Robert A Rifkin, MD, PhD

I am a translational researcher focused on tumor-related epilepsy (TRE), integrating clinical research and basic neuroscience to develop novel therapeutics and biomarkers for this disorder. Tumor-related epilepsy is a significant cause of morbidity for patients with brain tumors, leading to increased hospitalizations and reduced quality of life. Additionally, complex interactions between tumor cells and seizure activity can impact tumor growth. The molecular mechanisms by which tumors cause seizures are incompletely understood, and current treatments fail to control seizures in some patients. Additionally, for patients who present with a brain tumor, there are currently few validated tools to enable clinicians to predict which patients will later develop seizures. The goal of these projects is to provide clinicians with improved tools for predicting and treating tumor-related epilepsy.

Clinical Research: Working with a collaborative interdisciplinary team, I am leading multiple research studies to identify predictive biomarkers of tumor-related epilepsy. This research may enable earlier treatment and reduced morbidity from seizures in patients diagnosed with brain tumors.

• Retrospective EEG in Tumor-Related epilepsy at Yale (RETRY): This is a retrospective cohort study of patients at Yale between 2010 and 2025 with a diagnosis of glioma who had an EEG performed. Working with a team of clinical researchers, we are analyzing the EEG reports and chart records to identify EEG patterns that are associated with clinical seizures.
• EEG and Tissue Biomarkers of Tumor-Related Epilepsy: This is a prospective, multi-center study of patients with newly-diagnosed or recurrent glioma (grades 2-4), with or without seizures at the time of presentation. These patients will have research EEGs at pre-determined time points, to identify EEG patterns that predict later development of seizures.

Basic Neuroscience: Neuronal activity is controlled by a careful balance of excitatory and inhibitory neurotransmission. In the region around a glioma, this balance is disrupted by increased excitation as well as impaired inhibition. Specifically, the fast-acting (ionotropic) inhibitory pathway depends on the concentration of chloride inside the neuron, which is dysregulated in peri-tumoral neurons. Therefore, I am studying metabotropic inhibition in tumor-related epilepsy, an alternative pathway that can restore normal excitatory-inhibitory balance. So far, we have demonstrated that a novel drug activating this pathway can reduce seizure-like activity in a model of tumor-related epilepsy (http://doi.org/10.1016/j.neuropharm.2024.110259). Current research is focused on understanding (1) how the metabotropic pathway changes in peri-tumoral neurons, and (2) whether amplifying this pathway reduces clinical seizures in mice.