Research Notes: Seizure Disorders

From Treatment of Mitochondrial Cytopathies (Medscape Pediatrics)

Management of seizures typically involves the use of common anticonvulsants including (but not limited to) phenobarbital, phenytoin, carbamazepine, gabapentin, lamotrigine, benzodiazepines, and zonisamide. Valproate has been identified as a potentially dangerous medication because of its hepatotoxic side effect in some patients with metabolic diseases. There is considerable debate as to whether this medication should ever be used, regardless of the situation, or whether, in metabolic disease, it can be considered in the setting of seizures that have been refractory to other medications. Valproate is known to inhibit cytochrome oxidase (COX) as well as cause mitochondrial ultrastructural changes, but it is not know if these are clinically relevant. Phenobarbital and the benzodiazepines do interfere with mitochondrial function in vitro but it is not clear if this is clinically relevant. There may be a theoretical advantage to using some of the newer neuroprotective drugs such as gabapentin or lamotrigine. The ketogenic diet has been used safely in many patients with oxidative phosphorylation disorders. It should be avoided in those with fatty acid oxidation disease and in those patients that either do not enter rapid ketosis (indicating a primary or functional defect in fatty acid oxidation) or those that become encephalopathic with the onset of fasting or initiation of high-fat feeds. The use of levo-carnitine in all patients on the diet is controversial, but those with known metabolic disease should have carnitine monitoring every 6 months.

Brain Dev. 2005 Mar.
Electroclinical characteristics of seizures - comparing Prader-Willi syndrome with Angelman syndrome.
Wang PJ, Hou JW, Sue WC, Lee WT.
Department of Pediatrics, Tzu Chi University and Medical Center, 701, Sec 3, Chung-Yang Road, Hualien, Taiwan.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurobehavioral syndromes that are caused by deficiency of gene expression from paternally or maternally derived homologues on chromosome 15q11-q13, respectively. Clinical and genetic heterogeneities are common in both syndromes and they are now regarded as 'sister genetic imprinting syndromes'. This study aimed to describe and compare the electroclinical characteristics of seizures between PWS and AS, and to try to explore the possible mechanisms of epileptogenesis in these two syndromes. Fifty patients with genetically documented PWS and 18 patients with a putative diagnosis of AS were included in this study. These patients were diagnosed on the basis of characteristic physical findings and their neurobehavioral phenotype, as well as cytogenetic and molecular studies. Epileptic seizures were present in 16 of 18 patients with AS, but in only eight of 50 patients with PWS. Using electroencephalography (EEG), the most characteristic findings for AS were rhythmic 2-3 Hz delta waves of high-amplitude that were maximal over the frontal regions, and 3-4 Hz spikes and sharp wave runs posteriorly. These were never seen in PWS. Patients with AS had a much higher incidence of seizures with characteristic EEG findings, similar to those seen in mice that are deficient in a single gene (UBE3A) that displays regional brain-specific imprinting in humans and mice. In this series, cases with no detectable cytogenetic or molecular defect at the AS locus displayed similar AS phenotype, seizure severity and EEG abnormalities compared to those with such a defect. Thus, the UBE3A gene is presumed to be potentially involved in the epileptogenesis of AS. It is also possible that UBE3A and another gene located nearby, gamma-aminobutyric receptorbeta3 subunit, may interact in some way, and result in the severe epilepsy seen with AS. Some patients with PWS and AS share the common EEG features of persistent high-amplitude 4-6 Hz activity in recordings during sleep, and while awake. The significance of such EEG findings needs further experience to clarity.

J Intellect Disabil Res. 2006 Jan.
A long-term population-based clinical and morbidity review of Prader-Willi syndrome in Western Australia.
Thomson AK, Glasson EJ, Bittles AH.
Centre for Human Genetics, Edith Cowan University, Perth, Australia.

