Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

[Possible treatments for infantile spinal atrophy]. / Posibilidades de tratamiento en la atrofia espinal infantil.

The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future. Nusinersen, a methoxi-ethyl phosphotioate antisense oligonucleotide has recently approved for treatment of patients with SMA type 1 after having proved its efficacy in clinical trial phase 3. The results of nusinersen are reviewed. New modifications of antisense oligonucleotides with better access to brain, spinal cord and peripheral tissues are on the way. There are data of the efficacy of the genetic therapy with SMN1 gene through adenoassociated virus, now in phase 1 trial. A constant feature of these new treatments is that the earlier the treatment, the best are the results, and they are even better in presymptomatic stage. The general standards of care, particularly nutrition and respiratory management are needed in order to reach optimal results with the new therapies.

TITLE: Posibilidades de tratamiento en la atrofia espinal infantil.Se revisan los nuevos tratamientos de la atrofia muscular espinal (AME) producida por delecion del gen SMN1. Se describen las diferentes posibilidades de incrementar la proteina SMN, de su actividad y persistencia en el organismo. Farmacos neuroprotectores, como olesoxime y riluzol, y farmacos que actuan epigeneticamente, como inhibidores de histona deacetilasa, han mostrado cierto efecto positivo en fases preclinicas pero no han conseguido eficacia en los ensayos clinicos. Podrian proporcionar en un futuro un beneficio añadidos a otros farmacos modificadores geneticos. Los mayores cambios en estudios de modelos del raton SMA y en fases clinicas se han encontrado con oligonucleotidos antisentido que modifican el splicing del gen SMN2, y se espera que mejoren en el futuro proximo. Recientemente se ha aprobado el nusinersen, un metoxietilo fosforotioato-oligonucleotido antisentido, para uso en pacientes con AME de tipo I una vez demostrada su eficacia en pacientes en el ensayo en fase 3. Se revisan los resultados de este farmaco. Estan en marcha modificaciones de oligonucleotidos antisentido que amplien la liberacion en el sistema nervioso y en tejidos perifericos. Hay datos que sugieren eficacia de la terapia genica introduciendo el gen SMN1 mediante virus adenoasociados, actualmente en fase clinica 1. Una constante en estos nuevos tratamientos es que los resultados se optimizan en las etapas precoces de la enfermedad y, mejor aun, en estadio presintomatico. Se subraya la importancia de los cuidados generales optimos, especialmente nutricionales y respiratorios, para conseguir los mejores resultados con las nuevas terapias.

Ischaemic stroke in children with cardiopathy: An epidemiological study. / Ictus isquémico en niños con cardiopatía: estudio epidemiológico.

INTRODUCTION: Ischaemic stroke is rare during childhood. Congenital and acquired heart diseases are one of the most important risk factors for arterial ischaemic stroke (AIS) in children. PATIENTS AND METHODS: We conducted a retrospective study of all children with AIS and heart disease diagnosed between 2000 and 2014. RESULTS: We included 74 children with heart disease who were eligible for inclusion. 60% were boys with a mean stroke age of 11 months. 20% of the patients died during the study period. 90% of the patients had a congenital heart disease, while cyanotic heart disease was identified in 60%. Hypoplastic left heart syndrome was the most frequent heart disease. In 70% of patients AIS was directly associated with heart surgery, catheterisation or ventricular assist devices. Most patients with AIS were in the hospital. Seizures and motor deficit were the most frequent symptoms. Most patient diagnoses were confirmed by brain CT. The AIS consisted of multiple infarcts in 33% of the cases, affected both hemispheres in 27%, and involved the anterior and posterior cerebral circulation in 10%. CONCLUSIONS: Arterial ischaemic strokes were mainly associated with complex congenital heart diseases, and heart procedures and surgery (catheterisation). AIS presented when patients were in-hospital and most of the patients were diagnosed in the first 24hours.

[Visuospatial functions and prematurity]. / Funciones visuoespaciales y prematuridad.

