[Intracranial hypotension syndrome in a pediatric patient with Marfan syndrome].

Intracranial hypotension syndrome (IHS) is attributed to reduced cerebrospinal fluid (CSF) pressure. It may be spontaneous or secondary to a history of trauma or systemic disease. We present the case of an 11-year-old boy, with medical history of Marfan syndrome, with orthostatic headache and persistent vomiting (12 hours) following a fall on the sacrococcygeal region. Magnetic resonance showed extradural fluid collections at dorsal and lumbosacral levels, compatible with CSF leak. The condition was resolved with treatment, but the patient had two new episodes during the follow-up period. Thus, an epidural blood patch was performed two years after the first episode. Although HIS is uncommon in children, it should be suspected in patients with orthostatic headache, particularly if the patient presents a connectivopathy. Few studies have assessed the management of HIS in paediatric age. The case presented here and the reviewed available literature provides further data for these type of cases.

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

[Idiopathic intracranial hypertension: Experience over 25 years and a management protocol]. / Hipertensión intracraneal idiopática: experiencia en 25 años y protocolo de actuación.

INTRODUCTION: We present our experience on idiopathic intracranial hypertension (IIH), before and after the introduction of a specific diagnosis and management protocol. METHOD: A descriptive retrospective study was conducted on patients with IIH over a 25year period (1990-2015), comparing the last 7years (after introduction of the protocol) with the previous 18years. RESULTS: Among the 18,865 patients evaluated, there were 54 cases of IIH (29 infants and 25 children). A comparison was made between the two time periods: 32 cases in 1990-2008 -published in An Pediatr (Barc). 2009;71:400-6-, and 23 cases in 2008-2015. In post-protocol period, there were 13 patients aged between 3-10months (62% males) with transient bulging fontanelle, and 10 aged between 2-14years (50% males), with papilloedema. A total of 54% of infants had recently finished corticosteroid treatment for bronchitis. In the older children, there was one case associated with venous thrombosis caused by otomastoiditis, one case on corticosteroid treatment for angioma, and another case treated with growth hormone. Transfontanelle ultrasound was performed on all infants, and CT, MRI and angio-MRI was performed on every child. Lumbar puncture was performed on 2 infants in whom meningitis was suspected, and in all children. All patients progressed favourably, with treatment being started in 3 of them. One patient relapsed. DISCUSSION: Characteristics and outcomes of patients overlap every year. IIH usually has a favourable outcome, although it may be longer in children than in infants. It can cause serious visual disturbances, so close ophthalmological control is necessary. The protocol is useful to ease diagnostic decisions, monitoring, and treatment.

[A study of epilepsy according to the age at onset and monitored for 3 years in a regional reference paediatric neurology unit]. / Estudio de las epilepsias según la edad de inicio, controladas durante 3 años en una unidad de neuropediatría de referencia regional.

OBJECTIVE: A study of epilepsy, according to the age at onset of the crisis and its causes, monitored by a Paediatric Neurology Unit over a period of three years. PATIENTS AND METHODS: Historical cohorts study was conducted by reviewing the Paediatric Neurology medical records data base of epileptic children followed-up from 1 January 2008 to 31 December 2010. RESULTS: A total of 4,595 children were attended during the study period. The diagnosis of epilepsy was established in 605 (13.17%): 277 (45.79%) symptomatic, 156 (25.79%) idiopathic, and 172 (28.43%) with cryptogenic epilepsy. Absence epilepsy and benign childhood epilepsy with centro-temporal spikes are the idiopathic epileptic syndromes most prevalent, and the most prevalent symptomatic epilepsies are prenatal encephalopathies. More than one-quarter (26.12%) of epilepsies began in the first year of life, and 67.72% were symptomatic. Refractory epilepsy was observed in 25.29%, 42.46% with cognitive impairment, 26.45% with motor involvement, and 9.92% with an autism spectrum disorder, being more frequent at an earlier age of onset. CONCLUSIONS: The absence of a universally accepted classification of epileptic syndromes makes tasks like this difficult, starting with the terminology. A useful classification would be aetiological, with two groups: a large group with established aetiology, or very likely genetic syndromes, and another with no established cause. The age of onset of epilepsy in each aetiological group helps in the prognosis, which is worsened by refractoriness and associated neurodevelopmental disorders, and are generally worse at an earlier onset and in certain aetiologies.

GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females.

BACKGROUND: De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). METHODS: We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. RESULTS: Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. CONCLUSIONS: With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized.

[Prognosis of symptomatic epilepsies in relation to their age of onset, monitored at a neuropediatric section of regional reference over a period of three years]. / Pronostico de las epilepsias sintomaticas segun la edad de inicio, controladas durante tres años en una unidad de neuropediatria de referencia regional.

