Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet.

PURPOSE: To report the effect of the ketogenic diet (KD) on non-convulsive status epilepticus (NCSE) due to Angelman syndrome (AS) in two members of a large Georgian family affected by a novel frameshift variant in the UBE3A gene (NM_000462.3). METHODS: We evaluated two members of this family who were affected with clinical and EEG features of AS. Clinical history with special emphasis on development, seizure type, frequency, and treatment was reviewed. Routine and long-term video EEG monitoring were conducted, particularly during NCSE. A non-fasting inpatient KD protocol was implemented using blended food orally with full administration of 4:1 (fat to non-fat) ratio. Urine ketone bodies (KBs), measured with urine ketone acetone strips readings, reached 150 mg/dL in both patients. RESULTS: Patients had characteristic signs of AS and presented with epilepsy between the age of 2-4 years. As methylation tests were negative, next generation sequencing disclosed a c.2365del variant. For both, NCSE was revealed by cognitive deterioration and did not respond to anti-seizure medication. As recommended, IV pyridoxine, benzodiazepines, and valproic acid were administered, but without success. For both patients, NCSE resolved on the second-third day of KD initiation, before the appearance of ketonuria and resulting in improved communication, mood and sleep. CONCLUSION: KD is safe and effective for the treatment of NCSE due to AS. Resolution before the appearance of ketone bodies points to a possible mechanism of action of KD.

Possible Role of High-Dose Barbiturates and Early Administration of Parenteral Ketogenic Diet for Reducing Development of Chronic Epilepsy in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

We describe the efficacy of high-dose barbiturates and early administration of a parenteral ketogenic diet (KD) as initial treatments for acute status epilepticus (SE) in an 8-year-old girl with febrile infection-related epilepsy syndrome (FIRES). The patient was admitted to our hospital with refractory focal SE. Abundant epileptic discharges over the left frontal region were observed on electroencephalogram (EEG). Treatment with continuous infusion of thiamylal for 4 hours, increased incrementally to 40 mg/kg/h, successfully ended the clinical SE, and induced a burst-suppression coma. The infusion rate was then gradually decreased to 4 mg/kg/h over the next 12 hours. Parenteral KD was administered from days 6 to 21 of illness. Continuous infusion of thiamylal was switched to midazolam on day 10 without causing seizures or EEG exacerbations. The patient has remained seizure free in the 15 months since hospital discharge. The effectiveness of KD for the treatment of FIRES has attracted attention amongst clinicians, but KD treatment may need to last for 2 to 4 days before it can stop SE, a time period that could cause irreversible brain damage. Considering the severity of SE in our patient and the dose of barbiturates needed to treat it, we consider this case to have had a good clinical outcome. The results suggest that rapid termination of seizure using high-dose barbiturates in conjunction with early administration of parenteral KD could reduce the development of chronic epilepsy in patients with FIRES.

Ketogenic Diet Therapies for Seizures and Status Epilepticus.

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.

Role of the ketogenic diet in acute neurological diseases.

The current review outlines the role of ketogenic diet (KD) in the management of acute neurological conditions namely traumatic brain injury, ischemic stroke, status epilepticus and primary aggressive brain tumor. An overview of the scientific literature- both clinical and pre-clinical studies is presented along with the proposed mechanism of ketogenic diet. The review also describes different formulations of commercially available ketogenic diets along with the common adverse effects and dosing recommendations.

Medium-chain triglyceride ketogenic diet is effective for treatment of an adult with super-refractory status epilepticus: a case report and literature review.

BACKGROUND: The ketogenic diet (KD) has been shown to be effective in controlling super-refractory status epilepticus (SRSE) in adult. To the best of our knowledge, there has been no previous report of the MCT KD in adult with SRSE. CASE REPORT: A 19-year-old female was hospitalized due to SRSE from autoimmune encephalitis despite pulsed methylprednisolone, intravenous immunoglobulin, and eight antiepileptic drug treatments. The MCT KD treatment was initiated and rapid seizure control was observed within 6 days despite negative ketosis. CONCLUSION: We report the first successful treatment with MCT KD in a female adult with SRSE who was refractory to classic KD with severe hypertriglyceridemia, and reviewed all SE adults with KD treatment. Dramatic seizure control without positive ketosis might lead to a new focus on fatty acids instead, paving the way for further prospective study regarding the effects of the MCT KD in this fatal condition.

