Early Myoclonic Encephalopathy Research Articles

Schinzel–Giedion syndrome: A further cause of early myoclonic encephalopathy and vacuolating myelinopathy

Here, we report a male child with Schinzel–Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel–Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.

What causes epileptic encephalopathy in infancy?

Early-onset epileptic encephalopathies are characterized by severe seizures (often infantile spasms), very frequent interictal epileptiform activity on a disorganized EEG background, developmental regression or retardation, and onset before 1 year of age. Ohtahara syndrome, West syndrome, early myoclonic epileptic encephalopathy, migrating partial epilepsy of infancy, and Dravet syndrome are the most well-known epileptic encephalopathies recognized by the International League Against Epilepsy (ILAE); however, the majority of infants with these syndromes do not strictly fit into the electroclinical parameters of these syndromes. The most common causes of epileptic encephalopathy in infancy are structural abnormalities, either congenital (such as malformations of cortical development) or acquired (such as hypoxic-ischemic insults). In addition, there are rare but potentially treatable metabolic disorders including biotinidase deficiency, pyridoxine/pyridoxal 5′phosphate dependency, and GLUT1 deficiency, as well as disorders of biopterin synthesis, creatine synthesis, and folate metabolism.1 For this reason, metabolic testing of this subset of infants often includes analysis of serum, urine, and CSF for metabolites of the relevant biochemical pathways. The usual approach, when …

Electroclinical characterization and classification of symptomatic epilepsies with very early onset by multiple correspondence analysis

To characterize very early onset symptomatic epilepsies electroclinically, to identify meaningful factors to delineate epilepsy syndromes under this category, and to test validity of the current syndromic organization of these epilepsies by the International League Against Epilepsy (ILAE). Subjects were 38 epileptic patients with seizure onset before 3 months of age. We investigated the age of seizure onset, seizure types, myoclonus, EEG features, neuroimaging studies, outcome of seizures and development. We performed multiple correspondence analysis (MCA) to reveal associations among these characteristics and to find important characteristics to divide this epilepsy group into subgroups. Very early onset epilepsies were characterized by partial seizures and epileptic spasms, especially occurring in combination as a single ictal event (combined seizures), and poor outcome. Suppression-burst (SB), hypsarrhythmia, EEG asymmetry and structural brain abnormalities were common. MCA demonstrated that presence or absence of SB was the most meaningful factor to separate this group into subgroups. MCA on the subgroup with SB revealed a subset with early-onset spasms, partial seizures with single focus, no myoclonus, SB during wakefulness and sleep, no EEG asynchrony, hypsarrhythmia and combined seizures, and another subset with late-onset spasms, partial seizures with multiple foci, myoclonus, EEG asynchrony, no combined seizures, SB during sleep only, no EEG asymmetry, no structural abnormality and no hypsarrhythmia. These corresponded to Ohtahara syndrome and early myoclonic encephalopathy, respectively. Very early onset symptomatic epilepsies have the electroclinical characteristics distinct from those with later onset. This study supported the current ILAE organization on this epilepsy group from statistic approach.

Nonketotic Hyperglycinemia: Proposal of a Diagnostic and Treatment Strategy

Early myoclonic encephalopathy presents neonatally with fragmented myoclonus and a suppression-burst electroencephalography pattern. We describe a newborn boy with early myoclonic encephalopathy caused by nonketotic hyperglycinemia. He presented with severe hypotonia, progressive apneic episodes, and erratic myoclonus. Screening of deletions in GLDC, using the multiplex ligation-dependent probe amplification method, and a (13)C breath test confirmed the diagnosis of nonketotic hyperglycinemia. Treatment with the N-methyl-d-aspartate receptor antagonist ketamine exerted dramatic suppressive effects on his seizures, and ameliorated his clinical status.

The Burst-Suppression Electroencephalogram

The burst suppression (BS) pattern of the EEG was originally described as a response to large dosages of anesthetics and sedatives. It was subsequently found over/in isolated cortex due to surgical procedures or lesions underlying the cortex. Around 1960 with the introduction of modern intensive care treatment (intubation, artificial respiration) the BS pattern has become a typical EEG correlate of cerebral anoxia. These obvious consequences of this therapeutic approach with their impact on the EEG picture are more or less inexplicable.The BS pattern is also typical in two rare and severe central nervous system (CNS) disorders in infants: early infantile myoclonic encephalopathy (EIME) and Ohtahara syndrome.

