Neuropsychological Findings: Myoclonic Astatic Epilepsy (MAE) and Lennox-Gastaut Syndrome (LGS)

Summary:  Purpose: To identify a specific neuropsychological profile associated with myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS).
Methods: Seven patients diagnosed with MAE and four patients diagnosed with LGS were selected from patients referred to our Child Neurology Unit. The patients were assessed both clinically (awake, sleep, Holter EEG, seizures frequency, and semiology) and neuropsychologically (IQ, language, attention, visuospatial and visuomotor abilities, and behavior). One representative case of each syndrome is presented here.
Results: The clinical picture of the MAE patient resembled that of an MAE condition associated with transitory epileptic encephalopathy. The neuropsychological findings suggest that electroclinical anomalies can temporarily affect cognitive and behavioral functioning. Early effective antiepileptic drug (AED) treatment was found to improve cognitive outcome. In contrast, LGS was associated with mental retardation, which persisted after seizure control.
Conclusions: At present, it remains difficult to delineate a precise neuropsychological profile associated with MAE and LGS. The cognitive outcome of MAE is variable and depends on the clinical pattern. With regard to LGS, the hypothesis of a genetic predisposition underlying both the epilepsy and the mental retardation is still valid. Alternatively, exposure to subclinical electrophysiological anomalies during a critical period of cerebral development may be responsible for the mental retardation. At the time the clinical manifestations appear, drug treatment, even if effective, would have only limited impact on cognitive outcome. However, early multidisciplinary intervention may help to improve behavior and communicative abilities, enhancing the quality of life of these children and their families.     

The Lennox-Gastaut Syndrome

Summary: One of the most challenging areas in nosology is in the field of severe generalized epilepsy of early childhood. This is certainly true in the case of Lennox-Gastaut syndrome (LGS), an age-related epileptogenic encephalopathy which comprises several types of generalized seizures including tonic seizures, atypical absence seizures and frequent status epilepticus. EEG shows generalized slow spike waves, and as the disease progresses, cognitive functions deteriorate. LGS is listed in the 1989 classification of the International League Against Epilepsy alongside epilepsy with myoclonic astatic seizures and West's syndrome. A number of variants or atypical forms have been proposed. As a result, differential diagnosis presents a major challenge and includes specific generalized epilepsies, i.e., metabolic or inflammatory; secondarily generalized epilepsies, i.e., those arising from the frontal lobe; and severe forms of idiopathic generalized epilepsy, i.e., Doose syndrome. Antiepileptic drug (AED) treatment of LGS has been disappointing. Results obtained from anterior callosotomy have been promising, but only a small number of patients have been evaluated. Although the syndrome is rare, the severe nature and intractability of LGS emphasizes the need for the development of specific AEDs which would completely modify the quality of life for these patients.     

Levetiracetam in patients with generalised epilepsy and myoclonic seizures: an open label study.

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam (LEV) as either 'de novo' (monotherapy) or 'add-on' therapy in patients with different generalised epilepsies characterised by myoclonic seizures from an observational study. METHODS: We evaluated 35 patients (21 female, mean age 24.7 years) with different types of generalised epilepsies (juvenile myoclonic epilepsy (JME), severe myoclonic epilepsy of infancy (SMEI), Lennox-Gastaut syndrome (LGS), myoclonic-astatic epilepsy (MAE), myoclonic absences (MA), benign myoclonic epilepsy in infancy (BMEI) and 4 patients had unspecified epileptic syndromes). Patients received LEV as de novo monotherapy or add-on therapy. Seizure frequency changes and adverse events were observed. Follow-up was conducted for a period of 12 months after treatment. RESULTS: Patients received LEV 2000-3000 mg/day as de novo (n = 8) and as add-on therapy. In total, 29 (82%) of the 35 patients achieved > or = 50% seizure frequency reduction, 15 (42%) patients achieved seizure freedom while a further 14 (40%) patients achieved > or = 50-99% seizure frequency reduction. Six (17%) patients discontinued LEV due to inefficacy or seizure worsening. Not even a single patient discontinued due to adverse effects. CONCLUSIONS: Our results confirm that LEV as de novo (monotherapy) and add-on therapy at doses between 2000 and 3000 mg/day effectively reduces myoclonic seizure frequency in patients with generalised epilepsy. LEV was also well-tolerated.     

