[Leukoencephalopathy with vanishing white matter: A case report]. / Leucoencefalopatía con sustancia blanca evanescente: a propósito de un caso.

INTRODUCTION: Leukoencephalopathy with vanishing white matter is an autosomal recessive hereditary disease that was first reported in 1997. Some time later the genetic anomalies responsible for the disease were identified, these being different mutations in any of the five genes that code for the five subunits of the translation initiation factor, eIF2B. Since then, the clinical spectrum of this condition has proved to be much broader and far more frequent than was initially believed. We report on a case of the classical clinical form, which is to our knowledge the first to be published in Spain to date. CASE REPORT: A 5-year-old female who presented gait instability that recently got worse following a mild traumatic head injury. The examination revealed overall cerebellar ataxia and generalised spasticity. Magnetic resonance imaging (MRI) showed diffuse and symmetrical involvement of the white matter of the brain with the presence of cavities in which the signal intensity and the proton spectrum were similar to those of cerebrospinal fluid. The genetic study revealed a mutation of the gene that codes for eIF2B-epsilon. CONCLUSIONS: A suggestive MRI scan, even in an atypical presentation, would be enough to rule out a mutation of the genes that code for eIF2B. This would make it possible to reach an early diagnosis of this disease, which is probably more prevalent than is currently thought. This would allow genetic counselling to be conducted and would help to establish a genotype-phenotype correlate that would also make it possible to offer an estimated prognosis.

[Arteriovenous malformations in children: a report of four cases]. / Malformaciones arteriovenosas en la infancia: a proposito de cuatro casos.

INTRODUCTION AND AIMS: Vascular malformations are the most frequent cause of intracranial haemorrhage (IH) after the neonatal period that are not due to traumatic injury. Arteriovenous malformations (AVM) are the vascular malformations that most often give rise to symptoms in infancy and are the most common cause of IH in children over one year of age. CASE REPORTS: We reviewed the medical records of all patients under the age of 16 years diagnosed with AVM from the year 2000 to the present. Four cases aged between 7 and 15 years were found, all of whom were examined with computerised tomography and/or magnetic resonance imaging and cerebral arteriography scans. One patient started with headaches and another had learning disabilities. The other two began with IH, the most common clinical manifestations of which were a diminished level of awareness and vomiting. The final diagnosis was established by means of arteriography in all cases. Surgical treatment was carried out in three cases (using surgery, catheter embolisation and stereotaxic radiosurgery) and the patients' progress following the intervention was excellent. CONCLUSIONS: Spontaneous haemorrhage constitutes the most common presenting symptom of AVM. However, there are sometimes earlier manifestations that are a challenge to diagnosis and which should be the target of future research, since preventing IH would lead to a drastic reduction in the morbidity and mortality rate of AVM.

[Effectiveness and safety of levetiracetam in 133 children with medication resistant epileptic seizures]. / Eficacia y tolerabilidad del levetiracetam en 133 niños con crisis epilépticas farmacorresistentes.

INTRODUCTION: Levetiracetam (LEV) is the latest drug approved in the European Union for use in polytherapy in children over 4 years of age with partial epileptic seizures that are resistant to other antiepileptic drugs. AIM. To report our experience of associating LEV in children with medication resistant epileptic seizures. PATIENTS AND METHODS: We conducted an open, observational, respective study involving 133 children with refractory epilepsies: 106 with focal seizures and 27 with other types of seizures. LEV was associated over a period of more than 6 months and we evaluated its repercussion on the frequency of the seizures and the side effects related to the drug. RESULTS: With average doses of LEV of 1,192 +/- 749 mg/day the frequency of the seizures was reduced by over 50% in 58.6% of cases and seizures were quelled in 15.8% of patients. Side effects were produced in 27.8% of cases, and were usually transient or tolerable; these effects led to withdrawal of LEV in only eight cases (6.02%). In 37 children (27.8%), their relatives noted an improvement in their social behaviour and cognitive abilities. CONCLUSIONS: a) LEV is an effective drug that is well tolerated in children with refractory epilepsy; b) Its effectiveness in different types of seizures indicates a broad therapeutic spectrum; and c) LEV can even condition favourable secondary effects, a circumstance that has been reported only exceptionally in the case of other antiepileptic drugs.

