Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).

OBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

[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.

[The effect of refractory epileptic seizures on cognitive processes]. / Efecto de las crisis epilépticas refractarias sobre los procesos cognitivos.

A complete definition of all risk factors for intractability and/or mental retardation cannot currently be given because epilepsy is not a disease but a heterogeneous phenomenon from the physiological, clinical and etiological points of view so that no single way of addressing the issue can fit all situations. It is quite possible that some risk factors can be specific for subgroups and do not apply to the majority of cases. Such subgroups may be small enough to escape detection in large prospective studies that uniformly indict a limited number of factors mostly related to characteristics of the disease or patients. Yet, even factors that are at play only in small groups may be extremely important if they can be at the origin of effective preventive measures. This may well be the case for vigorous early treatment of complex febrile seizures as there is increasing evidence of a close, probably causal, relationship between lengthy early convulsions and mesial temporal sclerosis. It may also apply to the prevention of cognitive/behavioural deterioration in children with certain types of epilepsy even though the evidence in this regard is less strong. Exonerating seizures and/or subclinical paroxysmal activity of any responsibility in the production and/or aggravation of brain damage is not justified on the basis of known facts and vigorous although reasonable treatment of the epilepsies may do more, at least in certain forms, than simply decreasing the relapse rate of seizures

Efecto de las crisis epilépticas refractarias sobre los procesos cognitivos / The effect of refractory epileptic seizures on cognitive processes

Introducción. Los trastornos cognitivos (TC) transitorios en niños con epilepsia rolándica benigna (ERB), la más común de las epilepsias parciales idiopáticas (EPI), son secundarios a descargas epileptiformes interictales (DEI). Objetivos. Determinar la incidencia y factores de riesgo de los TC persistentes en escolares con EPI antes, durante y después de la administración de antiepilépticos (AE). Pacientes y métodos. Criterio de inclusión: edad de 6 a 12 años, EPI, control con AE durante dos 2 años y seguimiento durante cinco años. Evaluaciones: inteligencia (Wechsler-III), aprendizaje (Wechsler), nivel académico (Woodcock-Johnson) y atención/conducta (O'Conners-R). Variables: sexo, edad de comienzo, tipo de EPI, intervalo entre la primera crisis y comienzo del AE, resultado del EEG y tipo de AE. Análisis: ji cuadrado. Resultados. No se observaron TC antes de comenzar los AE ni durante los dos años con AE y sin crisis clínicas ni EEG. 14 pacientes tuvieron trastornos del aprendizaje, inatención, impulsividad, hiperactividad, baja tolerancia y agresividad durante la remisión; 12 (85,71 por ciento) con epilepsia del lóbulo temporal: seis (50 por ciento) con DEI en el lado izquierdo (hemisferio dominante izquierdo), dos (16,67 por ciento) con DEI en el derecho (hemisferio dominante izquierdo), dos (16,67 por ciento) en ambos lóbulos temporales y dos (14,29 por ciento) con ERB. La resonancia magnética cerebral fue normal. Conclusiones. Los niños con epilepsia del lóbulo temporal idiopática con DEI en el hemisferio dominante presentan mayor riesgo que el resto de los pacientes con EPI a sufrir TC. Se recomienda eliminar no sólo las cisis, sino también las DEI, para evitar estos trastornos. Los riesgos de intratabilidad y retraso mental en pacientes con epilepsia no se pueden estimar con certeza debido a que la epilepsia no es una enfermedad, sino un fenómeno heterogéneo desde el punto de vista fisiológico, clínico y etiológico. Es posible que factores aplicables a un grupo no se apliquen a otro. Y también es posible que estos subgrupos sean tan pequeños que dichos factores no se detecten en los estudios realizados, porque los subgrupos no se han considerado de forma aislada. No obstante, si estos subgrupos con factores remediables pudieran detectarse, el impacto en el futuro de estos pacientes puede ser el origen de tratamientos más efectivos en un mayor número de ellos. Esto puede ser el caso del tratamiento agresivo de la epilepsia parcial compleja y la prevención de esclerosis temporal; también puede ser el caso de la prevención del deterioro cognitivo en niños con ciertos tipos de epilepsia. No se justifica concluir que las convulsiones clínicas o subclínicas no producen ni agravan el daño; el tratamiento agresivo puede producir más daño (por lo menos en ciertas formas de epilepsia) con apenas la disminución de la recurrencia de las crisis (AU)

A complete definition of all risk factors for intractability and/or mental retardation cannot currently be given because epilepsy is not a disease but a heterogeneous phenomenon from the physiological, clinical and etiological points of view so that no single way of addressing the issue can fit all situations. It is quite possible that some risk factors can be specific for subgroups and do not apply to the majority of cases. Such subgroups may be small enough to escape detection in large prospective studies that uniformly indict a limited number of factors mostly related to characteristics of the disease or patients. Yet, even factors that are at play only in small groups may be extremely important if they can be at the origin of effective preventive measures. This may well be the case for vigorous early treatment of complex febrile seizures as there is increasing evidence of a close, probably causal, relationship between lengthy early convulsions and mesial temporal sclerosis. It may also apply to the prevention of cognitive/behavioural deterioration in children with certain types of epilepsy even though the evidence in this regard is less strong. Exonerating seizures and/or subclinical paroxysmal activity of any responsibility in the production and/or aggravation of brain damage is not justified on the basis of known facts and vigorous although reasonable treatment of the epilepsies may do more, at least in certain forms, than simply decreasing the relapse rate of seizures (AU)

Dreamy state: a case report from the selected writings of John Hughlings Jackson. Brain 1874.

