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Case Report Highlights Rare Case of Progressive Multifocal Leukoencephalopathy in Childhood NMOSD
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Key Takeaways
- PML, though rare, should be considered in NMOSD patients on rituximab, especially with atypical relapse presentations.
- The 17-year-old patient experienced visual deterioration and relapses despite treatment adjustments, leading to a fatal PML diagnosis.
A 17-year-old with NMOSD and rituximab treatment developed PML after several relapses and secondary hypogammaglobulinemia, leading to his death 3 months after diagnosis.
Saif Huda, MD
Recently published in the Multiple Sclerosis Journal, investigators reported the first pediatric and fatal case of progressive multifocal leukoencephalopathy (PML) in a child with neuromyelitis optica spectrum disorder (NMOSD) 9 years after his initial diagnosis. The study authors concluded that while although rare, PML should be considered in patients with NMOSD receiving rituximab, especially in cases of protracted relapse presentations with atypical radiological findings.
The case report featured a 17-year-old boy with a 9-year history of aquaporin-4 (AQP4)-IgG NMOSD who presented with painless and progressive visual deterioration over 6 weeks. Following several relapses while on mycophenolate mofetil and prednisolone, the patient switched to intravenous rituximab at 2.2 g per infusion, 1.1 g every 2 weeks. He relapsed 4 months after the initial infusion, coinciding with CD19+ B-lymphocyte repopulation. Treatment was then adjusted to a 4-month dosing schedule with periodic CD19+ B-cell monitoring, which consistently showed repopulation at 4-5 months.
Led by Saif Huda, MD a consultant neurologist at the Walton Center Foundation Trust, records showed that the boy remained relapse-free for the next 5 years on rituximab; however, he began to develop secondary hypogammaglobulinemia after 6 years of treatment. He started to experience recurrent lower respiratory tract infections and bronchiectasis, in addition to a history of recurrent cutaneous herpes simplex and warts. In the year before presenting, his CD4 count was 37 cells/uL (normal range, 500-1500) and his lymophocyte count was 0.78 x 109/L (normal range, 1-5 x 109/L).
"The rarity of PML in NMOSD is likely attributable to both the low prevalence of NMOSD and the avoidance of immunotherapies with a higher association with PML, such as natalizumab,” the study authors noted.1 "The reported incidence of PML with rituximab is approximately 1 in 32,000; and to date, only one case of PML has been reported with rituximab monotherapy in multiple sclerosis."
After undergoing HIV screening, trio whole genome sequencing, and primary immunodeficiency screening, the boy started prophylactic antibiotics and intravenous immunoglobulin 25 g every 3 weeks, with a plan to switch to anti-interleukin-6 therapy. Before his current presentation, his visual acuity was 20/15 in the right eye and hand movements in the left, with the rest of his neurological exam unremarkable. Upon presenting with bilateral visual loss (right eye: 20/80, left eye: light perception), his CD19+ B lymphocytes were elevated to 43% of peripheral blood mononuclear cells.
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Despite receiving treatment with intravenous methylprednisolone, followed by rituximab and an oral prednisone taper, a neurological examination 1 month later revealed cortical blindness, right-sided pyramidal weakness, and cognitive slowing, without hemianopia, ataxia, or seizures. On MRI, clinicians observed bilateral occipital and temporal T2 signal changes, which prompted more intravenous methylprednisolone, 5 cycles of plasma exchange, and intravenous immunoglobulin.
PML was confirmed with a positive cerebrospinal (CSF) fluid JCV PCR (>100,000 copies), despite normal CSF cell and protein counts. MRI showed progressive multifocal hyperintense T2 signal changes with peripheral diffusion restriction, but no post-contrast enhancement. His CD4+ T-cell count was 26 cells/uL (normal, 500-1500), and total lymphocyte count was 0.24 x 109/L (normal: 1-3 x 109/L). Unfortunately, the patient passed away 3 months after symptom onset and 40 days after their PML diagnosis.
Several factors may have contributed to the patient’s condition, including the redosing of rituximab due to B-cell repopulation, study authors noted. "Despite his complications, de-escalation of rituximab or extending dosing intervals with B-cell repletion poses a significant risk of relapse,” Huda et al added. “Furthermore, alternative monoclonal antibody therapies were not available in the National Health Service (NHS). Testing for FCGR3A polymorphisms was unavailable but may have explained rapid B-cell re-population. In addition, the cumulative impact of prior immunotherapies, including prednisolone and mycophenolate mofetil, were likely contributors. Despite negative genetic testing for primary immunodeficiency syndromes, this remained a suspicion given the low CD4+ T-cell count and severe recurrent infections."
The only prior report of PML in NMOSD, published in 2013, came from an elderly patient, aged 72 years old who developed progressively worsening gait unsteadiness and falls. This individual, who originally received azathioprine to treat her attacks, simultaneously developed PML-immune reconstitution inflammatory syndrome (IRIS) and longitudinally extensive transverse myelitis, leading to several questions about whether NMO itself or its treatment predisposed to PML. In the case report, the woman underwent intermittent plasmapheresis for long-term treatment to avoid cell-mediated immunosuppression, avoided treatment with rituximab, and saw improved strength and speed with high-dose methylprednisolone.2