The ketogenic diet for super-refractory status epilepticus patients in intensive care units.

OBJECTIVES: Super-refractory status epilepticus (SRSE) is one of the most challenging issues in intensive care units (ICUs) in that it is associated with high morbidity and mortality. Although the ketogenic diet (KD) has been reported to be effective in treating of SRSE, the use of the diet as therapy can be complicated by concomitant medical problems specific to critically ill patients. In this study, we aimed to describe our experience of the KD for SRSE patients in ICUs. METHODS: We retrospectively reviewed the medical records of 16 patients (10 males, 6 females) with SRSE who were treated with the KD in the ICUs at Samsung Medical Center from July 2005 to July 2017. RESULTS: The median age of seizure onset was 8 years (interquartile range 5-13.5). Prior to diet initiation, the patients were in convulsive or non-convulsive SRSE for a median of 23 days (range, 3-420). The median time to achieve ketosis was 3 days (range, 2-6). The KD was continued for a median of 2.1 months (range, 0.1-15.8). Of the 16 patients, nine (56.3%) achieved seizure freedom, six (37.5%) reported >50% seizure reduction, and one (6.2%) had <50% seizure improvement after the KD. There was no significant change in the number of antiepileptic drugs. The most commonly encountered complication during the KD was gastrointestinal disturbance. CONCLUSIONS: Our experience indicates that the KD is an effective alternative therapeutic strategy for SRSE patients in ICUs with adequate efficacy and safety in reducing seizure frequency and weaning from prolonged mechanical ventilation, although functional outcome was not favorable for most patients. Close monitoring and preventive management of potential adverse effects are critical elements for success with the KD in patients with SRSE.

The Feasibility, Safety and Effectiveness of a Ketogenic Diet for Refractory Status Epilepticus in Adults in the Intensive Care Unit.

BACKGROUND: Status, refractory status and super refractory status epilepticus are common neurologic emergencies. The objective of this study is to investigate the feasibility, safety and effectiveness of a ketogenic diet (KD) for refractory status epilepticus (RSE) in adults in the intensive care unit (ICU). METHODS: We performed a retrospective, single-center study of patients between ages 18 and 80 years with RSE treated with a KD treatment algorithm from November 2016 through April 2018. The primary outcome measure was urine ketone body production as a biomarker of feasibility. Secondary measures included resolution of RSE and KD-related side effects. RESULTS: There were 11 adults who were diagnosed with RSE that were treated with the KD. The mean age was 48 years, and 45% (n = 5) of the patients were women. The patients were prescribed a median of three anti-seizure medications before initiating the KD. The median duration of RSE before initiation of the KD was 1 day. Treatment delays were the result of Propofol administration. 90.9% (n = 10) of patients achieved ketosis within a median of 1 day. RSE resolved in 72.7% (n = 8) of patients; however, 27.3% (n = 3) developed super-refractory status epilepticus. Side effects included metabolic acidosis, hypoglycemia and hyponatremia. One patient (20%) died. CONCLUSIONS: KD may be feasible, safe and effective for treatment of RSE in the ICU. A randomized controlled trial (RCT) may be indicated to further test the safety and efficacy of KD.

Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus.

PURPOSE: To summarize the evidence regarding dietary, immunological, surgical, and other emerging treatments for refractory status epilepticus (RSE)/super-RSE (SRSE). METHODS: Narrative literature review including relevant human studies. RESULTS: Hypothermia and brenaxolone were tested in randomized controlled trials for RSE/SRSE management, while other interventions have only limited evidence for their efficacy and safety. Clinical trials including the HYBERNATUS study found the efficacy of therapeutic hypothermia to be no better than placebo for RSE/SRSE, and raised concerns about its safety. Ketogenic diet has shown possible efficacy in RSE/SRSE in several case series, with electrographic seizure resolution within 7 days in 20%-90% patients in larger (n = 8-17) reports. A review of 37 pediatric patients reported seizure control with immunotherapy in only 7 patients. A phase 3 double-blind trial showed that brexanolone was no better than placebo for successful wean of 3rd line anesthetic agent(s) and freedom from RSE for ≥24 hours. Epilepsy surgery has been reported to successfully control seizures in small series; however, pre-surgical evaluation is confounded by ongoing ictal activity and anesthetic infusions. Vagus nerve stimulation was reported to be associated with cessation of RSE/SRSE in 21/28 patients in a review of anecdotal reports. There is no evidence for use of pyridoxine and magnesium outside of specific indications. CONCLUSIONS: There is only anecdotal evidence for dietary, immunological, surgical, and other treatments for RSE/SRSE, often confounded by multiple concurrent treatments, and heterogeneity in their use and assessment of outcomes. Clinical trials for therapeutic hypothermia and brexanolone have not shown a significant advantage over comparators.