AIM: To analyze the factors involved in the prognosis of symptomatic epilepsies in relation to their age at onset, monitored at a neuropediatric section of regional reference over a period of three years. PATIENTS AND METHODS: Children diagnosed with symptomatic epilepsy, supervised from January 1, 2008 to December 31, 2010, collecting epidemiological, clinical and developmental data. RESULTS: Of the 4595 children attended during the period, the diagnosis of epilepsy was established at 605 (13.17%): 277 (45.79%) symptomatic epilepsies. Symptomatic etiology predomininates in epileptic patients that started below one year of age, 67.72%, and between 1-3 years, 61.39%. 37.54% of symptomatic epilepsy is refractory, 72.92% have cognitive impairment, 55.23% have motor impairment and 17.32% have autism spectrum disorder. The younger the patient, the higher the percentage of refractoriness and display of any neurological or associated development impact. Some etiologies have higher rates of refractoriness. CONCLUSIONS: A useful classification would be etiological, with two groups: a large group with established etiology or very likely genetic syndromes and another with no established cause. The age of onset of epilepsy in each etiological group adds prognostic orientation. Prognosis of epilepsy is overshadowed by refractoriness and associated neurodevelopmental disorders, which are generally worse at an earlier onset and in certain etiologies.

TITLE: Pronostico de las epilepsias sintomaticas segun la edad de inicio, controladas durante tres años en una unidad de neuropediatria de referencia regional.Objetivo. Analizar los factores implicados en el pronostico de las epilepsias sintomaticas en relacion con su edad de inicio, controladas en una unidad de neuropediatria de referencia regional durante tres años. Pacientes y metodos. Revision de los pacientes con diagnostico de epilepsia sintomatica, controlados desde el 1 de enero de 2008 hasta el 31 de diciembre de 2010, recogiendo datos epidemiologicos, clinicos y evolutivos. Resultados. Del total de 4.595 niños atendidos en el periodo, se establecio el diagnostico de epilepsia en 605 (13,17%), de las cuales 277 (45,79%) son epilepsias sintomaticas. En los pacientes que iniciaron la epilepsia por debajo del año de vida predominan las de etiologia sintomatica (67,72%), y tambien entre 1-3 años (61,39%). El 37,54% de las epilepsias sintomaticas son refractarias, el 72,92% asocian un deficit cognitivo, el 55,23%, alguna afectacion motora, y el 17,32%, algun trastorno del espectro autista. A menor edad, mayor porcentaje de refractariedad y de presentar alguna repercusion neurologica o del desarrollo asociada. Algunas etiologias tienen mayores tasas de refractariedad. Conclusiones. Una clasificacion util de la epilepsia es la etiologica, con dos grupos: un gran grupo con las etiologias establecidas o sindromes geneticos muy probables, y otro de casos sin causa establecida. La edad de inicio de la epilepsia en cada grupo etiologico añade orientacion pronostica. El pronostico lo ensombrecen la refractariedad y las alteraciones asociadas del neurodesarrollo, y es peor, en general, cuanto mas precoz es el inicio y en etiologias concretas.

[Prognosis of non-symptomatic epilepsy in relation to their age of onset, monitored at a neuropediatric section of regional reference over a period of three years]. / Pronóstico de las epilepsias no sintomáticas según la edad de inicio, controladas durante tres años en una unidad de neuropediatría de referencia regional.

AIM: To analyze the factors involved in the prognosis of non-symptomatic epilepsy (idiopathic and cryptogenic) in relation to their age of onset, monitored at a regional section of Neuropediatry reference over a period of three years. PATIENTS AND METHODS: Patients with diagnosis of non-symptomatic epilepsy supervised from January 1, 2008 to December 31, 2010, collecting epidemiological, clinical, complementary examinations and developmental data. RESULTS: Of the 4595 children attended during the period, the diagnosis of epilepsy was established in 605 (13.17%): 156 (25.79%) idiopathic epilepsies and 172 (28.43%) cryptogenic epilepsies. 15.7% of cryptogenic epilepsies and 14.1% of idiopathic epilepsies are refractory to treatment. Some epileptic syndromes, such as reflex epilepsies, Dravet syndrome, Ohtahara syndrome or Lennox-Gastaut syndrome, have higher rates of drug resistance. 84.62% of idiopathic epilepsies and 79.77% of cryptogenic epilepsies present no other associated neurological disorder. CONCLUSIONS: A useful classification would be etiological, with two groups: a large group with established etiology or very likely genetic syndromes and another with no established cause. The age of onset of epilepsy in each etiological group adds prognostic orientation. Prognosis of epilepsy is worsened by refractoriness and associated neurodevelopmental disorders, and are generally worse at an earlier onset and in certain etiologies.

