Visual and Neuro-Ophthalmic Manifestations of John Cunningham (JC) Virus-Related Natalizumab-Associated Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: A Systematic Review

Natalizumab (Tysabri®; Biogen, Cambridge, Massachusetts), a recombinant humanized monoclonal antibody targeting the α4-integrin subunit, is among the most efficacious approved therapies for relapsing-remitting multiple sclerosis (RRMS). Its principal serious adverse effect is progressive multifocal leukoencephalopathy (PML), an opportunistic demyelinating encephalitis caused by reactivation of the John Cunningham (JC) polyomavirus (JCPyV). Despite the established clinical significance of this complication, its visual and neuro-ophthalmic dimensions have not been systematically synthesized. To provide a comprehensive, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of the spectrum, prevalence, anatomical substrates, and clinical significance of visual and neuro-ophthalmic manifestations in natalizumab-associated PML, and to synthesize available evidence on risk stratification, magnetic resonance imaging (MRI) correlates, immune reconstitution inflammatory syndrome (IRIS), and long-term functional outcomes. A systematic literature search was conducted across PubMed/MEDLINE, ScienceDirect, Google Scholar, and ResearchGate (January 2012 to April 2025) in accordance with PRISMA 2020 guidelines. Medical Subject Headings (MeSH) and structured free-text keyword strategies were applied. Eligibility criteria, data extraction, and quality appraisal were predefined. Thirty-five studies were included: 20 observational cohorts or case series, seven systematic reviews or meta-analyses, and eight narrative reviews with extractable data. To prevent double-counting, quantitative outcome data were extracted exclusively from primary observational studies; reviews contributed contextual synthesis only. Neuro-ophthalmic involvement was documented in 20-50% of natalizumab-associated PML patients across the included studies. Homonymous hemianopia was the most prevalent overt manifestation, arising from lytic demyelination of the optic radiations; occipital lobe involvement was recorded in 20% of cases in the largest dedicated MRI distribution dataset. Visual symptoms constituted the initial presentation in up to 25% of affected individuals. Subclinical visual field deficits were identified in 17.4% of post-PML survivors by formal perimetry in the absence of spontaneous visual complaint. Asymptomatic MRI-detected PML was associated with a modified Rankin scale score of two or below at follow-up in 64% of patients, compared with 34% among those diagnosed after symptom onset (p = 0.012). IRIS developed in 57-69% of patients following natalizumab withdrawal; neuropathological analysis confirmed a hyper-inflammatory response characterized by CD138-positive plasma cell density approximately 125 times that of standard multiple sclerosis plaques. Visual pathway compromise is a frequent and clinically underrecognized dimension of natalizumab-associated PML. Structured neuro-ophthalmic evaluation, encompassing formal perimetry, visual evoked potential recording, and optical coherence tomography, should be incorporated into surveillance protocols for high-risk patients. These tools provide functional evidence of visual pathway involvement during the diagnostic window when cerebrospinal fluid (CSF) JCPyV polymerase chain reaction (PCR) yields false-negative results owing to small lesion volumes. Prospective studies designed to evaluate visual pathway outcomes in this population are needed.