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The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD).A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors' clinical networks and IDD-affiliated organizations from March to June 2021.In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%).COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.

BACKGROUND AND OBJECTIVES: Seizures (SZs) and other SZ-like patterns of brain activity can harm the brain and contribute to in-hospital death, particularly when prolonged. However, experts qualified to interpret EEG data are scarce. Prior attempts to automate this task have been limited by small or inadequately labeled samples and have not convincingly demonstrated generalizable expert-level performance. There exists a critical unmet need for an automated method to classify SZs and other SZ-like events with expert-level reliability. This study was conducted to develop and validate a computer algorithm that matches the reliability and accuracy of experts in identifying SZs and SZ-like events, known as “ictal-interictal-injury continuum” (IIIC) patterns on EEG, including SZs, lateralized and generalized periodic discharges (LPD, GPD), and lateralized and generalized rhythmic delta activity (LRDA, GRDA), and in differentiating these patterns from non-IIIC patterns. METHODS: We used 6,095 scalp EEGs from 2,711 patients with and without IIIC events to train a deep neural network, SPaRCNet, to perform IIIC event classification. Independent training and test data sets were generated from 50,697 EEG segments, independently annotated by 20 fellowship-trained neurophysiologists. We assessed whether SPaRCNet performs at or above the sensitivity, specificity, precision, and calibration of fellowship-trained neurophysiologists for identifying IIIC events. Statistical performance was assessed by the calibration index and by the percentage of experts whose operating points were below the model's receiver operating characteristic curves (ROCs) and precision recall curves (PRCs) for the 6 pattern classes. RESULTS: SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and “other” classes, SPaRCNet exceeds the following percentages of 20 experts—ROC: 45%, 20%, 50%, 75%, 55%, and 40%; PRC: 50%, 35%, 50%, 90%, 70%, and 45%; and calibration: 95%, 100%, 95%, 100%, 100%, and 80%, respectively. DISCUSSION: SPaRCNet is the first algorithm to match expert performance in detecting SZs and other SZ-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for an expedited review of EEGs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with epilepsy or critical illness undergoing EEG monitoring, SPaRCNet can differentiate (IIIC) patterns from non-IIIC events and expert neurophysiologists.

Effective treatment options for patients with life-threatening neurological disorders are limited. To address this unmet need, high-impact translational research is essential for the advancement and development of novel therapeutic approaches in neurocritical care. “The Neurotherapeutics Symposium 2019—Neurological Emergencies” conference, held in Rochester, New York, in June 2019, was designed to accelerate translation of neurocritical care research via transdisciplinary team science and diversity enhancement. Diversity excellence in the neuroscience workforce brings innovative and creative perspectives, and team science broadens the scientific approach by incorporating views from multiple stakeholders. Both are essential components needed to address complex scientific questions. Under represented minorities and women were involved in the organization of the conference and accounted for 30–40% of speakers, moderators, and attendees. Participants represented a diverse group of stakeholders committed to translational research. Topics discussed at the conference included acute ischemic and hemorrhagic strokes, neurogenic respiratory dysregulation, seizures and status epilepticus, brain telemetry, neuroprognostication, disorders of consciousness, and multimodal monitoring. In these proceedings, we summarize the topics covered at the conference and suggest the groundwork for future high-yield research in neurologic emergencies.