BACKGROUND: An investigation of the clinical morbidity and genetic profiles of individuals with Prader-Willi syndrome (PWS) in Western Australia (WA) was undertaken as part of a wider study into the effects of intellectual disability (ID) on the life course of individuals. METHODS: All persons with a diagnosis of PWS were identified from the records of the Disability Services Commission of WA (DSC). The DSC client files formed the main data source, and were supplemented by information from other state health data sets. The analysis was retrospective and quantitative in nature. RESULTS: A total of 56 individuals were identified, 10 of whom exhibited normal methylation patterns and so were analysed separately (PWS-like). The ages of the PWS group ranged from 0.9 to 48.3 years, with six persons deceased. Most people with PWS (76%) had mild or moderate ID, and 70% lived in their family home. The birth prevalence of the disorder was 1 in 29 500 births. Respiratory disorders, dentistry and gastrointestinal disorders were common reasons for hospital admission, with epilepsy or convulsions also reported at moderate frequency. The PWS-like group shared many clinical features in common with PWS patients, the principal exceptions being hypotonia and feeding difficulties in infancy. CONCLUSIONS: The estimated birth prevalence of PWS was lower than expected; however, the case ascertainment method may have excluded some individuals. Older people with PWS were generally living in sheltered accommodation. As the cohort ages, demand for places in similar accommodation will increase, adding to the existing burden on service providers. Substantial future increases in the use of medical services and hospital-based care also are predicted with the onset of age-associated disorders.

Clin Genet. 2005 Jan.
Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: study of 75 patients.
Varela MC, Kok F, Setian N, Kim CA, Koiffmann CP.
Human Genome Study Center, Department of Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.

Prader-Willi syndrome (PWS) can result from a 15q11-q13 paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. We describe here the phenotypic variability detected in 51 patients with different types of deletions and 24 patients with UPD. Although no statistically significant differences could be demonstrated between the two main types of PWS deletion patients, it was observed that type I (BP1-BP3) patients acquired speech later than type II (BP2-BP3) patients. Comparing the clinical pictures of our patients with UPD with those with deletions, we found that UPD children presented with lower birth length and started walking earlier and deletion patients presented with a much higher incidence of seizures than UPD patients. In addition, the mean maternal age in the UPD group was higher than in the deletion group. No statistically significant differences could be demonstrated between the deletion and the UPD group with respect to any of the major features of PWS. In conclusion, our study did not detect significant phenotypic differences among type I and type II PWS deletion patients, but it did demonstrate that seizures were six times more common in patients with a deletion than in those with UPD.

Srp Arh Celok Lek. 1989 May-Jun.
Case report of a boy with Prader-Willi syndrome and focal epilepsy. [Article in Serbian]
Vranjesevic D, Jovic N, Brankovic S.

An 11-old boy with Prader-Willi syndrome and partial epilepsy was reported. Muscular hypotonia in early infancy was extreme and developmental milestones were retarded, especially walk and speech. He achieved these landmarks within three years. The first seizure disorder was seen in the 9th year. The patient was characterized by hypotonic musculature, severe mental retardation, obesity (gynaecomasty, excess of fat on the thighs, the abdomen and the trunk), hypogonadism (a minute penis, hypoplastic scrotum and cryptorchidism). Apart from these characteristics, the patient presented some minor morphological anomalies (turicephalic skull, high-arched palate, abnormally shaped pinnae, clinodactily, defects on teeth enamel), and some skeleton and joint anomalies (small feet, kyphosis, lumbar lordosis, knock-knee, flat foot). Speech retardation, behaviour disturbance and inappropriate emotional reaction were noted. Karyotype was normal. Dermatoglyphic analysis showed some significant qualitative and quantitative characteristics. An abnormal glucose tolerance curve was obtained. Electroencephalogram showed an irritative paroxysmal discharge with primary focal activity in frontal-temporal cortical regions of the brain left hemisphere.

Epilepsia. 2007 Jan.
Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects.
Kang HC, Lee YM, Kim HD, Lee JS, Slama A.
Department of Pediatrics and Epilepsy Center, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea.

