Epileptic seizures,arthrogryposis, and migrational brain disorders: a syndrome?

Introduction – Arthrogryposis multiplex congenita (AMC) may be associated with multiple developmental defects. In some severely affected newborns with AMC, autopsy studies have suggested a common mechanism of malmigration at the spinal and cerebral levels. To our knowledge, a constellation of arthrogryposis, epileptic seizures, and brain migrational anomalies in adult patients has not previously been described in a clinical material. Material and methods – Six consecutive adult patients with arthrogryposis multiplex congenita and epileptic seizures form the basis of the present study. Five patients had joint contractures and reduced muscle volume restricted to the lower extremities, whereas one patient had predominantly upper extremity affection. They were studied with magnetic resonance imaging (MRI), EEG, EMG, a neuropsychological test battery, and chromosome analysis. Results – Four of them had clear evidence of migrational brain disorders, demonstrated by MRI, in three of them roughly corresponding to the focal epileptiform EEG activity. Five of the patients had partial seizures, whereas one only had generalized tonic-clonic seizures. The MRI findings included polymicrogyria, pachygyria, and fused schizencephaly. Four had neurogenic EMG changes, one had myopathic EMG features, and one had an unremarkable EMG pattern in affected muscles. All patients witL demonstrable migrational disorders showed abnormal neuropsychological features. Three patients were mentally retarded. A chromosome abnormality in the form of a ring chromosome 18 was present in one patient. Conclusion – We suggest that AMC, epileptic seizures, and migrational brain disorders may form the integral parts of a hitherto undescribed syndrome in adults. A wide-spread defect in neuronal migration along the entire neural axis may be the underlying mechanism of the cerebral and the peripheral symptoms.     

Pattern of childhood epilepsies with neuronal migrational disorders in Oman

Neuronal migrational disorders form a significant cause of psychomotor delay and intractable epilepsy in children. Pediatric neurology services are available at Sultan Qaboos University Hospital, Muscat, Oman, which is a tertiary care hospital for the whole country. The children undergoing evaluation for developmental delay and epilepsy formed the subjects of the study. Data were analyzed from children found to have neuronal migrational disorders on imaging (computed tomography [CT] or magnetic resonance imaging [MRI]). There were 40 cases of neuronal migrational disorders. Corpus callosum agenesis and lissencephaly or pachygyria formed the major group. There were 22 cases of corpus callosum agenesis, 12 of lissencephaly or pachygyria, 2 of schizencephaly, and 1 each of polymicrogyria, holoprosencephaly, hydranecephaly, and hemimegalencephaly. Nineteen of these 40 (47.5%) cases of neuronal migrational disorders had epilepsy. The break-down was 8 of 22 cases of corpus callosum agenesis (36%), 7 of 12 (58.3%) cases of lissencephaly or pachygyria, and 1 each of polymicrogyria, hydranencephaly, and hemimegalencephaly. The family history of developmental delay, similar to the index case, was present in two children with lissencephaly. However, the brain imaging did not reveal the abnormality. The types of seizures were infantile spasms in five, tonic-clonic in nine, myoclonic in two, partial in one, and mixed in five. Nineteen of 40 cases of neuronal migrational disorders had epilepsy. Only 2 of 19 (10.5%) with epilepsy had good seizure control. This raises the possibility of more and more surgical intervention in the management of such cases. Neuronal migrational disorders are related to exogenous and genetic factors from the 6th to 26th weeks of gestation. Molecular and genetic research is defining the mechanism of these disorders. This could help in early diagnosis, prevention, and eventual gene therapy in such conditions.     

Epilepsy and psychiatric disorder in the mentally retarded adult

302 mentally retarded adults, sampled by epidemiological criteria, were examined with regard to epilepsy and psychiatric disorder. Each of the complications was frequent and related to degree and origin of mental retardation. In 55 (18.2%) epilepsy had occurred at some time during their lives, in 25 (8.3%) of these in the past year. In 52% of persons with seizures in the past year a present state psychiatric diagnosis was established, compared to 26% in those without seizures. The nature of the combination of epilepsy and psychiatric disorder is complex, but in the mentally retarded most often reflecting underlying brain pathology in the form of widespread cortical and subcortical cerebral damage causing epilepsy of generalised or mixed type, and predominantly interictal psychiatric disorders unrelated in time to seizures and dominated by behaviour problems.     