BACKGROUND AND OBJECTIVES: The validity of brain monitoring using electroencephalography (EEG), particularly to guide care in patients with acute or critical illness, requires that experts can reliably identify seizures and other potentially harmful rhythmic and periodic brain activity, collectively referred to as “ictal-interictal-injury continuum” (IIIC). Previous interrater reliability (IRR) studies are limited by small samples and selection bias. This study was conducted to assess the reliability of experts in identifying IIIC. METHODS: This prospective analysis included 30 experts with subspecialty clinical neurophysiology training from 18 institutions. Experts independently scored varying numbers of ten-second EEG segments as “seizure (SZ),” “lateralized periodic discharges (LPDs),” “generalized periodic discharges (GPDs),” “lateralized rhythmic delta activity (LRDA),” “generalized rhythmic delta activity (GRDA),” or “other.” EEGs were performed for clinical indications at Massachusetts General Hospital between 2006 and 2020. Primary outcome measures were pairwise IRR (average percent agreement [PA] between pairs of experts) and majority IRR (average PA with group consensus) for each class and beyond chance agreement (κ). Secondary outcomes were calibration of expert scoring to group consensus, and latent trait analysis to investigate contributions of bias and noise to scoring variability. RESULTS: Among 2,711 EEGs, 49% were from women, and the median (IQR) age was 55 (41) years. In total, experts scored 50,697 EEG segments; the median [range] number scored by each expert was 6,287.5 [1,002, 45,267]. Overall pairwise IRR was moderate (PA 52%, κ 42%), and majority IRR was substantial (PA 65%, κ 61%). Noise-bias analysis demonstrated that a single underlying receiver operating curve can account for most variation in experts' false-positive vs true-positive characteristics (median [range] of variance explained ([Image: see text]): 95 [93, 98]%) and for most variation in experts' precision vs sensitivity characteristics ([Image: see text]: 75 [59, 89]%). Thus, variation between experts is mostly attributable not to differences in expertise but rather to variation in decision thresholds. DISCUSSION: Our results provide precise estimates of expert reliability from a large and diverse sample and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared with expert consensus.

Ketogenic diet therapy for epilepsy has been used in adults for over 100 years. Adults with medically refractory epilepsy as well as children on diet therapies transitioning to adult care need specialty providers to support diet use. About 20% to 60% of adults report at least a 50% improvement in seizure frequency on diet therapy, and many patients report improvement in cognition and other areas as well. Diet therapy is also used in status epilepticus, with resolution of refractory status epilepticus reported in over 70% of patients. Long-term cardiovascular effects and the effects of diet therapy in pregnancy are areas of ongoing study.

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Background and ObjectivesCase reports and case series have described fluorodeoxyglucose (FDG)-PET findings in critically ill patients with rhythmic or periodic EEG patterns, with one reporting that metabolic activity increases with increasing lateralized periodic discharge (LPD) frequency. However, larger studies examining the relationship between FDG-PET hypermetabolism and rhythmic or periodic EEG patterns are lacking. The goal of this study was to investigate the association of FDG-PET hypermetabolism with electroencephalographic features in patients with neurologic disorders.MethodsThis was a single-center, retrospective study of adult patients admitted with acute neurologic symptoms who underwent FDG-PET imaging and EEG monitoring within 24 hours. Subjects were divided into 2 groups based on their FDG-PET metabolism pattern: hypermetabolic activity vs hypometabolic or normal metabolic activity. Chi-square tests and logistic regression were used to determine the relationship of FDG-PET metabolism and EEG findings.ResultsSixty patients met the inclusion criteria and underwent 63 FDG-PET studies and EEGs. Twenty-seven studies (43%) showed hypermetabolism while 36 studies (57%) showed either hypometabolism or no abnormalities on FDG-PET. Subjects with hypermetabolic FDG-PET were more likely to have electrographic seizures (44% vs 8%,p= 0.001) and LPDs with/without seizures (44% vs 14%,p= 0.007), but not other rhythmic or periodic EEG patterns (lateralized rhythmic delta activity, generalized periodic discharges, or generalized rhythmic delta activity). Subjects with hypermetabolism and LPDs were more likely to have concurrent electrographic seizures (58% vs 0%,p= 0.03), fast activity associated with the discharges (67% vs 0,p= 0.01), or spike morphology (67% vs 0,p= 0.03), compared with subjects with hypometabolic FDG-PET and LPDs.DiscussionAdults admitted with acute neurologic symptoms who had hypermetabolic FDG-PET were more likely to show electrographic seizures and LPDs, but not other rhythmic or periodic EEG patterns, compared with those with hypometabolic FDG-PET. Subjects with hypermetabolic FDG-PET and LPDs were more likely to have LPDs with concurrent electrographic seizures, LPDs with a spike morphology, and LPDs +F, compared with subjects with hypometabolic FDG-PET.