Functional cortical deafferentation from the subcortical structures in a patient with early myoclonic encephalopathy: A functional neuroimaging study

We, for the first time, used functional neuroimaging analyses for a girl with early myoclonic encephalopathy (EME). The interictal single photon emission computed tomography (SPECT) and [18F]-fluoro-D-deoxyglucose positron emission tomography (FDG-PET) at 1 month of age showed hypoperfusion and hypometabolism of bilateral basal ganglia, thalami, and the right parietooccipital cerebral cortices, showing that there is profound dysfunction of the basal ganglia and thalamus as well as cerebral cortex. On the other hand, subtraction ictal SPECT of tonic spasms clearly showed hyperperfusion of the bilateral basal ganglia, thalami, brainstem, and deep cortical layer of bilateral frontoparietal cortices. The present study suggests that functional deafferentation of the cortex from subcortical structures exists in EME, and that these imaging abnormalities may provide insight into the pathophysiology of suppression-burst pattern in EME.

Early Myoclonic Encephalopathy and Nonketotic Hyperglycinemia

Early myoclonic encephalopathy is an epileptic syndrome with different etiologies. Nonketotic hyperglycinemia is one cause. We describe two cases of early myoclonic encephalopathy, secondary to nonketotic hyperglycinemia, with fatal evolution in the neonatal period. These two cases may better clarify clinical findings that can be associated with impairment of glycine metabolism. Distinguishing features include agenesis of the corpus callosum in patient 1, and weight loss exceeding 10%, associated with metabolic acidosis, in patient 2. The burst-suppression electroencephalography pattern is relatively common in neonatal encephalopathies, and is frequently associated with seizures. Nonketotic hyperglycinemia is an inborn error of metabolism caused by mutations in genes encoding protein in the mitochondrial glycine cleavage system. The neonatal form is a severe, frequently lethal neurologic disease. When associated with electro-clinical features, progressive lethargy and hypotonia occur in the first days of life, progressing to apnea and often death. Prospective treatment with oral sodium benzoate, the N-methyl-d-aspartate receptor antagonist ketamine, and dextromethorphan can favorably modify the early neonatal course of severe nonketotic hyperglycinemia, but does not prevent poor long-term outcomes.

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.

Malignant migrating partial seizures in infancy: An epilepsy syndrome of unknown etiology

The syndrome of malignant migrating partial seizures in infancy was first reported in 1995, and is now included among the childhood epilepsy syndromes in development in the proposal of the revision of the International League Against Epilepsy (ILAE) classification of the epilepsies and epilepsy syndromes. The main clinical features are seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal electroencephalography (EEG) discharges, and progressive deterioration of psychomotor development. Etiology is so far unknown. Seizures are markedly drug resistant and outcome is generally severe. Based on age at onset, migrating partial seizures in infancy (MMPEI) may be placed between early epileptic encephalopathies (early myoclonic encephalopathy [EME] and early infantile epileptic encephalopathy [EIEE]) and infantile spasms.

A case of Ohtahara syndrome with mitochondrial respiratory chain complex I deficiency

Ohtahara syndrome (OS) is known as an intractable epileptic syndrome in neonatal and early infantile period, differentiated from early myoclonic encephalopathy (EME) in its etiology. We report a patient with OS associated with mitochondrial respiratory chain complex (MRC) I defect. With ketogenic diet and mitochondrial cocktail therapy, seizures were completely controlled and suppression-burst patterns disappeared 3 months after starting treatment. It is suggested that OS could be caused by specific metabolic disorder such as MRC defect and the intensive therapies including ketogenic diet, vitamin and coenzyme therapy and antioxidant treatment might be helpful for some patients.

Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4

The tyrosine kinase receptor ErbB4 (erythroblastic leukemia viral oncogene homolog 4) plays a crucial role in numerous neurobiological processes in the developing and adult brain. Moreover, recent molecular genetics studies implicate ErbB4 in the pathophysiology of schizophrenia. However, the phenotypic consequences of haploinsufficiency of ErbB4 are not known, as no coding mutations have been identified until now. Here, we present a patient with early myoclonic encephalopathy and profound psychomotor delay with a de novo reciprocal translocation t(2;6)(q34;p25.3), disrupting the ErbB4 gene. This patient represents the first case of haploinsufficiency for one of the ErbB family members of tyrosine kinase receptors.

