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We present the case of a woman in her late 50s with anti-synthetase syndrome who developed progressive multifocal leucoencephalopathy (PML), a rare and potentially fatal complication of immunosuppressive therapy. She was admitted with transient left-sided paraesthesia, left hand weakness and incoordination, and intermittent blurry vision, initially suspected to be a cerebrovascular event. Imaging revealed multifocal subcortical white matter lesions, and brain biopsy confirmed PML. Notably, she had been treated with mycophenolate mofetil and low-dose prednisolone, without rituximab. Her symptoms improved following the cessation of immunosuppressive therapy. This case highlights the importance of considering PML in immunosuppressed patients presenting with neurological symptoms, even in the absence of monoclonal antibody exposure, and suggests a possible association with conventional immunosuppressive therapy, although causality cannot be established from a single observation.