ObjectiveTo evaluate current clinical practices and evidence-based literature to establish preliminary recommendations for the management of adults using ketogenic diet therapies (KDTs).MethodsA 12-topic survey was distributed to international experts on KDTs in adults consisting of neurologists and dietitians at medical institutions providing KDTs to adults with epilepsy and other neurologic disorders. Panel survey responses were tabulated by the authors to determine the common and disparate practices between institutions and to compare these practices in adults with KDT recommendations in children and the medical literature. Recommendations are based on a combination of clinical evidence and expert opinion regarding management of KDTs.ResultsSurveys were obtained from 20 medical institutions with >2,000 adult patients treated with KDTs for epilepsy or other neurologic disorders. Common side effects reported are similar to those observed in children, and recommendations for management are comparable with important distinctions, which are emphasized. Institutions differ with regard to recommended biochemical assessment, screening, monitoring, and concern for long-term side effects, and further investigation is warranted to determine the optimal clinical management. Differences also exist between screening and monitoring practices among adult and pediatric providers.ConclusionsKDTs may be safe and effective in treating adults with drug-resistant epilepsy, and there is emerging evidence supporting the use in other adult neurologic disorders and general medical conditions as well. Therefore, expert recommendations to guide optimal care are critical as well as further evidence-based investigation.

Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

Introduction: Aicardi syndrome is a rare neurodevelopmental disorder associated with epilepsy in females. Ketogenic diet therapy represents a possible nonpharmacologic treatment in Aicardi syndrome patients. Methods: All patients with Aicardi syndrome seen at Johns Hopkins Hospital (Baltimore, MD) and Johns Hopkins All Children’s Hospital (St Petersburg, FL) treated with ketogenic diet therapy since 1994 were evaluated retrospectively. Results: Fifteen patients, ages 4 months to 34 years, were identified. Ten (67%) patients experienced a ≥50% seizure reduction after 3 months, with 3 (20%) having a ≥90% reduction. Only 1 patient was seizure-free for a short period of time. The number of drugs tried prior to ketogenic diet therapy initiation was correlated with ≥50% seizure reduction at 3 months, 5.8 vs 2.6 in responders versus nonresponders ( P = .01). In addition, the mean number of drugs actively received also correlated, 3.0 vs 1.2, P = .005. Ketogenic diet therapy was slightly more successful in those without infantile spasms, 78% vs 50%, P = .33. Conclusion: Ketogenic diet therapy was helpful in Aicardi syndrome, although seizure freedom was rare. It was especially helpful for those who were more drug-resistant and did not have infantile spasms at ketogenic diet therapy onset.

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year’s different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.

Ketogenic diet therapy (KDT), particularly modified Atkins diet (MAD), is increasingly recognized as a treatment for adults with epilepsy. Women with epilepsy (WWE) comprise 50% of people with epilepsy and approximately one in three have catamenial epilepsy. The purpose of this study was to determine whether adding a medium chain triglyceride emulsion to MAD to target catamenial seizures was feasible and well-tolerated. This was a prospective two-center study of pre-menopausal WWE with a catamenial seizure pattern on MAD. After a 1-month baseline interval with no changes in treatment, participants consumed betaquik® (Vitaflo International Ltd.) for 10 days each menstrual cycle starting 2 days prior to and encompassing the primary catamenial seizure pattern for five cycles. Participants recorded seizures, ketones, and menses, and completed surveys measuring tolerability. Sixteen women aged 20–50 years (mean 32) were enrolled and 13 (81.2%) completed the study. There was 100% adherence for consuming betaquik® in the women who completed the study and overall intervention adherence rate including the participants that dropped out was 81.2%. The most common side effects attributed to MAD alone prior to starting betaquik® were constipation and nausea, whereas abdominal pain, diarrhea, and nausea were reported after adding betaquik®. The high adherence rate and acceptable tolerability of betaquik® shows feasibility for future studies evaluating KDT-based treatments for catamenial seizures.

Objective Thousands of years after dietary therapy was proposed to treat seizures, how alterations in metabolism relates to epilepsy remains unclear, and metabolism‐based therapies are not always effective. Methods We consider the state of the science in metabolism‐based therapies for epilepsy across the research lifecycle from basic to translational to clinical studies. Results This analysis creates a conceptual framework for creative, rigorous, and transparent research to benefit people with epilepsy through the understanding and modification of metabolism. Interpretation Despite intensive past efforts to evaluate metabolism‐based therapies for epilepsy, distinct ways of framing a problem offer the chance to engage different mindsets and new (or newly applied) technologies. A comprehensive, creative, and inclusive problem‐directed research agenda is needed, with a renewed and stringent adherence to rigor and transparency across all levels of investigation.