Sleep in the Prader-Willi syndrome. Clinical and polygraphic findings.

Nine patients with the Prader-Willi syndrome, ranging in age from 3 to 21 years, were examined clinically as well as studied in the sleep laboratory. They had striking disturbances of sleep-wakefulness patterns. All patients except one had the symptom of excessive daytime sleepiness. The most striking finding was the presence in five patients of rapid-eye-movement (REM) sleep occurring at sleep onset (SOREM). None of the patients had the condition of sleep apnea. One patient, however, demonstrated severe hypoventilation during REM sleep; the lowest value recorded for O2 saturation was 40%, with a consistent value below 50% for as long as ten to 15 minutes. Previous findings have indicated that the Prader-Willi syndrome is of hypothalamic origin. We hypothesize that both the SOREM and O2 desaturation findings in our patients with the Prader-Willi syndrome are also a result of hypothalamic changes.

Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile.

We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.

Biotinidase deficiency: result of treatment with biotin from age 12 years.

A boy with severe symptoms of biotinidase deficiency diagnosed at the age of 12 years showed a remarkable improvement of his neurological picture and normalization of brain magnetic resonance imaging abnormalities when prescribed oral biotin.

Rett's syndrome: a neurophysiological study.

Thirteen girls with Rett's syndrome were evaluated with wakefulness and sleep polygraphic records and EMG studies. The main EEG findings were paroxysmal activity during sleep, multifocal in younger and unifocal in older girls, and "pseudorhythmic flattening". In the opinion of the authors, the changes with age are related to evolution of the disease or maturational changes of CNS. The affectation of the peripheral nervous system was demonstrated in almost half the patients.

[Neurological assessment of learning disorders]. / Evalucaión neurológica de los trastornos del aprendizaje.

INTRODUCTION: The neurological concept of learning is approached from a cybernetic point of view, taking into account that a child should recognize a fact, learn it semantically and decided whether it is worth storing; the dynamic aspect of memory is the true motor of the ability to learn and all this is modulated by the attention factor. DEVELOPMENT: The neurological evaluation of learning disorders is based on clinical examination which includes the so-called minor signs of the noetic functions, specifically language, the praxes, gnosias, perceptive-motor function, laterality and the lexical, graphic and calculation functions together with the modulating element, mentioned above, of the level of attention with or without hyperactivity. These semiological elements are grouped into three major categories of syndromes: motor syndrome, dyslexic-dysgraphic-dyscalculation syndrome and the hyperkinetic syndrome or attention deficit with hyperactivity. We also note the differential diagnosis. We review the neurophysiological biological markers (EEG and brain mapping, cerebral evoked potentials, neurometry) and those based on neuroimaging techniques (cerebral CT, MR, SPECT and PET). CONCLUSIONS: The contribution of neurological assessment is considered as part of the functions of a multi-disciplinary team which should deal with the diagnosis and treatment of children with learning disorders.

[Epilepsies and language disorders]. / Epilepsias y trastornos del lenguaje.

