Predictors of elevations in fasting lipid levels in adults with epilepsy on a modified Atkins diet.

BACKGROUND: Ketogenic diet therapies can improve seizure control in patients with drug-resistant epilepsy (DRE). The current study investigated whether dietary fat composition is associated with elevations in serum lipid levels in adults with epilepsy who began a modified Atkins diet (MAD). METHODS: Adults with DRE were instructed to follow the MAD. Food records collected at baseline and follow-up were analyzed to extract median daily macro- and micronutrient composition. Total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, non-HDL and TC/HDL ratio were measured at baseline and follow-up. RESULTS: Study participants initiating MAD showed higher fat intake at 1 month (p<0.001) and 2 months (p<0.001) and lower carbohydrate intake at 1 month (p<0.001) and 2 months (p<0.001) compared to baseline. Study participants also showed higher intake of cholesterol (p<0.001), saturated fatty acid (p<0.001) and monounsaturated fatty acid (p<0.001) over time. Following MAD initiation, study participants showed significant increases in levels of TC (p = 0.007), LDL (p<0.001), and non-HDL (p = 0.009) over time. Dietary intake variables, including cholesterol and fat subtypes, were significantly associated with difference in 1 month TC and LDL levels from baseline but not absolute 1 month lipid values. In a sub-analysis, participants with baseline dyslipidemia showed smaller changes in lipid values during diet use. CONCLUSIONS: Adults with DRE starting MAD increased fat intake, particularly saturated and monounsaturated fat subtypes, and reduced carbohydrate intake. Changes in TC and LDL levels 1 month after MAD initiation are associated with dietary intake of cholesterol and fat.

The effect of anti-seizure medications on lipid values in adults with epilepsy.

PURPOSE: Certain anti-seizure medications (ASMs) adversely impact lipid values. Here, we explored the impact of ASMs on lipid values in adults with epilepsy. METHODS: A total of 228 adults with epilepsy were divided into four groups based on ASMs used: strong EIASMs, weak EIASMs, non-EIASMs, and no ASMs. Demographic information, epilepsy-specific clinical history, and lipid values were obtained through chart review. RESULTS: While there was no significant difference in lipid values between groups, there was a significant difference in the proportion of participants with dyslipidemia. Specifically, more participants exhibited elevated low-density lipoprotein (LDL) level in the strong EIASM group compared to the non-EIASM group (46.7% vs 18%, p < 0.05). In addition, more participants showed elevated LDL level in the weak EIASM group compared to the non-EIASM group (38% vs 18%, p < 0.05). Users of strong EIASMs showed greater odds of high LDL level (OR 5.734, p = 0.005) and high total cholesterol level (OR 4.913, p = 0.008) compared to users of non-EIASMs. When we analyzed the impact of individual ASMs used by more than 15% of the cohort on lipid levels, participants using valproic acid (VPA) showed lower high-density lipoprotein (p = 0.002) and higher triglyceride levels (p = 0.002) compared to participants not using VPA. CONCLUSION: Our study demonstrated a difference in the proportion of participants with dyslipidemia between ASM groups. Thus, adults with epilepsy using EIASMs should have careful monitoring of lipid values to address the risk of cardiovascular disease.

Potential mechanisms to modify impaired glucose metabolism in neurodegenerative disorders.

Neurodegeneration refers to the selective and progressive loss-of-function and atrophy of neurons, and is present in disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Although each disease presents with a unique pattern of neurodegeneration, and subsequent disease phenotype, increasing evidence implicates alterations in energy usage as a shared and core feature in the onset and progression of these disorders. Indeed, disturbances in energy metabolism may contribute to the vulnerability of neurons to apoptosis. In this review we will outline these disturbances in glucose metabolism, and how fatty acids are able to compensate for this impairment in energy production in neurodegenerative disorders. We will also highlight underlying mechanisms that could contribute to these alterations in energy metabolism. A greater understanding of these metabolism-neurodegeneration processes could lead to improved treatment options for neurodegenerative disease patients.

Six-month effects of modified Atkins diet implementation on indices of cardiovascular disease risk in adults with epilepsy.

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..

Fructose 1,6-bisphosphate is anticonvulsant and improves oxidative glucose metabolism within the hippocampus and liver in the chronic pilocarpine mouse epilepsy model.