Severe Myoclonic Epilepsy of Infants (Dravet Syndrome): Natural History and Neuropsychological Findings

Summary:  Severe Myoclonic Epilepsy in infancy (SMEI, or Dravet syndrome) is a drug-resistant epilepsy that occurs in the first year of life of previously healthy children. The main clinical features are prolonged and repeated febrile and afebrile generalized or unilateral convulsive seizures. In the course of the epilepsy, cognitive deterioration becomes evident, and interictal myoclonus, clumsiness and ataxia appear. One third of the children with SMEI show de novo mutations of the SCN1A gene, and additional familial genes probably contribute to the phenotype. While the clinical picture of SMEI has been well studied, neuropsychological data remain scarce. Global mental retardation, attention deficit and psychotic behavior have been reported but the long-term outcome has not been evaluated. We conducted a longitudinal neuropsychological study of children with SMEI. Twenty children, aged 11 months to 16 years, were prospectively examined using standardized neuropsychological tests. Correlation analysis with other clinical features was performed in 12 cases. Marked slowing or stagnation of psychomotor development, accompanied by psychotic or autistic traits and hyperactivity, was observed between the ages of one and four years. In the later stages (at ages 5 to 16 years), cognitive function stabilized but remained below normal. In children with a more favorable course, language capacities were better preserved than visuospatial functions, and behavior improved. The cognitive and behavioral impairment tended to correlate with the frequency of convulsive seizures (>5 per month). The data suggest that SMEI can be considered as a prototype of an epileptic encephalopathy.     

Atypical "benign" partial epilepsy or pseudo-Lennox syndrome. Part I: symptomatology and long-term prognosis

PURPOSE: Atypical benign partial epilepsy (ABPE) or pseudo-Lennox syndrome (PLS) is characterised by generalised minor seizures and focal sharp slow waves and spikes (SHW) as observed in Rolandic epilepsy (RE), but with exceptional pronounced activation during sleep. The aim of this study was to describe the full spectrum of ABPE in the hitherto largest group of patients. METHODS: We retrospectively analysed the clinical and EEG data of 43 children who fulfilled the following criteria: occurrence of generalised minor seizures as described for ABPE (i.e., atonicastatic seizures, myoclonic seizures, atypical absences) and focal SHW identical to those observed in RE, but with generalisation during sleep. RESULTS: Language development prior to onset of epilepsy was retarded in 26% of patients. In 74%, age at onset of epilepsy ranged from 2 to 6 years. Manifestation occurred earlier in boys than in girls. Generalised minor seizures constituted the predominating seizure type in 67% of patients. Twenty-eight percent of patients suffered from simple partial seizures of the oro-facial region or generalised tonic-clonic seizures originating from the oro-facial region. Additionally, generalised tonic-clonic (44%), unilateral (21%), partial motor (44%), versive (12%), focal atonic (9%), and complex-partial seizures (2%) were observed. A bioelectrical status was recorded in 56% of patients during sleep. No tonic seizures and no fast spike series (bursts of 10-20 Hz rhythms) were observed. At last follow-up, 84% of patients were in clinical remission. All subjects older than age 15 were seizure-free. However, 56% of patients attended a school for mentally handicapped children. CONCLUSIONS: ABPE or PLS broadly overlaps with RE, electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Regarding the epilepsy, the prognosis is excellent, mental deficit, however, seems to be frequent. The differentiation from Lennox-Gastaut syndrome and myoclonic astatic epilepsy is essential. Instead of ABPE, the term pseudo-Lennox syndrome is proposed.     

Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome).

The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.     

