Plasma amino acids in childhood epileptic encephalopathies

Abnormalities in plasma amino acid levels have been noted in patients with various epilepsies, and sometimes also in their first degree relatives. We sought to study plasma amino acid levels in children with epileptic encephalopathies and their parents, relating findings to the pattern of cortical glucose metabolism as determined by 18fluorodeoxyglucose (FDG) positron emission tomography (PET). Twenty-eight children with cryptogenic epileptic encephalopathies were studied prospectively. Cortical glucose metabolism was evaluated by FDG PET with combined visual and semiquantitative analysis used to detect focal cortical defects. The plasma concentration of 21 amino acids in the children and their parents was measured by ion exchange chromatography and compared with control values using non-parametric statistical methods. Multivariate analysis was used to assess antiepileptic drug effects. Children were classified as: Lennox-Gastaut syndrome following infantile spasms (six patients); de-novo Lennox-Gastaut syndrome (eight); severe myoclonic epilepsy in infancy (eight) and myoclonic-astatic epilepsy (two). Four patients remained unclassified. Fourteen patients had focal/multifocal abnormalities on PET scans. The plasma level of aspartate was significantly lower in both the children with epileptic encephalopathies and in their parents (P < 0.005). The lowered aspartate levels could not be accounted for by the antiepileptic drug medication taken by the children. Further analysis showed the lowered aspartate levels to be confined to children and their parents who lacked focal PET abnormalities. These findings suggest a possible genetic abnormality in the aspartate neurotransmitter systems in the pathogenesis of seizures in the childhood epileptic encephalopathies.     

Cortical and subcortical glucose metabolism in childhood epileptic encephalopathies

OBJECTIVES— Nearly one third of children withcryptogenic epileptic encephalopathies have been reported to have focalcortical defects on ¹⁸fluorodeoxyglucose (FDG) PET. Asdiffuse cortical dysfunction and involvement of subcortical structures,particularly the thalami, is postulated to underlie the propensity toseizures in these conditions, the aim was to determine the frequency ofbilateral and diffuse cortical metabolic defects and of subcorticalmetabolic abnormalities in the same patients.
METHODS—The interictal uptake of FDG was studiedin 32 children with epileptic encephalopathies. Using asemiquantitative technique, the ratio of uptake in cortical regions andsubcortical structures to that in the cerebellum was compared with thatof age matched historical controls. Uptake more than 2 SD above("hypermetabolic") or below ("hypometabolic") that of agematched controls was considered abnormal.
RESULTS—Diffusely abnormal cortical uptake(nearly always hypometabolic) occurred in almost two thirds ofpatients; in all but two of the remaining patients at least onecortical region showed significantly decreased uptake bilaterally. Whenanalysed as age cohorts, the mean cortical:cerebellar FDG uptake wassignificantly lower than that of controls in all cortical regions(P<0.005). Ninety per cent of patients had evidence of relativethalamic hypometabolism and in each age group there was a significantreduction in relative thalamic FDG uptake compared with that ofcontrols (P<0.005). In nine out of 11 patients with unilateralcortical hypometabolic defects thalamic FDG uptake was loweripsilateral to the cortical abnormality.
CONCLUSIONS—Diffuse cortical dysfunction iscommon in the epileptic encephalopathies and may reflect the underlyingcause of the condition or arise as a consequence of uncontrolledseizures. Altered thalamic glucose metabolism is further evidence ofsubcortical involvement in these conditions.

     

The age-dependent epileptic encephalopathies.

The most severe epilepsies that affect neonates, infants, and children include Ohtahara, West, and Lennox-Gastaut syndromes. These three syndromes display considerable similarities and transitional features in their clinical symptoms, seizure phenomena, and electroencephalographic abnormalities. This review examines the similarities and differences between these three syndromes and the other severe epilepsies of infancy and childhood, and discusses the hypothesis that the three disorders form a continuum of epileptic encephalopathies that have a predictable age-related evolution.     

