Erie G. Gutierrez’s research while affiliated with Johns Hopkins University and other places

Introduction: This study aims to test the hypothesis that increased ketone body production resulting from a ketogenic diet (KD) will correlate with reductions in pro-inflammatory cytokines and lipid subspecies and improved clinical outcomes in adults treated with an adjunctive ketogenic diet for super-refractory status epilepticus (SRSE). Methods: Adults (18 years or older) were treated with a 4:1 (fat: carbohydrate and protein) ratio of enteral KD as adjunctive therapy to pharmacologic seizure suppression in SRSE. Blood and urine samples and clinical measurements were collected at baseline ( n = 10), after 1 week ( n = 8), and after 2 weeks of KD ( n = 5). In addition, urine acetoacetate, serum β -hydroxybutyrate, lipidomics, pro-inflammatory cytokines (IL-1β and IL-6), chemokines (CCL3, CCL4, and CXCL13), and clinical measurements were obtained at these three time points. Univariate and multivariate data analyses were performed to determine the correlation between ketone body production and circulating lipids, inflammatory biomarkers, and clinical outcomes. Results: Changes in lipids included an increase in ceramides, mono-hexosylceramide, sphingomyelin, phosphocholine, and phosphoserines, and there was a significant reduction in pro-inflammatory mediators, IL-6 and CXCL13, seen at 1 and 2 weeks of KD. Higher blood β -hydroxybutyrate levels at baseline correlated with better clinical outcomes; however, ketone body production did not correlate with other variables during treatment. Higher chemokine CCL3 levels following treatment correlated with a longer stay in the intensive care unit and a higher modified Rankin Scale score (worse neurologic disability) at discharge and 6-month follow up. Discussion: Adults receiving an adjunctive enteral ketogenic diet for super-refractory status epilepticus exhibit alterations in select pro-inflammatory cytokines and lipid species that may predict their response to treatment.

Persons with epilepsy (PWE) often report that seizure triggers can influence the occurrence and timing of seizures. Some previous studies of seizure triggers have relied on retrospective daily seizure diaries or surveys pertaining to all past seizures, recent and/or remote, in respondents. To assess the characteristics of seizure triggers at the granularity of individual seizures, we used a seizure-tracking app, called EpiWatch, on a smart watch system (Apple Watch and iPhone) in a national study of PWE. Participants tracked seizures during a 16-month study period using the EpiWatch app. Seizure tracking was initiated during a pre-ictal state or as the seizure was occurring and included collection of biosensor data, responsiveness testing, and completion of an immediate post-seizure survey. The survey evaluated seizure types, auras or warning symptoms, loss of awareness, use of rescue medication, and seizure triggers for each tracked seizure. Two hundred and thirty four participants tracked 2493 seizures. Ninety six participants reported triggers in 650 seizures: stress (65.8%), lack of sleep (30.5%), menstrual cycle (19.7%), and overexertion (18%) were the most common. Participants often reported having multiple combined triggers, frequent stress with lack of sleep, overexertion, or menses. Participants who reported triggers were more likely to be taking 3 or more anti-seizure medications compared to participants who did not report triggers. Participants were able to interact with the app and use mobile technology in this national study to record seizures and report common seizure triggers. These findings demonstrate the promise of longitudinal, self-reported data to improve our understanding of epilepsy and its related comorbidities.

A large proportion of patients with focal-onset epilepsy have frequent seizures despite treatment with newer anti-seizure medications (ASMs). We describe our experience optimizing cenobamate treatment for 49 patients treated at one center for up to eight years. We assessed the influence of treatment response on measurements of quality of life (QOLIE). Forty-nine patients were evaluated from three cenobamate regulatory trials: two open-label extensions of randomized placebo-controlled studies and one open-label safety study at the Johns Hopkins Hospital (JHU). Patients had focal-onset seizures despite treatment with one to three ASMs and were 18 years of age and older. Patients kept seizure diaries for the duration of the study and had tri-monthly evaluations. Seizure responder rates were determined, and patients with long-term seizure freedom (≥six months seizure free) were identified. Cenobamate doses were adjusted within the range of 100–400 mg/day. Johns Hopkins Hospital patients who were continuing treatment when the studies ended (n = 37) were administered the QOLIE-31 survey and a separate survey to assess changes in independence and epilepsy-linked disability at the end of the study at JHU. Thirty-seven of 49 (76%) patients continued treatment for three to eight years (median 5.6 years). In their final three months of treatment, 45% of patients achieved ≥75% seizure reduction, 29% had ≥90% reduction, and 16% were seizure free (responder rates computed with n = 49). Posttraumatic etiologies did not reduce treatment responses. Increased dosage of cenobamate across 150–400 mg/day range was significantly associated with higher responder rates (p < 0.001). High seizure responses—particularly ≥90% reduction—correlated with high QOLIE scores. Patients with drug-resistant focal-onset epilepsy had stable treatment responses during up to eight years of cenobamate treatment. Patients often tolerated high doses of cenobamate; high responders appeared to benefit with high QOLIE scores.

