Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy

Abstract

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab.

Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation.

Design, setting, and participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy.

Exposures: Ocrelizumab monotherapy.

Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy.

Conclusions and relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

Figure 1.. Neuroimaging

Axial fluid-attenuated inversion recovery (FLAIR) sequences from 2 weeks prior (A), 2 weeks after (B), and 8 weeks after (C) symptom onset. There is progressive enlargement of a nonenhancing parietal lesion without mass effect or surrounding edema. There is also progressive extension of bilateral confluent parieto-occipital white matter T2 hyperintensity over time. Axial diffusion-weighted imaging (DWI) (D-F) sequences from the same time points demonstrate typical rim diffusion restriction. MRI indicates magnetic resonance imaging.

Figure 2.. Absolute Lymphocyte Count and Lymphocyte Subset Timelines

A, Absolute lymphocyte count values from 4 years prior to ocrelizumab initiation until shortly after progressive multifocal leukoencephalopathy (PML) onset. Prior to the development of PML, the patient exhibited intermittent mild (grade 1) lymphopenia, with absolute lymphocyte count values ranging from 800 to 1200 cells/μL (to convert to ×10⁹/L, multiply by 0.001). B, Lymphocyte subsets at several times points after ocrelizumab initiation. No prior lymphocyte subset panel was obtained. CD19 cell counts (not shown) remained near 0 at all time points. Horizontal dashed lines correspond with lower limit of normal of each y-axis value. Vertical dashed line corresponds with ocrelizumab initiation, and vertical dashed arrow corresponds with PML symptom onset.

Figure 3.. Histopathology (Paraffin Sections)

A, Occipital white matter: JC virus inclusions (arrowheads) in the infected oligodendrocytes (immunohistochemistry with immunomarker for SV40; hematoxylin counterstain; bar, 50 μm). B, Discrete demyelination patches (arrowheads) in occipital lobe white matter (low-power magnification; myelin stain with Luxol fast blue and periodic acid–Schiff counterstain; bar, 800 μm). C and D, Cerebral white matter showing patches of demyelination where myelin is replaced by mild inflammatory reaction (arrowheads; medium to high power; hematoxylin-eosin stain; bar, 400 μm).