TITLE: Pronostico de las epilepsias no sintomaticas segun la edad de inicio, controladas durante tres años en una unidad de neuropediatria de referencia regional.Objetivo. Analizar los factores implicados en el pronostico de las epilepsias no sintomaticas (idiopaticas y criptogenicas) en relacion con su edad de inicio, controladas en una unidad de neuropediatria de referencia regional durante un periodo de tres años. Pacientes y metodos. Analisis de los pacientes con diagnostico de epilepsia no sintomatica, controlados desde el 1 de enero de 2008 hasta el 31 de diciembre de 2010, recogiendo datos epidemiologicos, clinicos, examenes complementarios y datos evolutivos. Resultados. Del total de 4.595 niños atendidos en el periodo, se establecio el diagnostico de epilepsia en 605 (13,17%), de las cuales 156 (25,79%) fueron epilepsias idiopaticas, y 172 (28,43%), criptogenicas. El 15,7% de las epilepsias criptogenicas y el 14,1% de las idiopaticas son refractarias al tratamiento. Algunos sindromes epilepticos, como las epilepsias reflejas, el sindrome de Dravet, el sindrome de Ohtahara o el sindrome de Lennox-Gastaut, tienen mayores tasas de farmacorresistencia. No presentan otra alteracion neurologica asociada el 84,62% de las epilepsias idiopaticas y el 79,77% de las epilepsias criptogenicas. Conclusiones. Una clasificacion util de la epilepsia es la etiologica, con dos grupos: un gran grupo con las etiologias establecidas o sindromes geneticos muy probables y otro de casos sin causa establecida. La edad de inicio de la epilepsia en cada grupo etiologico añade orientacion pronostica. El pronostico lo ensombrecen la refractariedad y las alteraciones asociadas del neurodesarrollo, y es peor, en general, cuanto mas precoz sea el inicio y en etiologias concretas.

[Triplet expansion cytosine-guanine-guanine: Three cases of OMIM syndrome in the same family]. / Expansión del triplete citosina-guanina-guanina: 3 casos de síndrome OMIM en una misma familia.

INTRODUCTION: The dynamic increase in the number of triplet repeats of cytosine-guanine-guanine (CGG) in the FMR1 gene mutation is responsible for three OMIM syndromes with a distinct clinical phenotype: Fragile X syndrome (FXS) and two pathologies in adult carriers of the premutation (55-200 CGG repeats): Primary ovarian insufficiency (FXPOI) and tremor-ataxia syndrome (FXTAS) associated with FXS. CLINICAL OBSERVATION AND METHODS: CGG mutation dynamics of the FMR1 gene were studied in DNA samples from peripheral blood from the index case and other relatives of first, second and third degree by TP-PCR, and the percentage methylation. RESULTS: Diagnosis of FXS was confirmed in three patients (21.4%), eight patients (57.1%) were confirmed in the premutation range transmitters, one male patient with full mutation/permutation mosaicism (7.1%) and two patients (14.3%) with normal study. Of the eight permutated patients, three had FXPOI and one male patient had FXTAS. DISCUSSION: Our study suggests the importance of making an early diagnosis of SXF in order to carry out a family study and genetic counselling, which allow the identification of new cases or premutated patients with FMR1 gene- associated syndromes (FXTAS, FXPOI).

[A novel neurocutaneous syndrome: Legius syndrome. A case report]. / Un nuevo síndrome neurocutáneo: síndrome de Legius. A propósito de un caso.

INTRODUCTION: Legius syndrome is an autosomal dominant disorder caused by the mutation in the SPRED1 gene involving a negative regulator of the RAS-MAPK pathway, similar to neurofibromin and therefore shows some clinical similarities to neurofibromatosis type I (NF1) but less severe. These patients have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, dysmorphic features, lipomas, and mild learning disabilities. However, this syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules or tumor predisposition. CASE REPORT: We present a 10 months child, without a personal interest history, consulting by hypotonic extremities, cafe-au-lait spots and mild psychomotor difficult. Mother's sister and grandfather have some cafe-au-lait spots. In our patient, NF1 genetic study was negative, but we observe a mutation in the SPRED1 gene, compatible with Legius syndrome. Asymptomatic mother shows the same mutation in SPRED1 gene. CONCLUSION: We emphasize the relevance of the differential diagnosis of NF1 with respect to numerous complications to appear, with a better prognosis recently described entity as it is Legius syndrome.

