[Aicardi-Goutieres syndrome: an oft unrecognised familial early-onset encephalopathy]. / Le syndrome d'Aicardi-Goutières: une maladie neurologique infantile, à transmission familiale, encore méconnue.

INTRODUCTION: Aicardi-Goutieres syndrome, first described in 1984, is a progressive infantile familial encephalopathy featuring cerebral calcifications, mainly of the basal ganglia, cerebral white matter abnormalities and cerebrospinal fluid lymphocytosis. Most of the patients present with severe developmental retardation, microcephaly, abnormal eye movements, pyramidal tract signs, and prominent dystonic movements. An elevated level of interferon-alpha in the CSF is a constant feature, particularly during the first stages of the disease course. One locus has been mapped on chromosome 3p21 in about half of the families so far studied. PATIENTS: and results. We report two new French cases and discuss the limits of the clinical syndrome, the differential diagnosis and issues raised by the pathophysiological mechanisms involved. The major concern is to separate this condition from intrauterine infections because of the genetic and therapeutic consequences. A number of other questions remain unanswered. For example, we still do not know today at what age the absence of features like CSF lymphocytosis, and possibly absence of calcifications, rules out the diagnosis of the condition. The origin of the vasculitis lesions is not known, but seems to be related to dysregulation of interferon production and secretion. CONCLUSION: Currently about 75 patients have been reported, even though many more probably exist. The study of this syndrome can contribute to the understanding of some mechanisms of CNS calcification and in a broader perspective to that of chronic encephalopathies with dysregulation of immune mechanisms.

Syncopal attacks compulsively self-induced by Valsalva's maneuver associated with typical absence seizures. A case report.

A girl of borderline intelligence developed repeated syncopal attacks that were compulsively self-induced, apparently by forced expiration against a closed glottis (Valsalva's maneuver). In addition, she had typical absence seizures triggered by her apneic attacks, which could also be induced by hyperventilation. The absence seizures were suppressed by treatment with valproate sodium, which had no effect on the self-induced apneas. These were considerably improved with fenfluramine hydrochloride treatment, which was also associated with marked improvement of her previously abnormal behavior.

Absence of the septum pellucidum with porencephalia. A neuroradiologic syndrome with variable clinical expression.

We studied 12 patients with absence of the septum pellucidum associated with porencephalies. Seven patients had bilateral and five apparently unilateral defects of the cerebral mantle. The clinical manifestations were relatively mild in half of the patients and limited to isolated partial seizures in one. In one case, extensive calcification was present adjacent to the defects. In two cases, the presence of a cleft was demonstrated only by magnetic resonance imaging, although it had been suspected by computed tomography in one.

Clinical findings in children with occipital spike-wave complexes suppressed by eye-opening.

We studied the EEG abnormality of occipital sharp and slow waves significantly or completely suppressed by eye-opening in 16 patients. All had seizures consisting of transient loss of consciousness. Most experienced additional grand mal, partial (simple or complex), or clonic fits. Response to treatment was poor initially in 9 and subsequently in 11. Learning difficulties were present in 10 children. The cases illustrate the wide range of clinical disorders that may accompany the EEG abnormality and indicate that the prognosis associated with this EEG pattern is not necessarily benign.

The juvenile and chronic forms of GM2 gangliosidosis: clinical and enzymatic heterogeneity.

We report the cases of 5 patients from 2 sibships with the "adult" or chronic form of GM2 gangliosidosis and 2 patients from another sibship with the juvenile form. We demonstrated hexosaminidase A deficiency in all cases but in 1 sibship the enzymatic profile was identical to that in Tay-Sachs disease, whereas in the remaining 2 families it was that of the B1 variant. There was no correlation between the clinical features and the enzymatic profile. Hexosaminidase A deficiency should be considered in unexplained progressive neurologic disorders of childhood and adolescence, including isolated dementia. EMG evidence of anterior horn cell involvement in association with neurologic or cognitive deterioration may be a diagnostic clue in the juvenile forms.

Extensive macrogyri or no visible gyri: distinct clinical, electroencephalographic, and genetic features according to different imaging patterns.