High-Frequency Rhythmic Cortical Myoclonus in a Long-Surviving Patient With Nonketotic Hypergylcemia

An 11-year-old girl with nonketotic hyperglycinemia who typically presented with a picture of early myoclonic encephalopathy in the neonatal period is presented in this article. Treated early with sodium benzoate and dextromethorphan, she became seizure-free, while myoclonus persisted. During examination, multifocal rhythmic myoclonic jerks in gamma frequency enhanced by motor activity were noted. Coherence analysis of the electroencephalography-electromyography relationship indicated a cortical origin of the myoclonic jerks. Observation of this case suggests that rhythmic cortical myoclonus may represent a late evolution of this rare disorder.

Predictive Value of Sequential Electroencephalogram (EEG) in Neonates With Seizures and Its Relation to Neurological Outcome

The aim of this study was to evaluate the relationship of sequential neonatal electroencephalography (EEG) and neurological outcome in neonates with seizures to identify polysomnographic features predictive of outcome. Sequential EEGs recordings of 58 neonates that belonged to 2 historical cohorts of newborns with seizures from the same neonatal intensive care unit and who had follow-up at the Neurodevelopment Clinic of the Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) in Porto Alegre, Brazil, were analyzed and classified into 4 groups: normal-normal, abnormal-normal, abnormal-abnormal, normal-abnormal. In patients with more than 2 recordings, during the neonatal period, the first EEG was compared with the following more abnormal. A total of 58 pairs of 2 sequential EEGs were analyzed. Considering the first EEG, a statistically significant difference was observed between the relationship of the result of this exam, if it was abnormal, with developmental delay (P = .030) and postnatal death (P = .030). Abnormal background activity was also related to neurodevelopment delay (P = .041). EEG sequences abnormal-abnormal and normal-abnormal significantly correlated to the outcome epilepsy ( P = .015). Abnormal sequential background activity was associated with neurodevelopment delay (P = .006) and epilepsy (P = .041). The burst suppression pattern when present in any EEG correlated with epilepsy (P = .013) and postnatal death (P = .034). Sequential abnormal background patterns in the first and second EEG increased the risk for epilepsy (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.03-3.0) and neurodevelopment delay (RR = 2.20; 95% CI = 1.3-3.0). Abnormal background activity only in the second electroencephalogram increased the risk for neurodevelopment delay (RR = 2.20; 95% CI = 1.3-3.0). All the neonates (n = 33) with seizures related to probable hypoxic ischemic encephalopathy had abnormalities in the first EEG (P = .030). Postnatal epilepsy was diagnosed in 24 infants (41.4%). Five (20.8%) presented West syndrome, 7 (29.2%) focal symptomatic epilepsy, 6 (25%) generalized symptomatic epilepsy, 2 (8.3%) early myoclonic encephalopathy, 1 (4.2%) early infantile epileptic encephalopathy, and in 3, the epileptic syndrome was undefined (12.5%). All infants (n = 5) with West syndrome had some degree of neurodevelopment delay. In conclusion, our findings suggest that sequential EEG in neonates with seizures has more predictive value to estimate the outcomes of neurodevelopment delay, epilepsy, and postnatal death than a single EEG recording. The abnormal background activity in even 1 EEG of the sequential recordings was more significant to determine neurological outcome than abnormal ictal activity or abnormalities in the organization of sleep state.

Relation of Spasms and Myoclonus to Suppression-Burst on EEG in Epileptic Encephalopathy in Early Infancy

This study was intended to clarify the relation between spasms in series and a suppression-burst (SB) EEG pattern which have a common nature of repetitive bursting activity in epileptic encephalopathy in early infancy. The ictal EEG traces of spasms were temporally compressed and expanded to study the beginning and ending phases of series along with their spectral analysis in two patients with Ohtahara syndrome (OS) and one with early myoclonic encephalopathy (EME). The EEG bursts associated with myoclonus were also investigated. A mutual transition was indicated between the ictal activity of spasms and the bursts in the peri-series SB on EEG. Gamma rhythm was detected in common in the ictal activity and the peri-series and interictal bursts on EEG, and also in the bursts with myoclonus. The relation between the ictal activity of spasms and SB on EEG was shown to be close. The generative mechanisms of spasms and myoclonus might be linked to the bursting tendency intrinsic to immature brain function.

