Central Nervous System Demyelination Associated With Immune Checkpoint Inhibitors: Review of the Literature

Abstract

Immune checkpoint inhibitors (ICI) are a novel class of antineoplastic treatment that enhances immunity against tumors. They are associated with immune adverse events, and several neurological syndromes have been described, including multiple sclerosis and atypical demyelination. We performed a systematic literature review of case reports with neurological immune adverse events that presented with central nervous system demyelination, up to December 2019. We found 23 cases: seven with myelitis, four isolated optic neuritis, one neuromyelitis optica spectrum disorder, five multiple sclerosis, and six with atypical demyelination. Ipilimumab was the most frequently used ICI (11/23). The median time to develop symptoms from the onset of ICI was 6.5 weeks [range 1.0–43.0], and from last ICI dose was 14 days [range 0–161]. Anatomopathological examination was performed in four cases, with the finding of a T-cell mediated immune response. Outcomes were generally favorable after immunosuppression: 18 patients had improvement or a full recovery, three patients did not respond to treatment, three patients died, and in one, treatment was not reported. We describe the patients' clinical presentation, treatment administered, and outcomes. We further speculate on possible pathophysiological mechanisms and discuss potential treatments that may be worth investigating.

A review of neurotoxicities associated with immunotherapy and a framework for evaluation

“…MRI of the orbits can show optic nerve enhancement, typically sparing the retrobulbar and proximal segment. 29 , 30 CSF is usually abnormal: in an 18-case series, 78% had elevated protein (median 93.5, range 50–380 mg/dL), 56% had pleocytosis (median WBC count 22, range 14–1195 cells/mm3), and 39% had OBCs. 29 AQP4 antibodies may be positive, particularly in patients presenting with a longitudinally extensive transverse myelitis.…”

“… 29 , 30 CSF is usually abnormal: in an 18-case series, 78% had elevated protein (median 93.5, range 50–380 mg/dL), 56% had pleocytosis (median WBC count 22, range 14–1195 cells/mm3), and 39% had OBCs. 29 AQP4 antibodies may be positive, particularly in patients presenting with a longitudinally extensive transverse myelitis. 25 Though idiopathic demyelinating disease is often relapsing and remitting, ICI-related disease typically has a monophasic course and does not relapse after ICI discontinuation and treatment for initial symptoms.…”

“… 25 , 28 Autoantibodies are typically negative, though antibodies against glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein-5 (CRMP-5) have been reported. 28 , 29 Antibodies against aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) are typically negative, though when present these patients are categorized as having demyelinating disease rather than myelitis. 25 , 28 Interestingly, a substantial number of patients who develop myelitis have a history of thoracic radiation exposure (43% in one 7-patient series, and 23% in a systematic review), though it is unclear if radiotherapy is a true predisposing factor.…”

“…Demyelinating disease in the CNS includes multiple sclerosis, neuromyelitis optica spectrum disorder (NMSOD), transverse myelitis, and isolated optic neuritis, all of which have been reported after ICI treatment. 29 Symptoms can occur due to pre-existing disease exacerbation or de novo disease and vary based on the region affected, including weakness, sensory symptoms, vision loss, and cognitive dysfunction. 25 , 29 Optic neuritis is rare, but when present can be painless (in contrast the typical non-ICI-related presentation) and affects both eyes in 64% of patients.…”

“… 29 Symptoms can occur due to pre-existing disease exacerbation or de novo disease and vary based on the region affected, including weakness, sensory symptoms, vision loss, and cognitive dysfunction. 25 , 29 Optic neuritis is rare, but when present can be painless (in contrast the typical non-ICI-related presentation) and affects both eyes in 64% of patients. 30 Demyelinating disease can manifest with brain and/or spinal cord lesions, so clinical features overlap with encephalitis and myelitis, without consistent methods for differentiating them in published case series.…”