The critical interaction between valproate sodium and warfarin: case report and review.

BACKGROUND: Valproic acid (VPA) and warfarin are commonly prescribed for patients with epilepsy and concomitant atrial fibrillation (AF). When VPA and warfarin are prescribed together, clinically important interactions may occur. VPA may replace warfarin from the protein binding sites and result in an abnormally increased anticoagulation effect. This is commonly underrecognized. CASE PRESENTATION: In our case, we report a 78-year-old woman with a glioma who presented with status epilepticus. The patient was on warfarin to prevent cardiogenic embolism secondary to AF. Intravenous loading dose of VPA was administered, but international normalized ratio (INR) increased significantly to 8.26. Intravenous vitamin K1 was then given and the patient developed no overt bleeding during the hospitalization. CONCLUSION: By reviewing the literature and discussing the critical interaction between valproate sodium and warfarin, we conclude that intravenous VPA and the co-administrated warfarin may develop critical but underrecognized complications due to effects on the function of hepatic enzymes and displacement of protein binding sites.

Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus.

PURPOSE: To describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE). METHODS: RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20 mg/dl (1.9 mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7 days of starting KD, defined as absence of seizures and ≥50% suppression below 10 µV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded. RESULTS: Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13 days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2 days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7 days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline. CONCLUSIONS: This series suggests efficacy and safety of KD for treatment of pediatric RSE.

Newer Antiepileptic Drugs for Status Epilepticus in Adults: What's the Evidence?

Status epilepticus (SE) is one of the most frequent neurological emergencies. Despite this, understanding of its pathophysiology and evidence regarding its management is limited. Rapid, effective, and well-tolerated treatment to achieve seizure cessation is advocated to prevent brain damage or potentially lethal outcomes. The last two decades have witnessed an exponential increase in the number of available antiepileptic drugs (AEDs). These compounds, especially lacosamide and levetiracetam, in view of their intravenous formulation, have been increasingly prescribed in SE. These and other newer AEDs present a promising profile in terms of tolerability, with few centrally depressive effects, favorable pharmacokinetic properties, and fewer drug interactions than classical AEDs; conversely, they are more expensive. There is still no clear evidence to suggest a specific beneficial impact of newer AEDs on SE outcome, preventing any strong recommendation regarding their prescription in SE. Further comparative studies are urgently required to clarify their place and optimal use in the armamentarium of SE treatment.

Pharmacotherapy for Refractory and Super-Refractory Status Epilepticus in Adults.

Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA)A receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N-methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABAA receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.

Effect of diet with omega-3 in basal brain electrical activity and during status epilepticus in rats.

Western diets are high in saturated fat and low in omega-3. Certain animals cannot produce omega-3 from their own lipids, making it necessary for it to be acquired from the diet. However, omega-3s are important components of the plasma membrane, and altering their proportions can promote physical and chemical alterations in the membranes, which may modify neuronal excitability. These alterations occur in healthy individuals, as well as in patients with epilepsy who are more sensitive to changes in brain electrical activity. This study evaluated the effect of a diet supplemented with omega-3 on the basal brain electrical activity both before and during status epilepticus in rats. To evaluate the brain electrical activity, we recorded electrocorticograms (ECoG) of animals both with and without omega-3 supplementation before and during status epilepticus induced by pilocarpine. Calculation of the average brain wave power by a power spectrum revealed that omega-3 supplementation reduced the average power of the delta wave by 20% and increased the average power of the beta wave by 45%. These effects were exacerbated when status epilepticus was induced in the animals supplemented with omega-3. The animals with and without omega-3 supplementation exhibited increases in basal brain electrical activities during status epilepticus. The two groups showed hyperactivity, but no significant difference between them was noted. Even though the brain activity levels observed during status epilepticus were similar between the two groups, neuron damage to the animals supplemented with omega-3 was more slight, revealing the neuroprotective effect of the omega-3.

Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus.

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.

A Practical Approach to Ketogenic Diet in the Pediatric Intensive Care Unit for Super-Refractory Status Epilepticus.

