Age-dependent Epileptic Encephalopathy Research Articles

P01.4 Cardiac autonomic dysfunction in West syndrome

Background: West syndrome is an age-dependent epileptic encephalopathy. Autonomic changes are increasingly being recognized in patients with epilepsy: cardiac autonomic function is mediated by sympathetic and parasympathetic efferent activity to the heart and can provide information on the functional state of the autonomic nervous system. Methods: Cardiac autonomic function was evaluated in 13 patients with West syndrome by measuring heart rate variability during 5minute epochs of ECG in wake, stage 2 and slow wave sleep. In 5 patients who developed subsequently another type of epilepsy, a second evaluation was performed after 3 years of follow-up. Results: Results showed a lower heart rate in stage 2 sleep in patients with West syndrome. Spectral components did not show significant differences compared to age matched controls at the moment of presentation. After follow-up of 3 years we were able to demonstrate higher low frequency (LF), lower high frequency (HF) and a higher LF/HF ratio during slow wave sleep. Conclusion: This study shows a lower heart rate in patients presenting with West syndrome, already at the onset of the syndrome, even before treatment. After follow-up of only 3 years of epilepsy, chronic autonomic changes appear in the spectral components of heart rate variability.

Children treated for epileptic encephalopathies show improved glucose metabolism

Epileptic neurological disorders in infants are often difficult to distinguish, and call for disparate treatments. Positron emission tomography (PET) using an [18F] fluoro-2-deoxyglucose (18FDG) tracer, is a powerful non-invasive technique successful in improving the diagnosis of a number of conditions. Interestingly, this technique has shown that cerebral glucose hypometabolism is present in children with epileptic encephalopathies (EE). Ten children with age-dependent EE were recruited and routine 18FDG PET images were evaluated for their ability to indicate cerebral glucose metabolism both before and after anti-epileptic treatment. We found that there is diffuse glucose hypometabolism in both hemispheres before treatment, indicating EE. Following treatment, the number of epileptic episodes significantly decreased (P < 0.05), while cerebral glucose metabolism improved. Our findings suggest that 18FDG PET can be utilized to monitor cerebral glucose metabolism as a measure of treatment progress in EE.

8. Experimental epileptic encephalopathies

It is very difficult to model age-dependent epileptic encephalopathies because they represent very complex syndromes. We started to model one of the symptoms – flexion seizures – in the early nineties [ [1] Mareš P, Velíšek L. Dev Brain Res 1992;65:185–9. Google Scholar ]. These seizures could be elicited by administration of drugs acting as agonists on N-methyl-D-aspartate type of glutamate receptors during the first two weeks of postnatal life in rats. This age corresponds to perinatal and early postnatal (up to preschool age) developmental stages of the human brain. Based on flexion seizures, two models of epileptic encephalopathies exhibiting more characteristic symptoms were elaborated. Both models work with animals that are exposed to the first insult during early development; it is then possible to elicit model seizures in damaged animals. A model published in 2007 used prenatal administration of betamethasone and a postnatal (day 15) intraperitoneal injection of N-methyl-D-aspartate [ [4] Velísek L, Jehle K, Asche S, Velísková J. Ann Neurol 2007;61:109—19. Google Scholar ]. Another model from the same laboratory uses lipopolysaccharide and doxorubicin injected intracerebrally at postnatal day 3 and p-chlorophenylalanine at postnatal day 5 [ [3] Scantlebury MH, Galanopoulou AS, Chudomelova L, Raffo E, Betancourth D, Moshé SL. Neurobiol Dis 2010;37:604– 12. Google Scholar ]. These rat models also exhibit ictal and interictal EEG abnormalities and developmental decline typical for early-age human epileptic encephalopathies. A new genetic mouse model elaborated by expansion of the Arx gene exhibits spontaneous seizures including infantile spasms and cognitive and behavioral impairment persisting up to adulthood [ [2] Price MG, Yoo JW, Burgess DL, Deng F, Hrachovy RA, Frost Jr JD, et al. J Neurosci 2009;29:8752–63. Google Scholar ]. The last two models are promising but they have to be further analyzed.

