Brainstem dysgenesis: beyond Moebius syndrome. / Disgenesia troncoencefalica: mas alla del sindrome de Moebius.

Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate.

TITLE: Disgenesia troncoencefalica: mas alla del sindrome de Moebius.El termino 'disgenesia troncoencefalica' se aplica a los pacientes que presentan afectacion congenita de multiples pares craneales, hipotonia muscular y signos leves de afectacion de la via piramidal. Este termino es ventajoso respecto al uso de eponimos tales como Moebius, Robin, Cogan y Carey-Fineman-Ziter, ya que es menos restrictivo y ofrece un nuevo enfoque para comprender las causas y su patogenia, asi como para mejorar el tratamiento de este grupo de alteraciones del desarrollo que afectan exclusiva o predominantemente al tronco del encefalo. La revision de la bibliografia y nuestra experiencia muestran que la mayoria de los casos con afectacion selectiva del rombencefalo se deben a lesiones disruptivas prenatales, mientras que en los casos con afectacion del mesencefalo y el cerebelo, asi como en los sindromes polimalformativos con afectacion destacada del troncoencefalo, la topografia de las lesiones es mas difusa y menos especifica, y la causa hereditaria, mas probable. Debido a la amplia heterogeneidad fenotipica asociada a la disgenesia troncoencefalica, es esencial realizar una evaluacion individualizada y establecer un plan de tratamiento especifico. Los programas de rehabilitacion deben comenzar poco despues del diagnostico y centrarse en mejorar las habilidades motoras, dotando al paciente de las herramientas necesarias para afrontar las necesidades diarias en funcion de la morbilidad asociada. Aunque el pronostico de la disgenesia troncoencefalica secundaria a lesiones disruptivas depende de la localizacion y la extension del territorio vascular afectado, en general, el pronostico de los pacientes con disgenesia troncoencefalica es mejor de lo que las manifestaciones clinicas iniciales harian suponer.

[Concordance between a head circumference growth function and intellectual disability in relation with the cause of microcephaly]. / Concordancia entre una función de crecimiento del perímetro cefálico y la discapacidad intelectual en relación con la etiología de la microcefalia.

INTRODUCTION: Our aim was to investigate the correlations between patterns of head growth and intellectual disability among distinct aetiological presentations of microcephaly. PATIENTS AND METHODS: 3,269 head circumference (HC) charts of patients from a tertiary neuropediatric unit were reviewed and 136 microcephalic participants selected. Using the Z-scores of registered HC measurements we defined the variables: HC Minimum, HC Drop and HC Catch-up. We classified patients according to the presence or absence of intellectual disability (IQ below 71) and according to the cause of microcephaly (idiopathic, familial, syndromic, symptomatic and mixed). RESULTS: Using Discriminant Analysis a C-function was defined as C=HC Minimum + HC Drop with a cut-off level of C=-4.32 Z-score. In our sample 95% of patients scoring below this level, severe microcephaly, were classified in the disabled group while the overall concordance was 66%. In the symptomatic-mixed group the concordance between HC function and outcome reached 82% in contrast to only 54% in the idiopathic-syndromic group (P-value=0.0002). CONCLUSIONS: We defined a HC growth function which discriminates intellectual disability of microcephalic patients better than isolated HC measurements, especially for those with secondary and mixed aetiologies.

[Intracranial hypertension associated with cerebral venous sinus thrombosis and mastoiditis. Two paediatric case reports]. / Hipertensión intracraneal asociada a trombosis de senos venosos cerebrales y mastoiditis. A propósito de dos casos pediátricos.

INTRODUCTION: Cerebral venous sinus thrombosis is a rare condition that is generally associated with acute processes, one of the most important being mastoiditis. Associated prothrombotic disorders can be detected in approximately half of all cases, regardless of the aetiology. Patients usually present clinical symptoms like headache, convulsions and diminished level of awareness, this latter factor being linked to a poor prognosis. CASE REPORTS: We report the cases of two paediatric patients with a clinical picture of intracranial hypertension within a context of mastoiditis as a complication of an acute ear infection, in whom cerebral venous sinus thrombosis was identified. Both patients were treated with lumbar punctures to evacuate cerebrospinal fluid and diuretic therapy. Anticoagulant therapy was added in the case of the second patient. Nevertheless, because of the persistence of the symptoms of intracranial hypertension, a ventriculoperitoneal shunt had to be performed in this patient. CONCLUSIONS: The preferred diagnostic method is magnetic resonance imaging with venography, although in an emergency computerised tomography can help reach a diagnosis in a third of cases. In addition to treating the symptoms, anticoagulation is also accepted (degree of evidence 1B) to prevent further progression.