A ketogenic diet lowered benzodiazepine use during withdrawal in patients with AUD and blunted alcohol administration in rats., Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower “wanting” and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

The objective of this study was to develop an adaptive framework for seizure detection in real-time that is practical to use in the Epilepsy Monitoring Unit (EMU) as a warning signal, and whose output helps characterize epileptiform activity. Our framework uses a one-class Support Vector Machine (SVM) that is being trained dynamically according to past activity in all available channels. This is done to evaluate the novelty of the current instance according to previous activity. Our algorithm was tested on intracranial EEG from human epilepsy patients that are admitted to the EMU for presurgical evaluation. In this study, we compared multiple configurations for using a one-class SVM to assess if there is significance over specific neural features or electrode locations. Our results show our algorithm is capable of running in real-time and achieving a high performance for early seizure-onset detection with a low false-positive rate and robustness to different types of seizure-onset patterns as well as to the number of channels used. This algorithm offers a solution to warning systems in the EMU as well as a tool for seizure characterization during post-hoc analysis of intracranial EEG data for surgical resection of the epileptogenic network.HighlightsThis study proposes a dynamic training algorithm that efficiently detects sudden novel changes in intracranial electroencephalographic activity, creating a reliable seizure onset detection algorithm that does not need prior training.The algorithm described has the capability to be implemented in real-time, independently of the number of channels that are being analyzed.The presented detector shows high performance and reliability to be easily implemented in the Epilepsy Monitoring Unit to quickly alert clinical staff of seizure events.

BACKGROUND/AIMS: Ketogenic diet therapies (KDTs) offer a needed therapeutic option for patients with drug-resistant epilepsy. The current study investigated biochemical and anthropometric indices of cardiovascular disease (CVD) risk in adults with epilepsy treated with KDT over 6 months. METHOD: 65 adults with epilepsy naïve to diet therapy were enrolled in a prospective longitudinal study and instructed on modified Atkins diet (MAD) use. Seizure frequency, anthropometric measures, blood levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoproteins A1 and B, and lipoprotein sub-fractions were assessed at baseline, 3 months, and 6 months. RESULTS: Subsequent to study enrollment, 34 participants were lost to follow-up, elected not to start, or stopped MAD prior to study completion, leaving a total of 31 participants in the study at 6 months. Compared to baseline, participants on MAD showed significant reductions in median seizure frequency/week, weight, body mass index, waist and hip circumference, and percent body fat at 3 and 6 months. Compared to baseline, participants on MAD for 3 months showed significantly increased levels of total, small and medium LDL particles, ApoB and ApoB/A1 ratio. At 6 months, only small LDL particles and ApoB levels remained elevated and levels of ApoA1 had risen, suggesting possible compensatory adaptation over time. CONCLUSIONS: This study provides evidence demonstrating the efficacy and cardiovascular safety of 6 months of MAD use by adults with epilepsy. It also highlights an index of CVD risk – small LDL particles - that should be closely monitored.. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02694094.

Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care―all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.

Objectives Patients with epilepsy are known to exhibit high rates of comorbid psychiatric disorders such as depression, anxiety, and other mood disorders. Little is known about the psychiatric effects of a ketogenic diet therapy (KDT) on adults with epilepsy. The objective of this study was to better understand the relationship between KDT and psychological state based on depressive and anxiety symptoms in adults with chronic epilepsy. Methods Adults at the Johns Hopkins Adult Epilepsy Diet Center on a modified Atkins diet (MAD) for at least one month were surveyed retrospectively. Adults who were diet naive were given a baseline survey and an additional survey after 3 months or more on MAD. Surveys included validated measures of depressive and anxiety symptoms as well as their severity. Participant demographics, seizure frequency, and use of concomitant antiseizure drugs (ASDs), chronic anxiolytics (excluding as-needed benzodiazepines for seizure rescue only), and/or antidepressant drugs were extracted from electronic medical records. Results One-hundred participants aged 19–75 enrolled in the study. Sixty participants filled out a single retrospective survey. Of 40 diet naive participants who filled out a baseline prospective survey, 19 completed a follow-up survey while on MAD and 21 participants were lost to follow-up. Longer diet duration was significantly associated with fewer anxiety and depressive symptoms, based on psychiatric measure scores, in retrospective study participants. Lower seizure frequency was also significantly associated with less anxiety symptoms in the retrospective cohort. Prospective study participants did not experience significant change in anxiety or depressive symptoms on the diet. There was a significant correlation between higher ketone level and responder rate (≥50% seizure reduction) in the prospective cohort, although no correlation between ketone level and change in psychiatric symptoms was seen. Significance Psychiatric comorbidity among patients with epilepsy is quite common and can be influenced by multiple factors such as seizure frequency, the use of various ASDs, social factors, and underlying etiology. Although ketogenic diet therapies have been in clinical use for one century, the psychiatric impacts have been insufficiently explored. This study provides preliminary evidence that KDT may have a positive impact on psychological state independent of seizure reduction or ketone body production and may be influenced by longer duration of diet therapy. These results support further investigation into specific effects and potential therapeutic benefits on various psychiatric disorders.