Clinical Evaluation and Diagnosis of Severe Epilepsy Syndromes of Early Childhood

The developing brain is particularly susceptible to seizures. Diffuse central nervous system pathology or injury in early infancy, when the brain is most vulnerable, may lead to catastrophic epilepsies such as Ohtahara's epileptic encephalopathy and early myoclonic epileptic encephalopathy. These epileptic encephalopathies are difficult to treat and have poor prognoses. As the brain undergoes programmed synaptogenesis, apoptosis, and myelination, the epilepsy phenotypes and electroencephalography (EEG) findings change, producing age-dependent epileptic encephalopathies. Specifically, as they grow older, 40% to 60% of infants with infantile spasms and a concomitant hypsarrhythmia on EEG will develop Lennox-Gastaut syndrome with tonic and atonic seizures, associated with a synchronous, generalized 1.5- to 2-Hz spike and slow wave discharges on EEG. In the context of age-dependent epileptic encephalopathies, as an epilepsy syndrome is evolving, it is often difficult to accurately diagnose the specific epilepsy syndrome in a young child who presents with seizures. It is the clinical evolution of the seizure types and the EEG that helps the clinician make an accurate diagnosis. As more is known about the underlying pathophysiology for the various epilepsy syndromes, not only the clinical picture and EEG but also a genetic blood test will be used to accurately diagnose a specific epilepsy syndrome. A case in point would be severe myoclonic epilepsy of infancy (classically known as Dravet syndrome) and severe myoclonic epilepsy of infancy-borderland/ borderline, which are associated with specific mutations in the sodium ion channel gene SCN1A.

Multiple independent spike foci and epilepsy, with special reference to a new epileptic syndrome of “severe epilepsy with multiple independent spike foci”

Background Markand and Blume first realized the specificity of the EEG pattern of multiple independent spike foci (MISF) in the late 1970s; its close relation with hypsarrhythmia and slow spike-waves, extensive bilateral brain lesion, and intractable seizures. But they did not recognize it as an epileptic syndrome. On the other hand, the authors had been taken notice of severe epilepsy with MISF (SE-MISF) as a peculiar clinico-electrical entity showing “generalized seizures”, and pointed out its close relation to Lennox–Gastaut syndrome (LGS) from the long-term follow-up of LGS. Summary points SE-MISF is characterized by (1) interictal EEG showing multiple independent spike foci (three or more foci in both hemisphere, i.e. at least one in each hemisphere) and diffuse slowing of the background activity. Diffuse epileptic discharges are rare. (2) The main seizure type is frequent generalized minor seizures, often tonic spasms. (3) Mutual transition is often observed between the age-dependent epileptic encephalopathies, i.e. Ohtahara syndrome, West syndrome and LGS. (4) The age at epilepsy onset is early, but the onset of SE-MISF is variable. (5) It is often associated with mental retardation and neurological abnormalities, usually severe. (6) Etiology is variable and largely nonspecific, including prenatal, perinatal, and postnatal cerebral pathologies. (7) Prognoses for seizures and psychomotor development are poor. Seizures are very intractable and may cause psychomotor deterioration. Conclusion SE-MISF may be classified into symptomatic generalized epilepsy, namely a diffuse encephalopathy with mutual transition between other age-dependent epileptic encephalopathies. This characteristic entity may be acknowledged as a new epileptic syndrome.

Misleading Effects of Clonazepam in Symptomatic Electrical Status Epilepticus During Sleep Syndrome

Electrical status epilepticus during sleep syndrome and its variants are age-dependent epileptic encephalopathies associated with a sleep-related electroencephalographic pattern of continuous spike-waves, combined with motor or cognitive impairment. These epileptic encephalopathies are usually not responsive to conventional antiepileptic drugs. This report describes two children in whom clonazepam had no effect on cognitive and motor disorders but controlled spike activity, preventing a proper diagnosis. Withdrawal of clonazepam was accompanied by the recurrence of continuous spike-waves in slow sleep, permitting the diagnosis of electrical status epilepticus during sleep syndrome and appropriate therapeutic decisions. These two cases of the misleading effect of clonazepam in electrical status epilepticus during sleep syndrome illustrate the puzzling situation that can occur when therapeutic options only consider the electroencephalographic features without prior syndromic diagnosis.