Visuospatial functions are very important in learning process and development of abstract thought during childhood. Several studies show that preterm and low birth weight infants obtain lower scores in test that assess cognitive functions, specially in the first year of life. These differences are attenuated over time, but a developmental delay that affects working memory and visuospatial process still persists. It is unclear what factors are involved in development of these functions, and pre- or perinatal factors may interfere with the proper conduct of the same, but have been described anatomical and physiological differences between the preterm and term brain that could explain somewhere in these alterations. The different selective vulnerability to hypoxia between immature brain in which preoligodendrocytes and subplate neurons predominate, and mature brain, determine differences in the pattern of injury from hypoxia with greater involvement of the periventricular white matter in preterm children. This lesional pattern leaves to a dysfunction in attentional and visuospatial process, due to the increased vulnerability of the regions involved in the dorsal pathway of visual processing.

TITLE: Funciones visuoespaciales y prematuridad.Durante la infancia, las funciones visuoespaciales son importantes en los procesos de aprendizaje y en el desarrollo del pensamiento abstracto. Diferentes estudios muestran que los niños prematuros o con bajo peso al nacer obtienen menores puntuaciones en los tests que valoran las funciones cognitivas, siendo estas diferencias mas pronunciadas durante el primer año de vida. Con el tiempo, estas diferencias se van atenuando, pero persiste un retraso madurativo que afecta a la memoria de trabajo y a los procesos visuoespaciales. No esta claro cuales son los factores implicados en el desarrollo de estas funciones y que factores pre o perinatales pueden interferir en su buen desarrollo, pero se han descrito diferencias anatomicas y fisiologicas entre el cerebro del niño pretermino y el termino que podrian explicar, en parte, alguna de estas alteraciones. La diferente vulnerabilidad selectiva a la hipoxia entre el cerebro inmaduro, en el que predominan las neuronas de la subplaca y los preoligodendrocitos, y el cerebro maduro del niño nacido a termino determinan diferencias en el patron de lesion por hipoxia con mayor afectacion de la sustancia blanca periventricular en el niño pretermino. Este patron lesional conlleva una disfuncion en los procesos atencionales y visuoespaciales debido a la mayor vulnerabilidad de las regiones que intervienen en la ruta dorsal del procesamiento visual.

Significance of tuber size for complications of tuberous sclerosis complex.

INTRODUCTION: Tuberous sclerosis complex (TSC) is one of the most frequent neurocutaneous disorders. Cortical tubers are the most common pathological changes in TSC and they are directly related to the disease's main clinical manifestations: seizures, mental retardation, and autistic behaviour. OBJECTIVE: The aim of this study is to establish a correlation between tuber size and the severity of clinical features in TSC. MATERIAL AND METHODS: We performed a retrospective study of the clinical and imaging findings from 45 TSC patients (22 females and 23 males) and compared the clinical features with the location, size, and number of the cortical tubers in each patient. RESULTS: Four patients had voluminous tubers located in 1 or both cerebral hemispheres. All of these patients had intractable seizures and severe mental retardation; 3 of these cases also presented with autistic behaviour, despite tubers having been resected in all 4 patients. Thirteen patients had tubers of large-to-average size, and all patients in this group showed intractable seizures and mental retardation. Nine patients who had experienced infantile spasms during the first year of life presented autistic behaviour. Multiple tubers of small to average size were found in 28 patients. In general, this group had seizures that responded well to antiepileptic drugs and a low prevalence of autism. In 3 patients who all presented good seizure control and normal intelligence, single cortical/subcortical tubers were located in the frontal or occipital lobes. Of the total of 45 patients, 13 had cerebellar as well as cerebral tubers; these were generally present in cases with more severe clinical features. CONCLUSIONS: Although large tubers are less common than small to medium-sized ones, they are much more likely to be accompanied by severe clinical symptoms (seizures, mental retardation and autistic behaviour), even when the smaller tubers are quite numerous.

[Congenital cytomegalovirus infection and cortical/subcortical malformations]. / Citomegalia congénita y malformaciones corticales y subcorticales.

