Health-related quality of life in adults with drug-resistant focal epilepsy treated with modified Atkins diet in a randomized clinical trial.

Ketogenic diet, a high-fat, low-carbohydrate diet, is an established treatment for patients with severe epilepsy. We have previously reported a moderate reduction in seizure frequency after treatment with a modified Atkins diet. This study aimed to see whether dietary therapy impacts patients' health-related quality of life (HRQOL). In a randomized controlled design, we compared the change in self-reported HRQOL among adults with difficult-to-treat epilepsy after a 12-week diet intervention. Thirty-nine patients with drug-resistant focal epilepsy (age = 16-65 years) were randomized to eat a modified Atkins diet with maximum 16 g of carbohydrate per day (diet group, n = 19) or to continue eating habitual diet (control group, n = 20). No changes to the other epilepsy treatments were allowed. Patient-reported HRQOL was assessed with the Quality of Life in Epilepsy Inventory-89 (QOLIE-89). The diet group experienced a statistically significant improvement in mean total score of QOLIE-89 of 10 points compared to controls (p = .002). Moreover, although not statistically significant when using a cutoff of 50% seizure reduction, our data suggest an association between diet-induced reduction in seizure frequency and improvement in HRQOL. The improvement in HRQOL was not associated with diet-induced weight reduction.

Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.

OBJECTIVE: The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy. METHODS: In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons. RESULTS: We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures. SIGNIFICANCE: A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.

Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet.

OBJECTIVE: The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism. METHODS: Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin. RESULTS: After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (≥25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant. SIGNIFICANCE: Twelve weeks of MAD treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

Precision treatment with nicotine in autosomal dominant sleep-related hypermotor epilepsy (ADSHE): An observational study of clinical outcome and serum cotinine levels in 17 patients.

PURPOSE: To report the clinical outcome of nicotine exposure in patients with autosomal dominant sleep-related hypermotor epilepsy (ADSHE), along with serum concentrations of the major nicotine metabolite cotinine. METHODS: We recruited 17 ADSHE patients with CHRNA4 mutations (12 with p.S280F and 5 with p.L291 dup). Clinical characteristics were collected from hospital records. A telephone interview was performed on the use and seizure-reducing effect of nicotine applying a six-point rating scale from "none" to very good". Serum concentrations of cotinine were measured in 14 nicotine users. RESULTS: All patients but one had ever used nicotine. Nine had used snuff; seven were current users. Eleven had used transdermal nicotine; nine were current users. Seven reported long-lasting seizure control, all used nicotine, four transdermal nicotine and three snuff. In 78% of patients using continuous transdermal nicotine, the effect was rated as good or very good. Cotinine concentrations were 453 ± 196 (mean ± SD) nmol/l in seven patients using transdermal nicotine only vs. 1241 ± 494 nmol/l in seven using other forms of nicotine. No correlation with seizure control was found. Three patients experienced improvement with transdermal delivery compared to snuff. CONCLUSION: This is the hitherto largest observational study supporting a favorable effect of nicotine in this specific seizure disorder. Better seizure control from transdermal nicotine compared to only day-time consumption suggests benefit from exposure throughout the night. According to current clinical experience, patients with uncontrolled ADSHE harboring relevant mutations should be offered precision treatment with transdermal nicotine.

Effect and tolerability of perampanel in patients with drug-resistant epilepsy.

