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Progressive multifocal leukoencephalopathy on dimethyl fumarate with preserved lymphocyte count but deep T-cells
Jeanne Garcia1, Houria Hendel-Chavez2, Marie-Ghislaine De-Goer2
1Saint Antoine Hospital, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.
Background:
Progressive multifocal leukoencephalopathy (PML) among multiple sclerosis (MS) patients receiving dimethyl fumarate (DMF) is associated with iatrogenic lymphopenia, predominating on CD8+ T-cells.
Objectives And Methods:
We report an unusual case of DMF-related PML in a 66-year-old MS patient with preserved lymphocyte count (nadir: 810/mm3) and normal CD8+ T-cells count.
Results:
A massive overexpression of the inhibitory receptor Programmed Cell Death 1 (PD-1) on CD8+ and memory effector T-cells together with an impaired anti-JC virus (JCV) specific T-cells response were found, compatible with exhaustion. Following DMF withdrawal, PML progressively regressed, PD-1 was downregulated, and a functional anti-JCV response was established.
Conclusion:
T-cells exhaustion may favor PML onset on DMF independently of lymphocyte count.
Insights
Dimethyl fumarate (DMF) can cause progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. T-cell exhaustion, not just low lymphocyte count, may trigger PML, even with normal immune cell levels.
Area of Science:
- Immunology
- Neurology
- Pharmacology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a rare but serious opportunistic infection.
- PML is a known risk in multiple sclerosis (MS) patients treated with dimethyl fumarate (DMF).
- DMF-associated PML is typically linked to significant lymphopenia, particularly affecting CD8+ T-cells.
Observation:
- This report details an unusual case of DMF-related PML in an MS patient.
- The patient maintained a preserved lymphocyte count and normal CD8+ T-cell levels.
- This presentation deviates from the common understanding of DMF-induced PML pathogenesis.
Findings:
- The patient exhibited marked overexpression of the Programmed Cell Death 1 (PD-1) receptor on CD8+ and memory effector T-cells.
- An impaired T-cell response specific to the JC virus (JCV) was observed, indicative of T-cell exhaustion.
- Withdrawal of DMF led to PML regression, PD-1 downregulation, and restoration of anti-JCV T-cell function.
Implications:
- T-cell exhaustion, characterized by PD-1 upregulation, may be a critical factor in PML development.
- PML onset during DMF therapy might occur independently of absolute lymphocyte counts.
- These findings suggest a need to monitor T-cell exhaustion markers in MS patients on DMF therapy.