ObjectiveTo examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma.MethodsTwenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories ResultsTwenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHBRs= 0.52,p= 0.05). Subgroup analysis of isocitrate dehydrogenase–mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria.ConclusionThe GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.Trial Registration InformationClinicalTrials.gov Identifier:NCT02286167.

Ketogenic diet therapies are high-fat, low-carbohydrate diets designed to mimic a fasting state. Although initially developed nearly one century ago for seizure management, most clinical trials for the management of drug-resistant epilepsy in children as well as adults have been conducted over the last 3 decades. Moreover, ketogenic diets offer promising new adjunctive strategies in the critical care setting for the resolution of acute status epilepticus when traditional antiseizure drugs and anesthetic agents fail. Here, we review the history of ketogenic diet development, the clinical evidence supporting its use for the treatment of drug-resistant epilepsy in children and adults, and the early evidence supporting ketogenic diet feasibility, safety, and potential efficacy in the management of status epilepticus.

The current coronavirus-19 pandemic has changed dramatically how neurologists care for children and adults with epilepsy. Stay-at-home orders and resistance to hospitalizations by patients have led epileptologists to engage in telemedicine and re-evaluate how to provide elective services. Ketogenic diet therapy is often started in the hospital, with families educated in hospital-based classes, but this is difficult to do in this current pandemic. At our two academic centers, both our pediatric and adult epilepsy diet centers have had to quickly consider alternative methods to both start and maintain ketogenic diet therapy. This paper provides several examples of how ketogenic diet therapy can be provided to patients in unique ways, along with recommendations from other experts and patients learned over the past few months., Highlights • Ketogenic diet therapy can be successfully initiated in the hospital with shorter, focused admissions to minimize exposure. • Similarly, the classic ketogenic diet can be started as an outpatient with telemedicine visits for education and monitoring, a non-fasting approach, and close follow-up. • In adults, starting the modified Atkins diet has been successfully accomplished with live or pre-recording educational sessions and telemedicine as well. • Patients on ketogenic diets in this pandemic should ensure adequate high fat food supplies, medications, a scale for checking their weight, and telemedicine capability.

Distinguishing treatable causes for rapidly progressive dementia from those that are incurable is vital. Creutzfeldt-Jakob disease (CJD) and voltage-gated potassium channel complex–associated autoimmune encephalitis (VGKC AE) are 2 such conditions with disparate outcomes and response to treatment. To determine the differences in electroencephalography between CJD and VGKC AE, we performed a retrospective review of medical records and examined clinical data, neuroimaging, and electroencephalographs performed in patients admitted for evaluation for rapidly progressive dementia diagnosed with CJD and VGKC AE at the Johns Hopkins Hospital and Bayview Medical Center between January 1, 2007 and December 31, 2015. More patients in the VGKC AE group had seizures (12/17) than those with CJD (3/14; P = .008). Serum sodium levels were lower in those with VGKC AE ( P = .001). Cerebrospinal fluid (CSF) white blood cell count was higher in VGKC AE ( P = .008). CSF protein 14-3-3 ( P = .018) was more commonly detected in CJD, and tau levels were higher in those with CJD ( P < .006). On neuroimaging, diffusion restriction in the cortex ( P = .001), caudate ( P < .001), and putamen ( P = .001) was more frequent in CJD. Periodic sharp wave complexes ( P = .001) and generalized suppressed activity ( P = .008) were more common on initial EEG in CJD. On serial EEGs, generalized periodic discharges ( P = .004), generalized suppressed activity (P=0.008), and periodic sharp wave complexes ( P < .001) were detected more in CJD. This study shows that there are a number of differentiating features between CJD and VGKC AE, and electroencephalography can aid in their diagnoses. Performing serial EEGs better delineates these conditions.