[Oromotor disorders in a paediatric neurology unit. Their classification and clinical course]. / Trastornos oromotores en una unidad de neurología pediátrica. Clasificación y evolución clínica.

INTRODUCTION: The term 'oro-motor disorders' refers to a group of diseases that predominantly affect sensory inputs, motor systems and movement organization involved in sucking, chewing, swallowing, speech articulation and facial non-verbal communication. Loss of any of the aforementioned functions results in poor social integration and significant quality of life reduction. PATIENTS AND METHODS: Retrospective, observational study of 64 patients with oro-motor disorders diagnosed and followed-up at the Child Neurology Service of Vall d'Hebron University Hospital. The oro-motor disorder cause, age at the beginning of symptoms, type of feeding difficulties, type of speech disorders and other associated clinical manifestations were investigated in all patients. Changes in clinical manifestations throughout the period of follow-up in this cohort were analyzed as well. RESULTS: Classification of oro-motor disorders in childhood can be achieved combining the etiology and the anatomical location of the underlying disease. Four main groups can be distinguished: due to dysmorphological syndromes; secondary to bilateral perisylvian cortical dysplasias; due to brainstem dysgenesis, and secondary to congenital muscular diseases. CONCLUSIONS: Establishing the origin, nervous system location and pathophysiology of diseases leading to oro-motor disorders provides clues to natural history and permits anticipation in terms of treatment and care provision.

[Private mutations in the myophosphorylase gene: the first case in a patient of Latin American descent]. / Mutaciones privadas en el gen de la miofosforilasa: primer caso en un paciente de origen latinoamericano.

INTRODUCTION: McArdle's disease (glycogenoses type V) is a common metabolic myopathy caused by deficient myophosphorylase activity. The disease is due to mutations in the myophosphorylase (PYGM) gene and is present in a large number of countries. CASE REPORT: A 13-year-old male who suffered an episode of muscle pain and offered increased levels of creatinkinase in plasma, myoglobinuria and mild weakness of the proximal muscles, after short but vigorous exercise. The patient was born in Ecuador and was adopted by a Spanish family. The myophosphorylase gene was analysed completely and the patient was found to be a carrier of a missense mutation, a homozygous change where a G is replaced by an A in exon 11, changing a valine for a methionine in codon 456 (V456M). The mutation described above affects an amino acid that is conserved in the enzyme and which was not present in the control population that was studied. CONCLUSIONS: These findings show the presence of McArdle's disease in several ethnic groups and confirm that the ethnic origin of the patient is important when it comes to deciding what mutations should be analysed first in molecular diagnosis studies.

[Cerebellar atrophy following acute Mycoplasma pneumoniae cerebellitis]. / Atrofia cerebelosa secundaria a cerebelitis aguda por Mycoplasma pneumoniae.

INTRODUCTION: Acute cerebellitis is an uncommon complication following Mycoplasma pneumoniae infection. A benign and self-limited course has been described in the few reports found of this association. CASE REPORTS: We report two patients with an apparently M. pneumoniae-induced acute cerebellitis that resulted in cerebellar atrophy. Patients presented with a cerebellar syndrome including ataxia, hypotonia, dysarthric speech and dysmetria, which were preceded by signs of respiratory infection. Initial brain magnetic resonance imaging (MRI) in case 1 was normal but in case 2 it displayed striking cerebellar swelling, small fourth ventricle and supratentorial ventriculomegaly which was self-limited and did not require neurosurgical intervention. Serological studies confirmed a recent M. pneumoniae infection. Case 1 has followed an unfavourable clinical course, with incomplete resolution of cerebellar dysfunction, while case 2 has remained asymptomatic. Follow-up brain MRI have demonstrated prominent cerebellar atrophy in both patients. CONCLUSIONS: M. pneumoniae infection should be considered in those patients with acute cerebellitis showing an incomplete resolution of cerebellar dysfunction or those who develop early cerebellar atrophy. The presenting MRI findings do not seem to predict final neurological outcome.

