Doose Syndrome Research Articles

Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy

Background: Myoclonic-astatic epilepsy (MAE) is an epileptic syndrome characterized by unique myoclonus, myoclonic-astatic, or astatic seizures in childhood. MAE prognosis vary from spontaneous remission to intractable seizures with profound mental retardation. Aim: Identifying early risk factors may optimize the treatment of children with MAE. Our hypothesis is early onset age and focal spike discharges on EEG indicate a poor MAE prognosis. Methods: Using the medical records of 9 children with MAE, we analyzed their clinical histories, EEG findings, and seizure symptoms. All patients were given follow-up observations/treatments by our department for at least 2years after MAE onset. Results: Five of the patients were given favorable prognoses because their seizures disappeared within 2years of onset; the other 4 received poor prognoses because their seizures continued more than 2years. MAE onset in patient with refractory seizures was earlier than that in those with a favorable prognosis (7–24months vs. 23–38months). All the patients with refractory seizures showed moderate or severe mental retardation. Among the 5 patients with good prognosis, EEGs showed two with focal spike discharges and three with only generalized spike discharges. In contrast, all cases with a poor prognosis had focal spike discharges. Conclusions: MAE onset in patients with refractory seizures occurs earlier than in those with favorable prognosis. Prognosis was excellent when EEG findings show no focal spike discharges. Both early seizure onset and the focal spike discharges associated with MAE are indicators of poor prognosis.

Neuroimaging and electroencephalographic changes after vagus nerve stimulation in a boy with medically intractable myoclonic astatic epilepsy

Myoclonic astatic epilepsy (MAE) is characterized by multiple seizure types, which are often refractory. Although vagus nerve stimulation (VNS) is an alternative treatment for medically intractable seizures, its exact mechanism of action remains unclear. Herein, we report the case of a 4-year-old boy with intractable MAE who has been in a seizure-free status for 2 years and 3 months since 6 months after the implantation of a vagus nerve stimulator (Model 103, Cyberonics, Inc., Houston, TX). Various test results 6 months after VNS were compared with those before VNS. Results of an electroencephalograph revealed disappearance of epileptiform discharges and an increased beta-gamma spectrum rhythm. The brain diffusion-tensor imaging showed an increased ratio of fraction anisotropy in the right fimbria-fornix, indicating improved diffusion of the white matter tract, and (18)F-fluorodeoxyglucose positron emission tomography revealed globally improved cerebral glucose metabolism. His cognitive and social-emotional performances also improved at 2 years after VNS. To the best of our knowledge, this is the first report to describe the effects of VNS on fimbria-fornix and glucose metabolism in MAE.

Influence of ketogenic diet on the clinical effects and electroencephalogram features in 31 children with pharmacoresistant epileptic encephalopathy

To investigate the effect of ketogenic diet (KD) on the clinical and electroencephalogram features in children with pharmacoresistant epileptic encephalopathy. Thirty-one children (19 boys, 12 girls) aged 7 months to 7 years (mean 2 years 5 month) with epilepsy refractory to conventional antiepileptic drugs (AEDs) were included in this study. In addition to their original AED treatment, the children were assigned to different ketogenic diets based on their age. The prospective electro-clinical assessment was performed prior to the KD and then one week, one month and again 3 months after the initiation of therapy, respectively. The reduction of seizure frequency in 52%, 68% and 71% of all patients exceeded 50% one week, one month and three months after KD treatment respectively. KD is particularly effective in myoclonic astatic epilepsy (MAE; Doose Syndrome) and West syndrome with 100% and 81.25% of the patients having a greater than 50% seizure reduction, respectively. After 3 months of KD treatment, more than 2/3 patients experienced a reduction in interictal epileptiform discharges (IEDs) and improvement in EEG background. The clinical and electroencephalographic improvement confirms that KD is beneficial in children with refractory epilepsy.

Refractory epilepsy in a patient with Doose syndrome: favorable response after add-on therapy with bromide

Case Report: Potassium bromide (Br) is only used in a few countries mainly for patients with severe myoclonic epilepsy in infancy/Dravet syndrome.