The goal of this study was to determine the value of a certified child life specialist (CCLS) on the patient and staff experiences in an epilepsy monitoring unit (EMU). We integrated a CCLS into the EMU for all children as well as adults with intellectual disability. We surveyed families to determine the impact of child life services on their stay. EMU staff completed questionnaires to determine perceived impact to their job performance from the integration of the CCLS. All of the families (pediatric and adult patients) who responded to the survey reported the presence of the CCLS improved their hospital experience. Staff reported that the CCLS improved their daily work by allowing them to focus on their assigned medical duties. This preliminary pilot study suggests that CCLS can have a strong impact on the experience of patients and staff in an EMU.

The current review highlights the evidence supporting the use of ketogenic diets in the management of drug-resistant epilepsy and status epilepticus in adults. Ketogenic diet variants are compared and advantages and potential side effects of diet therapy are discussed.

As the ketogenic diet approaches 100 years of continuous use, we reflect on its successes and consider new avenues of research for the next century. One controversial question is regarding whether ketogenic dietary therapies could be successful first-line treatments for epilepsy. Second, is it possible to mimic the mechanisms of action of ketogenic dietary therapy with a drug (eg, a tablet formulation)? A third controversy worthy of future study involves its expanded usage in adults with refractory epilepsy and its role in treating women of childbearing age. Finally, as flexible, alternative diets have recently become widely available, is it feasible and safe to have families and patients start ketogenic dietary therapy successfully on their own with limited medical supervision?

Purpose To describe the clinical, laboratory, neuroimaging, electroencephalographic features, etiology, treatment, as well as short-term and long-term outcomes of adults with new-onset refractory status epilepticus (NORSE). Method A retrospective, single institution cohort study (2010–2018) of consecutive adult patients with NORSE. Results Among 20 patients with NORSE, nine (45 %) had prodromal febrile illness, 12 (60 %) had evidence of inflammation on CSF profile. Six patients (30 %) met criteria for definite autoimmune encephalitis (AE) while 8 patients (40 %) had probable AE. Eleven out of 13 (85 %) patients had an abnormal FDG-PET scan with the most common finding being regional hypermetabolism. Fourteen patients (70 %) received immunotherapy and ten (50 %) received the ketogenic diet (KD). Fifteen patients (75 %) progressed to super-refractory status epilepticus (SRSE) and seven patients (35 %) died in the hospital or within six months of discharge. Among the surviving patients, eight (40 %) had a good outcome (i.e., modified Rankin Scale score 0–2); 12 (80 %) received a diagnosis of epilepsy of which nine (75 %) developed drug-resistant epilepsy. Conclusions New-onset refractory status epilepticus is a syndrome associated with multiple complications, high mortality, and subsequent intractable epilepsy. There are multiple causes, some of which are autoimmune encephalitides; however, in this series the majority of patients had no clear etiology identified after extensive evaluation. Prospective studies are needed to determine optimal evaluation and treatment.

Background A short ketogenic diet (KD) treatment can prevent migraine attacks and correct excessive cortical response. Here, we aim to prove if the KD-related changes of cortical excitability are primarily due to cerebral cortex activity or are modulated by the brainstem. Methods Through the stimulation of the right supraorbital division of the trigeminal nerve, we concurrently interictally recorded the nociceptive blink reflex (nBR) and the pain-related evoked potentials (PREP) in 18 migraineurs patients without aura before and after 1-month on KD, while in metabolic ketosis. nBR and PREP reflect distinct brain structures activation: the brainstem and the cerebral cortex respectively. We estimated nBR R2 component area-under-the-curve as well as PREP amplitude habituation as the slope pof the linear regression between the 1st and the 2nd block of 5 averaged responses. Results Following 1-month on KD, the mean number of attacks and headache duration reduced significantly. Moreover, KD significantly normalized the interictal PREP habituation (pre: + 1.8, post: − 9.1, p = 0.012), while nBR deficit of habituation did not change. Conclusions The positive clinical effects we observed in a population of migraineurs by a 1-month KD treatment coexists with a normalization at the cortical level, not in the brainstem, of the typical interictal deficit of habituation. These findings suggest that the cerebral cortex may be the primary site of KD-related modulation. Trial registration ClinicalTrials.gov NCT03775252 (retrospectively registered, December 09, 2018).