Bilateral central macrogyria: epilepsy, pseudobulbar palsy, and mental retardation--a recognizable neuronal migration disorder

The neuronal migration disorders comprise several morphological entities that are recognizable during life using current imaging techniques. We studied 4 patients who had a characteristic bilateral central rolandic and sylvian macrogyria. The patients had pseudobulbar palsy with oromotor incoordination and developmental delay and were mildly retarded. Minor seizures developed between the ages of 8 and 9 years. Subsequently, atonic drop attacks became the predominant epileptic pattern. Epileptogenic electrographic abnormalities were secondary generalized or multifocal. The lesions were detected by computed tomography and magnetic resonance imaging in all patients. Bilateral symmetrical areas of thick cortex surrounding a large sulcus were seen. This syndrome consists of specific clinical, imaging, electroencephalographic, and epileptic features. It can be suspected clinically and confirmed by imaging studies. Callosotomy in two patients helped the intractable seizures.     

The correlation of seizure characteristics and hippocampal volumetric magnetic resonance imaging findings in children with idiopathic partial epilepsy

Cerebral volumetric measurements based on magnetic resonance imaging have been established as advanced morphometric techniques with anatomic and clinical utility in adults and children with epilepsy. This study investigated the cerebral and hippocampal volumes in children with idiopathic partial epilepsy to detect the factors correlated with volume reduction. Magnetic resonance imaging volumetric measurements were performed of the total cerebral and hippocampal formation volumes in 30 patients with idiopathic partial epilepsy between 3 to 18 years old. The cerebral and the total, right, and left hippocampal volumes of the study and control patients were detected using volumetric magnetic resonance imaging, and the volumes were compared between the 2 groups. In study patients, the correlation between volumetric findings and seizure characteristics was evaluated. The results suggested that children with idiopathic partial epilepsy had significant hippocampal volume reduction that was not influenced by the age of onset and the duration of epilepsy.     

Genetic and neuroradiological heterogeneity of double cortex syndrome

Mutations in the X-linked doublecortin gene appear in many sporadic cases of double cortex (DC; also known as subcortical band heterotopia), a neuronal migration disorder causing epilepsy and mental retardation. The purpose of this study was to examine why a significant percentage of sporadic DC patients had been found not to harbor doublecortin mutations and to determine whether clinical features or magnetic resonance imaging scan appearance could distinguish between patients with and without doublecortin mutations. Magnetic resonance imaging scan analysis differentiated patients into the following four groups: anterior biased/global DC with doublecortin mutation (16 of 30; 53%), anterior biased/global DC without mutation (8 of 30; 27%), posterior biased DC without mutation (3 of 30; 10%), and limited/unilateral DC without mutation (3 of 30; 10%). The presence of these atypical phenotypes suggests that other genetic loci or mosaicism at the doublecortin locus may be responsible for this diversity of DC cases.     

Subtest profiles of the WISC-R and WAIS in mentally retarded patients with epilepsy

In this study, WISC-R and WAIS subtest profiles of mentally retarded patients with epilepsy are analysed with respect to the Verbal-Performance IQ Discrepancy scores and rank order of mean subtest scores. The relative strengths and weaknesses in cognitive patterns of this sample are compared with subtest profiles mentioned in the literature on mentally retarded populations and samples of normal intelligent patients with epilepsy in order to determine the impact of epilepsy factors on cognition. The results indicate that people with mental retardation have problems with the verbal subtests Arithmetic, Vocabulary and Information, while patients with epilepsy have problems with Coding (Digit Symbol), Digit Span and Information. For this sample of mentally retarded patients with epilepsy, the most difficult subtests are Digit Span and Coding. The results concerning subtest profiles in different populations are discussed in light of the deleterious impact of epilepsy on cognition, which may superimpose the general effect of brain damage in mentally retarded patients. It is suggested that especially attentional processes, as measured with the subtest Coding, are vulnerable for epilepsy factors.     

Possible association between congenital cytomegalovirus infection and autistic disorder

We encountered seven children with symptomatic congenital cytomegalovirus (CMV) infection from 1988 to 1995, of whom two (28.6%) developed typical autistic disorder. Case 1: A boy born at 38 weeks' gestation with a birth weight of 3164 g showed generalized petechiae, hepatosplenomegaly, and positive serum CMV-specific IgM antibodies. He was profoundly deaf, mentally retarded, and exhibited a lack of eye contact, stereotyped repetitive play, and hyperactivity. Case 2: A boy delivered at 39 weeks gestation with a birthweight of 2912 g showed non-progressive dilatation of the lateral ventricles observed postnatally. CMV-specific IgM antibodies were positive and CMV-DNA in the urine was confirmed by PCR. The boy was mentally retarded but not deaf. He showed no interest in people and delayed speech development. Subependymal cysts were detected by cranial ultrasound after birth in both patients. This is the first report describing subependymal cysts and the later development of AD. Cranial magnetic resonance imaging revealed an abnormal intensity area in the periventricular white matter suggestive of disturbed myelination; however, no migration disorders were found in our patients. These findings suggest that the timing of injury to the developing brain by CMV may be in the third trimester in some patients with autistic disorder.     