肌阵挛-站立不能性癫痫的临床特征及其电压门控性钠通道α1亚基基因突变检测

目的 探讨肌阵挛-站立不能性癫痫(MAE)的临床特点、药物疗效及可能的分子遗传学机制.方法 根据2001年国际抗癫痫联盟癫痫综合征分类标准对自2006年至2008年在广州医学院第二附属医院神经内科就诊的MAE患者进行诊断,收集患者的临床资料及外周血DNA,采用高效液相色谱分析和直接测序法对电压门控性钠通道α1亚基(5CN1A)基因突变进行筛查,并对其临床治疗情况随访1年以上.结果 共收集10例MAE患者,其中散发8例,有热性惊厥或癫痫家族史者2例;起病年龄介于5～39个月间;有多种全面性发作形式;2例曾出现癫痫持续状态;起病后精神发育迟滞者7例.对其中8例患者进行SCN1A基因突变筛查,均未发现突变.丙戊酸、氯硝安定和左乙拉西坦疗效最好,部分患者托吡酯和拉莫三嗪治疗亦有效.结论 MAE是少见的癫痫综合征,分子遗传学机制不明,丙戊酸、氯硝安定和左乙拉西坦治疗有效,但预后较差.     

Community-Based Study of Lennox-Gastaut Syndrome

Summary: Purpose : Before 1986, the spectrum of childhood epilepsies, including Lennox-Gastaut syndrome (LGS) and Doose syndrome (DS), known collectively as "epilepsia myoclonica astatica", was believed to represent a single disease. More recently, some investigators have considered these syndromes to be parts of a continuum. To clarify these theories, neurobiologic factors of the syndromes were studied to determine which qualities were shared and which were unique.
Methods : A retrospective (1975–985), community-based (Helsinki metropolitan area and the province of Uusimaa) study was designed to seek children with features of LGS and DS. It was assumed that recall bias and the selection of documented history would be similar throughout the group. Ranks of increasing pathology were assigned to different seizure types, EEG results, and drug treatments. A similar procedure was applied to epidemiologic data. Spearman rank-order correlations were calculated to determine which features correlated with LGS and which correlated with less severe epilepsy.
Results : The survey comprised 75 patients with broadly defined LGS. The annual incidence was 2 in 100,000 children aged 0 to 14 years. Prenatal or perinatal abnormalities did not correlate with severity of epilepsy. As compared with the relatively favorable ranks, the severe epilepsy ranks were more often associated with an early onset of epilepsy, an infectious disease at the onset, delayed development before epilepsy, abnormalities in neurologic or neuroradiologic examinations, and a deteriorating course of the condition.
Conclusions : Patients with LGS are more likely than patients with less severe epilepsy to have a younger age at onset of epilepsy, an infection or both, and a deteriorating course of the condition.     

Genetic predisposition to severe myoclonic epilepsy in infancy

PURPOSE: To address genetic predisposition to febrile convulsions (FCs) and epilepsy as an etiologic background of severe myoclonic epilepsy in infancy (SMEI). METHODS: Familial antecedents of epilepsy and FCs were analyzed in four groups of patients with SMEI (65 cases), FCs (57 cases), childhood absences (67 cases), and a control group of patients with no neurologic problems (64 cases). RESULTS: Patients with SMEI and those with FCs had significantly increased incidence of FCs in their relatives compared with those with absence epilepsy and with the control group. The incidence of epilepsy in relatives of patients with SMEI and absence epilepsy was increased compared with that in the control group and reached statistical significance. Epilepsy in relatives with SMEI had the characteristics of idiopathic generalized epilepsy. CONCLUSIONS: A genetic predisposition could determine three types of epileptic syndromes: FCs, idiopathic generalized epilepsy, and SMEI.     

Severe Myoclonic Epilepsy of Infancy: Extended Spectrum of GEFS+?

PURPOSE: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI. METHODS: Probands with SMEI were identified, and systematic family studies were performed. Epilepsy syndromes were characterized in affected family members. RESULTS: Twelve probands with SMEI were identified. Eleven of the 12 probands with SMEI had a family history of seizures, and the twelfth was the result of a consanguineous marriage. We found that 16.7% of full siblings and 8.3% of parents had definite seizures. A total of 39 affected family members was identified. The most common phenotype was febrile seizures in 14, febrile seizures plus in seven, partial epilepsy in two, and there were single individuals with SMEI, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, and 13 cases with unclassified or unconfirmed seizures. CONCLUSIONS: The family history of seizures in SMEI is in keeping with the spectrum of seizure phenotypes seen in generalized epilepsy with febrile seizures plus (GEFS+). Our findings suggest that SMEI is the most severe phenotype in the GEFS+ spectrum.     