Glucose metabolism is altered in epilepsy, and this may contribute to seizure generation. Recent research has shown that metabolic therapies including the ketogenic diet and medium chain triglycerides can improve energy metabolism in the brain. Fructose 1,6-bisphosphate (F16BP) is an intermediate of glycolysis and when administered exogenously is anticonvulsant in several rodent seizure models and may alter glucose metabolism. Here, we showed that F16BP elevated the seizure threshold in the acute 6-Hz mouse seizure model and investigated if F16BP could restore impairments in glucose metabolism occurring in the chronic stage of the pilocarpine mouse model of epilepsy. Two weeks after the pilocarpine injections, mice that experienced status epilepticus (SE, "epileptic") and did not experience SE (no SE, "nonepileptic") were injected with vehicle (0.9% saline) or F16BP (1 g/kg in 0.9% saline) daily for 5 consecutive days. At 3 weeks, mice were injected with [U-13C6]-glucose and the % enrichment of 13C in key metabolites in addition to the total levels of each metabolite was measured in the hippocampal formation and liver. Fructose 1,6-bisphosphate increased total GABA in the hippocampal formation, regardless of whether mice had experienced SE. In the hippocampal formation, F16BP prevented reductions in the % 13C enrichment of citrate, succinate, malate, glutamate, GABA and aspartate that occurred in the chronic stage of the pilocarpine model. Interestingly, % 13C enrichment in glucose-derived metabolites was reduced in the liver in the chronic stage of the pilocarpine model. Fructose 1,6-bisphosphate was also beneficial in the liver, preventing reductions in % 13C enrichment of lactate and alanine that were associated with SE. This study confirmed that F16BP is anticonvulsant and can improve elements of glucose metabolism that are dysregulated in the chronic stage of the pilocarpine model, which may be due to reduction of spontaneous seizures. Our results highlight that F16BP may be therapeutically beneficial for epilepsies refractory to treatment.

Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism.

Metabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS). However, the molecular events that drive energy imbalances in ALS are not completely understood. In this study, we aimed to elucidate deficits in energy homeostasis in the SOD1G93A mouse model of ALS. SOD1G93A mice and their wild-type littermates underwent indirect calorimetry and intraperitoneal glucose/insulin tolerance tests at both the onset and mid-symptomatic stages of the disease. Glucose uptake and the plasma glucoregulatory hormone profiles were analyzed. Pancreatic islet cell mass and function were assessed by measuring hormone concentrations and secretion in isolated islets, and pancreatic α- and ß-cell immunoreactive areas. Finally, we profiled liver glycogen metabolism by measuring glucagon concentrations and liver metabolic gene expressions. We identified that mid-symptomatic SOD1G93A mice have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. The capacity for pancreatic islets to secrete insulin appears intact, however, islet cell insulin concentrations and ß-cell mass were reduced. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signaling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilized efficiently in SOD1G93A mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1G93A mice, which is linked to an increase in insulin-independent glucose uptake, and a loss of ß-cells, insulin production, and glucagon sensitivity. This suggests that the hormonal regulation of glucose concentrations may contribute to the progression of disease in this ALS mouse model.

The psychiatric effects of ketogenic diet therapy on adults with chronic epilepsy.

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 naïve 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 naïve 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.

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.

Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1G93A mice lacking RAGE and compared them with SOD1G93A transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1G93A pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.

Ketogenic diet therapy provision in the COVID-19 pandemic: Dual-center experience and recommendations.

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 reevaluate 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.

The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating the defective energy metabolism and components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the mechanisms by which the energy metabolism and the complement system are altered during the disease progression of ALS and how it can contribute to disease. Furthermore, it will also examine how complement activation can modify the energy metabolism in metabolic disorders, in order to highlight how the complement system and energy metabolism may be linked in ALS.

Triheptanoin alters [U-13C6]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model.