Antiepileptic Choice of Pediatric Neurologists: Istanbul Pediatric Neurology Study Group Survey

Objective: To reveal antiepileptic drug preferences of the pediatric neurologist using questionnaire surveys. Methods: The survey included neonatal seizures and 10 different patients with specific epileptic conditions. Participants were asked for the first drug of choice and attitudes in the case of treatment failure. Results: In neonatal seizures, phenobarbital was the first choice of all participants. Valproate was the first choice of 100 % of the participants in myoclonic astatic epilepsy, of 85 % in photo-sensitive epilepsy, of 74 % in absence epilepsy, of 73 % in electrical status at slow sleep. For complex partial seizures, valproate, carbamazepine and oxcarbazepine were preferred equally. Conclusion: Results of the survey showed that drugs used for many years such as phenobarbital, valproic acid and carbamazepine are more preferred by pediatric neurologists.

Treatment of Epileptic Encephalopathies

Epileptic encephalopathy is defined as a condition where the epileptic activity itself may contribute to the severe neurological and cognitive impairment seen, over and above that which would be expected from the underlying pathology alone. The epilepsy syndromes at high risk of this are a disparate group of conditions characterized by epileptic seizures that are difficult to treat and developmental delay. In this review, we discuss the ongoing debate regarding the significance of inter-ictal discharges and the impact of the seizures themselves on the cognitive delay or regression that is a common feature of these syndromes. The syndromes also differ in many ways and we provide a summary of the key features of the early-onset epileptic encephalopathies including Ohtahara and West syndromes in addition to later childhood-onset syndromes such as Lennox Gastaut and Doose syndromes. An understanding of the various severe epilepsy syndromes is vital to understanding the rationale for treatment. For example, the resolution of hypsarrhythmia in West syndrome is associated with an improvement in cognitive outcome and drives treatment choice, but the same cannot be applied to frequent inter-ictal discharges in Lennox Gastaut syndrome. We discuss the evidence base for treatment where it is available and describe current practice where it is not. For example, in West syndrome there is some evidence for preference of hormonal treatments over vigabatrin, although the choice and duration of hormonal treatment remains unclear. We describe the use of conventional and newer anti-epileptic medications in the various syndromes and discuss which medications should be avoided. Older possibly forgotten treatments such as sulthiame and potassium bromide also have a role in the severe epilepsies of childhood. We discuss hormonal treatment with particular focus on the treatment of West syndrome, continuous spike wave in slow wave sleep (CSWS)/electrical status epilepticus in slow wave sleep (ESES) and Landau Kleffner syndrome. The role of the ketogenic diet has in recent years come to the fore of the management of these severe epilepsies and we describe successful use in myoclonic astatic epilepsy, Lennox Gastaut syndrome and Dravet syndrome. It is important that resective epilepsy surgery is not ignored in the management of these children, particularly those with hemi-pathology who may present with ESES and respond well to hemispheric disconnection. Adjunctive and symptomatic surgical treatments such as vagal nerve stimulation and corpus callosotomy may improve seizure burden. Finally, it is vital that the identification and treatment of developmental, behavioural and psychiatric co-morbidities are not neglected and that a rational, holistic approach is taken to the management of epileptic encephalopathies.

Evaluation of Behavior and Cognitive Function in Children with Myoclonic Astatic Epilepsy

Background: Myoclonic astatic epilepsy (MAE) is an idiopathic and generalized childhood epileptic syndrome. Although several studies have reported on cognitive function and intellectual outcome in MAE, little is known about the behavioral problems associated with this disease. The aim of this study was to clarify behavior and cognitive function in children with MAE. Methods: Four children who were diagnosed as having MAE using the proposed criteria of the International Classification of Epilepsies were retrospectively analyzed using patient records with regard to clinical and neuropsychological findings such as age of seizure onset, semiology and severity of seizures, treatment course, behavioral problems, EEG findings, and WISC-III and Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores that indicate the tendency of autistic behaviors. Results: Disease onset in our cohort ranged from 9 to 35 months of age. Seizures were controlled within 3-8 months over a follow-up period of 4-12 years. All patients had borderline normal intelligence (mean IQ: 75.8 at 5-7 years of age) and exhibited impaired coordination, clumsiness, hyperactivity or impulsivity, and impaired social interaction after improvement of seizures. Though these autistic social problems manifested gradually, the children were able to adapt to school life with appropriate support. Interestingly, the behaviors of impaired social interaction and hyperactivity or impulsivity had already been observed before the onset of MAE in most patients, whose PARS scores were all higher than reference values (<9) during infancy. Conclusion: Our results showed that children with MAE tend to have autistic behavioral problems and mild intellectual impairment along with wide ranges in WISC-III subtest scores. These behavioral and cognitive features appear to exist before the onset of epilepsy.