Tuesday July 4, 2006 Tuesday July 4, 2006 7:30-9:00 Hall 1 Orphan Drug Symposium

Abstract 1 M. Baulac ( 1 Service de Neurologie, Hopital Pitie-Salpetriere, Paris, France ) Although epilepsy is one of the commonest neurological disorders, certain epileptic syndromes or diseases are nonetheless fulfilling all the criteria, in terms of epidemiology and severity, for being qualified as rare diseases. These epileptic conditions indeed are distinct entities, affecting no more than 5 in 10,000 persons in Europe, carrying a risk of chronic impairment, severe debilitation, and mortality, and there is a lack of specific treatments with durable effects on the seizures and the neuropsychological disorders. Most of the epileptic encephalopathies can be qualified as rare diseases. They include Ohtahara syndrome / early myoclonic encephalopathy, migrating partial seizures in infancy, West syndrome, Dravet syndrome or severe myoclonic epilepsy in Infancy (1/30,000), Lennox-Gastaut syndrome (2/10,000), Landau-Kleffner syndrome, continuous spike-wave during sleep, etc… In these specific conditions, the intense ictal and interictal epileptic activity contributes to the progressive disturbance in brain function. These epileptic encephalopathies can themselves be caused by rare mutations or other rare diseases, for instance tuberous sclerosis in West syndrome. Orphan drugs, which are still in development, have been designated by the EMEA for the Dravet syndrome (stiripentol) and for the Lennox-Gastaut syndrome (rufinamide). In other situations, epilepsy is the predominant clinical expression of a disease of genetic, metabolic or inflammatory origin, which is responsible for progressive brain damage. Progressive myoclonic epilepsies (less than 1/20,000) for which brivaracetam was recently designated, and Rasmussen encephalopathy (approximately 1 case per big center per year) are good examples. It is very important for our patients and their families to ensure that these conditions are well acknowledged as rare diseases, and that they can benefit from the various governmental and EU incentives dedicated to specific research and Orphan drugs development.

TREATMENT OF INTRACTABLE EPILEPTIC ENCEPHALOPATHIES IN INFANCY

Objectives: Ohtahara syndrome (OS), early myoclonic encephalopathy (EME), migrating partial seizures in infancy (MPSI) and severe myoclonic epilepsy in infancy (SMEI) do not respond to conventional antiepileptic therapies. We studied the best way to treat these disorders.

Vigabatrin Caused Rapidly Progressive Deterioration in Two Cases With Early Myoclonic Encephalopathy Associated With Nonketotic Hyperglycinemia

Vigabatrin, a structural analogue of gamma-aminobutyric acid (GABA), is used for the treatment of generalized and partial seizures in infants. The drug inhibits the GABA transaminase and elevates the GABA concentration in the brain. Here we present the vigabatrin experience in two patients with early myoclonic encephalopathy owing to nonketotic hyperglycinemia (glycine encephalopathy). Both patients had early infantile seizures characterized by fragmentary myoclonic jerks associated with burst-suppression pattern on electroencephalography. Nonketotic hyperglycinemia was diagnosed with elevated cerebrospinal fluid and plasma glycine levels. The seizures were initially thought to be infantile spasms, and vigabatrin (50 mg /kg/day) was started for the treatment of seizures. Rapidly progressive deterioration was noticed after a few days. Acute encephalopathy associated with sleepiness and respiratory failure developed. Vigabatrin produced acute encephalopathy, which regressed in a few days after vigabatrin was stopped in the first patient. However, in the second case, despite the discontinuation of vigabatrin, there was no recovery of general conditions. Our observations in two cases indicate the risk of using vigabatrin in patients with nonketotic hyperglycinemia. The elevated GABA concentration in the brain can enhance the encephalopathy, together with the elevated levels of glycine. (J Child Neurol 2006;21:82-84).

Épilepsies néonatales et erreurs innées du métabolisme

Metabolic disorders constitute an important cause of neurologic disease, including neonatal epilepsy. Epilepsy rarely dominates the clinical presentation, which is more frequently associated with other neurologic symptoms, such as hypotonia and/or vigilance disturbances. In most cases, epilepsy secondary to inherited metabolic disorders presents with polymorphic clinical and electrographic features that are difficult to classify into precise epileptic syndromes. However, specific types of seizures, such as myoclonic seizures or distinctive electroencephalographic patterns, such as suppression burst patterns, epileptic syndrome or early myoclonic encephalopathy, may suggest a specific metabolic disease. The aim of this article is to help clinicians in reviewing potential metabolic diagnoses and approaching metabolic evaluations.