We studied 43 children with extensive brain gyral anomalies diagnosed radiologically and defined by (a) the absence or paucity of sulci over cortical areas affecting at least two lobes in each hemisphere, and (b) the absence or reduction of interdigitation between gray and white matter. We correlated the clinical, EEG, and genetic findings with the imaging features. A seemingly homogeneous group of patients (group A, n = 30) presented a common imaging pattern characterized by four features: (1) a thickened neocortex, (2) widened lateral ventricles, (3) apparent verticalization and widening of sylvian fissures, and (4) bilateral and symmetric distribution of the abnormalities. Another group of patients (group B, n = 13) exhibited heterogeneous imaging anomalies, termed "nonlissencephalic brain malformation," differing in at least one of the following four ways from the radiologic criteria defining group A: absence of verticalization of sylvian fissures (n = 12), thin neocortex (n = 2), normal-size lateral ventricles (n = 2), and asymmetric brain defects (n = 3). In group A, some clinical features had a significantly lower frequency (p < or = 0.01) than in group B: microcephaly, a complete lack of postural development, and intractable epilepsy. There was a significant relationship, but only in group A, between the degree of gyral anomalies and the extent of neurodevelopmental delay. Some EEG patterns (rapid rhythms and delta-theta rhythms) were highly specific for the group A patients. There was lower risk of familial recurrence in group A (recurrence of convolutional anomalies was 3.5% of sibship in group A versus 44% of sibship in group B, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Diffuse cortical dysplasia, or the 'double cortex' syndrome: the clinical and epileptic spectrum in 10 patients.

Diffuse neuronal migration disorders associated with epilepsy can now be recognized by modern neuroimaging techniques, particularly high-resolution MRI. We report 10 patients with a recently described MRI picture of continuous or generalized band heterotopia underlying the cortical mantle, giving the appearance of a "double cortex." They have epilepsy, and almost all have mental retardation. The epileptic disorder varies in nature and degree of severity. Patients may present with infantile spasms, a Lennox-Gastaut syndrome, or other forms of secondary generalized or multifocal epilepsy. Response to medical treatment is variable. Callosotomy may lead to considerable reduction of drop attacks, present in 60%. Mental retardation is usually mild or moderate, and only rarely severe. It correlates with the type of epileptic syndrome, and is greater in patients with more disorganized cortex overlying the heterotopia. Recognition of this entity by MRI is important for appropriate diagnosis of the epileptic disorder, planning of therapeutic strategy, and prognosis.

Sturge-Weber syndrome: indications and results of surgery in 20 patients.

OBJECTIVE: To discuss the indications and timing for resective surgery in patients with Sturge-Weber syndrome (SWS) and medication-resistant epilepsy. BACKGROUND: SWS that causes epilepsy severe enough to merit surgery is rare. Because of the variable natural history of the disease, it is difficult to establish clear-cut indications for surgery and prospective studies are not feasible. Attitudes of clinicians and surgeons remain variable. METHODS: The authors assessed the presurgical epilepsy profile, criteria for surgery, monitoring techniques, and the postoperative outcome of epilepsy in all patients with SWS consecutively admitted between 1972 and 1990 to two referral centers (Paris and Montreal) and underwent surgery for intractable seizures. RESULTS: All 20 patients had a minimal postoperative follow-up of 4 years and all but one are still followed by one of the authors. One patient had a callosotomy, five underwent hemispherectomy, and 14 had cortical resection. Despite variability in the age at onset of seizures (range: 2 months to 12 years), age at operation (range: 8 months to 34 years) and surgical methods, almost all patients benefited from surgery. Visually guided complete resection of the pial angioma and underlying cortex, whenever possible, seemed sufficient; results were no better with intraoperative corticography. In children with previous hemiparesis, hemispherectomy proved particularly effective: all five became seizure free. None of the patients showed any aggravation of cognitive impairment following surgery; none of those who were operated on early presented with severe mental retardation, and 13 of 20 became seizure free. CONCLUSION: Although the natural history of SWS is imperfectly known, increasing duration of seizures and of postictal deficits, increase in atrophy or of calcified lesions or both, are indicative of its progressive nature. Despite the expected heterogeneity that renders formal comparison of the various approaches difficult, the current study provides new evidence to support early surgery in patients with SWS and drug-resistant epilepsy. The authors' results suggest that lesionectomy is a good approach, provided that the pial angioma is unilateral and the resection can be complete.

Schilder's myelinoclastic diffuse sclerosis.

The term "Schilder's disease" has been used to describe conditions as disparate as adrenoleukodystrophy, myelinoclastic diffuse sclerosis, and postinfectious and postvaccinal encephalomyelitis. The eponymic designation should be reserved for instances of myelinoclastic diffuse sclerosis that correspond to the case described by Schilder in 1912. The diagnosis cannot be made unless adrenoleukodystrophy has been ruled out by analysis of the long-chain fatty acids of plasma cholesterol esters. Schilder's myelinoclastic diffuse sclerosis, a variant of multiple sclerosis, is a very rare disease that occurs in children and adults of both sexes and appears to respond to vigorous treatment with corticosteroids and/or corticotropin. A case of this disease is reported and the recent literature of cases that have been called Schilder's disease is reviewed.

