Tonic and atonic seizures: Medical therapy and ketogenic diet

Tonic and atonic seizures are typically seen in what are often referred to as the catastrophic epilepsies. In simply considering what each of the terms signifies (either the complete loss of tone or a marked increase in tone), they would appear to be at the most diverse ends of the spectrum. They would appear to be as opposite as hot and cold or hard and soft. And yet they are often found to occur in the same patient. This article examines the nature of these seizures and discusses some of the syndromes in which they are seen. Although these seizures are often very difficult to control, some of our medications/therapies have been shown to be effective. Recommendations concerning the efficacy of these therapies and a review of the newer therapies are provided. In addition, the ketogenic diet has been particularly successful in treating these seizures; this is discussed in some detail. Finally, although outcomes for these children are generally less than ideal, many can be helped with a persistent approach that balances seizure control against the side effects of medication.     

Ketogenic diet in patients with Dravet syndrome

PURPOSE: The ketogenic diet (KD) has been used as a therapeutic alternative to antiepileptic drugs (AEDs) for refractory epilepsy. Severe myoclonic epilepsy in infants or Dravet syndrome (DS) is one of the most malignant epileptic syndromes. In this retrospective study, we evaluated the efficacy and tolerability of the KD in patients with diagnostic criteria of DS. METHODS: Between March 1, 1990, and August 31, 2004, 52 patients who met diagnostic criteria for DS were enrolled in a study at our department. Twenty of them were placed on the KD with the Hopkins protocol and followed up for a minimum of 1 year. RESULTS: Three of the 20 original children stayed on the diet for 12 months, four children for 2 years, four children for 3 years, and two children for 4 years. One year after initiating the diet, 13 (65%) of the initial patients remained on the diet. Two (15%) patients were seizure free, eight (61.7%) children had a 75-99% decrease in seizures, and the remaining three (23%) children had a 50-74% decrease in seizures. Thus 1 year after starting the diet, 10 (77%) children had achieved a >75% decrease in their seizures. Four patients have been off the diet for >2 years; one of them is seizure free, two have sporadic seizures, and one, who abandoned the diet after 2 years of adhering to it, relapsed. No differences in seizure control when compared with age, sex, or seizure type were found. CONCLUSIONS: Considering the severity and intractability of seizures in patients with DS, the fact that 10 of the 13 children who remained on the diet had a significant reduction in number of seizures shows that the KD is at present an interesting therapeutic alternative. Even in patients in whom seizure reduction was not dramatic, quality of life improved, and in all of them, the number of AEDs was reduced to one or two. We consider that children with DS should be offered the KD immediately after three adequate trials of AEDs have failed.     

Ketogenic diet treatment in adults with refractory epilepsy

The ketogenic diet (KD) is an effective treatment for refractory epilepsy in children. It has been little studied in adults. We evaluated the efficacy of, safety of, and compliance with adjunctive KD treatment in adults with refractory epilepsy in a prospective open-label pilot study. Seizure frequency was evaluated for 4 baseline months, 4 months of adjunctive KD treatment with a 3:1 [fat]:[carbohydrate+protein] weight ratio and 1600 kcal/day, and subsequent elective open-ended KD treatment. A 3:1 ratio was used instead of the 4:1 ratio employed in children because of greater palatability. Average monthly seizure frequency and seizure-free months at baseline were compared with KD months 1-4 (phase 1) and all KD treatment (phase 2). Diet compliance was evaluated with daily urine ketone body and monthly serum β-hydroxybutyrate levels. Twelve subjects were treated for up to 26 months. Three stopped treatment early for psychosocial reasons (n=2) or lack of efficacy. Seven of the 12 subjects were fully compliant, 4 were partially compliant, and 1 was noncompliant. Mean seizure frequency declined by 38.4 and 44.1% for phases 1 and 2, respectively (P=0.04). Forty-two percent and 50% of subjects had a >50% reduction during phases 1 and 2, respectively. Four of 12 subjects (33%) had a >85% seizure reduction. Twenty percent of subject-months were seizure free at baseline versus 56% during both study phases (P=0.04). Adverse effects were mild: nausea, vomiting, diarrhea, constipation, and weight loss.     