A history of neuroimaging in epilepsy 1909–2009

Profound advances in the field of clinical imaging in epilepsy occurred between 1909 and 2009, the century of the International League Against Epilepsy, and these are reviewed briefly in this paper. Initially imaging was carried out with plain x-ray, air encephalography, and angiography, and these techniques had a relatively minor role in epilepsy. Computerized tomographic (CT) scanning was introduced in 1971, and magnetic resonance imaging (MRI) a decade or so later, and both these technologies had an immediate and far-reaching impact on epilepsy. MRI techniques continued to evolve during the 1990s and profoundly influenced many aspects of epilepsy clinical practice. These structural imaging techniques revealed pathological lesions in large numbers of patients with hitherto cryptogenic epilepsy, widened the indications for surgical therapy, and improved our understanding of the pathogenesis and etiology of epilepsy. In recent years, the research focus has turned to fMRI but its impact on epilepsy currently is relatively small. Magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT) also have had a limited impact on clinical practice in epilepsy.     

Incidence of epilepsy in extremely low-birthweight infants (<1,000 g): A population study of central and southern Sardinia

Purpose:   With the development of intensive care, the survival of extremely low-birthweight (ELBW) infants (<1,000 g) has greatly improved. The aim of our study was to report the incidence of epilepsy after a follow-up of >7 years in a population of ELBW children, born in central and southern Sardinia between 1991 and 2000.
Methods:   We analyzed data of 104 children. All infants had had serial cranial ultrasound echography (CUE) in the neonatal period and some also had magnetic resonance imaging (MRI). At last follow-up we evaluated the occurrence of epilepsy through a review of clinical charts and a structured telephone interview.
Results:   In 11 (10.6%) of 104 of children we observed febrile seizures (FS). Epilepsy occurred in 9 (8.6%) of 104 ELBW children, and in these patients a frequent positive family history for epilepsy and/or FS was present. In four epilepsy patients CUE was highly pathologic, showing intraventricular hemorrhage (IVH) of grade IV and in two mildly abnormal (IVH of grade I–II). In three additional children with normal neonatal ultrasound scan, a later magnetic resonance imaging (MRI) study revealed lesions related to neonatal insult.
Discussion:   In our ELBW population, epilepsy had an incidence clearly superior to that expected in infancy (8.6% vs. 0.6–0.8% ) . A frequent positive familiar history for epilepsy and/or FS suggests that a genetic predisposition may also play a role. Subjects with highly abnormal CUE are a subgroup with high risk for seizures; however, epilepsy can occur even with normal CUE.     

Cortical dysplasia in temporal lobe epilepsy: magnetic resonance imaging correlations

Cortical dysplasia has been documented in histological specimens surgically removed for treatment of refractory temporal lobe epilepsy. We studied 10 patients with cortical dysplasia and complex partial seizures who underwent temporal lobectomy. Magnetic resonance imaging revealed abnormalities in 5 of the patients who had microscopically detectable major abnormalities. Magnetic resonance imaging revealed an abnormal cortical-white matter architectonic pattern in 2 patients with moderate cortical dysplasia. In the remaining 3 patients, magnetic resonance imaging findings were unremarkable. These observations suggest that magnetic resonance imaging is sensitive in the detection of certain dysplastic lesions in temporal lobe epilepsy. Preoperative identification of these abnormalities by magnetic resonance imaging may permit early and optimal surgical treatment in patients with refractory epilepsy.     

