Increased occurrence of status epilepticus in patients with brain metastases and checkpoint inhibition

Abstract

Integration of immune checkpoint inhibitors (ICIs) has improved the efficacy of treatment regimens for various cancers. The array of potential side effects keeps evolving and includes neurological complications. An increased risk of seizures and status epilepticus (SE) has been discussed and appears likely. In this report, we present clinical data from brain metastases patients undergoing ICI treatment revealing, for what we believe is the first time, SE as a serious adverse effect of ICI treatment. In our cohort of 3202 patients with brain metastases, we observed an increasing incidence of SE since the approval of ICIs in 2014 (16 patients in 2008-2013 vs. 36 patients in 2014-2019). Almost half of the patients treated in 2014-2019 received ICIs during the course of their disease, and in more than 80% of cases last dose of ICIs was given less than 30 days before SE. These findings suggest that ICIs may lead to an increased rate of SE in patients with brain metastases. Additional mechanistic research and prospective trials are necessary to elucidate the pathomechanism causing SE in patients treated with ICIs.

Tumor-Associated Epilepsy in Patients With Brain Metastases: Necrosis-to-Tumor Ratio Forecasts Postoperative Seizure Freedom

“…This nding is in line with previous work [9,4]. Patients with BM due to underlying melanoma or lung cancer exhibit the most frequent incidence of TRE among patients with BM [9,13]. In the present study, no association was apparent between underlying cancer type and the preferential development of preoperative epilepsy in patients with BM.…”

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

“…In 6 of 12 patients, pseudoprogression manifested as a first occurrence of epileptic seizure or as a worsening of a known structural epilepsy. Details on EEG findings and treatment with antiseizure medication have previously been published ( 20 ). Three patients showed a paresis of arms or legs.…”

New-Onset Refractory Status Epilepticus (NORSE) as a Recurrence of Anti-Neuronal Nuclear Antibody 2 (ANNA-2) Encephalitis After Immune Checkpoint Inhibition Therapy

“…Having said that, this therapy may have precipitated NORSE. Several mechanisms have been reported in the association of immune checkpoint inhibition therapy and status epilepticus: increased immune cell infiltration generating an inflammatory environment with increased perilesional edema and/or release of proconvulsive cytokines and a possible generation of autoantibody-mediated mechanism [ 15 ]. These cases responded relatively well to treatment with steroids or the discontinuation of immune checkpoint therapy alone [ 15 ].…”

“…Several mechanisms have been reported in the association of immune checkpoint inhibition therapy and status epilepticus: increased immune cell infiltration generating an inflammatory environment with increased perilesional edema and/or release of proconvulsive cytokines and a possible generation of autoantibody-mediated mechanism [ 15 ]. These cases responded relatively well to treatment with steroids or the discontinuation of immune checkpoint therapy alone [ 15 ]. To support the relevance of the side effect of this therapy, the patient never resolved her symptom of opsoclonus completely but never had seizures until having received the therapy, and the ANNA-2 titer during the NORSE admission was lower than the first admission years prior.…”