Acute measles encephalitis in children with immunosuppression.

Four cases of encephalitis occurring in children treated for lymphatic malignancies by immunosuppressive drugs are reported. Measles virus was isolated from the brain in one case and identified immunologically in another. Nucleocapsids identical to those seen in subacute sclerosing panencephalitis were demonstrated in three cases. Severe immunosuppression was evidenced in two patients by failure of rosette formation and low phytohemagglutinin tests. Pathologically, the inflammatory reaction was absent in one brain and moderate in two. Clinically, epilepsia partialis continua was a prominent feature in three patients. A history of measles or of contact was elicited in three cases, five weeks to three months before onset. All cases ran an acute fatal course. Measles virus can behave as an opportunistic invader of the central nervous system in children and the diagnosis of measles encephalitis should be considered in immunosuppressed patients.

Ullrich's congenital atonic sclerotic muscular dystrophy. A case report.

A 5-year old girl with Ullrich's atonic-sclerotic muscular dystrophy is reported and 16 previously reported cases are reviewed. The clinical features, in particular proximal contractures, distal hyperextensibility, mild dysmorphism and hyperhidrosis, allow recognition of this subtype of congenital muscular dystrophy, which has no specific pathological characteristics. There is evidence in favour of an autosomal recessive mode of inheritance.

Delay in the maturation of muscle fibers in infants with congenital hypotonia.

Muscle biopsies of hypotonic children have shown delayed maturation of a fetal type of muscle fibers: subsarcolemmal halo devoid of activity for mitochondrial dehydrogenases, type II predominance and in some cases abnormal dispersion of fiber diameter. Fiber subtypes within group II were also abnormal. One case has definite embryonic characteristics with presence of myoblasts. Not a single clinical pattern was present in these patients and a variety of associated disorders were recognized. Some patients had a clinical picture corresponding to congenital benign hypotonia as described by Walton.

Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy.

IFN-alpha was detected in cerebrospinal fluid and/or sera from 7 of 8 patients with a progressive familial encephalopathy associated with calcifications of the basal ganglia and white matter alterations. The secretion of IFN-alpha was prolonged, as shown by its presence at different times between birth and 5 years, and was not associated with IFN-gamma. Virological investigations excluded various congenital infections. In only 2 patients, high levels of Epstein-Barr virus antibodies were observed, indicating the possibility of an abnormal response to viral infection rather than a congenital infection. Further investigations are required for characterization of the recessive autosomal trait of this syndrome and its relation to the IFN system.

Epilepsy in children with shunted hydrocephalus.

OBJECT: The incidence of epilepsy among children with hydrocephalus and its relation to shunts and their complications, raised intracranial pressure (ICP), and developmental outcome are explored in a retrospective study. METHODS: The authors studied a series of 802 children with hydrocephalus due to varying causes, who were treated by ventriculoperitoneal shunt placement between 1980 and 1990, with a mean follow-up period of 8 years. Patients who had tumoral hydrocephalus and those whose files lacked significant data were excluded. Data extracted from medical records, including history of the hydrocephalus and history of seizures, if any, were analyzed. Thirty-two percent of the children had epilepsy, the onset of which frequently occurred at approximately the same time that the diagnosis of hydrocephalus was made. The majority of the affected children had severe uncontrolled epilepsy. The incidence of epilepsy was significantly affected by the original cause of the hydrocephalus. The presence of radiological abnormalities was also found to be a significant predictor of epilepsy. Similarly, shunt complications predisposed to epilepsy. Episodes of raised ICP related to hydrocephalus or in association with shunt malfunction may also predispose to epileptic seizures. Furthermore, the presence of a shunt by itself seems able to promote an epileptogenic focus. Finally, epilepsy appears to be an important predictor of poor intellectual outcome in hydrocephalic children with shunts. CONCLUSIONS: A prospective study is needed to identify clearly and confirm avoidable factors predisposing to seizures in these children so that we can strive to reduce the incidence of these seizures and, subsequently, improve these children's quality of life.

Surgery of epilepsy associated with focal lesions in childhood.