BACKGROUND: Super-refractory status epilepticus (SRSE) ensues when there is no improvement of seizure control in response to anesthetic therapy or seizure recurrence after reduction of anesthetic agents. There is no consensus on standard of care for SRSE. Ketogenic diet (KD) has reported success, but technical challenges exist including inability to feed patients, concomitant steroid use, acidotic states, and lack of dieticians with experience. The optimal protocol for KD is yet to be determined. We describe our approach to initiation of KD in the pediatric intensive care unit (PICU). METHODS: Patients with SRSE who had KD initiation in the PICU were identified. Data from the hospital course were supplemented by review of the electronic medical record. RESULTS: Nine children with SRSE who had KD initiated in the PICU were identified. Descriptive analysis was performed. Mean age was 5.4 years (SD 2.24). Median number of days to start KD from detection of seizures was 13 [interquartile range (IQR) 10-16]. Mean time to achieve ketosis was 4.2 days (SD 3.4). The median number of antiepileptic drugs (AEDs) trialed before KD was started was 4 [IQR 3-4], and the median number of continuous infusions was 2 [IQR 2-3]. After initiation of KD, most patients were weaned off anesthetic infusions by 1 week. Outcomes were variable. CONCLUSIONS: We demonstrated the feasibility of a practical approach to initiation of KD for children with SRSE. These children were successfully weaned off continuous anesthetic infusions. Larger studies are needed to determine effectiveness, safety, and tolerability of KD in the management of SRSE as well as ease of implementation.

How effective is the ketogenic diet for electrical status epilepticus of sleep?

Electrical status epilepticus of sleep (ESES), with the activation of profuse amounts of epileptiform discharges in sleep, may lead to intractable epilepsy and neurocognitive decline in children. Numerous varied treatments including antiseizure medications, steroids, and surgery have been investigated as possible treatment options. The ketogenic diet (KD) is an additional treatment option which may add to our treatment armamentarium for ESES. The KD may theoretically improve ESES by affecting GABA systems and reducing inflammation. Clinical reports of the KD for ESES have been heterogeneous, but to date 38 children have been described in six publications. Overall, 53% had EEG improvement, 41% had>50% seizure reduction, 45% had cognitive improvement, but only 9% had EEG normalization. This review will assess the efficacy of the KD in the treatment of ESES based on known data as well as possible mechanisms of action and the need for future study.

From intravenous to enteral ketogenic diet in PICU: A potential treatment strategy for refractory status epilepticus.

BACKGROUND: Ketogenic diet (KD) has been used to treat refractory status epilepticus (RSE). KD is a high-fat, restricted-carbohydrate regimen that may be administered with different fat to protein and carbohydrate ratios (3:1 and 4:1 fat to protein and carbohydrate ratios). Other ketogenic regimens have a lower fat and higher protein and carbohydrate ratio to improve taste and thus compliance to treatment. We describe a case of RSE treated with intravenous KD in the Pediatric Intensive Care Unit (PICU). CASE REPORT: An 8-year-old boy was referred to the PICU because of continuous tonic-clonic and myoclonic generalized seizures despite several antiepileptic treatments. After admission he was intubated and treated with intravenous thiopental followed by ketamine. Seizures continued with frequent myoclonic jerks localized on the face and upper arms. EEG showed seizure activity with spikes on rhythmic continuous waves. Thus we decided to begin KD. The concomitant ileus contraindicated KD by the enteral route and we therefore began IV KD. The ketogenic regimen consisted of conventional intravenous fat emulsion, plus dextrose and amino-acid hyperalimentation in a 2:1 then 3:1 fat to protein and carbohydrate ratio. Exclusive IV ketogenic treatment, well tolerated, was maintained for 3 days; peristalsis then reappeared so KD was continued by the enteral route at 3:1 ratio. Finally, after 8 days and no seizure improvement, KD was deemed unsuccessful and was discontinued. CONCLUSIONS: Our experience indicates that IV KD may be considered as a temporary "bridge" towards enteral KD in patients with partial or total intestinal failure who need to start KD. It allows a prompt initiation of KD, when indicated for the treatment of severe diseases such as RSE.

Ketogenic diet treatment for pediatric super-refractory status epilepticus.

PURPOSE: We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. METHOD: A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. RESULTS: Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti-N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients' EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration of status epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after diet initiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation. CONCLUSION: Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus.