[Microcephaly]. / Microcefalia.

Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. It is an important neurological sign and predictor of future disability. One of its diagnostic difficulties lies in the ranks of the head circumference reference against which we measure each child. The WHO developed growth curves that could be used universally, topic on which there may be discrepancies. Recently, Zika virus epidemic demanded to review the criteria for the diagnosis of microcephaly. The classification of the microcephaly in congenital and postnatal makes it possible to define the etiology, the associated symptoms and the prognosis. The evaluation of a child with microcephaly requires a thorough analysis of its history, clinical examination and complementary studies. MRI is the first step in the etiologic research. Genetic causes forming part of a syndrome or not, and prenatal infections are the most frequent etiologies but in half of the cases, no cause is found. The comparative hybridization genomic array (array-CGH) and full exome sequencing are techniques that more and more help us in the evaluation of patients with microcephaly. Depending on the cause and severity, children with microcephaly may have different problems such as intellectual disabilities, development retardation, epilepsy, cerebral palsy, as well as vision and hearing disorders. The microcephaly requires a multidisciplinary approach both in its initial assessment as it is its post-program monitoring.

[The impact of congenital heart disease on neurodevelopment]. / El impacto de las cardiopatías congénitas en el neurodesarrollo.

It is estimated that about 1 in 100 live births has a congenital heart disease (CHD). Cognitive deficit, academic difficulties, and behavioral abnormalities, in combination, represent the most common morbidity affecting quality of life in survivors with CHD. Developmental dysfunction results from a complex interaction between patient-specific factors such as genetic susceptibility, cardiac diagnosis, fetal development, and environmental factors such as preoperative events, supportive techniques during surgical repair, postoperative events, socioeconomic status. A comprehensive neurodevelopmental assessment in all children with CHD is critical to identify any need for intervention early and provide the support needed to optimize their long-term development.

Se estima que aproximadamente 1 de cada 100 nacidos vivos presenta una cardiopatía congénita (CC). El déficit cognitivo, las dificultades académicas y anomalías conductuales, en combinación, representan la morbilidad más común que afecta la calidad de vida en sobrevivientes con CC. La disfunción del desarrollo resulta de una interacción compleja entre factores específicos del paciente como susceptibilidad genética, tipo de cardiopatía, desarrollo fetal y factores ambientales tales como eventos preoperatorios, técnicas de apoyo durante la reparación quirúrgica, eventos posoperatorios, estatus socioeconómico. Una evaluación integral del neurodesarrollo en todos los niños con CC es fundamental para identificar tempranamente cualquier necesidad de intervención y proporcionar el apoyo necesario para optimizar su desarrollo a largo plazo.

The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

[Environmental toxic and its effect on neurodevelopment]. / Tóxicos ambientales y su efecto sobre el neurodesarrollo.

Neurodevelopmental disorders are the result of a disturbance of brain function. They are frequent, with varied symptomatology, manifest themselves at different times of life and tend to be persistent with impact at the individual, family and social level. The association of these disorders with genetic entities is low. Although the research supports a mode of genetic inheritance, epigenetic factors and environmental factors can play an important role. In recent years there was a striking increase of these disorders especially attention deficit hyperactivity disorders and pervasive development disorder. Environmental factors such as the intoxication of the fetus by especially heavy metals lead and mercury are to blame in some children, of these disorders. Other substances of wide use, little degradation and maintenance in the food chain as pesticides, polychlorinated biphenyls and now the recycling of electronic waste put especially infants and children at risk, and even more so in the developing countries.

[Acute encephalitis anti-ionotropic glutamate receptor activated N-methyl-D-aspartate (NMDAR): analysis of eleven pediatric cases in Argentina (Benito Yelín Award)]. / Encefalitis aguda mediada por anticuerpos contra el receptor ionotrópico de glutamato activado por N-metil-D-aspartato (NMDAR): análisis de once casos pediátricos en Argentina (Premio Benito Yelín).

Encephalitis are an inflammatory processes of various origin, among which include autoimmune origin. The identification of antibodies against the N-methyl-D- aspartate, allowed clinical immunological characterization of an entity susceptible to immunomodulatory therapy. Originally described in young women associated with ovarian teratoma, is now a recognized entity in children even in the absence of detectable tumors. The aim of the study was conducted through review of medical records, was to describe the clinical, developmental and findings in further studies of eleven children with confirmed diagnosis of this entity through identification of specific antibodies. All debuted with psychiatric symptoms in nine associating seizures, and two extrapyramidal movements. In the evolution of language all had commitment nine severe autonomic symptoms, one with hypoventilation and requirements of ARM. Brain MRI was abnormal in three. Eight had voltage EEG asymmetry and / or amplitude, three of them had spikes. Six had CSF pleocytosis and three of seven positive oligoclonal bands. Five IgM serology for mycoplasma were positive. CPK increase occurred in conjunction with antisychotics in five. With immunomodulatory treatment, five had complete recovery three behavioral disorders / cognitive deficits and one severe. A patient's clinical picture resolved without treatment. In any associated tumor was detected. We conclude that in front of a child with acute encephalopathy and clinical support this entity after infectious cause were ruled out, immunomodulatory therapy should be started early, avoid the use of antipsychotic drugs and search for possible hidden tumors.

[Environmental factors influencing developmental disorders]. / Factores ambientales que influyen en los trastornos del desarrollo.

Neurodevelopmental disorders have been associated with multiple causes especially, genetic a nd environmental -nutritional, infectious, toxic, traumatic and psychosocial stress among others- that in general do not operate alone, but interact with each other. Of special interest is to identify the mechanism(s) that lead to these disorders. Inflammation and epigenetic changes may play a common end for many forms of environmental risk.

Los trastornos del neurodesarrollo, se han asociado con múltiples causas, especialmente genéticas y ambientales ­nutricionales, infecciosas, tóxicas, traumáticas y estrés psicosocial, entre otras­ que en general interactúan entre sí. De especial interés es identificar el/los factores que contribuyen a estos trastornos. Factores ambientales que están relacionados con inflamación y cambios epigenéticos pueden ser una vía común final.

Spontaneous remission in juvenile myasthenia gravis: A cohort of 13 cases and review of the literature.

We describe the clinical course of patients with juvenile myasthenia gravis who experienced spontaneous remission and review the literature. This is a retrospective study of 13 patients with spontaneous remission from a cohort of 133 patients younger than 18-years-old. We compared several variables with potential prognostic value in patients with and without spontaneous remission. Ten percent of patients (13/133) experienced spontaneous remission. There was no difference in age at onset or sex compared to the overall JMG population. Spontaneous remission occurred in 2/40 (5.0%; 95% CI: 0.6-16.9) patients in Class I (ocular); in 11/53 (20.8%; 95% CI: 10.8-34.1) patients in Class II-III (mild, moderate, generalized) (p < 0.0018) and in 0/40 patients in Class IV-V (severe, needs intubation). Of the AChR antibody positive patients, 10/97 (10.3%; 95% CI: 5.0-18.1) had spontaneous remission, compared with 2/29 (6.9%; 95% CI: 0.9-22.8) of those without AChR antibodies (p = 0.583). Strikingly, none of the 36 patients with thyroid antibodies had spontaneous remission compared with 13/58 (22.4%) of those without thyroid antibodies (95% CI: 7.3-21.8; p < 0.001). Ten percent of patients with juvenile myasthenia gravis achieved spontaneous remission, mainly in those with Class II-III disease and no associated thyroid antibodies.

[Opsoclonus-myoclonus syndrome]. / Síndrome de opsoclonus-mioclonus.

The opsoclonus-myoclonus syndrome in children is a rare entity which is characterized by irritability, chaotic ocular movements with vertical, horizontal, rotatory components (opsoclonus) along with myoclonus and ataxia. In a high proportion of cases, it is associated with neuroblastoma although other etiologies involving infectious or toxic agents have been reported. An autoimmune mechanism would be responsible for the dysfunction of structures in brain stem and cerebellum thus explaining some of the cardinal symptoms such as opsoclonus, myoclonus and ataxia. However, encephalopathic symptoms and the high percentage of patients with neurocognitive and psychiatric sequels are in favor of a wider dysfunction. Treatment with steroids, ACTH, immunomodulatory or immunosuppressive drugs is being used although prospective studies are needed to determine whether the prolonged use of these drugs influences favorably the evolution of these patients.

[Subependymal nodules-sudependymal giant cell astrocytoma complex in children with tuberous sclerosis]. / Complejo nódulo subependimario-astrocitoma subependimario gigantocelular en niños con esclerosis tuberosa.