OBJECTIVE: Perampanel is one of the most recently approved antiseizure medications. The aim of the present study was to assess clinical efficacy and tolerability, in combination with pharmacokinetic variability, of perampanel treatment in patients at a tertiary referral center for epilepsy. METHODS: We performed a retrospective observational study of patients given perampanel as adjunctive treatment in the period January 2013 - February 2019 at the National Center for Epilepsy at Oslo University Hospital, Norway. RESULTS: Clinical data were available for 175 mainly adult patients with drug-resistant epilepsy with mean treatment duration of 16.1 months. We found that 23% (40 patients) were responders (i.e., achieving more than 50% reduction in seizure frequency), four of whom became seizure free, 29% (51 patients) experienced a modest effect, whereas for 29% (50 patients) perampanel had no seizure-reducing effect. A paradoxical effect, with seizure aggravation, was reported in 9% (15 patients). The responder rate was significantly higher in those with slow vs. fast dosage titration. Logistic regression analysis showed better efficacy among those with generalized vs. those with focal epilepsy. Adverse effects were reported by 135 patients (77%), ranging from mild (34%), to moderate (41%) and severe (2%). In 55 patients (41%), these adverse effects resulted in discontinuation of treatment with perampanel. The most frequent adverse effects were psychiatric symptoms (34%), dizziness (31%), and sleepiness (26%). Of the 31 patients for whom serum concentration measurements were available, the mean daily perampanel dose was 6.3 mg (SD 3.0), with a mean serum concentration at steady state of 1.03 µmol/L (range: 0.15-3.59 µmol/L). There were pronounced differences between patients, as demonstrated by a 12-fold variability in the range of concentration/dose (C/D)-ratios (0.06 to 0.69 µmol/L/mg), where enzyme inducers contributed. CONCLUSION: Our results demonstrate that perampanel had a modest seizure-reducing effect in this very treatment-resistant patient group. Predictors of treatment success were generalized epilepsy and slow dosage titration. In patients without a history of psychiatric problems, clinicians could consider increasing dose of perampanel beyond 6 mg daily, taking co-medication and serum concentrations into account.

Are the new anti-epileptic drugs any better than their predecessors? / Er nye legemidler mot epilepsi bedre enn gamle?

Since 1993, fifteen new anti-epileptic drugs have entered the market. But while the potential for personalised treatment has never been greater, the proportion of patients achieving seizure freedom is no higher than it was before.

Effects of modified Atkins diet on thyroid function in adult patients with pharmacoresistant epilepsy.

INTRODUCTION: The use of ketogenic diet as a supplement to antiseizure medication (ASM) in refractory epilepsy has increased the past decades. This high-fat, low-carbohydrate diet mimics the metabolic state of fasting and is generally well-tolerated. However, the long-term adverse effects of the diet are unclear. The purpose of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, may have an impact on thyroid hormone levels. METHODS: We assessed thyroid function by measuring thyroid stimulation hormone (TSH), fT4, T3, fT3, and rT3 before diet start (baseline) and after 12 weeks on the diet in 53 adult patients with drug-resistant epilepsy. Further, we examined the correlation between the changes in thyroid function during dietary treatment and type of (i) change in seizure frequency, (ii) drugs in use, and (iii) degree of ketosis. RESULTS: After 12 weeks on the diet, we found a significant reduction in T3 and fT3 values (13.4% and 10.6%, respectively) and a significant increase in fT4 values (12.1%) compared with baseline. In addition, there was an insignificant increase in TSH and rT3. These changes were similar in women and men, and there was no correlation to drugs in use (enzyme-inducing vs. nonenzyme-inducing drugs), changes in seizure frequency, or level of ketosis. CONCLUSION: This study indicates that dietary treatment for epilepsy may bring about a modest fall in thyroid hormone levels. This could be relevant for those patients with low thyroid hormones and those treated with ASMs known to lower thyroid hormone levels. A cumulative effect of ASMs, low basal thyroid hormone levels, and ketogenic diet may therefore be of clinical importance in the case of thyroid hormones when treating patients with MAD.

Assisted reproductive treatment in women with epilepsy. / Assistert befruktning blant kvinner med epilepsi.

BACKGROUND: Women with epilepsy give birth to fewer children than women without epilepsy. We wished to compare the use of assisted reproductive technology in Norwegian women who have epilepsy with Norwegian women in general. MATERIAL AND METHOD: In an international prospective registry study, the purpose of which was to identify the teratogenic effects of antiepileptic drugs, we included a total of 1510 births among Norwegian women who have epilepsy in the period 2000-2017. The women were recruited from 18 hospital neurological departments, and a protocol was completed for each pregnancy with demographic and clinical data. The use of assisted fertility among Norwegian women in general in the same period was retrieved from the medical birth registry. RESULTS: In women with epilepsy, altogether 96 of 1510 births (6.4 %) were a result of assisted reproductive technology, whereas the corresponding figure in the general population in the same period was 285 474 of 1 052 901 (2.7 %) (p<0.001). Among women with epilepsy, the proportion who used carbamazepine in pregnancy was significantly higher among those who conceived using assisted reproductive technology than among those who had become pregnant in the regular manner (p=0.02). INTERPRETATION: Compared to healthy Norwegian women, the use of assisted reproductive technology was more than twice as high among women with epilepsy. This may be an intimation of reduced fertility among these women.

Zonisamide serum concentrations during pregnancy.

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.