OBJECTIVE: To study the effects of the epilepsies, the seizures and electroencephalographic discharges on the cognitive function of the child, specifically his language. We consider the relationship between developmental dysphasia and epilepsy, bearing in mind that this association may occur fortuitously, as a consequence of the same cause or taking the epilepsy to be responsible for the language disorder, as seizures or continuously (epileptic aphasia). DEVELOPMENT: We assess the relation between developmental aphasia and seizure aphasia in the epilepsies, especially the syndrome of acquired epileptic aphasia of Laundau-Kleffner (LKS). Based on the findings in the literature and a personal series of nine cases, we studied their general characteristics, clinical heterogeneity, associated clinical signs and EEG changes (present in all patients); coexistence of convulsive seizures (67-90%); aetiopathogenic findings invoked but not currently conclusive; negative neuroimaging findings apart from some SPECT and PET data; differential diagnosis; clinical course and prognosis difficult to predict. The pharmacological and/or surgical treatment, complemented by logopedics and psychopedagogics (good results in < or = 50% of the cases), the unpredictable course of LKS has to be assessed cautiously. CONCLUSIONS: No direct relation can be confirmed between epilepsy and language disorders, although a relationship may be found in some cases. The hypothesis that LKS, continuous spike-and-wave during slow sleep and partial benign atypical epilepsy are the severe, moderate and mild forms of the same epileptic syndrome is generally accepted. This appears during a phase of maturation in which the brain is particularly vulnerable, and is characterized by continuous spike-and-wave complexes during slow sleep, which lead to cognitive and behaviour disorders.

[Therapeutic strategy in severe encephalopathies]. / Estrategia terapéutica de las encefalopatías severas.

INTRODUCTION: The severe epileptic syndromes of infancy are dependent on age, symptomatic or cryptogenic aetiology and are drug-resistant so that overall prognosis control of epilepsy and adequate cognition is poor so that some authors consider it to be catastrophic. All may be identified and differentiated on electroclinical criteria. DEVELOPMENT: We study the neonatal myoclonic encephalopathies in the two clinical forms described by Aicardi and Ohtahara, West s syndrome (infantile spasms), severe myoclonic epilepsy of Dravet-Dalla Bernardina and the Lennox-Gastaut syndrome, briefly describing their electroclinical semiology and therapeutic strategies using the range of available drugs, together with other medical and surgical therapeutic options. CONCLUSIONS: Treatment of severe epileptic encephalopathies of childhood is useless/not viable in neonatal myoclonic encephalopathies and severe myoclonic epilepsy of childhood, whilst in the West and Lennox-Gastaut syndromes the results depend on the aetiology, and are better in the cryptogenic types with control of 20% and 30% of the cases but with normal intelligence in only 5% and 9%.

[Orphan drugs and orphan diseases]. / Medicamentos huérfanos y enfermedades huérfanas.

OBJECTIVES: To define the concepts of orphan drugs and diseases, the current situation of clinical investigation of them, the attitude of the pharmaceutical industry and aspects of health legislation, especially in the European Community. DEVELOPMENT: We review the history of orphan drugs, the name used for those drugs, apparatus, biological agents and dietetic preparations used to treat diseases so rare as to affect 650 1,000 persons per million inhabitants. Approximately 5,000 of such disease have been identified. Of these, 80% are genetic disorders which are very common in neuropaediatrics, since 50% appear in childhood. Half of these disorders affect the nervous system but in general there are no relative preventive and/or therapeutic methods. In view of the expense involved, the pharmaceutical industry is loath to develop products which are only used in rare diseases. Society cannot tolerate the fact that these patients do not have access to medical progress. For this reason organizations of affected persons (especially the National Organization for Rare Diseases) put pressure on the USA authorities leading to the Orphan Drug Act of 1983 which was subsequently copied by other countries. Since January 2000 there is a similar Regulation in the European Community. Orphan diseases need to be diagnosed early by specialists who have had patients referred to them by general practitioners. However, initial recognition of the disorder is often delayed and late diagnosis occurs in 45% of these rare diseases which make up 10% of human illnesses. Currently over 150 orphan drugs are being used for over seven million patients. CONCLUSION: The struggle to treat rare diseases must continue, since its true importance is shown when suffered personally.

[Practical considerations regarding the diagnosis and treatment of disorders of movement in childhood]. / Algunas consideraciones prácticas sobre el diagnóstico y tratamiento de los trastornos del movimiento en la infancia.