This masterly account of a remarkable type of epileptic attacks with "dreamy state" was published in Brain, volume XI, pp. 179-207 in 1888 [1]. The patient was himself a physician and a highly articulate person endowed with an unusual capacity for introspection in addition to an interest in poetry and travelling 1. Jackson disagreed with some of the terms used by his doctor-patient; he preferred the word "reminiscence" to that of "recollection" and put between inverted commas that of "aura", indicating that he did not use it for any form of the "dreamy state" although the term remains easy to understand 2. Edited by James Taylor, Gordon Holmes and F.M.R. Walshe, Nijmegen: Arts and Boeve, 1996.

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.

[Risks and benefits of new antiepileptic agents in children]. / Riesgos y beneficios de los nuevos antiepilépticos en niños.

INTRODUCTION AND DEVELOPMENT: New antiepileptic drugs (AED) have generally a good pharmacokinetic profile. Their mode of action remains imperfectly known. Gabapentin (GBP), oxcarbazepine (OCBZ), topiramate (TPM), vigabatrin (VGB) and tiagabine (TGB) are mostly effective for partial seizures; lamotrigine (LTG) is efficacious for both partial and generalized seizures, it is also active in treatment of Lennox-Gastaut syndrome for which felbamate (FBM) is also effective. West syndrome often responds to VGB. The tolerance of the new AED is generally satisfactory but some serious, late side-effects have become apparent. Because of such possible toxicity, of the cost and of the remaining uncertainties about indications, the new AED are used mostly as add-on therapy for epilepsies resistant to conventional AED or as secondary monotherapy following withdrawal of other drugs used as monotherapy. Some new AED (LTG, GBP, TPM, OCBZ) have proved equal or sometimes superior to conventional agents. CONCLUSION: They may be especially useful in the treatment of certain resistant epilepsy syndromes such as Lennox-Gastaut and West syndromes for which conventional drugs often fail.

Riesgos y beneficios de los nuevos antiepilépticos en niños / Benefits vs risks of new antiepileptic drugs

Introducción y desarrollo. Los nuevos fármacos antiepilépticos (FAE) tienen generalmente un buen perfil farmacocinético. Sus mecanismos de acción continúan sin conocerse totalmente. La gabapentina (GBP), oxcarbacepina (OCBZ), topiramato (TPM), vigabatrina (VGB) y tiagabina (TGB) son principalmente eficaces en las crisis parciales. La lamotrigina es efectiva tanto en las crisis generalizadas como en las parciales, y es también útil en el tratamiento del síndrome de LennoxGastaut, para el cual el felbamato (FBM) es asimismo eficaz. Los pacientes con síndrome de West a menudo responden bien al tratamiento con VGB. La tolerancia de los nuevos FAE es generalmente satisfactoria, aunque se han manifestado algunos efectos secundarios significativos. Debido a su posible toxicidad, al coste y la existencia de ciertas dudas sobre sus indicaciones, los nuevos FAE se administran principalmente en terapia combinada en las epilepsias resistentes a los fármacos convencionales, o como tratamiento de segunda elección en monoterapia, tras la retirada de otras sustancias utilizadas previamente en monoterapia. Algunos nuevos FAE (LTG, GBP, TPM, OCBZ) han mostrado resultados similares o, en algunas ocasiones, superiores a los obtenidos con sustancias convencionales. Conclusión. Los FAE pueden ser especialmente útiles en el tratamiento de ciertos síndromes epilépticos resistentes, tales como el síndrome de Lennox-Gastaut y el de West, en los que los fármacos convencionales a menudo son ineficaces (AU)

Developmental amnesia associated with early hypoxic-ischaemic injury.

We recently reported on three young patients with severe impairments of episodic memory resulting from brain injury sustained early in life. These findings have led us to hypothesize that such impairments might be a previously unrecognized consequence of perinatal hypoxic-ischaemic injury. Neuropsychological and quantitative magnetic resonance investigations were carried out on five young patients, all of whom had suffered hypoxic-ischaemic episodes at or shortly after birth. All five patients showed severe impairments of episodic memory (memory for events), with relative preservation of semantic memory (memory for facts). However, none had any of the major neurological deficits that are typically associated with hypoxic-ischaemic injury, and all attended mainstream schools. Quantitative magnetic resonance investigations revealed severe bilateral hippocampal atrophy in all cases. As a group, the patients also showed bilateral reductions in grey matter in the regions of the putamen and the ventral part of the thalamus. On the basis of their clinical histories and the pattern of magnetic resonance findings, we attribute the patients' pathology and associated memory impairments primarily to hypoxic-ischaemic episodes sustained very early in life. We suggest that the degree of hypoxia-ischaemia was sufficient to produce selective damage to particularly vulnerable regions of the brain, notably the hippocampi, but was not sufficient to result in the more severe neurological and cognitive deficits that can follow hypoxic-ischaemic injury. The impairments in episodic memory may be difficult to recognize, particularly in early childhood, but this developmental amnesia can have debilitating consequences, both at home and at school, and may preclude independent life in adulthood.