TITLE: Un nuevo sindrome neurocutaneo: sindrome de Legius. A proposito de un caso.Introduccion. El sindrome de Legius es un trastorno autosomico dominante resultante de la mutacion del gen SPRED1, que implica perdida de funcion de una de las proteinas implicada en la via patogenica RAS-MAPK, similar a la neurofibromina y por ello muestra similitudes clinicas con la neurofibromatosis tipo 1 (NF1), pero con menor gravedad. Estos pacientes presentan multiples manchas cafe con leche y pueden asociar efelides, rasgos dismorficos, lipomas y trastornos del aprendizaje sin relacionarse con la aparicion de neurofibromas, gliomas opticos, nodulos de Lisch o predisposicion tumoral. Caso clinico. Niño de 10 meses, sin antecedentes personales de interes, que consulta por hipotonia de extremidades, manchas cafe con leche y leve retraso psicomotor. En los antecedentes familiares destaca una hermana de la madre y el abuelo materno con manchas cafe con leche. En nuestro paciente, el estudio genetico fue negativo para NF1, pero se hallo una mutacion en el gen SPRED1, compatible con el sindrome de Legius. La madre asintomatica presenta la misma mutacion en el gen SPRED1. Conclusion. Es de destacar la importancia del diagnostico diferencial de NF1, con las numerosas complicaciones que puede conllevar, con una entidad recientemente descrita de mejor pronostico como es el sindrome de Legius.

[Mesial temporal sclerosis in paediatrics: its clinical spectrum. Our experience gained over a 19-year period]. / Esclerosis mesial temporal en pediatría: espectro clinico. Nuestra experiencia de 19 años.

INTRODUCTION: Mesial temporal sclerosis (MTS) is defined as neuron loss and gliosis in the hippocampus and adjacent structures. Here we report on our 19 years' experience in dealing with this condition. PATIENTS AND METHODS: A retrospective, descriptive study was conducted of patients diagnosed with MTS between May 1990 and January 2009. RESULTS: A diagnosis of MTS was established in 16 cases (62.5% males). By location these cases were distributed as follows: 12 were unilateral (seven left temporal and five right) and four were bilateral. It was associated to cortical dysplasia in six patients (37.5%) and to hippocampal arachnoid cysts in two other cases. As regards possible causations, in one case herpes simplex encephalitis was suspected; in three cases, a prenatal cerebral vascular pathology; and in three others, prenatal infection by cytomegalovirus. The distribution of the clinical spectrum was as follows: five patients with isolated clinical epilepsy; one with isolated psychomotor retardation or mental retardation (PMR-MR); one with isolated autism spectrum disorder (ASD); three with epilepsy associated to PMR-MR; one with epilepsy associated to ASD; two with PMR-MR and ASD; and two with the triad consisting of epilepsy together with PMR-MR and ASD. In one case, MTS was discovered in migraine studies, without any other symptoms. Crises were controlled with monotherapy in all the patients who received antiepileptic treatment except in three, one of whom required surgery. CONCLUSIONS: The definitive diagnosis of MTS is pathologic, but the latest neuroimaging techniques have allowed a very reliable approximate diagnosis to be reached. It may be associated to other malformative disorders, such as focal cortical dysplasia or cysts. MTS can be observed in epilepsy (whether refractory or not), but also in ASD, PMR-MR or asymptomatic patients.

[Cerebrovascular accidents in paediatric care. Our experience gained over an 18-year period]. / Accidente cerebrovascular en pediatría. Nuestra experiencia de 18 años.

PATIENTS AND METHODS: This study reviews our experience over the last 18 years with paediatric patients diagnosed with non-haemorrhagic cerebrovascular accidents (CVA) after the perinatal period. Data were collected for the period between May 1990 and May 2008 (n = 10 270 children) and special attention was given to cases with no previous pathology. RESULTS: We found 41 cases that were diagnosed with post-natal non-haemorrhagic CVA, of which 13 did not present any known pathology at the onset of the symptoms. Nine patients were diagnosed as having ischaemic CVA (ICVA), three cases had thrombosis of the venous sinuses and there was one case of haemorrhagic infarction (HI). No causation was found in five cases, three of which were heterozygotic for the C677T mutation of methylenetetrahydrofolate reductase. ICVA was caused by fibromuscular dysplasia, aneurysm of the auricular septum and patent foramen ovale, homocystinuria and chickenpox. A recent ear infection and diminished levels of protein C were noted in two cases of venous thrombosis. Five patients with ICVA and the case of HI were treated with oral antiaggregants, anticoagulants were administered in two of the thromboses, and the remaining cases did not receive any treatment. Seven patients (four ICVA, two thromboses and the HI) did not present any kind of sequelae, four ICVA presented different degrees of hemiparesis and two died (one ICVA and one thrombosis). CONCLUSIONS: The scarcity of studies and therapeutic clinical trials in the paediatric age makes it difficult to lay down clear guidelines of conduct, especially from the therapeutic point of view. The different specialists involved must collaborate with each other.