OBJECTIVE: Disorders of movement in children frequently cause difficulties with both the semiology and the diagnostic approach. DEVELOPMENT: Based on our experience, we analyze useful strategies to overcome these difficulties and consider the clinical semiology, use of complementary tests and therapeutic approach. CONCLUSION: Correct clinical identification is the essential basis for differential diagnosis and therapeutic management of the disorders of movement.

[Neuropsychology and epilepsy]. / Neuropsicología y epilepsia.

AIMS: The epileptic child has three times more risk of presenting cognitive disorders than other children with no neurological pathology, in accordance with three essential facts: 1. The effect exerted by the actual epilepsy. 2. Any associated previously-existing neuropsychosocial deficits. 3. The side effects of the antiepileptic drug (AED). A certain amount of deterioration is universally accepted, without defining the factors involved in its production, but which are multifactorial according to computer studies. From this point of view, we analyse the relation between neuropsychology and epilepsy in Paediatrics. DEVELOPMENT: The relation between epilepsy and behaviour must be seen as an exception and not the rule, unless there are coexisting personality disorders and/or mental deficiency. The cognitive effects of AED depend on the drug, the doses used and on the polypharmacy, and these effects may be both adverse and beneficial. The differences from one drug to another are questionable due to the methodology used in the different studies and it should be remembered that with suitable doses the side effects are generally moderate, and AED monitoring is useful in this case. We recommend the use of MEDDRA assessment to obtain a more reliable definition of side effects, which in turn will allow them to be better evaluated. Scaling time in the introduction of the drug is important, especially with some of the new AED. The mechanisms governing the production of the side effects vary, but both the classical and the new ones, which are well used owing to the greater knowledge we have of their mechanism of action, improve cognitive functioning by controlling the seizures. In infancy, idiopathic cognitive reactions are produced. In childhood, the main disorders are a diminished reaction and information processing time with alterations affecting memory, attention and language. CONCLUSIONS: Epilepsy is associated to a number of different, generally mild, cognitive problems. The age of onset of epilepsy, type of syndrome, its aetiology, the response to treatment and polypharmacy are multifactorial elements conditioning side effects. There is a need for batteries of tests capable of forecasting the future and controlling the progression of cognition during therapy. It can be concluded that the side effects of AED affecting cognition and behaviour are generally mild, but the cognitive side effect of an AED can be important for a particular child.

[Communication disorders: differential diagnosis]. / Trastornos de la comunicación: diagnóstico diferencial.

OBJECTIVE: To evaluate components of clinical semiology in the differential diagnosis of communication disorders (TC) and their possible biological markers. We consider two groups, according to the communication disorders themselves and their effects on social interaction. In the first case both aspects are affected in parallel and in the second it is predominantly social interaction which is affected. DEVELOPMENT: In the first groups we studied dyslalias, dyrhrythmias, acquired aphasias, TC relation to epilepsy, types of seizures and EEG discharges. The dysphasia of development and epilepsy may be associated by chance, as a result of the same cause or the epilepsy be responsible for the TC, either because of seizures or continuously (acquired epileptic aphasia, SLK). Based on personal data and the literature we studied the semiology, possible biological markers and differential diagnosis. We consider disorders of neurone migration and metabolic alterations of initial neuropsychological semiology and cerebellar anomalies involved in cognitive functions. In the second group we assessed autism, generalized disorders of development and particular syndromes with semantic pragmatic TC. CONCLUSIONS: The development of language cannot be separated from other aspects of neurological maturation. One cannot affirm that there is a direct relationship between epilepsy and TC, although this does occur in some cases. We accept the hypothesis that SLK, POCSL and atypical EPB are clinical forms of the same syndrome of epilepsy. Recognition of the cognitive affective cerebellar syndrome by its involvement in social executive function, language and personality characterizes certain conditions (Williams, Asperger, fragile X, autism). A progressive rational battery of complementary studies on clinical data is essential to determine biological markers in syndromes which still lack them.