Triheptanoin is anticonvulsant in several seizure models. Here, we investigated changes in glucose metabolism by triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy model. After injection of [U-13C6]-glucose (i.p.), enrichments of 13C in intermediates of glycolysis and the tricarboxylic acid (TCA) cycle were quantified in hippocampal extracts and maximal activities of enzymes in each pathway were measured. The enrichment of 13C glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of 13C in several glycolytic intermediates compared to control mice suggesting glucose utilization may be impaired and/or glycogenolysis increased in the untreated interictal hippocampus. Triheptanoin prevented the interictal reductions of 13C incorporation in most glycolytic intermediates, suggesting it increased glucose utilization or - as an additional astrocytic fuel - it decreased glycogen breakdown. In the TCA cycle metabolites, the incorporation of 13C was reduced in the interictal state. Triheptanoin restored the correlation between 13C enrichments of pyruvate relative to most of the TCA cycle intermediates in "epileptic" mice. Triheptanoin also prevented the reductions of hippocampal pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase activities. Decreased glycogen breakdown and increased glucose utilization and metabolism via the TCA cycle in epileptogenic brain areas may contribute to triheptanoin's anticonvulsant effects.

Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) in Long-term Care Centers in Québec, Canada: A Strategy for Best Practices.

OBJECTIVES: Antipsychotic medications are often used for the first-line management of behavioral and psychological symptoms of dementia (BPSD) contrary to guideline recommendations. The Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) strategy aims to improve the well-being of long-term care (LTC) residents with major neurocognitive disorder (MNCD) by implementing a resident-centered approach, nonpharmacologic interventions, and antipsychotic deprescribing in inappropriate indications. DESIGN: Prospective, closed cohort supplemented by a developmental evaluation. SETTING AND PARTICIPANTS: Residents of designated wards in 24 LTC centers in Québec, Canada. METHODS: Provincial guidelines were disseminated, followed by the implementation of an integrated knowledge translation and mobilization strategy, including training, coaching, clinical tools, evaluation of clinical practices, and a change management strategy. Antipsychotic, benzodiazepine, and antidepressant prescriptions; BPSD; and falls were evaluated every 3 months, for 9 months, from January to October 2018. Semistructured interviews (n = 20) were conducted with LTC teams to evaluate the implementation of OPUS-AP. RESULTS: Of 1054 residents, 78.3% had an MNCD diagnosis and 51.7% an antipsychotic prescription. The cohort included 464 residents with both MNCD and antipsychotic prescription. Antipsychotic deprescribing (cessation or dose decrease) was attempted in 220 of the 344 residents still admitted at 9 months. Complete cessation was observed in 116 of these residents (52.7%) and dose reduction in 72 (32.7%), for a total of 188 residents (85.5%; 95% confidence interval: 80.1%, 89.8%). A decrease in benzodiazepine prescriptions and improvements in Cohen-Mansfield Agitation Inventory scores were observed among residents who had their antipsychotics deprescribed. Caregivers and clinicians expressed satisfaction as a result of observing an improved quality of life among residents. CONCLUSIONS AND IMPLICATIONS: Antipsychotic deprescribing was successful in a vast majority of LTC residents with MNCD without worsening of BPSD. Based on this success, phase 2 of OPUS-AP is now under way in 129 LTC centers in Québec.

Lessons learned from recent clinical trials of ketogenic diet therapies in adults.

PURPOSE OF REVIEW: Although ketogenic diet therapies (KDTs) were first developed as a treatment for patients with epilepsy, their potential efficacy for a broader number of neurologic and nonneurologic disorders and conditions has been explored over the last 10-20 years. The most recent clinical trials of KDTs in adults have highlighted common methodological aspects that can either facilitate or thwart appropriate risk/benefit analyses, comparisons across studies, and reproducibility of findings in future studies. RECENT FINDINGS: Recent evidence suggests that KDTs not only improve seizure control, but also improve other neurologic conditions, including nonmotor Parkinson's disease symptoms. Therapies targeting nutritional ketosis without comprehensive diet modification improve cognition and cerebral blood flow in Alzheimer's disease patients. KDTs lower hemoglobin A1c levels and diabetes medication use in patients with Type 2 diabetes and mixed results have been observed when used for performance enhancement in athletes and healthy volunteers. SUMMARY: Clinical studies of KDTs show promise for a variety of clinical indications. Future studies should factor in high potential participant attrition rates and utilize consistent and standard reporting of diet type(s), compliance measures, and side-effects to enable the reproducibility and generalizability of study outcomes.

Impairments in Oxidative Glucose Metabolism in Epilepsy and Metabolic Treatments Thereof.