A 3-Year-Old Boy with Severe Anemia and Neutropenia

3-year-old boy with a medical history of Doose syndrome (myoclonic-astatic epilepsy) presented to his primary care physician’s office with symptoms of listlessness; decreased appetite; episodes of nonbloody, nonbilious emesis; and diarrhea. The family reported no fever, rash, breakthrough seizure activity, recent sick contacts, or travel history. He was pale and tachycardic. In the office, three separate hemoglobin tests ranged from 2 to 2.5 mg/dL. He was transferred to the pediatric emergency room and intensive care unit for additional evaluation and management of severe anemia. A further review of his medical history showed that his seizures had been well controlled on a strict ketogenic, organic diet. He drank only bottled water and was on no prescription medications. His immunizations were up to date save for pneumococcal conjugate vaccine and influenza. The child had developmental delay, spoke only single words, and required full assistance with activities of daily living. There was no family history of anemia, leukemia, or cancer.

Ketogenic Diet: An Early Option for Epilepsy Treatment, Instead of A Last Choice Only

Ketogenic diet (KD) was usually tried as a last resort in the treatment of intractable epilepsy after failure of many antiepileptics and even epilepsy surgery. Glucose transporter-1 deficiency and pyruvate dehydrogenase deficiency must be treated with KD as the first choice because of inborn errors of glucose metabolism. Infantile spasms, tuberous sclerosis complex, Rett syndrome, Doose syndrome, Dravet syndrome, etc., appear to respond to KD, and it has been suggested by the international consensus statement to use KD early. We believe that all patients with epilepsy, except those with contraindicated situations such as pyruvate carboxylase deficiency, porphyria, β-oxidation defects, primary carnitine deficiency, etc., may try KD before trying other regimens.

Effects of ketogenic diet on the clinical and electroencephalographic features of children with drug therapy-resistant epilepsy

The aim of this study was to investigate the effects of a ketogenic diet (KD) on the clinical and electroencephalographic (EEG) features of children with drug therapy-resistant epilepsy. A total of 31 children with drug therapy-resistant epilepsy were selected, including 19 males and 12 females. The youngest was 7 months old and the oldest was 7 years old. Clinical seizures in the children prior to and 1 week, 1 month and 3 months after the initiation of the KD were compared and the clinical effect of the KD was evaluated. The ratio of fat to carbohydrate + protein in the KD was 4:1. Following the initiation of the KD treatment, the original antiepileptic drugs were not changed. The changes in occipital region background rhythm and interictal spike wave discharge index (SI) were evaluated prior to and 1 week, 1 month and 3 months after the initiation of the KD. The efficacy had an upward trend over time, with a total efficacy rate of 51.61% 1 week later, 67.74% 1 month later and 70.97% 3 months later. Doose syndrome showed the greatest response to KD, with a 100% efficacy rate. However, since there were only two cases in the study, its efficacy remains to be assessed. Infantile spasm also showed a good response to KD; 9 of the 16 patients were seizure free and the total efficacy rate was 81.25%. As the length of the KD treatment was increased, the background rhythms of the children underwent significant changes and the SI was significantly reduced. KD not only demonstrated good clinical efficacy, but also significantly reduced the frequency of interictal epileptic discharges and improved the EEG background rhythm.

Myoclonic astatic epilepsy (Doose syndrome) – A lamotrigine responsive epilepsy?

PurposeMyoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients. Patients and methodsIn an exploratory, retrospective study, 10 pharmacoresistant MAE patients were included who had been admitted to the Northern German Epilepsy Center between 07/2007 and 12/2010 and had been treated with LTG. Documentation was performed with the electronic seizure diary Epivista®. A total observation period of 32 weeks was defined: 8-week ‘pre LTG treatment phase’ (before starting with LTG), 16-week ‘titration phase’ (starting with very low LTG doses), 8-week ‘follow-up phase’. Seizure frequency, medication and adverse events were extracted from the electronic diary and evaluated in each particular patient. The individual reduction of seizure frequency per day was defined as primary outcome variable. Additionally, a dose-effect-relationship was analyzed for each patient. ResultsSix out of ten patients were seizure free during the follow-up phase. Statistical analysis indicated a significant seizure reduction in seven patients at follow-up compared to the pre LTG treatment phase. Seizure frequency did not significantly decrease in two patients and increased in one patient. A significant relationship between seizure frequency per day and LTG dosage during titration and follow-up phase could be demonstrated in nine patients. Group statistics using the exact Wilcoxon test revealed a significant reduction in seizure frequency (p = 0.049, two-sided). ConclusionOur data provide evidence that adjunctive LTG is an eligible therapeutic option for the treatment of pharmacoresistant MAE and encourage further prospective studies to verify this observation.

Dissecting the genetic basis of myoclonic‐astatic epilepsy

Herman Doose first described the generalized childhood epilepsy syndrome of myoclonic astatic epilepsy (MAE) in 1970, attributing a genetic cause from this first description. However, although the International League Against Epilepsy (ILAE) defined criteria for MAE in 1989, the diagnostic boundaries of the syndrome continue to be debated. Moreover, 40 years since Doose's first description of MAE, although a genetic predisposition is acknowledged and many studies have demonstrated familial aggregation of seizures within MAE families, the actual genetic determinants of MAE still remain unknown. Although initially thought to be within the same spectrum as severe myoclonic epilepsy of infancy, the exclusion of SCN1A mutations in non-generalized epilepsy with febrile seizures plus (GEFS+) MAE cases has confirmed the genetic distinction of MAE. In this critical review, we shall trace the historical evolution of concepts around MAE and its distinction from Lennox-Gastaut syndrome, review the described phenotypic features of MAE from updated studies that will allow its distinction from other overlap epilepsy syndromes, review the evidence of genetic influences and clues for genetic heterogeneity, and discuss strategies that may be helpful in elucidating the etiology of MAE in light of current genetic techniques.

Immunoglobulin Treatment for Severe Childhood Epilepsy

We have used intravenous immunoglobulin to treat pediatric patients with various severe epileptic conditions. This retrospective, multicenter study comprised 64 consecutive patients treated with immunoglobulins for either epileptic encephalopathy or refractory epilepsy. The rate of full or partial improvement according to specific syndrome involved three of four patients with idiopathic West syndrome, six of 12 patients with electrical status epilepticus in sleep, eight of 19 patients with an undefined syndrome, one of three patients with Landau-Kleffner syndrome, and one of two patients with Rasmussen encephalitis. Intravenous immunoglobulins were ineffective in 10 patients with symptomatic West syndrome, nine with febrile infection-related status epilepticus, three with myoclonic astatic epilepsy, and two with Lennox-Gastaut syndrome. Nine patients (14%) demonstrated complete resolution, and 10 (15.6%) exhibited partial improvement. Of these 19 responders (29.7%), eight relapsed. Although intravenous immunoglobulin is not suitable for all cases of epilepsy, it may prove efficacious for specific epileptic syndromes, mainly idiopathic West syndrome and electrical status epilepticus during sleep.

Ketogenic diets

Despite myriad anticonvulsants available and in various stages of development, there are thousands of children and adults with epilepsy worldwide still refractory to treatment and not candidates for epilepsy surgery. Many of these patients will now turn to dietary therapies such as the ketogenic diet, medium-chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome). Adults are also one of the most rapidly growing populations being treated nowadays; this group of patients previously was not typically offered these treatments. In 2009, two controlled trials of the ketogenic diet were published, as well as an International Expert Consensus Statement on dietary treatment of epilepsy. Ketogenic diets are also now being increasingly studied for neurological conditions other than epilepsy, including Alzheimer's disease and cancer. Insights from basic science research have helped elucidate the mechanisms by which metabolism-based therapy may be helpful, in terms of both an anticonvulsant and possibly a neuroprotective effect. Dietary therapy for epilepsy continues to grow in popularity worldwide, with expanding use for adults and conditions other than epilepsy.