A plausible explanation for superiority of adreno-cortico-trophic hormone (ACTH) over oral corticosteroids in management of infantile spasms (West syndrome)

West syndrome (WS), an age dependent epileptic encephalopathy is identified as a triad of infantile spasms (IS), psychomotor retardation and a specific EEG pattern known as hypsarrhythmia. The exact pathophysiology still remains unclear, although a majority of cases reveal history of exposure to stress, mainly hypoxic-ischemia. The management remains empirical with a poor prognosis. Adrenocorticotrophic hormone (ACTH) and oral steroids continue to remain gold standard treatment. Vigabatrin (VGB), a newer anti-epileptic drug has emerged as an effective alternative but recent observation of a serious visual defect (constriction of peripheral field of vision that is likely to exaggerate the disability status of the WS patient) associated with its administration is gradually limiting its therapeutic usage and popularity. A number of studies have shown superiority of ACTH over oral steroids in the management of West syndrome, but the explanation for this long-standing observation is missing; however, this clinical observation has led to a wide acceptance of the implication of corticotropin releasing hormone (CRH) in causing spasms and at the same time also explaining the relief in spasms obtained by the inhibition of CRH secretion by ACTH and oral steroids. This hypothesis-article compares the negative feedback influences of ACTH and oral steroids on CRH secretion and shows that ACTH exerts a dual significantly stronger inhibitory influence on CRH secretion that far exceeds the inhibition exerted by oral steroids. Thus, this difference in feedback mechanism may be the major factor responsible for the superior therapeutic efficacy of ACTH over oral steroids in the management of West syndrome.

A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures

Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel α subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep–wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.

Severe epilepsy with multiple independent spike foci.

Severe epilepsy with multiple independent spike foci is an electroclinical entity with the following characteristics: (1) EEG showing multiple independent spike foci (three or more foci in both hemisphere, i.e., at least one in each hemisphere) and diffuse slowing of the background activity, (2) very frequent multiple types of seizures but mainly generalized minor seizures, (3) frequent association with mental retardation and neurologic abnormalities, (4) underlying causes of various nonspecific prenatal, perinatal, and postnatal cerebral conditions, and (5) poor prognoses for seizures and psychomotor development. It represents a diffuse encephalopathy with mutual transition between other age-dependent epileptic encephalopathies. This electroclinical condition may be appropriately named Markand-Blume-Ohtahara syndrome, after Markand and Blume, who initially described in detail the EEG pattern of multifocal spike discharges with its major clinical correlates, and Ohtahara, who extensively studied the group of patients with both clinical and EEG characteristics and proposed the concept of severe epilepsy with multiple independent spike foci, classifying it as one type of generalized epilepsy.

Cerebral blood flow abnormalities in symptomatic West syndrome: a single photon emission computed tomography study.

Infantile spasm (IS) is an age-dependent epileptic encephalopathy of variable etiology. Although IS is well studied, its pathogenesis is unclear. Infantile spasm is usually considered a generalized epilepsy, but recent studies point to focal cerebral blood flow (CBF) abnormalities. In six symptomatic IS patients, single photon emission computed tomography (SPECT) with [99Tc]-HMPAO, electroencephalography (EEG), magnetic resonance imaging (MRI)/computed tomography (CT) and their correlation were evaluated. Single photon emission computed tomography showed unifocal (regional) cerebral hypoperfusion in two infants, multifocal (diffuse) cerebral hypoperfusion in three infants and normal perfusion in the other infant. Electroencephalograms obtained in near-time of the SPECT studies showed diffuse abnormalities in five infants with hypoperfusion on SPECT. Cranial MRI/CT showed diffuse and/or localized cerebral lesions in all infants, all of whom had corresponding areas of hypoperfusion on SPECT. In one patient whose spasms were stopped with anticonvulsants, SPECT was normal, in two patients SPECT showed unifocal lesions, while in another three patients whose spasms were decreased but not stopped, SPECT showed multifocal hypoperfusion. This pilot study may indicate that there are CBF anomalies in symptomatic IS. The degree of CBF may be a predictor of prognosis and multifocal hypoperfusion may be a poor prognostic criteria in IS.