[Congenital ataxias of genetic origin with structural anomalies of the cerebellum]. / Ataxias congénitas de origen genético con anomalías estructurales del cerebelo.

Congenital ataxia is not a rare condition for who is involved in the practice of pediatric neurology. After a brief description on the normal development of the cerebellum, we present an extensive review on the neurological disorders due to malformations or metabolic disorders associated with hypoplasia of the cerebellum and congenital ataxia.

[Non specific leukodystrophy. A new case of vacuolizing leukoencephalopathy with megalencephaly]. / Leucodistrofias indeterminadas. Un nuevo caso de leucoencefalopatía vacuolizante con megalencefalia.

INTRODUCTION: Amongst the conditions affecting the white matter, the disorders of myelinization, including the leukodystrophies, are important in the field of paediatric neurology. Although classically they have been classified according to whether the metabolic defect was known or not, at the present time great advances in neuroimaging have clarified many genetic disorders involving the white matter and new classifications have been devised. The group of unknown aetiology includes the so called non specific leukodystrophies, characterized by their onset in infancy with a usually more moderate clinical course, and neuro imaging (computerized tomography CT magnetic resonance MR ) with alteration of the signal from the white matter which is symmetrical, bilateral and diffuse. Study and investigation of the patterns of MR has permitted isolation of two new clinical conditions of the non specific leukodystrophies group: leukodystrophy with megalencephaly and temporal cysts (Van der Knaap, 1995) for which currently the term vacuolizing leukoencephalopathy with megalencephaly is preferred and the CASH syndrome (childhood ataxia with central hypomyelinization or vanishing white matter disease) (Van der Knaap, 1997). DEVELOPMENT: We present a review of nine cases of non specific leukodystrophies with an average course of 13 years. They were studied using the protocol of the European working party on demyelinating diseases. One of these fulfilled clinical and radiological criteria for the diagnosis of vacuolizing leukoencephalopathy with megalencephayl: onset in early childhood, macrocephaly, normal metabolic studies, moderate progression and alteration of the white matter signal which was bilateral, symmetrical and diffuse with the presence of oedema and temporal subcortical cysts. We discuss the most relevant articles currently published on this condition.

[Ischemic and hemorrhagic cerebral vascular accidents in the full-term newborn infant. Study protocol and therapeutic directions]. / Accidentes vasculares isquémicos y hemorrágicos cerebrales del recién nacido a término. Protocolo de estudio y orientaciones terapéuticas.

OBJECTIVE: Ischemic and hemorrhagic cerebral vascular accidents in newborn are an important component in the determination of neonatal morbidity and mortality. The frequency is 1-2% for each condition. The etiopathogenesis is closely related to hypoxemia and ischemia in ischemic accidents and to traumatic birth in hemorrhagic accidents. Identification of the forms of clinical presentation with the help of neuroimaging and other complementary diagnostic investigations is the first step before prophylactic and/or therapeutic treatment. DEVELOPMENT: Based on integrated physiopathological models, we establish the anatomopathological patterns which permit the definition of clinical forms of hypoxia-ischemia, and also establishment of the topographical classification of hemorrhages according to their site, as subarachnoid, subdural, intraventricular, cerebellar or intraparenchymatous, together with their pathological study, clinical presentation and diagnosis of lesions at each of these sites, emphasising the importance of neuroimaging and the therapeutic possibilities. CONCLUSIONS: The diagnostic approach that we suggest allows etiopathogenic and therapeutic decisions which determine improved prognosis and often even cure at the present time. The basic principles of a therapeutic protocol should be based on monitorization of the newborn baby during the acute phase. There should be close observation of the arterial blood pressure, temperature, biochemical parameters, treatment of seizures and the possibility of correction within the 'therapeutic window' of reperfusion and subsequent recovery of cerebral tissue involved by using mechanisms of neuroprotection.