The object of this paper is to describe the imaging and clinical characteristics of subependymal nodule (SN) - subependymal giant cell astrocytoma (SGCA) complex in tuberous sclerosis and analyze its evolution in order to attempt early detection and the prevention of intracranial hypertension. We evaluated 22 patients with the pathological diagnosis of SGCA. The diagnosis was made at a median of 10.1 years old. We were able to observe the evolution of SN to ASGC: these SN were localized adjacent to the foramen of Monro and with time they underwent an important development with intense contrast enhancement and hydrocephalus. The acceleration in SN growth and its "transformation" into SGCA occurred at an average of 10 years of age, with a mean diameter of 9 mm. No SN located far from the foramen of Monro evolutioned to SGCA. Fifteen patients (68%) were operated with symptoms of intracranial hypertension. Average age at surgery was 10.8 years old. Six patients presented visual deficit and in these, the average diameter of the tumor was 31.5 mm, a high value when compared to 18.7 mm in the patients without visual deficit. The imaging and clinical follow-up of any subependymal lesion close to the foramen of Monro will permit, at a presymptomatic stage, an anticipation of surgical treatment thus reducing intracranial hypertension incidence. Prospective studies could determine whether the SN-SGCA complex corresponds to the same entity in distinct evolution stages or to two lesions with different growth potential.

[Treatment of juvenile myasthenia gravis]. / Tratamiento de la miastenia gravis juvenil.

Juvenile myasthenia gravis is a rare autoimmune disease, which has made it difficult to collect data from prospective randomized controlled trials to evaluate the efficacy and results of different treatments. Although there are differences between the juvenile myasthenia gravis and that of the adult, the data provided by some researches in adults in the treatment of juvenile myasthenia gravis have been used. The different therapeutic options will be evaluated, with the different evidences that sustain it and a treatment algorithm will be elaborated keeping always in mind that each patient offers us different challenges.

La miastenia gravis juvenil es una enfermedad autoimmune poco frecuente, por lo que ha sido difícil recopilar datos de estudios controlados aleatorizados prospectivos para evaluar la eficacia y los resultados de distintos tratamientos. Si bien hay diferencias entre la miastenia gravis juvenil y la del adulto, se han utilizado los datos aportados por algunas investigaciones en adultos en el tratamiento de la miastenia gravis juvenil. Se evaluarán las distintas opciones terapéuticas, con las distintas evidencias que lo sostienen y se elaborará un algoritmo de tratamiento teniendo siempre presente que cada paciente nos ofrece distintos desafíos.

[Migraine and other primary headaches in children and adolescents]. / Migraña y otras cefaleas primarias en la infancia y la adolescencia. La nueva Clasificación Internacional de Cefaleas (II Edicion) de La Sociedad Internacional de Cefaleas.

Migraine diagnosis only relies on clinical characteristics of the episodes and therefore on the doctor's skill and experience. It is recognized that migraine inclusively in the pediatric group is underdiagnosed and inadequately treated. The International Headache Society recently reviewed the international headache classification and incorporated some clinical criteria according to the different age groups. Pediatricians and pediatric neurologists now have a new document and should become familiar with it. This paper discusses these new criteria for migraine and other primary headaches.

Mitochondrial DNA deletions detected by Multiplex Ligation-dependent Probe Amplification.

The genetic diagnosis algorithm for mitochondrial (mt) diseases starts looking for deletions and common mutations in mtDNA. MtDNA's special features, such as large and variable genome copies, heteroplasmy, polymorphisms, and its duplication in the nuclear genome as pseudogenes (NUMTs), make it vulnerable to diagnostic misleading interpretations. Multiplex Ligation-dependent Probe Amplification (MLPA) is used to detect copy number variations in nuclear genes and its application on mtDNA has not been widely spread. We report three Kearns Sayre Syndrome patients and one Chronic Progressive External Ophthalmoplegia adult, whose diagnostic mtDNA deletions were detected by MLPA using a very low amount of DNA. This managed to "dilute" the NUMT interference as well as enhance MLPA's efficiency. By this report, we conclude that when MLPA is performed upon a reduced amount of DNA, it can detect effectively mtDNA deletions. We propose MLPA as a possible first step method in the diagnosis of mt diseases.

Epilepsy, occipital calcifications, and oligosymptomatic celiac disease in childhood.