Neuroimaging and connectomics of drug‐resistant epilepsy at multiple scales: From focal lesions to macroscale networks

Epilepsy is among the most common chronic neurologic disorders, with 30%‐40% of patients having seizures despite antiepileptic drug treatment. The advent of brain imaging and network analyses has greatly improved the understanding of this condition. In particular, developments in magnetic resonance imaging (MRI) have provided measures for the noninvasive characterization and detection of lesions causing epilepsy. MRI techniques can probe structural and functional connectivity, and network analyses have shaped our understanding of whole‐brain anomalies associated with focal epilepsies. This review considers the progress made by neuroimaging and connectomics in the study of drug‐resistant epilepsies due to focal substrates, particularly temporal lobe epilepsy related to mesiotemporal sclerosis and extratemporal lobe epilepsies associated with malformations of cortical development. In these disorders, there is evidence of widespread disturbances of structural and functional connectivity that may contribute to the clinical and cognitive prognosis of individual patients. It is hoped that studying the interplay between macroscale network anomalies and lesional profiles will improve our understanding of focal epilepsies and assist treatment choices.     

Coexisting muscular dystrophies and epilepsy in children

Muscular dystrophies are composed of a variety of genetic muscle disorders linked to different chromosomes and loci and associated with different gene mutations that lead to progressive muscle atrophy and weakness. Fukuyama congenital muscular dystrophy is frequently associated with partial and generalized epilepsy and congenital brain anomalies, including cobblestone complex and other neuronal migration defects. We report generalized convulsive epilepsy in a boy with normal brain magnetic resonance imaging and Duchenne muscular dystrophy with deletion of dystrophin gene, and we report absence epilepsy with normal brain magnetic resonance imaging in another boy with limb girdle muscular dystrophy with partial calpain deficiency. We, therefore, review coexisting muscular dystrophies and epilepsy in children. In addition to Fukuyama congenital muscular dystrophy, partial or generalized epilepsy has also been reported in the following types of muscular dystrophies, including Duchenne/Becker dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 (merosin) chain, and limb girdle muscular dystrophy with partial calpain deficiency.     

Effect of vigabatrin on epilepsy in mentally retarded patients: a 7-month follow-up study

We studied the antiepileptic potency of vigabatrin (gamma-vinyl GABA, GVG) as an open trial in a group of 36 mentally handicapped patients with drug-resistant epilepsy (30 had seizures of partial onset and 6 had primary generalized [PG] tonic-clonic convulsions). With this treatment, 13 (43%) of the patients with seizures of partial onset and 2 (33%) with PG had more than 50% reduction in seizure frequency. The antiepileptic effect appeared during the first month of therapy and continued throughout the 7-month study. The side effects were mild: tiredness, aggressiveness, and ataxia. Other antiepileptic drugs remained at baseline levels during GVG therapy. GVG did not alter EEG recordings. Our results suggest that GVG is effective for treatment of intractable epilepsy, especially the partial type, in mentally retarded patients. Longer follow-up is needed, however, to determine that the clinical effect is maintained and that no severe side effects appear.     

Unusual MRI appearance of diffuse subcortical heterotopia or "double cortex" in two children

Two children with mild epilepsy and learning and behaviour problems had magnetic resonance imaging (MRI) scans showing an almost identical generalised disorders of neuronal migration. Their computer tomography (CT) scans showed abnormal hypodense white matter. The MRI showed a four layered appearance of the cerebral parenchyma extending from the frontal to the occipital region. There was a normal appearance to the white matter in the periventricular region which had an abnormally smooth junction with a thick diffuse layer of heterotopic grey matter. This was surrounded by a thin layer of white matter which had normal digitations with the overlying cortex. The appearance of the overlying cortex was normal. These and other recently described cases broaden the concept of generalised disorders of neuronal migration and illustrate that it is possible to have a generalised cerebral malformation with few clinical consequences.     

The open opercular sign: diagnosis and significance

Four children with varying clinical manifestations, but with the unifying feature of severe developmental delay, had bilateral enlargement of the sylvian fissure confirmed by magnetic resonance imaging (MRI). Subsequently, we examined 125 consecutive MRI scans of the heads of pediatric patients, looking for this insular exposure, and did not find it. Pathological correlation in 1 child revealed arhinencephaly and abnormal gyral formation; another is known to have migrational abnormalities. We suggest that the open operculum is a sign of arrested development and is associated with other anomalies and a poor prognosis.     

Epileptic and non-epileptic cerebral palsy: EEG and cranial imaging findings

The aims of the study were to compare the clinical types, electroencephalogram (EEG) and cranial magnetic resonance imaging/computed tomography findings of epileptic and non-epileptic cerebral palsy (CP) patients. Seventy-four patients with CP were evaluated in 2 years. Tetraplegic CP had a higher incidence of epilepsy (60.5%). EEG was confirmed abnormal in epileptic CP as 90.3%, and in non-epileptic CP as 39.5%. Focal epileptiform activity, generalized slowing, and multifocal epileptiform activity were significantly frequent in epileptic CP. There were cranial imaging abnormalities of 74.2% in epileptic and 48.8% in non-epileptic CP. Although there was not any statistically significant difference between the two groups, epileptic group revealed more structural abnormalities. Further studies concerning a possible risk of epilepsy development and its relations with the EEG and cranial imaging findings are needed in presenting the other risk factors involved and the factors affecting the CP prognosis.     