Long-Term Prognosis of the Lennox-Gastaut Syndrome

Abstract: A long-term follow-up study of 89 patients of Lennox-Gastaut syndrome (LGS) disclosed the persistent occurrence of seizures in 68 patients (76.4%) and severe mental defect in 48 (53.9%). An analysis of the correlation between the mental and seizure prognoses confirmed that the persistence of minor seizures could result in mental deterioration. An examination of the evolutional changes in EEG demonstrated that diffuse slow spike-waves characteristic of LGS gradually disappeared, while focal epileptic discharges, especially multifocal spikes, appeared in spite of the persistence of minor seizures. The diagnostic criteria were satisfied in only 31 (47.0%) of 66 patients with the persistence of minor seizures. Patients with multiple independent spike foci and minor seizures were considered to belong to a specific type of epilepsy, namely the severe epilepsy with multiple independent spike foci (the severe epilepsy with MISF). The seizure and mental prognoses were poorer in patients who evolved into the severe epilepsy with MISF than others.     

Refractory grand mal seizures with onset during infancy including severe myoclonic epilepsy in infancy.

In 1978, Dravet proposed a clinical entity called severe myoclonic epilepsy in infancy (SMEI). In the same year, a patient group, which was later called high voltage slow wave-grand mal syndrome (HVSW-GM), is reported in Japan. Both syndromes are very similar, except for seizure manifestation: generalized tonic-clonic convulsions (GTC) with myoclonic and other polymorphic seizures in SMEI vs. GTC only in HVSW-GM. To study the pathophysiology of these refractory epilepsies, the author formulated new clinical diagnostic criteria common to both syndromes as follows: GTC with onset before the age of 1 year as the principal seizure type; an epilepsy entity unclassifiable either as partial or generalized by all the clinical data including EEG findings; mental and motor dysfunction absent prior to seizure onset but appearing later; absence of epileptiform activities on EEG in the initial stage; stubborn refractoriness to conventional antiepileptic medication. Twenty-two patients meeting all of five clinical criteria above mentioned were recruited in the study. Detailed analysis of clinico-electrical features and long-term follow-up of these patients led the author to the conclusion that GTC in combination with seizures of other types will contribute to an unfavorable pathophysiological or prognostic conditions, and, especially when GTC exists in combination with myoclonic seizures, the severity of epilepsy will increase. The author claimed that the three clinical entities, SMEI, HVSW-GM, and their variant form, share certain characteristics in common and may constitute a unique epilepsy syndrome for which a new name of infantile refractory grand mal syndrome (IRGMS) was offered. This is a more basic concept with broader spectrum than SMEI, encompassing not only SMEI but also related borderlands like HVSW-GM. More recently, the author observed that early zonisamide medication within 1 year after seizure onset may improve seizure prognosis in IRGMS, by preventing the development of myoclonic seizures.     

Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy

Myoclonic astatic epilepsy (MAE) is a genetically determined condition of childhood onset characterized by multiple generalized types of seizures including myoclonic astatic seizures, generalized spike waves and cognitive deterioration. This condition has been reported in a few patients in generalized epilepsy with febrile seizures plus (GEFS+) families and MAE has been considered, like severe myoclonic epilepsy of infancy (SMEI), to be a severe phenotype within the GEFS+ spectrum. Four genes have been identified in GEFS+ families, but only three (SCN1A, SCNlB, GABRG2) were found in MAE patients within GEFS+ families. We analysed these three genes in a series of 22 sporadic patients with MAE and found no causal mutations. These findings suggest that MAE, unlike SMEI, is not genetically related to GEFS+. Although MAE and SMEI share the same types of seizures, only SMEI patients are sensitive to fever. This is probably its main link to GEFS+. A different family of genes is likely to account for MAE.     