歯肉肥大を伴ったＬｅｎｎｏｘ症侯群の１例

Lennox syndrome is infantile epilepsy characterized by mental retardation and diffuse slow spike and waves on the electroencephalogram. It is classified as a type of agedependent epileptic encephalopathy and is the most severe of all epileptic syndromes.A case of Lennox syndrome associated with gum hypertrophy in a 20-year-old man is described. Gum hypertrophy was apparently a side effect of phenytoin, given to treat epilepsy.Intraoral examination revealed lower and upper gum hypertrophy. The hypertrophied gums were resected under general anesthesia.The gum disease was evaluated with respect to its cause and clinical course. Suggestions based on our experience are described.

Epileptic encephalopathies in early infancy.

Of the epileptic syndromes beginning in early infancy, we described the clinical and electrical characteristics of early myoclonic encephalopathy (EME) and Ohtahara syndrome (OS), and the differential diagnosis between the two syndromes, reviewing previous articles and our own study of 6 cases with EME and 15 cases with OS. With regard to the clinical seizure types, the main seizure type was tonic spasms in OS while myoclonias, especially erratic myoclonias, and frequent partial seizures were predominant in EME. The suppression-burst (S-B) pattern was a common feature of both syndromes, although their form, time of appearance, and duration of appearance differed considerably. The S-B pattern in OS was characterized by periodic and consistent appearances during both waking and sleeping states, whereas in EME, the S-B pattern was enhanced by sleep and often not manifested in the awake states. OS showed a specific pattern of evolution as age-dependent epileptic encephalopathy with concomitant EEG change while EME had no specific evolution with age. In OS, obvious brain lesions such as brain malformations were often seen. In contrast, frequent occurrence of familial cases suggested some kind of congenital metabolic disorder as the etiological factor in EME.

Prenatal etiologies of West syndrome.

We investigated the etiology of West syndrome (WS) with special reference to prenatal factors in 180 cases. Prenatal cause was the most frequent diagnosis (77 cases, 42.8%), followed by perinatal (25 cases, 13.9%) and postnatal factors (12 cases, 6.7%); 48 cases (26.7%) were of uncertain etiology; eighteen cases (10.0%) were idiopathic. Of the three forms of age-dependent epileptic encephalopathy, prenatal cause was present in 12 of 15 cases (80.0%) of early-infantile epileptic encephalopathy with suppression-burst, 77 of 180 cases (42.8%) of WS, and 31 of 123 cases (25.2%) of Lennox-Gastaut syndrome (LGS). Prenatal factors of WS included tuberous sclerosis (23), chromosome abnormalities (10), cerebral dysgenesis (10), porencephaly (7), hydrocephalus (5), Aicardi syndrome (3), Aicardi syndrome associated with chromosome abnormality (1), and other causes (18). Chromosome abnormalities with WS consisted of 6 cases with 21 trisomy and one case each with 18q duplication, t(1;y) translocation, 7q duplication, and partial 2p trisomy. One patient with Aicardi syndrome also had a t(12;21) translocation. No significant difference was observed in the age of onset of WS among the five etiologic groups. The evolution from WS to LGS was not influenced by etiology, except for the idiopathic group. In patients followed for over 3 years, seizure remission occurred in 46.8% (22 of 47 cases) of the prenatal group. This was lower than the other four groups. Intellectual prognosis was also relatively poor in those with prenatal onset. Pyridoxal phosphate (PAL-P) treatment was effective in 9 of 70 (12.9%) prenatal cases and 5 of 18 (27.8%) idiopathic cases.(ABSTRACT TRUNCATED AT 250 WORDS)

A Case of Age Dependent Epileptic Encephalopathy with CT Appearance and Neuropathological Findings

A Case of Age Dependent Epileptic Encephalopathy with CT Appearance and Neuropathological Findings

