Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital

The low glycemic index treatment, a dietary therapy that focuses on glycemic index and reduced carbohydrate intake, has been successful in reducing seizure frequency in the general epilepsy population. Epilepsy is a common feature of Angelman syndrome and seizures are often refractory to multiple medications, especially in those with maternal deletions. Dietary therapy has become a more frequently used option for treating epilepsy, often in combination with other antiepileptic drugs, due to its efficacy and favorable side effect profile. This study aimed to assess the effectiveness of the low glycemic index treatment for seizure control in Angelman syndrome. Through a retrospective medical record review of 23 subjects who utilized the low glycemic index treatment at the Clinic and Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital, we found that the high level of seizure control and favorable side effect profile make the low glycemic index treatment a viable treatment for seizures in Angelman syndrome. The majority of subjects in our cohort experienced some level of seizure reduction after initiating the diet, 5 (22%) maintained complete seizure freedom, 10 (43%) maintained seizure freedom except in the setting of illness or non-convulsive status epilepticus, 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. The low glycemic index treatment monotherapy was successful for some subjects in our cohort but most subjects used an antiepileptic drug concurrently. Some subjects were able to maintain the same level of seizure control on a liberalized version of the low glycemic index treatment which included a larger amount of low glycemic carbohydrates. No correlation between the level of carbohydrate restriction and level of seizure control was found. Few subjects experienced side effects and those that did found them to be mild and easily treated. The efficacy of the low glycemic index treatment and its favorable side effect profile make it an excellent alternative or supplement to antiepileptic drug therapy for the treatment of seizures in Angelman syndrome.     

Ketogenic diets: Evidence for short- and long-term efficacy

The use of dietary treatments for epilepsy (ketogenic, modified Atkins, and low glycemic index diets) has been in continuous use since 1921. These treatments have been well studied in the short term, with approximately half of children having at least a 50% reduction in seizures after 6 months. Approximately one third will attain >90% reduction in their seizures. Animal studies confirm these findings, with broad evidence demonstrating acute anticonvulsant effects of the diet. Furthermore, the diet appears to maintain its efficacy in humans when provided continuously for several years. Interestingly, benefits may be seen long term even when the diet is discontinued after only a few months of use, suggesting neuroprotective effects. This potential antiepileptogenic activity has been recently demonstrated in some animal studies as well. This review discusses the animal and human evidence for both short- and long-term benefits of dietary therapies.     

Metabolic treatments for intractable epilepsy

When a child on anticonvulsant medications continues to have seizures, what other options should be considered? Over the past 100 years, dietary therapies for the treatment of intractable epilepsy have become more widely recognized, and their use has continued to expand throughout the world. An increasing number of studies has shown efficacy of these metabolic treatments in improving seizure control. Currently, 4 types of dietary therapy are available in the clinic: the classic long chain fatty acid "ketogenic" diet, the medium chain triglyceride diet, the modified Atkins diet, and the low glycemic index treatment. These therapies should be considered earlier in the treatment of intractable epilepsy because they offer a different approach to treatment that has proven efficacious, tolerable, and cost-effective.     

Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy

The ketogenic diet is often effective for intractable epilepsy, but many patients have trouble complying with the strict regimen. The authors tested an alternative diet regimen, a low-glycemic-index treatment, with more liberal total carbohydrate intake but restricted to foods that produce relatively little increase in blood glucose (glycemic index < 50). Ten of 20 patients treated with this regimen experienced a greater than 90% reduction in seizure frequency.     

Low Glycemic Index Treatment in pediatric refractory epilepsy: The first Middle East report

PurposeIntractable epilepsy is a challenging aspects of pediatric epilepsy. This study was conducted to determine the efficacy and tolerability of Low Glycemic Index Treatment (LGIT) in pediatric patients referred to a Children's Hospital in Iran with intractable epilepsy.MethodsWe studied 42 children with refractory epilepsy aged between 1.5 and 17 years of age, from October 2009 to April 2011 in the pediatric neurology department of Mofid Children's Hospital. Patient information on clinical status, seizure type, and baseline frequency, blood and urine biochemistry, neuro-imaging and the EEG were collected. LGIT was initiated on an outpatient basis and the diet was composed of 65% fat, 25% protein and 10% carbohydrate (40–60 g), and the glycemic index of foods was limited to below 50.Results84% of patients were categorized as having more than one seizure per day at study entry, with the remaining children as experiencing over one seizure per week. A greater than 50% seizure reduction was observed in 71.4% of the patients after the second week, in 73.8% at the end of the first month and in 77.8% at the end of the second month. In 30% of the patients a mild increase in blood urea nitrogen (BUN) was detected. The most important reasons for discontinuation of LGIT were restrictiveness, lack of satiation and excessive meat in this diet. No significant complications were observed during the administration of the diet.ConclusionLGIT is a safe and effective adjuvant antiepileptic therapy and may be used as an alternative to the ketogenic diet in conditions when this diet cannot be used.     