The genetics of monogenic idiopathic epilepsies and epileptic encephalopathies

The group of idiopathic epilepsies encompasses numerous syndromes without known organic substrate. Genetic anomalies are thought to be responsible for pathogenesis, with a monogenic or polygenic model of inheritance. Over the last two decades, a number of genetic anomalies and encoded proteins have been related to particular idiopathic epilepsies and epileptic encephalopathies. Most of these mutations involve subunits of neuronal ion channels (e.g. potassium, sodium, and chloride channels), and may result in abnormal neuronal hyperexcitability manifesting with seizures. However non-ion channel proteins may also be affected. Correlations between genotype and phenotype are not easy to establish, since genetic and non-genetic factors are likely to play a role in determining the severity of clinical features. The growing number of discoveries on this topic are improving classification, prognosis and counseling of patients and families with these forms of epilepsy, and may lead to targeted therapeutic approaches in the near future. In this article the authors have reviewed the main genetic discoveries in the field of the monogenic idiopathic epilepsies and epileptic encephalopathies, in order to provide epileptologists with a concise and comprehensive summary of clinical and genetic features of these seizure disorders.     

Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome

Background: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Methods: Thirty‐eight patients (19 males, 19 females), aged between 4 and 34 (mean 13.7 ± 8.3, median 12.5), all affected by different types of childhood‐onset refractory epileptic encephalopathies other than Lennox–Gastaut syndrome, were treated with rufinamide as adjunctive drug for a mean period of 11.4 months (range 3–26 months). Results: Fifteen of 38 patients (39.5%) had a ≥50% seizure reduction in countable seizures. Complete seizure freedom was achieved in one of these patients (2.6%). Three patients (7.9%) had a 25–49% seizure reduction, whilst seizure frequency remained unchanged in 15 (39.5%) and increased in five patients (13.1%). Eleven patients (28.9%) reported adverse side effects. Vomiting was reported in five patients (13.1%); drowsiness, decreased appetite and irritability with migraine manifested in other four patients. They were transient and mild in all cases. Conclusion: Rufinamide may be an effective and well‐tolerated adjunctive drug for the treatment of refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Rufinamide was most effective in patients with drop‐attacks and (bi)frontal spike–wave discharges.     

Long-term outcome of developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies are conditions where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. Usually they have multiple etiologies. Therefore, long-term outcome is related to both etiology-related factors and epilepsy-related factors–age at onset of epilepsy, type(s) of seizure(s), type of electroencephalographic abnormalities, duration of the epileptic disorder. This paper focuses on long-term outcome of six developmental and epileptic encephalopathies with onset from the neonatal period to childhood: early epileptic encephalopathy with suppression bursts, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures and epileptic encephalopathy with continuous spike and waves during slow-wave sleep including Landau-Kleffner syndrome. For each syndrome, definition, main etiologies if multiple, and long-term outcome are discussed.     

Oxidative stress in children affected by epileptic encephalopathies

Environment and genetic are both relevant in determining development of Multiple Sclerosis. Many epidemiological observations converge on indicating EBV infection and Vitamin D levels as major players among the environmental factors. Bacteria and bacterial products are however potent triggers of immune responses, and recent work from several laboratories indicates that the microbiota plays a prominent role in "priming" or protecting individuals for development of experimental autoimmune diseases. Here we report our recent work dealing with the role of non-pathogenic mycobacteria and their innate receptors in relapsing-remitting experimental autoimmune encephalomyelitis in the SJL mouse and in mobilization of CNS-reactive T cells. We finally discuss how bacteria are likely involved in the pathogenesis of Multiple Sclerosis, expecially with regard to their role in driving the recurring acute episodes of disease.     

Mozart's music in children with drug-refractory epileptic encephalopathies

Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal EEG discharges and recurrence of clinical seizures in both adults and young patients. In this prospective, open-label study, we evaluated the effect of listening to a set of Mozart's compositions, according to the Tomatis method, on sleep quality and behavioral disorders, including auto-/hetero-aggression, irritability, and hyperactivity, in a group of children and adolescents with drug-resistant epilepsy.The study group was composed of 11 outpatients (7 males and 4 females), between 1.5 years and 21 years of age (mean age: 11.9 years), all suffering from drug-resistant epileptic encephalopathy (n = 11). All of them had a severe/profound intellectual disability associated with cerebral palsy. During the study period, each patient had to listen to a set of Mozart's compositions 2 h per day for fifteen days for a total of 30 h, which could be distributed over the day depending on the habits and compliance of each patient.The music was filtered by a device preferably delivering higher sound frequencies (> 3000 Hz) according to the Tomatis principles. The antiepileptic drug therapy remained unchanged throughout the study period. During the 15-day music therapy, 2 out of 11 patients had a reduction of 50–75% in seizure recurrence, and 3 out of 12 patients had a reduction of 75–89%. Overall, 5 (45.4%) out of 11 patients had a ≥ 50% reduction in the total number of seizures, while the percentage decrease of the total seizure number (11/11) compared with baseline was − 51.5% during the 15-day music therapy and − 20.7% in the two weeks after the end of treatment. All responders also had an improvement in nighttime sleep and daytime behavior.     

