Immune-related aseptic meningitis and strategies to manage immune checkpoint inhibitor therapy: a systematic review

Abstract

Introduction Immune checkpoint inhibitors (ICIs) can induce adverse neurological effects. Due to its rarity as an adverse effect, meningitis has been poorly described. Therefore, meningitis diagnosis and management can be challenging for specialists. Moreover, meningitis can be an obstacle to resuming immunotherapy. Given the lack of alternatives, the possibility of reintroducing immunotherapy should be discussed on an individual basis. Here, we present a comprehensive systematic review of meningitis related to ICIs. Review We performed a search for articles regarding immune-related meningitis published in PubMed up to November 2021 with the MeSH terms “meningitis” and “immune checkpoint” using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We summarized the studies not only by category but also based on whether it was a primary article or case report to provide a systematic overview of the subject. We reviewed a total of 38 studies and herein report the clinical experiences, pharmacovigilance data and group knowledge from these studies. Conclusion This review summarizes the existing information on immune-related meningitis and the possibility of reintroducing immunotherapy after the development of central neurological side effects. To the best of our knowledge, there is little information in the literature to guide clinicians on decisions regarding whether immunotherapy should be continued after a neurological adverse event occurs, especially meningeal events. This review emphasizes the necessity of systematic examinations, steroid treatment (as a cornerstone of management) and the need for further exploratory studies to obtain a clearer understanding of how to better manage patients who experience these side effects. The findings summarized in this review can help provide guidance to practitioners who face this clinical situation.

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity

“…Encephalitis MRI shows patchy T2 and FLAIR hyperintensities in about 50% of cases, more commonly with focal encephalitis [ 45 , 54 ]. Meningitis will show meningeal enhancement in up to half of cases [ 45 , 88 ]. Lumbar puncture tests include cerebrospinal fluid (CSF) cell count, protein, glucose, gram stain, culture, polymerase chain reaction for herpes simplex virus and other viruses, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic panels [ [17] , [18] , [19] , 55 ].…”

“…Lumbar puncture tests include cerebrospinal fluid (CSF) cell count, protein, glucose, gram stain, culture, polymerase chain reaction for herpes simplex virus and other viruses, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic panels [ [17] , [18] , [19] , 55 ]. A CSF analysis in irAE encephalitis and meningitis cases almost always shows pleocytosis with lymphocytic predominance, elevated protein, normal glucose, and a negative culture/Gram stain [ 54 , 84 , 88 , 89 ]. An EEG should be obtained if non-convulsive seizures are suspected [ 17 , 18 ].…”

“…The NCCN and SITC guidelines are similar to the ASCO recommendations but are more aggressive, stating that any grade of encephalitis should receive pulse-dose methylprednisolone (1 g/d) and intravenous immunoglobulin (IVIG) or plasmapheresis [ 18 , 19 ]. Steroid-refractory cases may require immunosuppressive drugs, such as rituximab [ 17 , 19 ] or infliximab [ 82 , 88 ], see Table 1 .…”

Neurologic Complications of Cancer Immunotherapy

“…9 Time to onset is typically shorter than for other neurologic immune-related adverse events, with median onset after two cycles and a delay of 9 days from the last infusion. 28,29 Symptoms of ICI-related aseptic meningitis include altered mental status, headache, photophobia, nausea, and vomiting. Motor or sensory symptoms such as myoclonus, ataxia, or paresthesias are less commonly reported.…”

“…The initiation of steroids typically leads to a response within days; however, the use of IVIg and infliximab has also been described in more refractory cases. 29 Prognosis is excellent with complete recovery in the vast majority of patients. The reintroduction of ICIs may be possible in patients with immune-related meningitis; however, rechallenge with anti-CTLA-4 therapy is more controversial due to the increased association with meningitis.…”