[Subacute sclerosing panencephalitis: combined treatment with interferon alpha and intraventricular ribavirin]. / Panencefalitis esclerosante subaguda: tratamiento combinado con interferón alfa y ribavirina intraventricular.

INTRODUCTION: Subacute sclerosing panencephalitis (SSPE) is a chronic neurodegenerative disease secondary to an infection of the central nervous system by the measles virus, with no effective treatment. The introduction of therapy with intraventricular interferon alpha (IFN-alpha) and its later association with ribavirin aroused new expectations. In experimental studies the two drugs were seen to exert a synergic effect in reducing viral replication. Therapeutic studies carried out in patients with SSPE with the two pharmaceuticals have offered contradictory findings. CASE REPORTS: We present the cases of two patients with an early-onset, fast progressing form of SSPE, who were treated with a combined regime of oral isoprenosin, intraventricular IFN-alpha and ribavirin, which was administered intravenously in one case and intraventricularly in the other. At the beginning of treatment the patients' deterioration stabilised briefly and temporarily, but then renewed its progress. CONCLUSIONS: Combined therapy with intraventricular IFN-alpha and ribavirin was not effective in our patients. The late onset and rapidly progressing symptoms of the disease may have had an effect on the poor results obtained.

[Congenital insensitivity to pain with anhidrosis associated with congenital myasthenic syndrome]. / Insensibilidad congénita al dolor con anhidrosis asociada a síndrome miasténico congénito.

INTRODUCTION: Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive disorder featuring recurrent fever episodes, inability to sweat, absent response to noxious stimuli, self mutilating behavior and mental retardation. It has been associated with mutations in the NTRK1 gene, located in 1q21-22 and encoding a high-affinity NGF receptor. CASE REPORT: An 8-year-old boy, the first son of consanguineous parents, presented with hypotonia, episodic hyperpyrexia and global developmental delay since the neonatal period. In addition to these signs, typical of CIPA, he displayed some other not previously described in this disease, such as facial dysmorphism, a severe swallowing disorder and a myogenic EMG pattern, that led to the initial suspicion of a muscle disorder. Molecular genetics studies uncovered a mutation c.C2011T in exon 15 of the NTRK1 gene. Genetic counselling was possible in the following pregnancy of the couple, where the female fetus was found to harbour the mutation in heterozygosity. The subsequent diagnosis of a congenital myasthenic syndrome in this sister led to neurophysiological re-evaluation of the probandus, in whom a myasthenic pattern of muscle activation was also found. CONCLUSIONS: A patient with CIPA and congenital myasthenic syndrome is described. CIPA must be the first diagnostic hypothesis when assessing a patient with insensitivity to pain, anhidrosis and self-mutilation. Given the rather homogeneous presentation of CIPA, the occurrence of atypical myopathic manifestations should raise the suspicion of a concurrent disorder. The present consanguineous kindred illustrates a rare instance of transmission of two mutated alleles giving rise to two unrelated, infrequent neurological syndromes.

[Brainstem dysgenesis: Möbius, Cogan and Pierre Robin syndromes revisited]. / Disgenesia troncoencefálica: los síndromes de Möbius, Cogan y Pierre Robin en revisión.

We propose the term brainstem dysgenesis to designate patients with congenital dysfunction of the cranial nerves and muscle tone due to prenatal lesions or anomalies of the brainstem. In some patients, the dysgenesis is genetically determined and can be isolated or form part of a more extensive polymalformation syndrome (mutations of organizing or regulatory genes). In most patients with brainstem dysgenesis, however, the disorder is caused by prenatal destructive or disruptive lesions of vascular origin. Depending on the vessels involved and the magnitude of the lesion, clinical manifestations can range from intrauterine death to mild involvement of several cranial nerves. Clinical findings in some of these patients may coincide with those described in Möbius, Pierre Robin or Cogan syndromes and, if that is the case, the eponym will indicate the location of the brainstem lesion. Clinical manifestations in most patients with brainstem dysgenesis, however, do not fit into any of the aforementioned syndromes. In these circumstances the term brainstem dysgenesis should be used followed by a detailed description of each patient's clinical findings and/or the brainstem segment presumably involved. The prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved and, in most cases, is better than the initial clinical manifestations would indicate.