OBJECT: Surgery in children with epilepsy is a new, evolving field. The important practical issues have been to define strategies for choosing the most suitable candidates and the type and optimal timing of epilepsy surgery. This study was undertaken to elucidate these points. METHODS: To identify the factors that correlated with outcome, the authors analyzed a series of 200 children (aged 1-15 years (mean 8.7 years) who underwent surgery between 1981 and 1996 at the Hôpital Necker-Enfants Malades. In 171 cases (85.5%) the epilepsy was medically refractory and was associated with focal cortical lesions. Surgery consisted of resection of the lesion without specifically attempting to identify and remove the "epileptogenic area. "In the group of children whose seizures were medically refractory, the mean follow-up period was 5.8 years. According to Engel's classification, 71.3% of these children became seizure free (Class 1a,) whereas 82% were in Class I. A multivariate statistical analysis revealed that among all the factors studied, the success of surgery in a patient in whom there was a good clinical/electroencephalogram/imaging correlation depended on the patient's having undergone a minimally traumatic operation, a complete resection of the lesion, and a short preoperative seizure duration. After the surgical control of epilepsy, behavior disorders were more improved (31% of all patients) than cognitive function (25%). The patient age at onset, duration and frequency of seizures, intractability of the disease to therapy, and seizure characteristics were correlated with cognitive, behavioral, and academic performance pre- and postoperatively. Multivariate statistical analysis revealed that cognitive dysfunction correlated highly with the duration of epilepsy prior to surgery, whereas behavioral disorders correlated more with seizure frequency. CONCLUSIONS: These data must be taken into account when selecting patients for surgical treatment and when deciding the timing of surgery. Early surgical intervention allows for optimum brain development.

Myoclonic epilepsies of infancy and childhood.

This chapter has reviewed the multiple types of childhood epilepsies customarily referred to as "myoclonic epilepsies" and has made an attempt at classification. A distinction was made on a clinical neurophysiological basis between true myoclonic and pseudomyoclonic seizures that include brief tonic and atonic attacks. The epilepsies characterized mainly by pseudomyoclonic seizures include infantile spasms (West's syndrome) and the Lennox-Gastaut syndrome. The epilepsies manifested principally by true myoclonic seizures comprise two subgroups: a symptomatic type, in which myoclonias are the result of fixed diffuse brain damage; and several cryptogenic forms. The latter may be divided, according to age of onset and clinical features, into several myoclonic syndromes: cryptogenic myoclonic epilepsy of infancy and early childhood, myoclonic epilepsy of childhood with absences, and myoclonic epilepsy of adolescence. Many intermediate and atypical forms exist; thus the proposed classification is only tentative.

Syndromic classification in the management of childhood epilepsy.

Epilepsy syndromes, defined as clusters of symptoms or signs occurring consistently together, form the basis of the currently accepted classification of the epilepsies. The concept of epilepsy syndrome is practical for the diagnosis, prognosis, orientation of treatment, and selection of appropriate investigations, but it is of variable specificity and usually does not give information on causes and mechanisms of an epilepsy. Some syndromes, such as childhood absences, partial epilepsy with centrotemporal spikes, or juvenile myoclonic epilepsy, are precisely characterized while other syndromes such as grand mal on awakening or the multiple syndromes with myoclonic seizures are poorly delineated. The usefulness of the concept is limited to well-defined and generally accepted syndromes and many cases of epilepsy do not fit easily in recognizable syndromes.

Pelizaeus-Merzbacher disease: clinical and nosological study.

Pelizaeus-Merzbacher disease can be diagnosed on genetic and clinical criteria. These include: involvement of several males in a lineage in a manner consistent with X-linked recessive inheritance; early nystagmoid movements; precocious psychomotor deterioration; progressive pyramidal, dystonic, and cerebellar signs. We present seven cases from three families and review 148 cases in 19 families from the literature. Laryngeal stridor present in two of our patients may be a presenting feature. Neurophysiological investigations may be helpful in the diagnosis.

Ischemic strokes in children.

Of 44 infants and children (neonates excluded) with ischemic strokes of arterial origin documented by CT scan and/or cerebral angiography, idiopathic strokes, occurring in 22 cases, accounted for half the total. Eight of these patients had basal ganglia and/or capsular infarcts without cortical involvement. The outcome in the idiopathic group was favorable: after an average follow-up duration of 48 months, no child had recurrence, two children developed secondary epilepsy, and only two were severely mentally retarded. However, residual dystonia and dyskinesia constituted an incapacitating handicap, having been observed in 14 children of the idiopathic group and in 18 of the whole series. It may be concluded from the present study that the long-term prognosis of ischemic strokes in children is excellent except for the risk of secondary evolutive dystonia in the absence of any detectable cause.

Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases.

Five children presented in the first months of life with progressive megalencephaly and leukodystrophy characterized by diffuse swelling of the white matter, cystic cavitations in frontal and temporal lobes, and a slow progressive course contrasting with the intensity of the leukodystrophic process. Four had epilepsy. Two were brothers and three had consanguineous parents. No metabolic defect was detected. The clinical and magnetic resonance imaging features are similar to those of patients previously reported. These five new cases add arguments to delineate a new type of leukodystrophy with megalencephaly in infancy and autosomal recessive inheritance.