Atypical semiology of rolandic epilepsy in some related syndromes.

Atypical seizures, especially generalized or focal atonic attacks and atypical absences may occur in association with the classical seizures of rolandic epilepsy. They are often associated with unusual EEG features, especially a marked activation of paroxysms during sleep that may amount to continuous spike-wave complexes of slow sleep. These electroclinical features are often accompanied by cognitive and/or behavioral disturbances and may belong to several syndromes (atypical benign partial epilepsy, syndrome of continuous spike-waves during sleep, Landau-Kleffner syndrome and status of rolandic epilepsy) whose relationship with typical rolandic epilepsy and among themselves remains to be clarified.

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.

[The contribution of molecular genetics to the nosology and diagnosis of neurological disorders of childhood]. / La contribución de la genética molecular a la nosología y el diagnóstico de las enfermedades neurológicas en la infancia.

INTRODUCTION: The recent spectacular development of molecular genetics has considerably amplified the role of genetics in classification and diagnosis, especially in degenerative diseases but also in other conditions such as developmental brain disorders and predisposition to some acquired diseases (e.g. infections and immunological maladies). OBJECTIVE: The aim of this article is not to review the ever growing list of disorders due to gene abnormalities but to present a few reflections on their consequences and to try to assess their impact on some of the basic concepts in clinical medicine. DEVELOPMENT: The main advantages attributable to the use of molecular genetics are the identification of clinical conditions with different clinical phenomena and due to a single cause and vice versa the existence of clinical conditions in which many different genetic abnormalities can be found. Its main drawbacks derive from its application for establishing nosologic classifications only on the basis of its findings, mainly due to the lack of congruence between phenotype and genotype. CONCLUSION: The information from molecular biology should be integrated with that of other sources in a significant profile, which is the intellectual basis of clinical medicine.

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.

Hemifacial spasm or subcortical epilepsy?

A child with Goldenhar's syndrome presented at about one week of age with stereotyped, repetitive paroxysmal episodes of hemifacial contraction, suggestive of partial seizures or hemifacial spasm. Later in life he also developed independent, permanent abnormal eye and chin movements identical in rhythm to those seen in myorhythmias, suggesting involvement of the dentato-olivary pathway. MRI demonstrated a hamartomatous lesion at the level of the pontomedullary junction. We speculate that the nature of the lesion could be responsible for the partial seizures mimicking hemifacial spasm and that because of its location, this same lesion could also be implicated in the genesis of myorhythmias. The presence of a hamartomatous lesion in a region affected by the abnormal development of the first and second branchial arches is not fortuitous.

Evolution of epilepsy surgery in childhood: the neurologist's point of view.

Surgical treatment of epilepsy in children has been slow to develop because of uncertainties regarding the prognosis of early epilepsies, difficulties in the diagnosis of causal lesions, the frequency of severe, extensive brain damage, and technical problems. Surgery for epilepsy in infants and children raises problems quite different from those in adults. This applies especially to severe infantile epilepsies for which the aim of treatment may be more to facilitate neurodevelopment than to control the seizures. In addition, intractability cannot be defined in the same terms at different ages, the time scale being usually much shorter in young children and the operations required often extensive. The results of surgery in childhood are comparable to those in adults. However, indications for surgery and assessment of its results in catastrophic epilepsies of infants requires different rules to those that apply to adults and older children.

[Landau-Kleffner sydnrome]. / El síndrome de Landau-Kleffner.

The Landau-Kleffner syndrome consists of the association of paroxysmal EEG abnormalities, more marked during sleep, acquired aphasia usually of receptive type, and epileptic seizures in three quarters of cases. Additional features include behavioral disturbances that may even present with autistic features, cognitive regression of variable degree, and sometimes motor difficulties, indicating the pervasive nature of the disorder. The epileptic activity, as manifested by the EEG, seems responsible for the pervasive dysfunction. Treatment with antiepileptic drugs is often ineffective. ACTH and corticosteroids are currently regarded as the best therapy but surgical treatment by subpial transection is being actively studied.

Aicardi-Goutières syndrome: an update and results of interferon-alpha studies.

Twenty-seven patients with familial encephalopathy with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis (Aicardi-Goutières syndrome) are reviewed. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in 7 children. High levels of interferon-alpha were found in serum and CSF in 14 patients. The higher CSF levels suggest intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in 4 additional children. The 19 patients still alive (6 older than 10 years) are profoundly disabled. However, the syndrome may present with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in 2 patients failed to detect significant inflammatory lesions and showed only foci of necrosis and wide-spread demyelination. This study supports an autosomal recessive inheritance for this syndrome. The high level of interferon-alpha is not explained but may play a role in the pathogenesis of the disorder.