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = –0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

BACKGROUND There has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma. METHODS 25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories RESULTS 21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria. CONCLUSIONS The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.

Objective:To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults.Methods:We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes.Results:Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died.Conclusions:KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials.Classification of evidence:This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis.

Purpose Evaluation of ketogenic diet (KD) therapies for seizure control during pregnancy when safety and appropriate management become considerations. Until now, no information has been available on seizure reduction and human pregnancy related outcomes in women treated with KD therapies. Method We describe two cases of pregnant women with epilepsy treated with KD therapy either as monotherapy (Case 1) or as adjunctive therapy (Case 2). Results Case 1: A 27 year old woman, gravida1, started the classic KD with medium chain triglyceride (MCT) emulsion and 75g carbohydrate-restriction, later reduced to 47g. Glucose levels were 4–6mmol/L and blood ketone levels ranged from 0.2 to 1.4mmol/L. Seizure frequency decreased and seizure-free days increased. Mild side effects included intolerance to MCT, reduced serum carnitine and vitamin levels, and mild hyperlipidemia. Fetal and neonatal growth was normal as was growth and development at 12 months. Case 2: A 36 year-old nulliparous woman was treated with a 20 gram carbohydrate-restricted Modified Atkins Diet (MAD) and lamotrigine, resulting in reduction of seizure frequency to once per month prior to pregnancy. Once pregnant, carbohydrates were increased to 30g. When seizures increased, lamotrigine dose was doubled. Urine ketones trended down during second trimester. A male was born with bilateral ear deformities of unknown significance. The child had a normal neurodevelopment at eight months. Conclusion Non-pharmacological epilepsy therapies like KD and MAD may be effective during human pregnancy. However, safety still has to be established. Further monitoring to identify potential long term side effects is warranted.

Highlights • Ketogenic diets offer adjunctive therapy for chronic epilepsy and refractory status epilepticus. • Studies support feasibility and efficacy of the classic ketogenic diet and its variants in adults. • Potential complications and side effects of diet therapy are often preventable and manageable. • Strategies are needed to improve diet adherence., Ketogenic diet (KD) therapies are high fat, low carbohydrate diets designed to mimic a fasting state. Although studies demonstrate KD’s success in reducing seizures stretching back nearly a century, the last 25 years have seen a resurgence in diet therapy for the management of drug-resistant epilepsy in children as well as adults. With ≥50% seizure reduction efficacy rates in adults of 22–55% for the classic KD and 12–67% for the modified Atkins diet, diet therapy may be in many instances comparable to a trial of an additional anti-epileptic medication and potentially with fewer side effects and other health benefits. Moreover, ketogenic diets offer promising new adjunctive strategies for the treatment of acute status epilepticus in the intensive care setting. Here, we review the efficacy and utility of ketogenic diets for the management of chronic epilepsy and refractory status epilepticus in adults and offer practical guidelines for diet implementation and maintenance.

Ten adults were treated with ketogenic diet monotherapy for epilepsy. Four patients were naive to antiseizure drugs (ASDs), and six previously tried and stopped ASDs. Of four treatment-naive participants, two (50%) were free from disabling seizures on Modified Atkins Diet (MAD) monotherapy for > 1 year. Two (50%) stopped. Four of six patients (67%) who had previously tried ASDs became seizure-free on diet monotherapy, and two experienced > 50% seizure reduction. Side effects included amenorrhea, weight loss, osteoporosis, and hyperlipidemia. Diet monotherapy may be feasible, well-tolerated, and effective for adults with epilepsy who refuse pharmacotherapy and those for whom lifelong diet therapy is recommended.