Dietary treatment of epilepsy: rebirth of an ancient treatment

Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy.     

Efficacy,safety, and tolerability of the low glycemic index treatment in pediatric epilepsy

Purpose: To report the efficacy, safety, and tolerability of the low glycemic index treatment (LGIT) in pediatric epilepsy. Methods: A retrospective chart review was performed on patients initiating the LGIT at the Massachusetts General Hospital between January 2002 and June 2008. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistries, side effects, and anthropometrics were collected. Initiation of the LGIT was done in an outpatient setting. Patients were educated by a dietitian to restrict foods with high glycemic index and to limit total daily carbohydrates to 40–60 g. Change in seizure frequency was assessed at 1‐, 3‐, 6‐, 9‐, and 12‐month follow‐up intervals. Results: Seventy‐six children were included in the study. Eighty‐nine percent had intractable epilepsy (≥3 antiepileptic drugs). A greater than 50% reduction from baseline seizure frequency was observed in 42%, 50%, 54%, 64%, and 66% of the population with follow‐up available at 1, 3, 6, 9, and 12 months, respectively. Increased efficacy was correlated with lower serum glucose levels at some time points, but not with β‐hydroxybutyrate (BOHB) changes or ketosis status at any time point. Only three patients reported side effects (transient lethargy). Blood urea nitrogen (BUN) was elevated in approximately one‐third of follow‐up laboratory studies. No significant changes were seen in body mass index (BMI) or BMI z‐score at any follow‐up interval. The most cited reason for treatment discontinuation was the restrictiveness of the diet, in 18 patients (24%). Conclusion: The LGIT was associated with reduced seizure frequency in a large fraction of patients, with limited side effects.     

Low glycemic index treatment for seizures in Angelman syndrome

Purpose: The low glycemic index treatment (LGIT) is a high fat, limited carbohydrate diet used in the treatment of epilepsy. The purpose of this study was to assess the efficacy and tolerability of the LGIT for the treatment of refractory seizures in pediatric patients with Angelman syndrome. Methods: A pediatric Angelman syndrome cohort with refractory epilepsy was treated with the LGIT and followed prospectively over 4 months. Parents recorded a daily seizure log for a minimum of 1 month prior to the start of treatment as well as throughout the LGIT trial. Electroencephalography (EEG) and neuropsychological assessments (Scales of Independent Behavior‐Revised and the Vineland Adaptive Behavior Scales‐2nd Edition were obtained for each subject at both baseline and 4‐month follow‐up time points. Clinical evaluations of subjects were completed by a neurologist and dietitian at the time of enrollment, as well as following both the first and fourth months of dietary therapy. At each time point, blood for laboratory chemistries was drawn and anthropometric measures were obtained. Key Findings: Six children (mean age 3.3 years, range 1.1–4.8) with genetically confirmed Angelman syndrome initiated the LGIT, and completed the trial with no significant adverse events. Cohort averages for indices of seizure severity were as follows: age of 1.6 years at seizure onset, 3 lifetime antiepileptic drugs tried (range 1–6), and baseline seizure frequency of 10.1 events/week (range: 0.4–30.9). All subjects had a decrease in seizure frequency on the LGIT, with five of six exhibiting >80% seizure frequency reduction. All posttrial EEG studies showed improvement and three of four children with epileptiform activity on his or her baseline EEG had no discharges present on follow‐up EEG. Developmental gains were noted by parents in all cases, although few of these neurocognitive gains were statistically significant on neuropsychological assessment. Significance: This is the first prospective study assessing the LGIT for epilepsy. Our results indicate that this dietary therapy is highly effective in treating Angelman syndrome–related seizures. The diet was well tolerated by subjects as evidenced by five of six subjects remaining on the LGIT after completion of the trial. Beyond the prospective trial window, all five subjects who remained on the diet had >90% seizure reduction after 1 year of LGIT therapy. Despite the small sample size in this prospective study, the results indicate a potentially higher degree of efficacy of the LGIT for the Angelman syndrome population than that observed in the general epilepsy population. Although this study is too small to make definitive recommendations, these results suggest that the LGIT is a promising treatment option for Angelman syndrome–related epilepsy.     