Objective The objective of the present study was to determine the association between respiratory stertor and focal and bilateral seizure types. Methods We characterized ictal and postictal behaviors during symmetric bilateral tonic–clonic (TC) and asymmetric TC seizures in the Johns Hopkins University (JHU) epilepsy monitoring unit, comparing these to focal unaware seizures. We measured the presence and duration of postictal stertorous respirations, postictal generalized electroencephalographic suppression (PGES), immobility/motor dysfunction, and encephalopathy and determined their associations and relationship to seizure types. Results In initial seizures recorded in 80 consecutive patients, bilateral symmetric TC seizures (N = 35) were strongly associated with PGES (97%, p < 0.001) and postictal stertorous respirations (89%, p < 0.001). Only 10% of the 20 patients with asymmetric TC seizures had brief PGES; focal unaware seizures (N = 25) were not associated with PGES or stertorous breathing. Some patients (24%) with asymmetric or bilateral symmetric TC seizures had severe postictal encephalopathy with stertor that was separate or extended beyond periods of PGES. Conclusion Bilateral symmetric TC seizures, but not focal unaware seizures, have postictal stertor during PGES. Severe postictal encephalopathy, however, is also associated with motor dysfunction and stertor. Stertor appears to be a compensatory postictal respiratory pattern for ictal/postictal hypoxemia and occurs with PGES or postictal encephalopathy.

Purpose: To determine whether use of a ketogenic formula during the first month of the modified Atkins diet (MAD) in adults with drug-resistant epilepsy (DRE) improves seizure reduction and compliance compared to MAD alone. Methods: Eighty adults (age ≥18 years) with DRE and ≥4 reliably quantifiable seizures/month were enrolled. All participants were trained to follow a 20 g/day net carbohydrate limit MAD. Patients were randomized to receive one 8-ounce (237 mL) tetrapak of KetoCal®, a 4:1 ketogenic ratio formula, daily in combination with MAD during the first month (treatment arm) or second month (control/cross-over arm). Patients recorded urine ketones, weight, and seizure frequency and followed up at 1 and 2 months. Results: By 1 month, 84% of patients achieved ketosis (median of 4-4.5 days). At 1 month, the treatment arm had a significantly higher ketogenic ratio and more patients with a ≥1:1 ketogenic ratio compared to the control arm. There was no difference in median seizure frequency, proportion of responders (≥50% seizure reduction), or median seizure reduction from baseline between groups. However, patients treated with KetoCal® during the first month were significantly more likely to continue MAD for 6 months or more. Conclusion: Although supplementing MAD with a ketogenic formula in the first month did not increase the likelihood of reducing seizures compared to MAD alone, significantly more adults remained on MAD long-term with this approach. This suggests a potential strategy for encouraging compliance with MAD in adults with DRE.

Sudden unexpected death in epilepsy (SUDEP) is a common cause of death in epilepsy and frequently occurs following generalized tonic–clonic seizures (GTCS). Non–electroencephalography (EEG) seizure detection systems using mobile sensor devices permit caregivers to assist patients during seizures and may reduce risks for complications of seizures such as injuries and SUDEP. We review changes in accelerometry, electrodermal activity, and heart rate associated with tonic–clonic seizures and their use in detection systems, including multimodal detectors. We reviewed current and past publications reporting data on linkage between GTCS, post‐ictal generalized EEG suppression (PGES), and ventilatory dysfunction. The timing and duration of postictal immobility and respiratory dysfunction associated with convulsions help identify which patients might benefit the most from seizure monitoring and from benchmarks for the timing of seizure detection, caregiver alerting, and interventions.