Clinical characterization of myoclonic-astatic epilepsy

Clinical characterization of myoclonic-astatic epilepsy

A patient with myoclonic epilepsy in infancy followed by myoclonic astatic epilepsy

Myoclonic epilepsy in infancy (MEI) is a primary generalized epilepsy. According to the literature, the outcome of MEI is usually benign. Here we report a patient who developed myoclonic astatic epilepsy at age four, having been seizure free without antiepileptic drug treatment for 2 years after his recovery from MEI. At age four, a video-EEG-recording showed frequent head nodding (atonic seizures) and myoclonic astatic seizures associated with diffuse spikes or polyspikes and waves. The interictal EEG revealed frequent bursts of generalized 100–200μV, 2–4Hz spike-and-slow-wave complexes. Despite a general favorable outcome, more severe epilepsy syndromes may develop after MEI, and mental retardation is sometimes observed. Our case and the previous literature suggest that epilepsies following on from MEI often involve myoclonic seizures.

First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome)

IntroductionWe evaluated the long-term efficacy and tolerability of the orphan drug rufinamide (RUF) in children with pharmacoresistant myoclonic-astatic epilepsy (MAE, Doose syndrome). MethodsThis was a retrospective European multicenter study on eight patients who had started an intention-to-treat trial of RUF between July 2007 and June 2010. Clinical information was collected via questionnaire. Responder rate was defined as reduction of seizure frequency ≥50% in comparison to four weeks before starting RUF. Maximum follow-up was eighteen months. ResultsResponder rates were 7/8 patients after 3 months, 6/8 patients after 6 months and 5/8 patients after 12 months. RUF seemed particularly effective in the prevention of myoclonic-astatic seizures (comparable with drop attacks in Lennox-Gastaut-Syndrome, for which RUF is particularly effective). Some loss of efficacy was noticed in the long-term observation. Side-effects occurred in two patients. Seizure aggravation was not observed. ConclusionRUF seems to be a promising therapeutic option in children with MAE. Further studies are warranted to confirm these first observations.

Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

Glucose Transporter 1 Deficiency and Myoclonic Astatic Epilepsy

Researchers at University of Melbourne, Australia; University of Florence, Italy; and University of Antwerp, Belgium performed genetic analysis on 84 unrelated probands with myoclonic-astatic epilepsy (MAE).

Myoclonic astatic epilepsy: An age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution

The objective of the study was to explore clinical, electroencephalography (EEG), neuropsychological features and prognosis of myoclonic-astatic epilepsy (MAE). Of 327 children aged between 1 and 9 years with a diagnosis of generalized epilepsy followed between 2000 and 2008, 18 (5.5%) had MAE. Male significantly predominated (88.9%). Age at onset ranged from 2.3 to 4.9 years (mean 3.6 years). Median follow-up period was 6.3 years. In addition to myoclonic-astatic seizures patients had myoclonic seizures (66.7%), drop attacks (72.2%), head drops (77.8%) absences (88.9%), tonic-clonic generalized seizure (77.8%), tonic seizures (38.9%), non-convulsive status epilepticus (16.7%). Seven patients (38.9%) had an epileptic encephalopathy. At onset, interictal epileptiform and slow abnormalities were recorded, respectively, in 100% and 77.8% of patients. EEG abnormalities disappeared in all patients within 4 years since the onset. At long-term follow-up, two patients developed focal abnormalities typical of rolandic epilepsy and two patients photosensitivity. On neuropsychological testing 66.7% of patients had a normal IQ (mean 81.2±17.0, range 47-105, median 84.5) after a mean period of 4.4 years since the last seizure. Sixteen out of 18 patients remitted within 3.5 years since the onset and in two patients tonic seizures persisted. MAE is generalized childhood epilepsy: although cognitive functions might deteriorate, outcome is good regarding seizures.