Clinical analysis of the effectiveness and safety of vigabatrin

The efficacy and safety of vigabatrin (VGB) has been extensively evaluated in preclinical and clinical studies but level of effectiveness in different type of seizures has yet to be established. The aim of our study is the prospective evaluation of anticonvulsant efficacy and toxicity of VGB. This long-term observation mainly focusing on efficacy of VGB in partial vs. secondarily generalized seizures were considered separately. In our study the criterion of drug resistance is occurrence per month of at least 1 tonic-clonic seizure or at least 2 complex partial seizures in 3 following months. The studies are based on 73 patients (39 F and 34 M), with average age of 26 years. After two weeks of treatment with sabril the drug was withdrawn in 5 patients because of side effects. The period of observation was 12 months. In group I--from total of 73 patients with partial seizures (including secondarily generalized)--31 (42%) of patients suffered only from partial seizures. Complex partial seizures occurred in 18 of patients; in this group were also 13 patients with simple partial seizures. Group II consisted of 42 patients (58%) who suffered from secondarily generalized tonic-clonic seizures. Number of seizures in group of patients with tonic-clonic seizures was from 1 to 16 per month (average 3.4) and in group of patients with complex partial seizures was from 1 to 70 per month (average 13.29). After titration period, Vigabatrin was given in doses of 500 to 3500 mg daily. Mean monthly fit frequency was calculated for over 3 months prior to the addition of vigabatrin and 12 months of therapy at the patient's maximum dose. Monthly fit frequency expressed as mean +/- standard error of the mean, and this statistical significance was determined using MANOVA for repeated measurement. Average monthly fit frequency of partial seizures has been reduced from 13.29 to 6.96 (p < 0.0001) and of generalized seizures from 3.38 to 1.38 (p < 0.0001). The percentage of patients achieving an increase of at least 75%--(Ratio < -0.6)--of seizures was greater in generalized seizures (27.3) than in partial ones (21.3). VGB is effective and well tolerated in refractory patients requiring add-on antiepileptic treatment and it has shown efficacy both in therapy of refractory partial seizures as well of secondarily generalized ones.     

Acute pancreatitis causing death in a child on the ketogenic diet

The ketogenic diet has demonstrated good efficacy in children with pharmacologically resistant seizures. Relatively few serious complications have been reported in the more than 70 years in which the diet has been used. We report a child who developed acute pancreatitis and died. A 9-year-old girl had a seizure disorder with associated developmental delay owing to glucose transport protein deficiency. The ketogenic diet with medium chain triglyceride oil had been initiated shortly after diagnosis in infancy. She was not on anticonvulsants. She presented in coma with decreased respiratory effort and shock, requiring resuscitation. Investigations were consistent with pancreatitis. Despite fluid resuscitation and inotropic support, she had prolonged hypotension and acidosis. She subsequently had a cardiac arrest and died. A postmortem examination confirmed hemorrhagic pancreatitis. Hypertriglyceridemia is a risk factor for developing acute pancreatitis. The high fat content of the ketogenic diet often causes hyperlipidemia. The outcome for this patient raises concern regarding a potential consequence of the ketogenic diet.     

Gabapentin in refractory partial epilepsy — a trial in India

Gabapentin (GBP) has been shown to be effective an add-on drug for the treatment of refractory partial epilepsy. We undertook an open clinical trial to test its efficacy for the first time in India. Twenty-six patients with refractory partial seizures (> 4 per month) were given GBP in a titrated dose and the seizure frequency was noted for 3 months. The mean reduction in seizures was significant: 15.87 (SD = 4.5) vs 5.80 (SD = 10.25). The mean percentage change (PCH) from the baseline was - 36. Twenty-one of 26 (80%) patients had a reduction in the number of seizures, and 13/26 (50%) were identified as responders (> 50% reduction in seizures). The responders were significantly younger than the nonresponders. Adverse events were mild and noted in 46% patients. Although the trial has its limitations, this is probably the first trial of GBP in a developing country.     

Efficacy of lamotrigine in institutionalized, developmentally disabled patients with epilepsy: a retrospective evaluation.