PURPOSE: To evaluate the clinical efficacy and safety of the ketogenic diet (KD) for patients with intractable childhood epilepsy and mitochondrial respiratory chain (RC) complex defects. METHODS: A retrospective analysis evaluated outcomes in 14 children with intractable epilepsy and RC complex defects who were treated with the classic KD involving a 4:1 lipid to nonlipid ratio (% by weight), but without an initial fast and fluid restriction. Outcome measures included seizure frequency, electroencephalography (EEG) findings, the number of antiepileptic drugs, and adverse reactions. RESULTS: Of the 14 patients, 9 had Complex I defects, 1 had a Complex II defect, 3 had Complex IV defects, and 1 had combined Complex I and IV defects. Two patients with Complex IV defects showed clinical progress compatible with the Leigh disease. The epileptic diagnoses were as follows: 5 patients were diagnosed with infantile spasms, 4 with the Lennox-Gastaut syndrome, 1 with the Landau-Kleffner syndrome, 1 with nonspecific generalized seizure disorder, and 3 with partial seizure disorder. The study found that 7 patients became seizure-free after commencing the KD, three of whom successfully completed the diet without relapse. One patient with a greater than 90% seizure reduction, and 2 patients with seizure reductions between 50% and 90%, remained on the diet. Four patients, including two diagnosed with the Leigh disease, did not show any favorable responses to the diet or ceased the diet due to complications. CONCLUSIONS: The KD was a safe and effective therapy for seizures in children with intractable epilepsy and RC complex defects.

J Child Neurol. 2002 Dec.
Role of carnitine and fatty acid oxidation and its defects in infantile epilepsy.
Tein I.
Division of Neurology, The Hospital for Sick Children, 555 University Ave., Toronto, ON.

Defects in fatty acid oxidation are a source of major morbidity and are potentially rapidly fatal. Fatty acid oxidation defects encompass a spectrum of clinical disorders, including recurrent hypoglycemic, hypoketotic encephalopathy or Reye-like syndrome in infancy with secondary seizures and potential developmental delay, progressive lipid storage myopathy, recurrent myoglobinuria, neuropathy, and progressive cardiomyopathy. As all of the known conditions are inherited as autosomal recessive diseases, there is often a family history of sudden infant death syndrome in siblings. Early recognition and prompt initiation of therapy and the institution of preventive measures may be life saving and significantly decrease long-term morbidity, particularly with respect to central nervous system sequelae. Seizures may be the result of cerebral bioenergetic failure associated with acute episodes of hypoglycemic, hypoketotic encephalopathy, or hypoxic-ischemic encephalopathy in the context of cardiac arrhythmias and/or cardiomyopathy. This review provides an overview of the fatty acid oxidation pathway and the central role of carnitine, as well as a discussion of normal fasting adaptation and the critical metabolic adaptations that occur at birth. The increased vulnerability of infants and young children to fasting and defective fatty acid oxidation is discussed in the context of the heightened bioenergetic demands of the developing brain. Clinical and laboratory features of specific genetic defects in fatty acid oxidation, approaches to diagnosis, and current treatment methodologies are described. Indications for carnitine supplementation in childhood epilepsy are also discussed.

Neurology. 2001 May 22.
Epileptic phenotypes associated with mitochondrial disorders.
Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T, Lamantea E, Savoiardo M, Uziel G, Villani F, Zeviani M, Avanzini G.
Department of Clinical Neurophysiology, Epilepsy Center, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

Objective: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME). Methods: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect. Results: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or "overlapping" characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome. Conclusions: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.

Brain Dev. 1991 May.
EEG findings in children and adolescents with mitochondrial encephalomyopathies: a study of 25 cases.
Tulinius MH, Hagne I.
Department of Pediatrics II, University of Goteborg, Sweden.

EEG was studied in 25 children and adolescents with mitochondrial encephalomyopathies, defined on the basis of clinical, biochemical and morphological criteria. Twenty cases conformed to well-known mitochondrial syndromes: Alpers syndrome [6], Leigh syndrome [2], MERRF (myoclonus epilepsy and ragged red fibers) syndrome [3], MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome [5] and Kearns-Sayre syndrome [4]. Many patients were followed for several years with repeated EEG. In all, 112 EEG records were included in the study. A common feature of all the mitochondrial encephalomyopathic syndromes was slowing of the alpha rhythm. Epileptic discharges were seen in most syndromes. In spite of the small number of cases in each group, in Alpers, MERRF and MELAS syndromes we found sequential EEG patterns which seemed to be typical of the respective syndromes. In contrast, in Kearns-Sayre syndrome, a slow background rhythm was the only consistent finding. We conclude that EEG, especially repeated recordings, may be of help in the diagnostic evaluation of mitochondrial encephalomyopathies.