[A patient with bilateral lesion in the striatum and slowly progressive dystonia secondary to T14487C mutation in the ND6 gene of complex I of the mitochondrial respiratory chain]. / Paciente con lesión bilateral del estriado y distonía lentamente progresiva secundarias a la mutación T14487C en el gen ND6 del complejo I de la cadena respiratoria mitocondrial.

INTRODUCTION: A large number of diseases present as bilateral striatal lesion syndrome (BSLS). Clinical manifestations, course and prognosis of these diseases are extremely variable. On the basis of their evolutive course, they can be separated into two major groups: acute, which include toxic, infectious or parainfectious causes, and subacute or chronic, in which inborn errors of metabolism, especially mitochondrial disorders, are the main causes. CASE REPORT: We report a detailed clinical follow-up of a 18 years old Caucasian male who, at the age of four, presented with BSLS. A respiratory chain defect was suspected on the basis of slowly progressive dystonia and cognitive impairment, changes in serial MRI studies, and the finding of 'trabecular fibers' as well as a 50% decrease of the complex I activity in striated-skeletal muscle specimen. Blood, urine and CSF markers classically associated with respiratory chain diseases were normal. Molecular studies identified a new pathogenetic mutation (T14487C) in the mitochondrial ND6 gene of the respiratory chain complex I. CONCLUSION: Mitochondrial metabolism disorders should be ruled out in patients presenting with a subacute or chronic form of BSLS even in the absence of other common mitochondrial disease markers.

[Muscle regeneration following glycerol injection mimic that of mdx-mice degenerative-regenerative groups]. / La regeneración tras inyección intramuscular de glicerol remeda la de los grupos degenerativos-regenerativos del ratón mdx.

INTRODUCTION: In recent years several authors have proposed that muscle pathological changes in humans with dystrophin disorders and in mdx-mice are the result of regeneration attempts of this tissue subjected to constantly repeated bouts of necrosis. AIM: We compared morphological aspects of degenerative-regenerative groups observed in the mdx-mice with the regenerative phases that follow an intramuscular injection of 30 mL glycerol. MATERIALS AND METHODS: Gastrocnemius samples from mdx-mice, 1 to 5 months old and from glycerol injected C57Bl10/ScSn mice, 4 to 8 months old, were processed and analyzed in parallel. RESULTS: We were able to recognize degenerative-regenerative group stages in the mdx-mice that closely matched the anomalies found 1, 2, 3, 4-5, 7 and 21-28 days following the injection with glycerol. CONCLUSION. This study reinforces the hypothesis that muscle pathologic abnormalities of mdx-mice are the result of chronic muscle necrosis-regeneration. Morphologic mdx-mice degenerative-regenerative group staging will be a helpful tool for future investigation of muscle regeneration.

[The efficiency of carbamazepine in a case of post-streptococcal hemichorea]. / Eficacia de la carbamacepina en un caso de hemicorea posestreptocócica.

INTRODUCTION: Chorea is an infrequent disorder at the paediatric age which has a number of both hereditary and acquired causes. Post-streptococcal or Sydenham's chorea (SC) is still the main cause of chorea in children, in spite of the drop in prevalence of rheumatic fever in the last few years. SC is a benign, self-limiting disorder, but may last for several months and can be highly disabling. Several different types of symptomatic treatment have been proposed, for example corticoids, haloperidol, valproic acid, and carbamazepine. In each case, both the speed with which the clinical improvement is brought about, and the degree to which they are tolerated and the absence of side effects must be evaluated. CASE REPORT: We present a new case of SC that had been developing for three months. Carbamazepine was effective from the tenth day onwards and total remission of the symptoms was achieved in six weeks. Total follow-up time was nine months, and in this time no relapses or side effects were observed. CONCLUSIONS: This contribution offers new evidence supporting carbamazepine as another first choice medication in the treatment of this type of chorea.