There is mounting evidence that oxidative glucose metabolism is impaired in epilepsy and recent work has further characterized the metabolic mechanisms involved. In healthy people eating a traditional diet, including carbohydrates, fats and protein, the major energy substrate in brain is glucose. Cytosolic glucose metabolism generates small amounts of energy, but oxidative glucose metabolism in the mitochondria generates most ATP, in addition to biosynthetic precursors in cells. Energy is crucial for the brain to signal "normally," while loss of energy can contribute to seizure generation by destabilizing membrane potentials and signaling in the chronic epileptic brain. Here we summarize the known biochemical mechanisms that contribute to the disturbance in oxidative glucose metabolism in epilepsy, including decreases in glucose transport, reduced activity of particular steps in the oxidative metabolism of glucose such as pyruvate dehydrogenase activity, and increased anaplerotic need. This knowledge justifies the use of alternative brain fuels as sources of energy, such as ketones, TCA cycle intermediates and precursors as well as even medium chain fatty acids and triheptanoin.

Ketogenic Diets for Adult Neurological Disorders.

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.

The Expanding Role of Ketogenic Diets in Adult Neurological Disorders.

The current review highlights the evidence supporting the use of ketogenic diet therapies in the management of adult epilepsy, adult malignant glioma and Alzheimer's disease. An overview of the scientific literature, both preclinical and clinical, in each area is presented and management strategies for addressing adverse effects and compliance are discussed.

Improving compliance in adults with epilepsy on a modified Atkins diet: A randomized trial.

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.

The effect of dichloroacetate in mouse models of epilepsy.

A recent report has found that glucose oxidation and the activity of pyruvate dehydrogenase (PDH) are reduced in the chronic stage of the pilocarpine mouse epilepsy model. This is likely caused by increased phosphorylation by PDH kinase of the E1α subunit of PDH, downregulating its activity. Inhibition of this phosphorylation has not yet been explored as a possible approach to treat epilepsy. Chronic dichloroacetate (DCA, 50 and 100 mg/kg/day) treatment was tested in acute seizure and the chronic pilocarpine models. We also determined the effects on phosphorylation state, activity and protein levels of PDH in the chronic stage of the pilocarpine model. DCA treatment did not increase latencies to seizures in the acute flurothyl seizure test and was slightly proconvulsant in the 6 Hz test. The latencies to seizures in a second-hit flurothyl test were decreased in SE vs. No SE mice in the chronic stage, but were not restored by DCA. In mice that had experienced pilocarpine-induced SE and were in the chronic "epileptic" stage of the model, PDH activity was reduced by 65% compared to "healthy" No SE mice. This was partially alleviated with DCA treatment. Also, PDH protein levels were decreased by 37% and phosphorylation at Ser300 of PDH was increased by 52% in SE mice, but were not significantly changed with DCA. Moreover DCA treatment decreased the amounts of total PDH by 23% in No SE mice, which may explain the proconvulsant effects in the 6 Hz test. The reduction in PDH protein levels during the chronic epileptic stage suggests increased degradation of the protein, which may contribute to the deficient glucose oxidation found in epilepsy. Taken together, DCA did not have any anti-convulsant effects in the tested models. Future studies utilising other PDH kinase inhibitors are required to determine whether this treatment approach is viable.

Impact of the modified Atkins diet on cardiovascular health in adults with epilepsy.

AIM: The current study investigated biochemical and vascular markers of cardiovascular health in adult patients with epilepsy treated with long-term (greater than 1year) ketogenic diet therapy compared with controls. METHOD: Anthropometric measures, serum fasting lipid panel, apolipoproteins A-1 and B, lipoprotein sub-fractions as well as common carotid intima-media thickness (cIMT), and plaque presence were assessed in 20 adult patients with epilepsy on a modified Atkins diet (MAD) for >1year started as an adult compared with 21 adult patients with epilepsy naïve to diet therapy. RESULTS: Patients treated with MAD had significantly lower weight, body mass index, waist and hip circumference, percent body fat, and serum triglyceride levels when compared with control patients. In contrast, they had significantly higher serum levels of small low-density-lipoprotein (LDL) particles and were significantly more likely to have LDL pattern B in which small LDL particles predominate when compared with controls. However, there was no significant difference in cIMT or plaque presence between groups. CONCLUSION: Our results provide clinical evidence demonstrating the cardiovascular safety of a high-fat, low-carbohydrate diet used in adults with epilepsy for at least 12months. It also highlights potential markers of cardiovascular risk - small dense LDL particles - that should be closely monitored in adults treated with diet therapy long-term.