over several weeks, accompanied by new multifocal T2-hyperintense, enhancing brain lesions on MRI.

Key Findings

Laboratory workup revealed mild lymphopenia, and cerebrospinal fluid analysis showed a mildly elevated white blood cell count with lymphocytic predominance. Extensive infectious PCR testing was negative except for EBV, which was detected at high copy number in blood and was PCR-positive in CSF. Brain biopsy of a left frontal lesion demonstrated a polymorphous lymphoplasmacytic infiltrate with kappa light chain–restricted plasma cells, necrosis, and extensive EBV positivity on in situ hybridization, confirming EBV-positive CNS-restricted iatrogenic immunodeficiency-associated lymphoproliferative disorder.

Mycophenolate was permanently discontinued, and the patient was treated with induction IV rituximab followed by maintenance dosing every 6 months, a regimen selected to simultaneously address the lymphoproliferative disorder and continue attack prevention for NMOSD. Cognition and swallowing function recovered, and follow-up imaging over the ensuing months showed progressive reduction in lesion size and enhancement.

When asked whether lymphopenia should be routinely monitored in patients on long-term mycophenolate and whether this case would change his approach, Flanagan said the practice is already standard. “We do monitor for that as routine and if persistent lymphopenia, would consider reducing the dose or switching to an alternative medication,” said to NeurologyLive.

Given the risk of CNS lymphoproliferative disorders with long-term mycophenolate use, Flanagan was also asked whether this case shifts his threshold for switching patients to a newer biologic, such as rituximab or eculizumab. “In general, the evidence is weaker for mycophenolate compared to the biologic treatments, which have class 1 evidence, and therefore we often use an FDA-approved biologic as first line," Flanagan said.

"However, in some less-resourced countries, these medications are used more commonly, as some of these other treatments may not be available,” Flanagan added. “That said, now that rituximab is on the WHO Essential Medicines List, it's a good option to consider in less-resourced settings, as it has class 1 data to support its use and would be favored over mycophenolate given this efficacy data and the potential risk of lymphoproliferative disorders in the longer term."

Clinical Context and Interpretation

AQP4+ NMOSD is a rare, relapsing autoimmune CNS disorder with a global prevalence estimated at roughly 1 to 5 per 100,000 population.² Each attack carries risk of cumulative, often irreversible visual and motor disability, underscoring the importance of effective long-term attack-prevention therapy. Mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor, has long been used off-label for AQP4+ NMOSD attack prevention based on retrospective data.

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Current management guidance favors monoclonal antibody therapies as preferred long-term attack-prevention options, reserving conventional immunosuppressants such as mycophenolate and azathioprine largely for settings where biologics are inaccessible.³ Supporting this shift, the CD19-targeting agent inebilizumab significantly reduced adjudicated NMOSD attack risk compared with placebo in the phase 2/3 N-MOmentum trial (NCT02200770).⁴ CNS lymphoproliferative disorder is classically associated with solid organ transplantation, but the authors of the present case noted that mycophenolate has been linked to a comparatively higher risk of primary CNS lymphoproliferative disease than other immunosuppressants.¹

The authors framed persistent lymphopenia as a potential red flag for lymphoproliferative risk in patients on long-term mycophenolate, suggesting it may warrant dose reduction or a switch to alternative therapy. They emphasized that new neurologic or systemic symptoms in this population should prompt consideration of lymphoproliferative disease alongside more common differentials, including NMOSD relapse, opportunistic CNS infection, and neoplasm. Rituximab's dual utility, treating EBV-driven lymphoproliferation while also serving as an approved attack-prevention agent, made it a practical treatment choice in this case.

Limitations and Future Research

As a single case report, the findings are inherently limited in generalizability, and no genetic or mechanistic testing was performed to clarify the familial NMOSD clustering observed in this patient and her twin sister. Surveillance strategies for EBV reactivation in non-transplant immunosuppressed patients remain undefined, and the authors note EBV DNA elevation in blood may be a comparatively late diagnostic marker.

The findings highlight an underrecognized long-term risk of mycophenolate mofetil, a mainstay maintenance therapy for AQP4+ NMOSD, and reinforce the value of a structured diagnostic approach when new neurologic symptoms arise in immunosuppressed patients. The authors called for greater awareness of CNS lymphoproliferative disorder as a rare but serious complication of chronic mycophenolate therapy and suggest further study of lymphopenia as a monitoring parameter to guide earlier immunosuppressant modification.

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REFERENCES
1. Ajwani S, Weinshenker BG, Giannini C, et al. Immunity Gone Viral: Subacute Cognitive Decline With Multifocal Brain Lesions in Neuromyelitis Optica Spectrum Disorder. Neurol Neuroimmunol Neuroinflamm. 2026;13(4):e200607. doi:10.1212/NXI.0000000000200607
2. Hor JY, Asgari N, Nakashima I, et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020;11:501. Published 2020 Jun 26. doi:10.3389/fneur.2020.00501
3. Kümpfel T, Giglhuber K, Aktas O, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management. J Neurol. 2024;271(1):141-176. doi:10.1007/s00415-023-11910-z
4. Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352-1363. doi:10.1016/S0140-6736(19)31817-3