[Clinical characteristics of migraine in childhood]. / Características clínicas de la migraña en la edad pediátrica.

INTRODUCTION: The clinical presentation and progression of childhood migraine has still not been clearly defined. However, major advances in prognosis and treatment would follow this. OBJECTIVE: To trace the clinical features and course of childhood migraine. PATIENTS AND METHODS: A prospective study, lasting 10 years, in a population of 284 children with migraine, seen at two hospitals. The data obtained were analysed using techniques of statistical significance and logistic regression. RESULTS: In 24.3% headaches started before the age of 6 years, and in 57% at between 6 and 10 years of age. In 77.5% of the patients there was a family history of migraine, this figure rose to 82.6% in the children whose headaches started before the age of 6 years. Characteristics such as duration, site and accompanying factors differed from those seen in adults. There was spontaneous improvement in 88.3%, who did not require prophylactic medication. CONCLUSIONS: Childhood migraine has some characteristics which distinguish it from adult migraine. This should be noted in classification. Most children with migraine have mild headaches which do not require prophylaxis. A genetic factor appears to play an important rol in phenotype expression of the disorder.

[Ophthalmoplegia-ataxia-areflexia in pediatrics. Three new patients and review of the literature]. / Oftalmoplejía-ataxia-arreflexia en pediatría. Tres nuevos pacientes y revisión de la literatura.

OBJECTIVE: The objective of this study was to investigate if pediatric patients with benign brainstem encephalitis (Bickerstaff Syndrome) or with Miller-Fisher Syndrome are the extremes of the same nosological entity which, in adults, has been named ophalmoplegia-ataxia-areflexia syndrome. PATIENTS AND METHODS: The subjects included in the study were three patients of our institution and 24 patients found in the revision of the English and Spanish pediatric literature who fulfilled the diagnostic criteria of ophtalmoplegia-ataxia-areflexia syndrome. The topographical location of the lesion in the nervous system was based on previously established criteria by using clinical and complementary studies. RESULTS: Of the 27 patients included in the study we were able to reach an accurate topographical diagnosis in 9. None had an exclusive involvement of the peripheral nervous system, (6) had exclusively central nervous system involvement and 2 showed involvement of both system. In 12, the topographical location of the lesion could be only ascertained as probable; 3 of them in the peripheral nervous system, 2 in the central nervous system and mixed involvement in 7. In the remaining 7 patients there were insufficient clinical data to allow topographical classification. CONCLUSIONS: The ophtalmoplegia-ataxia-areflexia syndrome can also be found in pediatric patients. The lesion in the majority of patients in this age group is located in the central nervous system, either alone or combined with peripheral nervous system involvement.

[Chronic encephalopathy in patients with sex-linked agammaglobulinemia]. / Encefalopatía crónica en pacientes con agamaglobulinemia ligada al sexo.

The clinical and neuroradiological findings of two patients with X-linked agammaglobulinemia, who developed a chronic encephalopathy, are presented. The main neurological manifestations in both patients were: progressive spastic tetraparesis, cortico-subcortical type of dementia and seizures. No infectious agent was identified in either patient. A systematic review of the clinical findings of 37 patients reported in the literature with X-linked agammaglobulinemia and chronic encephalopathy allows the distinction of two subgroups of patients according to their form of presentation (acute or insidious). In each subgroup there are significant clinical differences. The clinical-neuroradiological similarities between this complication and the ones derived from the vertically transmitted form of the human immunodeficiency virus are pointed out. Finally, emphasis is made on the need for CSF viral cultures on patients with X-linked agammaglobulinemia as soon as a neurological complication is suspected.

[Anomalous course of a lipomeningocele]. / Anómala evolución de un lipomeningocele.

A 9 months old male with a lipomeningocele developed progressive flaccid paraparesis with loss of deep tendon reflexes and sensation to pink prick on the lower extremities. The clinical picture was secondary to a tethered spinal cord syndrome associated to the lipomeningocele. Surgical untethering of the spinal cord was followed by clinical recovery over a 3 months period.