Lissencephaly-pachygyria associated with congenital cytomegalovirus infection.

We report the presence of major cerebral migrational defects in five severely, multiply handicapped children with congenital cytomegalovirus (CMV) infection. These patients had both computed tomographic (CT) scan and magnetic resonance imaging (MRI) evidence of marked migrational central nervous system defects consistent anatomically with the spectrum of lissencephaly-pachygyria, a disorder commonly idiopathic or associated with chromosomal abnormalities or with unknown early gestational insults. Neuroradiologic features included broad, flat gyri, shallow sulci, incomplete opercularization, ventriculomegaly, periventricular calcifications, and white-matter hypodensity on CT scans or increased signal intensity on long-TR MRI scans. Evidence for congenital CMV infection included prenatal onset of microcephaly, periventricular calcifications, neonatal jaundice, hepatomegaly, elevated CMV-specific immunoglobulin M, or viral isolation from urine. Previous reports of the neurologic sequelae of CMV have emphasized varying degrees of psychomotor retardation, cerebral palsy and epilepsy due to polymicrogyria, periventricular calcification, microcephaly, or rarely, hydrocephalus. Our patients appear to represent extremely severe examples of the effects of CMV on neurologic growth, maturation, and development. Recognition of these severe migrational abnormalities was improved by use of MRI, a technique that affords superior definition of the nature and extent of gyral and white-matter abnormalities. We suggest that these abnormalities may be more common than has previously been recognized.     

Intractable Epilepsy in a Population-Based Series of Mentally Retarded Children

Summary: Purpose: The characteristics of intractable epilepsy were analyzed in a population-based study of active epilepsy in mentally retarded children aged 6–13 years.
Methods: Diagnostic registers, EEG laboratory registers, and registers for the Education of the Subnormal were searched. Medical files were scrutinized. Clinical examinations and interviews with parents and caregivers or both were performed. EEG recordings, computed tomography (CT) and magnetic resonance imaging (MRI) of the CNS were reevaluated.
Results: Forty-five percent (44 of 98) of the children with mental retardation (MR) and active epilepsy had intractable seizures, defined as one or more seizures every day or week. The median age at onset was 0.8 years, as compared with 3.0 years for those with controlled epilepsy. Predictive factors for frequent seizures were the number of seizure types, severe MR, status epilepticus (SE) and tonic seizures. Epileptiform EEG activity was present in 91%, and focal activity in 65%. Brain lesions were detected on CT and MRI in 70%, with generalized lesions in 60%. Concurrent focal epileptiform activity and focal brain lesions on CTIMRI were detected in 26%. The percentages and prevalence rates for infantile spasms (IS) and Lennox-Gastaut syndrome (LGS) were 18% (0.25 in 1,000) and 7% (0.06 in 1,000), respectively. One of 8 children with IS had had previous neonatal seizures, 3 had SE and 1 later developed LGS.
Conclusions: Children with MR and intractable epilepsy have a high frequency of severe MR and additional major neuroimpairments. EEG recordings frequently showed focal changes despite generalized lesions in neuroradiology.     

The Cavum Septi Pellucidi; A Magnetic Resonance Imaging Study of Prevalence and Clinical Associations in a Pediatric Population

The cavum septi pellucidi is formed when the two leaves of the septum pellucidum fail to fuse as the fetal brain matures. When observed at autopsy or by computed tomography or magnetic resonance imaging (MRI), it is often considered clinically insignificant. Using MRI, this study evaluated the prevalence of cavum septi pellucidi in 445 pediatric patients and correlated the findings to the patients' functional level. A cavum septi pellucidi of 1.3 to 12.0 mm was observed in 64 (14%) of the patients. Of the children with cavum septi pellucidi, 12 (19%) were mentally retarded or severely developmentally delayed and 24 (38%) were less severely handicapped. In a random sample of 64 patients without cavum septi pellucidi from the original population, only 14 (22%) had any functional abnormality. The data suggest that cavum septi pellucidi is clinically significant as a marker for increased risk of disturbed brain function.