Acute encephalitis with refractory,repetitive partial seizures

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) represents a peculiar form of encephalitis mainly affecting children. They usually present abruptly with seizure or impaired consciousness as well as high-grade fever following antecedent infection. Seizures in AERRPS are almost exclusively of localized origin, whose semiology includes eye deviation, hemifacial twitching, hemiclonic convulsion, and autonomic manifestations. Partial seizures are brief, but repeat with increasing frequency and develop status epilepticus at nadir. They are extremely pharmaco-resistant and are only suppressed by intravenous administration of high-dose barbiturates. Although acute seizures are hardly controlled, patients gradually recover with decreasing seizure frequency and continuously evolve into post-encephalitic epilepsy without latent period. Residual cognitive impairment is common. Electroencephalograms in active stage demonstrate electrical seizure activities and interictal periodic discharges. Magnetic resonance imaging reveals late cerebral atrophy with limited signal abnormality. Persistent fever during active stage, cerebrospinal fluid (CSF) pleocytosis, and up-regulation of neopterin raise the hypothesis that inflammatory process is involved in this condition. Furthermore, early production of autoantibody against NMDA receptor 2B in serum and CSF, although its disease specificity is still in controversy, is suggestive of autoimmune etiology. Exploration for definite clinical marker is currently in progress.     

Ketogenic diet for refractory epilepsy with MEHMO syndrome: Caution for acute necrotizing pancreatitis

BackgroundThe MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients’ quality of life.CaseA 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient’s clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient’s refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death.ConclusionThe pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and β-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.     

Acute encephalitis with refractory, repetitive partial seizures

BACKGROUND: Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a new epileptic syndrome described by Sakuma in Japan in 2001. The clinical manifestations, neuroimaging findings and outcome of AERRPS in Taiwan have not been reported. METHODS: From 2000 to 2006, we collected cases that fulfilled the diagnostic criteria of AERRPS and analyzed the clinical course, virology, medication, electroencephalographic findings, neuroimaging characters and prognosis retrospectively. RESULTS: Fourteen children aged from 1 year and 2 months to 15 years and 6 months were enrolled. They presented with prodromic symptoms including fever (n=13, 92.9%), upper respiratory tract infection symptoms (n=12, 85.7%) and gastrointestinal tract discomfort (n=6, 42.9%). Seizures occurred 3-14 days after antecedent symptoms with patterns of generalized tonic-clonic seizures, focal seizures or myoclonic seizures. The seizures were refractory to combinations of antiepileptic drugs (AEDs). Prolonged fever (n=14, 100.0%), hypersensitivity to AEDs (n=11, 78.6%) and liver function impairment (n=8, 57.1%) were noted during the period of hospitalization. The follow-up EEG findings were similar to those of initial findings including epileptiform discharges and/or generalized background slow waves. Initial brain MRI scans were normal but later showed focal or multifocal abnormal signal intensity followed by generalized brain atrophy in more than 50% of cases. The general prognosis was poor with variable psychomotor retardation and persistence of refractory epileptic seizures. CONCLUSIONS: The similarities of the clinical features support AERRPS as a new epileptic syndrome. More study is needed to specify the etiology of the syndrome as the first step for more effective treatment.     

The role of ketogenic diet in the treatment of refractory status epilepticus

Ketogenic diet (KD) is known to be effective in intractable epilepsy. However, the role of KD in refractory status epilepticus (RSE) has not been well described. The aim of this study is to explore the role of KD in patients with RSE. We retrospectively reviewed the medical records of four children and one adult with RSE between October 2006 and August 2010. All presented with status epilepticus (SE) that was presumed to be associated with viral encephalitis. After we failed to control the seizures with standard measures for SE, we tried KD. The overall seizure frequency decreased to <50% of baseline in median eight (1-19) days. At one month of KD, two patients were seizure-free, one patient showed >90% seizure reduction, and the others had >75% decrease without generalized seizures. With improvement in the RSE, we were able to taper the antiepileptic drugs (AEDs) and wean patients from prolonged mechanical ventilation. The adverse events of KD in RSE included aspiration pneumonia, gastroesophageal reflux, constipation, and hypertriglyceridemia. Those results demonstrate that KD can be a valuable therapeutic option for patients with RSE.     