The paper evaluates the efficacy of the newer anticonvulsant lamotrigine in a developmentally disabled patient population. A retrospective evaluation was done at two institutional centres to assess adjunctive lamotrigine (Lamictal) efficacy in a developmentally disabled population. Mean seizure frequency was compared between a 2-month pre-lamotrigine baseline period and a 2-month treatment period. A 3-month lamotrigine titration phase occurred between baseline and treatment periods. Seizure frequency data was obtained from standardized, daily seizure records. Adverse effect data was obtained from medical and nursing notes. An intent to treat analysis was performed. Data were analysed using Student's t-test for paired data. We evaluated 44 centre residents (25 male, 19 female, average age 33 +/- 11 years). Mean lamotrigine dose was 272 +/- 133 mg per day. A significant reduction in seizure frequency was noted. Seizure frequency (all seizures) was 10.1 +/- 11.2 during the baseline period vs. 5.8 +/- 7.9 seizures per month during the treatment period (P = 0.002). Thirty-two percent of patients (n = 14) had greater than a 75% reduction in seizure frequency. Twenty-three percent of patients (n = 10) had a 50-74% seizure reduction. Twenty-five percent of patients (n = 11) had less than a 50% reduction in seizures, while 20% (n = 9) had an increase in seizures. A significant reduction of 48% in generalized seizures (9.5 +/- 11.6 vs. 4.9 +/- 6.5 seizures per month, P = 0.013) was noted. Reductions in partial seizure frequency of 48% (7.9 +/- 10 vs. 4 +/- 6.6 seizures per month, P = 0.16) as well as in mixed-type seizures (19.9 +/- 9.3 was vs. 15 +/- 12.1 seizures per month, P = 0.11) were also seen; however, these changes did not reach significance. Overall, lamotrigine was well tolerated by the subject population. Adjunctive treatment with lamotrigine appears to be an efficacious and well-tolerated treatment for seizures in a significant percentage of developmentally disabled patients with epilepsy.     

Managing Lafora body disease with vagal nerve stimulation

A 17‐year‐old female, of consanguineous parents, presented with a history of seizures and cognitive decline since the age of 12 years. She had absence, focal dyscognitive, generalized myoclonic, and generalized tonic‐clonic seizures, all of which were drug resistant. The diagnosis of Lafora body disease was made based on a compatible clinical, EEG, seizure semiology picture and a disease‐causing homozygous mutation in the EPM2A gene. A vagus nerve stimulator (VNS) was inserted and well tolerated with a steady decrease and then stabilization in seizure frequency during the six months following insertion (months 1–6). At follow‐up, at 12 months after VNS insertion, there was a persistent improvement. Seizure frequency during months 7–12, compared to pre‐VNS, was documented as follows: the absence seizures observed by the family had decreased from four episodes per month to 0 per month, the focal dyscognitive seizures from 300 episodes per month to 90 per month, the generalized myoclonic seizures from 90 clusters per month to eight per month, and the generalized tonic‐clonic seizures from 30 episodes per month to 1.5 per month on average. To our knowledge, this is the second case reported in the literature showing efficacy of VNS in the management of seizures in Lafora body disease.     

Influence of protein-restricted diet on motor response fluctuations in Parkinson's disease]

The clinical management of Parkinson's disease has been revolutionized by the introduction of levodopa therapy. It has significantly reduced disability and has extended life expectancies of patients with Parkinson's disease. However, motor response fluctuations frequently appear in patients after long-term treatment with levodopa. In this study, we investigated the effect of protein-restricted diet on fluctuations in eight patients with Parkinson's disease who had been receiving long-term levodopa treatment (mean 12.5 years). Two weeks of protein-restricted daytime diet (7.5 g total at breakfast and lunch) was followed by 12.5 g total at breakfast and lunch. At night, high-protein diet (40-50 g at dinner) was offered to the patients in order to maintain total daily protein intake at Japanese standard level. The medication schedule of levodopa and other antiparkinsonian drugs was not changed within 2 weeks after the study was began. Fluctuations were reduced in 7 of the 8 patients. But in only one patient (case 6), dyskinesia and general condition got worse and stopped this therapy. Body weight, serum protein and albumin levels did not change significantly for at least three month after the study was begun in every 6 patients who were examined. Homovanillic acid level of cerebrospinal fluid reduced in every 4 patients who were examined. We concluded that protein-restricted diet during the daytime offers a fascinating technique for the control of motor response fluctuations in patients with Parkinson's disease undergoing long-term levodopa treatment. But this therapy must be indicated carefully. Mechanism of this therapy may has something to do with improvement of dopamine metabolism in the brain.     

Adjunctive Therapy for Intractable Epilepsy with Ethotoin

In a retrospective study, records of 46 patients (24 women and 22 men aged 17-51 years; mean 29.2 years), who had been treated with ethotoin (EHN) as adjunctive therapy for control of intractable seizures were reviewed. Overall, approximately 51% of this highly selected patient population had a reduction greater than 50% in overall seizure frequency 1 month after initiation of treatment. This was reduced to approximately 25% for the last 3 months of follow-up (mean follow-up period 10.6 months). Tonic seizure frequency was reduced most dramatically, by greater than 50%, in 60% of patients at 1 month and in 35% of patients for the last 3 months of follow-up. This study suggests that prospective controlled trials of EHN, especially for tonic seizures, are needed.     