The association of epilepsy, occipital calcifications, and celiac disease has been recognized as a distinct syndrome. The objective of this study was to present the clinical, electrophysiologic, and neuroradiologic features in a series of patients with this syndrome. Thirty-two patients with the constellation of epilepsy, occipital calcifications, and celiac disease were identified in our epilepsy clinic. The mean age was 11 years and the mean length of follow-up was 7.4 years. The 1990 criteria of the European Society of Pediatric Gastroenterology and Nutrition were used to diagnose celiac disease. The Kruskal-Wallis statistics test was employed with a signficance of P < .05. Thirty-one patients had partial seizures, 21 of them with symptoms related to the occipital lobe. In most patients, the epilepsy was controlled or the seizures were sporadic. Three developed severe epilepsy. Occipital calcifications were present in all cases. Computed tomography in 7 patients showed hypodense areas in the white matter around calcifications, which decreased or disappeared after a period of gluten-free diet in 3 patients. A favorable outcome of epilepsy was detected in patients with the earliest dietary therapy. This study presents the largest series of children with this syndrome outside Italy. White-matter hypodensities surrounding calcifications are rarely reported. A prompt diagnosis of celiac disease might improve the evolution of the epilepsy and may improve cognitive status.

Tratamiento de la miastenia gravis juvenil / Treatment of juvenile myasthenia gravis

La miastenia gravis juvenil es una enfermedad autoimmune poco frecuente, por lo que ha sido difícil recopilar datos de estudios controlados aleatorizados prospectivos para evaluar la eficacia y los resultados de distintos tratamientos. Si bien hay diferencias entre la miastenia gravis juvenil y la del adulto, se han utilizado los datos aportados por algunas investigaciones en adultos en el tratamiento de la miastenia gravis juvenil. Se evaluarán las distintas opciones terapéuticas, con las distintas evidencias que lo sostienen y se elaborará un algoritmo de tratamiento teniendo siempre presente que cada paciente nos ofrece distintos desafíos.

Juvenile myasthenia gravis is a rare autoimmune disease, which has made it difficult to collect data from prospective randomized controlled trials to evaluate the efficacy and results of different treatments. Although there are differences between the juvenile myasthenia gravis and that of the adult, the data provided by some researches in adults in the treatment of juvenile myasthenia gravis have been used. The different therapeutic options will be evaluated, with the different evidences that sustain it and a treatment algorithm will be elaborated keeping always in mind that each patient offers us different challenges.

[Acute non-traumatic myelopathy in children and adolescents]. / Mielopatías agudas no traumáticas en niños y adolescentes.

The term 'acute myelopathies'--referred to a spinal cord dysfunction--represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. The objective of this review is to discuss the non-traumatic acute myelopathies. Acute myelopathy can be due to several causes as infective agents or inflammatory processes, such as in acute myelitis, compressive lesions, vascular lesions, etc. The clinical presentation is often dramatic with tetraparesis or paraparesis, sensory disturbances and bladder and/or bowel dysfunction. History and physical examination are used to localize the lesion to the root or specific level of the cord, which can guide imaging. Different syndromes are recognized: complete transverse lesion, central grey matter syndrome, anterior horn syndrome, anterior spinal artery syndrome, etc). The first priority is to rule out a compressive lesion. If a myelopathy is suspected, a gadolinium-enhanced MRI of the spinal cord should be obtained as soon as possible. If there is no structural lesion such as epidural blood or a spinal mass, then the presence or absence of spinal cord inflammation should be documented with a lumbar puncture. The absence of pleocytosis would lead to consideration of non inflammatory causes of myelopathy such as arteriovenous malformations, fibrocartilaginous embolism, or possibly early inflammatory myelopathy. In the presence of an inflammatory process (defined by gadolinium enhancement, cerebrospinal fluid pleocytosis, or elevated cerebrospinal fluid immunoglobulin index), one should determine whether there is an inflammatory or an infectious cause. Different virus, bacterias, parasites and fungi have to be considered as autoimmune and inflammatory diseases that involve the central nervous system.

TITLE: Mielopatias agudas no traumaticas en niños y adolescentes.El termino 'mielopatias agudas' se refiere a una disfuncion de la medula espinal y representa un grupo heterogeneo de trastornos con distintas etiologias y caracteristicas clinicas (imaginologicas y de pronostico). El objetivo de esta revision es tratar las mielopatias agudas no traumaticas. La mielopatia aguda puede deberse a varias causas, como agentes infecciosos o procesos inflamatorios, compresion y lesiones vasculares, entre otros. La presentacion clinica es a menudo dramatica con tetraparesia o paraparesia, alteraciones sensitivas y disfuncion de la vejiga o del intestino. La historia y el examen fisico se utilizan para localizar la lesion o el nivel especifico de la medula, que puede guiar la solicitud de la imagen. La primera prioridad es descartar una lesion compresiva. Si se sospecha una mielopatia, debe obtenerse tan pronto como sea posible una resonancia magnetica medular con gadolinio. Si no hay ninguna lesion estructural, entonces la presencia o ausencia de inflamacion de la medula espinal debe documentarse con una puncion lumbar. La ausencia de pleocitosis daria lugar a la consideracion de causas no inflamatorias como malformaciones arteriovenosas, embolia fibrocartilaginosa o posiblemente el inicio de una mielopatia inflamatoria. En presencia de un proceso inflamatorio (realce con gadolinio, pleocitosis o elevado indice de inmunoglobulina en el liquido cefalorraquideo), se debera determinar si hay una inflamacion o una causa infecciosa. Se tienen que considerar hongos, bacterias, parasitos y virus, asi como enfermedades autoinmunes e inflamatorias que involucran al sistema nervioso central.