[Idiopathic epilepsies: some therapeutic aspects]. / Epilepsias idiopáticas: aspectos terapéuticos.

AIMS: The purpose of this study was to determine the therapeutic approach to be used in localisation-related and generalised epilepsies and idiopathic epileptic syndromes. DEVELOPMENT: Recent literature on the subject was reviewed, as were the records on a total of 118 patients from two paediatric neurology units between the years 2000 and 2003. With regard to the localisation-related cases, the following recommendations are made: 1. Treatment with monotherapy; 2. Low doses, since any antiepileptic drug can make epilepsy worse, and more so in the case of RBEI; 3. If the seizures get worse with treatment, the doses must be reduced instead of increased; 4) Carbamazepine (CBZ) and oxcarbazepine (OXC) are first choice drugs; clobazam (CLB) is indicated in OBEI and in some atypical BPEI, in which steroids in monotherapy can occasionally prove useful; valproate (VPA) is an alternative for cases of intolerance and exacerbation, and 5. Two-year treatment and electroencephalogram (EEG) monitoring for exacerbation. As regards idiopathic generalised epilepsies: 1. VPA in monotherapy is recommended in all the forms, 48% were controlled; 18% were controlled with VPA + lamotrigine (LTG); 2. Childhood absence epilepsy is controlled up to 50% with VPA and 85% with VPA + ethosuximide (ESM); 3. LTG, CLB, topiramate (TPM) and Rivotril (CLN) are alternatives to be considered in all types of epilepsies and syndromes that are resistant to medication, and 4. In GCTS, VPA should be chosen in low doses in juvenile myoclonic epilepsy of Janz.

[Clinical aspects of epileptic ion channel disorders]. / Aspectos clínicos de las canalopatías epilépticas.

OBJECTIVE: One of the recent findings in the investigation of epileptogenesis is the localization of new gene situses and mutations of the ion channels. The pathology of these ion channel disorders is responsible for a considerable number of disorders affecting the central nervous and musculoskeletal systems. Their clinical expression is often paroxystic. Mutations cause inactivation of the channel, which depending of the degree, conditions the phenotype of the disorder. DEVELOPMENT: We studied the main ion channel disorders related to simply inherited idiopathic epileptic syndromes in which four genes have been codified to date: benign familial neonatal convulsions, generalized epilepsy with febrile seizures plus and autosomal dominant nocturnal frontal lobe epilepsy. CONCLUSIONS: The ion channels, both voltage dependent and receptor channels, are involved in the genesis of idiopathic epileptics syndromes. Their importance is due to their contribution to the understanding of epileptogenesis and its application to the investigation of drugs which modify the initial cause of the seizure. At present, it may be affirmed that the idiopathic epilepsies, or at least some of them, seem to form a family of ion channel disorders.

[The phenomenon of genomic "imprinting" and its implications in clinical neuropediatrics]. / El fenómeno del 'imprinting' genómico y sus implicaciones en clínica neuropediátrica.

OBJECTIVE: We comment on the most important advances related to the phenomenon of genomic 'imprinting' in clinical paediatric neurology. DEVELOPMENT: Initially, we review the biological findings related to this subject and establish various concepts. Later, we attempt to clarify the different mechanisms of expression of the phenomenon 'imprinting' and its application in clinical practice. We give a detailed review of the various neurological disorders in which this genetic phenomenon has been involved to date. Finally, we attempt to determine when this genetic alteration should be suspected and which molecular biology techniques should be used to confirm the diagnosis. CONCLUSIONS: 1. Clinical diagnosis suspecting that the presence of genomic 'imprinting' may be the mechanism causing a particular pathology should be based on a family tree showing that both sexes and all generations are affected and that the severity of the same disease varies among different members of the same family; 2. Study strategy includes studying the methylation pattern of the DNA. If there are changes in this, PCR should be done to show the exact pattern of the alteration.