A pilot trial with modified Atkins' diet in adult patients with refractory epilepsy

OBJECTIVES: At Ghent University Hospital, the feasibility and efficacy of the modified Atkins' diet was evaluated in adult patients with refractory epilepsy. The Atkins' diet restricts carbohydrate intake and was originally designed for weight loss. PATIENTS AND METHODS: During a 6-month trial period, a carbohydrate restriction of 20g/day was in place. During a 36h hospital admission, patients were instructed about the diet. Patients underwent clinical neurological testing, EEG, ECG, blood and urine analyses and mood evaluation before and during the trial. Seizure frequency and side effects were recorded in seizure diaries and followed up at monthly clinic visits. RESULTS: Eight patients were included in the study. Three out of eight patients followed the diet for 6 months. One out of three patients showed a >50% seizure reduction, 1/3>30%, and 1/3<30%. Side effects such as constipation and diarrhoea were mild and occurred mainly during the initial week of the diet. Patients reported improved concentration and well being. This was confirmed by improved scores on the Beck Depression Inventory Scale. CONCLUSION: This pilot study shows that the modified Atkins' diet is feasible in an adult population, and that seizure frequency reduction is possible. The results need to be confirmed in larger prospective, controlled studies with comparison groups.     

Ketogenic diet in adolescents and adults with epilepsy

PurposeThe ketogenic diet is an alternative treatment for patients with refractory epilepsy. Most studies to date report dietary response in children. There are limited data evaluating the efficacy of the ketogenic diet in adults. This is a report of the long-term outcome in a largely adult population of patients treated with the ketogenic diet for epilepsy.MethodTwenty-nine adult and adolescent patients (mean age 32 years, range 11–51) were initiated on the ketogenic diet and followed until diet discontinuation. Clinical response and adverse effects were noted during the duration of the diet.ResultsFifty-two percent of patients had a significant reduction in seizure frequency on the ketogenic diet, including 45% with ≥50% reduction in seizure frequency. Thirty-one percent had no improvement, seven percent were unable to successfully initiate the diet, and 10% had a >50% increase in seizure frequency. The diet was continued for a mean of 9 months (range 0.13–35 months), with five patients completing ≥23 months. There was a trend toward better response and better tolerability/longer duration in patients with symptomatic generalized epilepsy. The diet was generally well-tolerated, but undesired weight loss and constipation were the most frequent adverse effects.ConclusionThe ketogenic diet can be used safely in the adult and adolescent population, with a response rate similar to those seen in children. Patient with symptomatic generalized epilepsy may be particularly good candidates for this type of dietary treatment.     

Ketogenic parenteral nutrition in three paediatric patients with epilepsy with migrating focal seizures

Aims. Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare epilepsy syndrome, characterized by an onset of multifocal seizures before the age of six months and a rather typical ictal EEG pattern. The ketogenic diet (KD) has been shown to be a treatment option in these patients with variable results. The KD is generally given by enteral formula or solid food, however, patients on the KD often have coexisting medical disorders that may impair the gastrointestinal tract and, in these cases, parenteral nutrition support may be needed. We present our experience with three patients who had been on the KD because of EIMFS, who were acutely unable to absorb nutrients through the intestinal tract. Results. For these patients, we were unable to reach ketogenic ratios higher than 1.5:1 because of the limited fat intake via the parenteral route. This ratio, nevertheless, was adequate for maintenance of seizure control while allowing short‐term bowel rest. Conclusions. Even though our report is limited as it provides no controlled evidence, ketogenic parenteral nutrition should be considered in children on the KD when enteral nutrition is not feasible. Special care should be taken to maintain ketosis and avoid undesired carbohydrates. Patients may respond well to ketogenic parenteral nutrition in spite of a lower ketogenic ratio.     

Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep

Purpose: To evaluate the effect of the ketogenic diet on electroclinical characteristics and cognitive function in children with continuous spikes and waves during slow sleep (CSWS). Methods: Five children (four boys, one girl) aged between 8 and 13 years with CSWS refractory to conventional antiepileptic drugs (AEDs), including levetiracetam, and steroids were included. The prospective electroclinical assessment was performed prior to the ketogenic diet and once every 6 months post initiation during the 2‐year period. All children underwent neuropsychological testing prior to the ketogenic diet and four of the children again 12 months after the diet’s introduction. In case 4 the testing has been performed after 7 months and the diet was withdrawn after 9 months because of the lack of efficacy and the parent’s wishes. In two patients the cognitive functions were also evaluated after 24 months since the diet’s initiation. During the period on the ketogenic diet the concomitant AED treatment was unchanged. Results: Electrographic evaluation after 24 months on the ketogenic diet showed CSWS resolution in one patient, mild decrease of the spike–wave index in one, and lack of response in three patients. The ketogenic diet did not influence the neuropsychological outcome, and intelligence quotient (IQ) scores remained low at the end of the follow‐up period. However, in two patients an improvement in attention and behavior was demonstrated. Discussion: This is the first study evaluating the efficacy of the ketogenic diet in children with CSWS. Five presented cases were refractory to AEDs and steroids. Only one case responded with complete CSWS disappearance; in one the effect of the ketogenic diet was partial and intermittent, whereas in three patients no response has been observed. These results show that the ketogenic diet did not appear to influence the neuropsychological outcome; however, the absence of a control group makes it impossible to conclude with certainty.     

Ketogenic diet using a Japanese ketogenic milk for patients with epilepsy: A multi-institutional study

Background

In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s.

The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus

Prolonged status epilepticus (SE) can be refractory to conventional interventions, with high rates of subsequent morbidity and mortality. A high fat, low protein, low carbohydrate ketogenic diet (KD) has been used successfully to treat intractable epilepsy. However, its possible role in prolonged SE has not been well described. We report successful use of the KD in two adult patients with prolonged nonconvulsive SE (NCSE) refractory to multiple other interventions. Our observations suggest induction of ketosis may be a novel strategy to safely and effectively treat status in adults even after weeks to months of refractory seizures. Although there are few data regarding the use of the ketogenic diet in the treatment of adult epilepsy syndromes, it may be an option for the treatment of adults with refractory, prolonged SE.     

Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures

Purpose:   To evaluate efficacy and tolerability of levetiracetam (LEV; Keppra^®) as add-on therapy in Chinese patients with refractory partial-onset seizures.
Methods:   In this multicenter, double-blind, randomized, placebo-controlled trial, 206 patients aged 16–70 years with uncontrolled partial-onset seizures were randomized to receive LEV (n =103) or placebo (n =103); 202 patients (LEV, n =102; placebo, n = 100) comprised the intent-to-treat population. An 8-week historical baseline period confirmed eligibility according to seizure count. The 16-week treatment period consisted of a 4-week up-titration period (LEV, 1,000–3,000 mg/day in two equal divided doses) followed by a 12-week maintenance period. Efficacy assessments were based on weekly frequency of partial-onset seizures during the 16-week treatment period.
Results:   LEV significantly decreased weekly partial-onset seizure frequency over placebo by 26.8% (p  < 0.001). Median percentage reductions in weekly partial-onset seizure frequency from historical baseline were 55.9% for LEV and 13.7% for placebo (p  < 0.001). The ≥50% responder rates were 55.9% for LEV, compared with 26.0% for placebo (p  < 0.001). Freedom from partial-onset seizures during treatment period was achieved by 11 LEV patients (10.8%) and 2 placebo patients (2.0%) (p = 0.012). Adverse events were reported by 65 LEV-treated patients (63.1%) and 62 placebo-treated patients (60.2%); most were of mild-to-moderate intensity. The most common adverse events were somnolence (LEV, 17.5%; placebo, 17.5%), decreased platelet count (LEV, 9.7%; placebo, 9.7%), and dizziness (LEV, 7.8%; placebo, 13.6%).
Discussion:   Add-on LEV was effective and well-tolerated in Chinese patients with refractory partial-onset seizures.     