Lamotrigine Adjunctive Therapy in Childhood Epileptic Encephalopathy (the Lennox Gastaut Syndrome)

Summary: Purpose : We assessed efficacy and safety of adjunctive lamotrigine (LTG) therapy in patients with the Lennox-Gastaut syndrome (LGS).
Methods : The study was a single-center, retrospective chart review of open-label adjunctive LTG therapy in patients with LGS. Initial LTG dose and titration was dependent on concomitant antiepileptic drugs (AEDs). Efficacy was based on the change in seizure frequency between the initiation of LTG therapy and December 1, 1995 (or LTG discontinuation). Seizure diaries were used to count patient seizures. A secondary evaluation of efficacy was a parental or guardian assessment of the patient's global status. The evaluation of safety involved chart review for treatment-emergent adverse events (AE).
Results : Data from 16 LGS patients were analyzed. Fifty-three percent (8 of 15) had a >50% reduction in seizure frequency with LTG adjunctive therapy. Tonic, atonic, generalized tonic-clonic (GTCS), and atypical absence seizure frequency but not myoclonic seizure frequency decreased significantly during LTG therapy. Fifty-three percent of the patient's parents (8 of 15) reported that their child's quality of life (QOL) was much or very much improved during the study. The major treatment-emergent AE were infection (50%, 8 of 16) and sleep disturbance (19%, 3 of 16). A rash was noted in 13% (2 of 16) of the patients and resulted in LTG discontinuation in 1. No clinically significant changes were noted in neurologic examination or laboratory tests during the study.
Conclusions : Our results indicate that LTG adjunctive therapy is effective and well tolerated in patients with LGS.     

Epilepsy in severely handicapped children

Clinical and electroencephalographic studies were performed to elucidate the characteristics of epilepsy in severely handicapped children. The subjects were 56 severely mentally and physically handicapped children whose ictal seizures were documented by simultaneous EEG-VTR monitoring. Seizure types were infantile spasms in 17 (30.4%), atypical absence in 5 (8.9%), myoclonic seizures in 3 (5.4%), generalized tonic-clonic seizures in 2 (3.6%), secondary generalized partial seizures in 11 (19.6%), and undetermined in 4 (7.1%). Epilepsy types were also classified by the ictal seizure types and clinical courses: West syndrome in 27 (48.1%), Lennox-Gastaut syndrome (LGS) (at onset) in 5 (8.9%), partial epilepsy in 13 (23.2%) and others (at onset) in 11 (19.8%). Among 29 cases with West syndrome, 22 (81%) developed LGS, and among 11 cases with others group, 64% developed LGS. After all, LGS appeared in 60.7% of all 56 severe epileptic children associated with severe physical and mental handicaps.     

Epidemiology of Severe Myoclonic Epilepsy of Infancy

Severe myoclonic epilepsy of infancy (SMEI) is a newly recognized epileptic syndrome. It is characterized by multiple febrile seizures, often prolonged, subsequent development of uncontrollable mixed-myoclonic seizures, and, eventually, psychomotor retardation. Drugs for myoclonic epilepsy--valproate (VPA), the suximides, and the benzodiazepines--have been shown to be useful in SMEI. Among children with seizures in the National Institute of Neurological and Communicative Disorders and Stroke Collaborative Perinatal Project (NCPP), one individual with SMEI was identified. This finding from the NCPP suggests that the incidence of SMEI is approximately 1 in 40,000 children. Such an incidence is supported by observations at the Texas Tech University Health Sciences Center.     

The core Dravet syndrome phenotype

Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic-clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70-80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years.     

Early diagnosis of severe myoclonic epilepsy in infancy.

Of 329 epileptic patients referred in a six year period with the first seizure occurring in the first year of life, 20 met the following criteria: generalized seizures excluding infantile spasms, myoclonic, tonic or absence seizures, at least one afebrile seizure, normal development prior to the first seizure, normal CT scan, and no etiology. Seventeen of these 20 patients developed the full pattern of severe myoclonic epilepsy in infancy (SMEI). This syndrome was recognizable from the second or third seizure in the first year of life, although epileptiform EEG abnormalities were lacking until the age of 11 to over 30 months. Therefore, based on the clinical pattern, the diagnosis of SMEI can be made with quite good reliability by the end of the first year of life.