A genetic diagnostic approach to infantile epileptic encephalopathies

Epileptic encephalopathies are characterized by frequent severe seizures, and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or deterioration, and usually a poor prognosis. The epileptiform abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function. Determining the underlying aetiology responsible for infantile epileptic encephalopathy is a clinical challenge worth undertaking to facilitate advice on the recurrence risk and to allow for the option of prenatal testing, as often this category of epilepsy is associated with devastating hardship for families. This review takes advantage of recently published studies that have identified new genes associated with epilepsy and focuses on known monogenic causes where detection is useful for the process of genetic counselling. Based on the review, we present a diagnostic work-up in order to triage specific genetic testing for infants presenting with an epileptic encephalopathy.     

Developmental and epileptic encephalopathies: recognition and approaches to care

The term “developmental and epileptic encephalopathy” (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non‐progressive diseases with cognitive impairment and co‐existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term “developmental encephalopathy” (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term “epileptic encephalopathy” (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.     

Epileptic encephalopathies in early infancy with suppression-burst.

Early infantile epileptic encephalopathy with suppression-burst, or Ohtahara syndrome (OS), and early myoclonic encephalopathy (EME) are epileptic encephalopathies with onset of frequent seizures in the neonatal and early infancy period and with a characteristic EEG pattern, namely, suppression-burst, in which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phase. Their nosologic independence is now widely accepted, although some controversy initially occurred because of their common characteristics such as age of onset, EEG features, seizure intractability, and poor prognosis. Major differences between the two syndromes include (1) tonic spasms in OS versus partial seizures and erratic myoclonias in EME, (2) continuous suppression-burst pattern in both waking and sleeping states in OS versus this EEG pattern almost limited to sleep in EME, and (3) static structural brain damage in OS versus genetic or metabolic disorders in EME. The most important differentiating point is their evolutional pattern with age, which may reflect their pathophysiologic difference. Ohtahara syndrome evolves to West syndrome and further to Lennox-Gastaut syndrome with age, but EME demonstrates no unique evolution; namely, it continues as such for a long time or changes into partial epilepsy or severe epilepsy with multiple independent spike foci.     

KCNQ2 related early-onset epileptic encephalopathies in Chinese children

Journal of Neurology - To study the phenotype, genotype, treatment strategies, and short-term prognosis of Chinese children with KCNQ2 (potassium voltage-gated channel subfamily Q member 2) related...     

Cerebrospinal fluid pterins and neurotransmitters in early severe epileptic encephalopathies

Early-onset epileptic encephalopathies are devastating conditions. Little is known about pathophysiology and biological markers. We aimed to identify a relationship between the type and prognosis of epileptic encephalopathies starting in infancy and the cerebrospinal fluid profile of pterins and neurotransmitters. Cerebrospinal fluid samples of 23 infants with epileptic encephalopathies were analysed for biogenic amine metabolites (homovanillic and 5-hydroxyindoleacetic acids), and pterins (neopterin and biopterin). West syndrome, early-infantile epileptic encephalopathy with suppression-bursts or Ohtahara syndrome, severe epilepsy with multiple independent spike foci and partial epilepsy with multiple independent spike foci were the four types of epileptic encephalopathy studied. We report clinical, electroencephalographic, neuroimaging and follow-up data. Among the 23 patients studied, 7 had high neopterin levels. Four of them had partial epilepsy with multiple independent spike foci. High neopterin values were associated with mortality (chi square = 7.304, p = 0.007). 5-Hydroxyindoleacetic acid levels were above reference values in three patients, two with partial epilepsy with multiple independent spike foci and one with West syndrome. Homovanillic acid was normal in almost all infants studied. In conclusion, high neopterin levels suggest a cellular immune activation in the central nervous system of these infants, with apparent prognosis implications.