Effect of topiramate, in combination with lidocaine, and phenobarbital, in acute encephalitis with refractory repetitive partial seizures

Objective: Acute encephalitis with refractory repetitive partial seizure (AERRPS) is a peculiar type of post-encephalitic/encephalopathic epilepsy. Here we report an analysis of AERRPS in a series of children and propose an effective treatment option for seizure control in these children. Methods: We retrospectively reviewed cases of AERRPS treated in a pediatric intensive care unit, between February 2002 and June 2006. Clinical characteristics were systemically assessed. Burst suppression coma was induced by high-dose suppressive therapy; 24-h electroencephalogram (EEG) monitoring was performed on each patient. The goal of treatment was to achieve complete clinical seizure control or burst-suppression pattern on EEG, aiming for an interburst interval of >5 s. Brain imaging was done for each patient. Results: There were nine patients (seven boys), aged 5–15 years. Clinical symptoms included fever (100%), upper respiratory symptoms (66.7%) and altered consciousness (66.7%). All patients received multiple high-dose suppressive drugs and were intubated with/without inotropic agents. Seizures in three patients were stopped after high-dose lidocaine infusion (6–8 mg/kg/h) in the acute stage and three patients were stopped after high dose phenobarbital (serum level 60–80 ug/mL) combined with high-dose oral topiramate (15–20 mg/kg/day). Follow-up for this study was 16–61 months. Two subjects died while seven developed epilepsy and/or neurologic deficits; none returned to baseline. All survivors were discharged and continued multiple antiepileptic medications. Conclusions: Our data indicates that children with AERRPS have high mortality and morbidity rates. High-dose topiramate combined with high-dose lidocaine infusion or high-dose phenobarbital in the acute stage might be an effective treatment option for children with AERRPS.     

Long-term follow-up of the ketogenic diet for refractory epilepsy: Multicenter Argentinean experience in 216 pediatric patients

Purpose

In this Argentinean retrospective, collaborative, multicenter study, we examine the efficacy and tolerability of the ketogenic diet (KD) for different epilepsy syndromes.

Materials and methods

we evaluated the clinical records of 216 patients started on the KD between March 1, 1990 and December 31, 2010.

Results

One hundred forty of the initial patients (65%) remained on the diet at the end of the study period. Twenty-nine patients (20.5%) became seizure free and 50 children (36%) had a 75–99% decrease in seizures. Thus, 56.5% of the patients had a seizure control of more than 75%. The best results were found in patients with epilepsy with myoclonic-astatic seizures, Lennox–Gastaut syndrome, and West syndrome. Good results were also found in patients with Dravet syndrome, in those with symptomatic focal epilepsy secondary to malformations of cortical development, and in patients with tuberous sclerosis. Seizures were significantly reduced in four patients with fever-induced refractory epileptic encephalopathy in school-age children and in two patients with epileptic encephalopathy with continuous spikes and waves during slow sleep. The median period of follow-up after discontinuation of the diet was 6 years. Twenty patients who had become seizure free discontinued the diet, but seizures recurred in five (25%). Of 40 patients with a seizure reduction of more than 50% who discontinued the diet, 10 presented with recurrent seizures.

Conclusion

The ketogenic diet is a good option in the treatment of refractory epilepsy. After discontinuing the diet, seizures recurrence occurred in few patients.     

Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study

Purpose

To evaluate the GABA_A receptor in the autistic brain, we performed ¹²³I-IMZ SPECT in patients with ASD. We compared ¹²³I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings.

Subjects and methods

The subjects consisted of 24 patients with ASD (mean age, 7.3 ± 3.5 years), including 9 with autistic disorder (mean age, 7.0 ± 3.7 years) and 15 with Asperger’s disorder (mean age, 7.5 ± 3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8 ± 3.6 years) without intellectual delay as a control group.For an objective evaluation of the ¹²³I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically.

Results

In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of ¹²³I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings.

Conclusion

The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of ¹²³I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).