Natalizumab is a highly effective therapy but may impair central nervous system (CNS) immune surveillance, leading to rare opportunistic infections. We report a fatal case of cerebral toxoplasmosis under natalizumab. A 61-year-old man with stable multiple sclerosis (MS) developed acute hemiparesis on natalizumab therapy. Magnetic resonance imaging (MRI) showed multiple ring-enhancing lesions. Brain biopsy and polymerase chain reaction (PCR) confirmed reactivated Toxoplasma gondii. A low-risk IgG κ monoclonal gammopathy of undetermined significance (MGUS) was identified. Despite antiparasitic therapy, the patient developed coma and died. Natalizumab-induced CNS immune compartmentalization, combined with subtle MGUS-related immune dysfunction and immunosenescence, may have facilitated intracerebral reactivation. Vigilance for opportunistic infections may be warranted in older patients with hematologic comorbidities receiving natalizumab.

This review addresses the biological mechanisms and contributions of frailty in multiple sclerosis (MS), a chronic disease of the central nervous system that causes physical and cognitive disability. The risk of frailty among persons with MS (pwMS) exceeds that of other chronic diseases, and the interactions between frailty and MS pathologies can aggravate physical disability. The hallmarks of frailty include increased vulnerability, reduced ability to respond to stressors, and elevated risk of adverse health outcomes. Although frailty is often conflated with aging, it can affect individuals with chronic conditions, such as MS, regardless of chronological age. The overlap between MS-related disability and frailty and the nexus among ambulatory impairment, fatigue, and metabolic alterations contribute to accelerated frailty risk. The utility and limitations of frailty measures such as the Fried Frailty Phenotype and the Frailty Index in MS are presented. The shared pathophysiology of MS and frailty includes metabolic dysregulation, sarcopenia, and systemic inflammation. The pathways underlying these shared pathophysiological interactions, along with their implications, are reviewed. Recognizing frailty as a distinct, intersecting condition in MS may inform care strategies, improve quality of life, and improve long-term outcomes.