Microcefalia / Microcephaly

La microcefalia se define como un perímetro cefálico de más de dos desviaciones estándar por debajo de la media para edad y sexo. Es un importante signo neurológico y predictor de discapacidad futura. Una de las dificultades de su diagnóstico radica en los rangos de referencia del perímetro cefálico contra la que medimos a cada niño. La OMS elaboró curvas de crecimiento del perímetro cefálico que podrían ser utilizadas en forma universal, tema sobre el que puede haber discrepancias. La epidemia por virus del Zika exigió revisar recientemente los criterios del diagnóstico de microcefalia. La clasificación de la microcefalia en congénita y postnatal posibilita definir la etiología, los síntomas asociados y el pronóstico. La evaluación de un niño con microcefalia requiere un exhaustivo análisis de sus antecedentes, examen clínico y estudios complementarios. La resonancia magnética es el primer escalón en la investigación etiológica. Las causas genéticas formando parte o no de cuadros sindrómicos y las infecciones intraútero, son las etiologías más frecuentes, pero en la mitad de los casos no se encuentra una causa. La hibridación comparativa matriz genómica (array-CGH) y la secuenciación del exoma completo son técnicas que cada vez más ayudan en la evaluación de pacientes con microcefalia. Dependiendo de la causa y la gravedad, los niños con microcefalia pueden tener diferentes problemas como discapacidad intelectual, retraso del desarrollo, epilepsia, parálisis cerebral, así como trastornos oftalmológicos y auditivos. La microcefalia exige un enfoque multidisciplinario tanto en su evaluación inicial como es su seguimiento posterior.

Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. It is an important neurological sign and predictor of future disability. One of its diagnostic difficulties lies in the ranks of the head circumference reference against which we measure each child. The WHO developed growth curves that could be used universally, topic on which there may be discrepancies. Recently, Zika virus epidemic demanded to review the criteria for the diagnosis of microcephaly. The classification of the microcephaly in congenital and postnatal makes it possible to define the etiology, the associated symptoms and the prognosis. The evaluation of a child with microcephaly requires a thorough analysis of its history, clinical examination and complementary studies. MRI is the first step in the etiologic research. Genetic causes forming part of a syndrome or not, and prenatal infections are the most frequent etiologies but in half of the cases, no cause is found. The comparative hybridization genomic array (array-CGH) and full exome sequencing are techniques that more and more help us in the evaluation of patients with microcephaly. Depending on the cause and severity, children with microcephaly may have different problems such as intellectual disabilities, development retardation, epilepsy, cerebral palsy, as well as vision and hearing disorders. The microcephaly requires a multidisciplinary approach both in its initial assessment as it is its post-program monitoring.

NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern.

OBJECTIVE: To identify the mutated gene in a group of patients with an unclassified heritable white matter disorder sharing the same, distinct MRI pattern. METHODS: We used MRI pattern recognition analysis to select a group of patients with a similar, characteristic MRI pattern. We performed whole-exome sequencing to identify the mutated gene. We examined patients' fibroblasts for biochemical consequences of the mutant protein. RESULTS: We identified 6 patients from 5 unrelated families with a similar MRI pattern showing predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum. The 4 tested patients had a respiratory chain complex І deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex І, in all patients. Upon identification of the mutated gene, we analyzed the MRI of a previously published case with NUBPL mutations and found exactly the same pattern. A strongly decreased amount of NUBPL protein and fully assembled complex I was found in patients' fibroblasts. Analysis of the effect of mutated NUBPL on the assembly of the peripheral arm of complex I indicated that NUBPL is involved in assembly of iron-sulfur clusters early in the complex I assembly pathway. CONCLUSION: Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern, which facilitates fast diagnosis and obviates the need for other tests, including assessment of mitochondrial complex activities in muscle or fibroblasts.