Selected Papers: AED

Abstract *Kuriko Kagitani Shimono, *Katsumi Imai, *Rie Sakakibara, *Takeshi Okinaga, and *Keiichi Ozono *[Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine]. Purpose: A new antiepileptic drug (AED), clobazam (CLB), was introduced in Japan in 2000. In previous studies, CLB was effective in 30–80% of epilepsy patients. A retrospective study of the clinical efficacy and adverse effects of CLB was performed in patients with refractory epilepsy. The development of tolerance to CLB and related factors also was studied. Methods: Patients with refractory epilepsy who had one or more seizures per month despite treatment with three or more AEDs were included in the study. CLB was prescribed as an add-on therapy, once or twice per day. In patients who were taking other benzodiazepines (BZDs), the other BZDs were gradually tapered as the dosage of CLB was increased. The patients were followed up for >6 months. Results: Seventy-two patients were studied. Their ages ranged from 1 to 37 years (16.4 ± 10.2 years, mean ± SD). Twenty-one patients had symptomatic generalized epilepsy (early myoclonic encephalopathy, one; West syndrome, four; Lennox–Gastaut syndrome, 12), 48 had localization-related epilepsy (cryptogenic, one), and three had severe myoclonic epilepsy in infancy. The mean minimum dosage of CLB was 0.13 mg/kg/day in patients with body weight <20 kg, or 5.3 mg/day in those with body weight of ≥20 kg. The mean maximum dosage was 0.4 mg/kg/day in patients with body weight <20 kg, or 16.7 mg/day in those with body weight of ≥20 kg. CLB reduced the frequency of seizures by ≥50% in 48% of the subjects (18% with no seizure, 6% with 75% reduction, and 24% with 50–75% reduction). CLB was effective for both generalized epilepsy (42.5%) and focal epilepsy (50%), and especially for temporal lobe epilepsy (TLE) (60%). CLB was effective for partial seizures (55.5%), primary (57%) and secondarily generalized (40%) tonic–clonic seizures, and tonic seizures (46%). It was not effective for spasms (0), atonic seizures (0), and the majority of absence seizures (25%). CLB was effective in 10 nonresponders to clonazepam (CZP). Among the adverse effects of CLB, the incidences of somnolence, salivation, and aggressiveness were 29%, 1.3%, and 13.8%, respectively, which was lower than the incidence previously reported for patients taking CZP; and the incidence of depression was 13.8%, which was higher than that reported for patients taking CZP. Similar to several other BZDs, in some patients, tolerance to CLB developed. In 65% of patients, tolerance to CLB developed within 1 year (55% within 6 months). Tolerance was not observed in other patients who had taken CLB for >1 year. In 55% of the cases in whom tolerance to CLB developed, the frequency of seizures returned to the original frequency before starting CLB treatment, whereas in the remaining 45% of cases, the frequency of seizures increased slightly and was lower than the frequency before starting CLB treatment. The mean CLB dosage in patients in whom tolerance did not develop (16.7 mg/day) was lower than the dosage in those in whom tolerance developed (19.0 mg/day). The mean serum N-desmethyl CLB concentration in long-term users who did not develop tolerance was very high (3,071 ng/ml). Conclusions: CLB was effective for both refractory generalized and localization-related epilepsies and was especially effective for TLE. CLB was effective at a lower dosage than previously reported. The incidence of some adverse effects such as somnolence, salivation, and aggressiveness was lower for CLB than for CZP. CLB was also effective in some patients who had tolerance to other BZDs. In those who developed tolerance to CLB, tolerance appeared within 6 months in most cases. Patients who did not develop tolerance to CLB had a higher serum N-desmethyl CLB concentration, which may be an important factor.

Repetitive EEG recordings are necessary for the diagnosis of early myoclonic encephalopathy

Early myoclonic encephalopathy (EME) is a rare malignant epileptic syndrome. The erratic myoclonus with or without focal motor seizures, time of onset before 3 months of age, and suppression-burst (SB) pattern in EEG are accepted as the diagnostic criteria for EME. We report a 40-day-old infant with the diagnosis of non-ketotic hyperglycinemia (NKHG). The infant developed myoclonic and focal tonic seizures on the first day of life. His first sleep EEG recorded after onset of seizure was normal. Because of the diagnosis of NKHG and early developed myoclonic seizure, we thought the infant might be EME, and repeated sleep EEG on admission in which asymmetrical SB pattern was seen. We concluded that the absence of SB pattern in the first EEG recording does not exclude the diagnosis of EME, but repetition of EEG is necessary to demonstrate the presence of SB pattern to meet the diagnostic criteria for EME.