Clinical Course and Prognosis of Childhood Epilepsy

Remarkable progress has been accomplished in epileptology in recent years. The remission rate in childhood epilepsy has been improved by the introduction of new technologies and better diagnostic as well as therapeutic methods. Investigation of prognosis is an important field of epileptology, because prognostic improvement reflects its overall progress. A long-term follow-up study of childhood epilepsy was undertaken in the Okayama University Hospital. Ten to 15 years of follow-up was possible in 730 of 1,295 patients who were first diagnosed at ages below 15 years, from 1968 to 1971. The 3-year remission rate amounted to 82.0% and 5-year remission was obtained in 79.1%. These high rates of remission indicate the favorable prognosis of childhood epilepsy. On the other hand, cases of intractable epilepsy also amounted to a considerable number. Intractable epilepsy consisted mainly of age-dependent epileptic encephalopathy (Ohtahara's syndrome, West syndrome and Lennox-Gastaut syndrome) and severe myoclonic epilepsy in infancy. Development of effective therapy for these intractable epileptic syndromes will be an important subject of future studies.

Early infantile epileptic encephalopathy with suppression burst: Ohtahara syndrome.

Eleven infants with neonatal onset of intractable epilepsy are described, who showed the clinical and electroencephalographic features of Ohtahara syndrome. With time, transition to West and Lennox-Gastaut syndromes occurred. No cause could be found in eight cases. All nine survivors are severely mentally and physically handicapped and continue to have seizures. Early infantile epileptic encephalopathy represents the earliest of the age-dependent epileptic encephalopathies.

Reappraisal of the Treatment for the Age-dependent Epileptic Encephalopathy with ACTH

Reappraisal of the Treatment for the Age-dependent Epileptic Encephalopathy with ACTH

The early-infantile epileptic encephalopathy with suppression-burst: Developmental aspects

A clinico-electroencephalographic study on 14 cases of the early-infantile epileptic encephalopathy with suppression-burst (EIEE) including long-term follow-up studies for one year 8 months to 12 years 2 months disclosed the specificity of EIEE in its developmental aspects. With age, clinical evolution from EIEE to the West syndrome was observed in as many as 10 cases, among which two cases showed further transition to the Lennox-Gastaut syndrome. Electroencephalographically, suppression-burst pattern gradually began to disappear from age of 3 months and disappeared by 6 months in all the cases, transforming to hypsarhythmia in 10 cases from 2 to 6 months of age, showing further transition to diffuse slow spike-and-waves in 2 cases at one year and one month and at 3 years and one month of age, respectively. Changing pattern of EEG were classifiable into two types which strongly related to the prognosis. These findings indicated EIEE to be an independent epileptic syndrome as the earliest form of the age-dependent epileptic encephalopathy.

Developmental aspects of epilepsy with special reference to age-dependent epileptic encephalopathy.

The specificity of childhood epilepsy was characterized by investigating the evolutional changes with age and prognoses of age-dependent epileptic encephalopathy from the developmental aspect through a long-term follow-up. Three types of age-dependent epileptic encephalopathy showed mutual evolutional changes at certain ages. This indicated an important role of the brain development in the clinicoelectroencephalographical manifestations of age-dependent epileptic encephalopathy. Furthermore, the evolutional changes demonstrated an association with organic brain damage and etiology in addition to the age factors. The evolutional changes occurred more frequently in the cases with overt organic brain pathology. The prognosis was poorer in cases which underwent an evolutional change.

Polygraphical study on age dependent epileptic encephalopathy — Relationship between body movements during sleep and prognosis —

Body movements (BMs) during sleep in patients with age dependent epileptic encephalopathy (ADEE) were studied polysomnographically in order to clarify the underlying mechanism of intractability and the age dependent trend. Twenty patients were divided into two groups according to the prognosis of convulsions. In the good prognosis group, BMs were nearly normal except for a low frequency in some cases. In the intractable group with seizures which were uncontrollable by medication and recurred within a year, BMs showed abnormalities as follows: abnormal distribution according to sleep stages, and/or a low frequency; increased BMs on therapy with prednisolone or ACTH. Moreover, a paradoxical increase of BMs with age and recurrence of seizures concomitantly occurred in the course of the disease. Status epilepticus appeared in cases under 1-DOPA administration or with a strikingly high frequency of BMs. Since electrophysiological evidence indicates that BMs during sleep are modulated by the dopaminergic (DA) system, the present data might suggest that prognosis of convulsions in ADEE depend upon, at least in part, the DA system. And denervated supersensitivity of that system might give rise to recurrence of seizures and status epilepticus.