The ketogenic diet inhibits epileptogenesis in EL mice: a genetic model for idiopathic epilepsy

PURPOSE: The ketogenic diet (KD) is a high-fat, low-carbohydrate and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its effects on epileptogenesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy. METHODS: Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice were weighed and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze. RESULTS: KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 weeks on the diet. Plasma glucose levels and associative learning were similar in the treated and control groups, but the plasma beta-hydroxybutyrate levels were significantly higher in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice. CONCLUSION: The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogenesis. The KD did not influence plasma glucose levels or associative learning. Therefore, the EL mouse may serve as a good model to study the antiepileptogenic mechanisms of the KD.     

The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: efficacy and tolerability in clinical practice

The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet that is used as a treatment for patients with difficult-to-control epilepsy. The present study assesses the efficacy and tolerability of the KD as an add-on therapy in adults with chronic refractory epilepsy. 15 adults were treated with the classical diet or MCT diet. During a follow-up period of 1 year we assessed seizure frequency, seizure severity, tolerability, cognitive performance, mood and quality of life (QOL). We found a significant reduction in seizures among the patients who followed the diet at least 1 year (n=5). Of these 5 patients, 2 had a reduction between 50 and 90%. Analyzing the study months separately, we found a seizure reduction of ≥50% in 26.6% of the patients during at least 1 month of treatment. Common side-effects were gastrointestinal disorders, loss of weight and fatigue. There was a considerable, non-significant improvement found in mood and QOL scores. Improvements were independent of reduction in seizure frequency, indicating that the effects of the KD reach further than seizure control.     

Children with seizures exhibit preferences for foods compatible with the ketogenic diet

Although highly effective for the treatment of intractable epilepsy, the ketogenic diet is not always included in the treatment option hierarchy presented to families, in part due to perceptions that children will find the high-fat/low-carbohydrate regimen unpalatable. This study assessed if children with seizures exhibit food preferences compatible with the diet, as well as if caregivers were accurate in predicting preferences. Children aged 2-17, with (n=29) and without (n=30) a history of seizures, participated in a paired choice food preference assessment while parents estimated child preferences verbally. Children with seizures exhibited significantly higher preferences for fat versus carbohydrate foods compared with controls, and parents demonstrated low accuracy. Future studies could use similar assessment methods to prospectively track whether such preferences predict diet compliance and/or efficacy. Research into the underlying metabolic basis for this preference and possible related neurophysiological mechanisms in seizure etiology and treatment is warranted.     

Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report

A 56 year old woman had a 19 month history of a severe subacute progressive cerebellar degeneration, peripheral sensory neuropathy, and urinary incontinence. She was confined to a wheelchair, needed assistance with eating, and her speech was almost unintelligible. No underlying cancer was found despite repeated investigations, and no autoantibodies were demonstrated. She received a 3-month course of intensive immunosuppressant therapy with intravenous immunoglobulin 400 mg/kg per day for 5 days every month, oral cyclophosphamide 50 mg twice or three times a day to maintain the total lymphocyte count between 500 and 750/mm(3), and prednisone 60 mg per day. She experienced dramatic subjective and objective improvement. The dysarthria and the upper extremity dysmetria disappeared, and she regained the ability to write and cook. The lower extremity ataxia improved and she became able to walk with a cane. Urinary incontinence disappeared. A trial of intensive immunosuppressant treatment is worth considering in a patient with a clinical syndrome resembling paraneoplastic disorders, even if an underlying neoplasm and autoantibodies are not demonstrated.     

Chronic, Habitual Cocaine Abuse and Kindling-Induced Epilepsy: A Case Report

Kindling has been suggested as a possible mechanism for cocaine-induced seizures in chronic cocaine abusers, even though no convincing examples have been reported. We report a 37-year-old woman who initially experienced generalized tonic-clonic seizures (GTC) only immediately after "crack" use. She had a normal examination, negative family or past history for seizures, and normal cranial computed tomography and EEG. After she had abused cocaine almost daily for 2 years, her EEG demonstrated bitemporal slowing with independent spikes, and seizures were no longer temporally associated with acute cocaine use. Thereafter, despite complete abstinence from cocaine and treatment with phenytoin, she continued to experience four to six GTC a month. In light of the lack of other predisposing factors for epilepsy, this case may represent an example of cocaine-induced kindling in humans.