Objectives Over 250 medical centers worldwide offer ketogenic diets to children with epilepsy; however, access to these therapies has been extremely limited for adults until recent years. We examine our 5-year experience creating and implementing a dedicated Adult Epilepsy Diet Center designed to provide adults with epilepsy access to ketogenic diets. Material and methods Outpatients seen at the Johns Hopkins Adult Epilepsy Diet Center from August 2010 thru September 2015 age 18 years and older were enrolled in a prospective open-label observational study. Patients that also enrolled in ongoing clinical diet trials were excluded from this study. Participant demographics, diet type, urine and/or serum ketones, laboratory studies, seizure frequency, diet duration, reason for discontinuing diet therapy, and side effects were recorded. A subgroup analysis of participants that met International League Against Epilepsy (ILAE) criteria for drug-resistant epilepsy (DRE) and were treated de novo with a Modified Atkins Diet (MAD) was performed to compare outcomes with the current literature regarding efficacy of other antiseizure treatments for DRE. Results Two hundred and twenty-nine adults attended the Adult Epilepsy Diet Center, and 168 met inclusion criteria. Two-thirds (n = 113, 67%) were women with an age range of 18–86 years at the initial visit. Thirty-five participants (21%, n = 133) were already on a therapeutic diet while 79% (n = 133) were naive to diet therapy at the time of the initial visit. Diet-naive participants were typically prescribed MAD (n = 130, 98%), unless unable to intake adequate oral nutrition, in which case they were prescribed KD (n = 1) or a combination of oral MAD and ketogenic formula (n = 2). Twenty-nine of 130 (22%) participants prescribed MAD elected not to start or were lost to follow-up, and 101 (78%) began MAD. A subgroup analysis was performed on one hundred and six participants naive to diet therapy that met International League Against Epilepsy criteria for DRE, were able to tolerate oral nutrition, and were prescribed a MAD. Relative to the number of enrolled participants who had reliable follow-up results for a given duration (including those that ultimately elected not to start or were later lost to follow-up), at 3 months, 36% of these participants responded (≥ 50% seizure reduction) to diet therapy, and 16% were seizure-free. At 1 year, 30% responded, and 13% were seizure-free. At 4 years, 21% responded, and 7% were seizure-free. Hyperlipidemia was the most common side effect (occurring in 39% of screened participants, including those on a therapeutic diet prior to the initial visit). Weight loss was also common (occurring in 19% of all participants treated with a ketogenic diet therapy) yet was often an intended effect. Significance This study, the largest series of adults with epilepsy treated with ketogenic diet therapies to date, provides evidence that ketogenic diets may be feasible, effective, and safe long-term in adults, although long-term adherence was limited and further adequately controlled studies are necessary to determine the efficacy of ketogenic diets in the treatment of adults with epilepsy.

Behavioral responses to a perceptual stimulus are typically faster with repeated exposure to the stimulus (behavioral priming). This implicit learning mechanism is critical for survival but impaired in a variety of neurological disorders, including Alzheimer's disease. Many studies of the neural bases for behavioral priming have encountered an interesting paradox: in spite of faster behavioral responses, repeated stimuli usually elicit weaker neural responses (repetition suppression). Several neurophysiological models have been proposed to resolve this paradox, but noninvasive techniques for human studies have had insufficient spatial-temporal precision for testing their predictions. Here, we used the unparalleled precision of electrocorticography (ECoG) to analyze the timing and magnitude of task-related changes in neural activation and propagation while patients named novel vs repeated visual objects. Stimulus repetition was associated with faster verbal responses and decreased neural activation (repetition suppression) in ventral occipito-temporal cortex (VOTC) and left prefrontal cortex (LPFC). Interestingly, we also observed increased neural activation (repetition enhancement) in LPFC and other recording sites. Moreover, with analysis of high gamma propagation we observed increased top-down propagation from LPFC into VOTC, preceding repetition suppression. The latter results indicate that repetition suppression and behavioral priming are associated with strengthening of top-down network influences on perceptual processing, consistent with predictive coding models of repetition suppression, and they support a central role for changes in large-scale cortical dynamics in achieving more efficient and rapid behavioral responses.

The current review highlights the evidence supporting the use of ketogenic diet therapies in the management of a growing number of neurological disorders in adults. An overview of the scientific literature supporting posited mechanisms of therapeutic efficacy is presented including effects on neurotransmission, oxidative stress, and neuro-inflammation. The clinical evidence supporting ketogenic diet use in the management of adult epilepsy, malignant glioma, Alzheimer’s disease, migraine headache, motor neuron disease, and other neurologic disorders is highlighted and reviewed. Lastly, common adverse effects of ketogenic therapy in adults, including gastrointestinal symptoms, weight loss, and transient dyslipidemia are discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-018-0666-8) contains supplementary material, which is available to authorized users.