INTRODUCTION: Intrauterine infection due to cytomegalovirus is the most common of the intrauterine viral/parasitic infections that affect the central nervous system and cause permanent lesions in the cortex as well as the subcortical white matter. Studies using brain magnetic resonance imaging (MRI) are limited. MATERIAL AND METHODS: Six patients (4 females and 2 males) were studied in the first months of life in order to make a diagnosis of congenital cytomegalovirus, and identify the cortical and subcortical lesions using the necessary MRI sequences. RESULTS: The six patients showed malformations of cortical development (MDC) (schizencephaly, polymicrogyria or lissencephaly-pachygyria) from the neonatal period, and diffuse changes of the white matter, which remained with few changes during the first two years. They then began reducing in size in the form of high signal areas in T2, restricted to certain areas, and were evident for a few years more with little change. CONCLUSION: Intrauterine infection due to cytomegalovirus causes changes in the cortical grey matter, which consists of MDC, and in the subcortical white matter. The latter show a changing aspect as they appear as diffuse and wide areas of high signal intensity, which is usually due to delay in myelinisation, but could also be caused directly by the cytomegalovirus. These changes in the white matter are subjected to morphological changes throughout the first years of life, leading to brain atrophy. The neurological sequelae of these lesions left by these alterations are severe and chronic.

Focal cortical dysplasia. Clinical-radiological-pathological associations.

INTRODUCTION: The term focal cortical dysplasia (FCD) describes a particular migration disorder with a symptomatology mainly characterised by drug-resistant epileptic seizures, typical neuroradiological images, and histological characteristics, as well as a very positive response to surgical treatment in the majority of cases. MATERIAL AND METHODS: A total of 7 patients were studied, comprising 6 children with a mean age of 34.3 months and one 25-year-old male with very persistent focal seizures and MRI images that showed FCD. RESULTS: Three of the patients (all girls) were operated on while very young, with extirpation of the FCD and the surrounding area; with the histopathology study showed agreement between the MRI images and the macroscopic study of the slices. The histology study showed findings typical of a Taylor-type FCD (poor differentiation between the cortical grey matter and the subcortical white matter, and balloon cells). Three years after the FCD extirpation, the same 3 patients remained seizure-free with no anti-epilepsy medication. Two others have seizure control with medication, another (the adult) is on the surgical waiting list, and the remaining patient refused the operation. CONCLUSION: Taylor-type FCD is associated with a high percentage of all drug-resistant focal seizures, and it needs to be identified and extirpated as soon as possible. Well planned and well-performed surgery that leaves no remains of dysplasia can cure the disease it in many cases.

Schizencephaly: a study of 16 patients.

OBJECTIVE: To present 16 patients with schizencephaly and neurological involvement, and analyse their characteristics and neuroimages. MATERIAL AND METHODS: The study included 16 patients, 8 males and 8 females, all of whom were diagnosed with schizencephaly at less than 3 years of age; 2 patients were diagnosed prenatally. Schizencephaly was identified by computerized tomography (CT) in 1 patient and by MR or three-dimensional MR (3DMR) with a 1.5tesla apparatus in the others. Most patients were referred for evaluation because of psychomotor delay, motor disabilities and/or seizures. RESULTS: Five patients had bilateral schizencephaly with open lips (2 of them had suffered intrauterine cytomegalovirus infections); 2 showed unilateral schizencephaly with separated lips, 8 presented unilateral schizencephaly with fused lips, and 1 had schizencephaly with open lips on one side and fused lips on the other. Prenatal cytomegalovirus infection was diagnosed in 2 patients. A cerebral malformation that affected the midline was diagnosed by routine ultrasound studies in 2 patients. Eight patients (50%) presented with seizures that were focal, except for one patient who showed secondary generalisation. The latter was the only patient whose disease was refractory to complete seizure control with antiepileptic medication. All patients had some degree of motor deficit, which was either unilateral (hemiparesis) or bilateral (tetraparesis). CONCLUSION: 3D MR imaging was very important in diagnosing of schizencephaly in our patients because it showed the polymicrogyria that covered the area of the cleft and permitted us to rule out porencephaly. Neuronal migration disorders such as heterotopias and, more frequently, cortical dysplasias, were observed in several patients. Half of the patients had epilepsy which was controlled with antiepileptic medication, except in 1 patient.

Cutaneous, mediastinal and hepatic hemangiomas in a girl followed during 12 years.

We present in this paper the case of a 12-year-old girl who had the clinical features of 2 different disorders: neurofibromatosis 1 (NF1) and 3 hemangiomas located in the skin, liver and mediastinum. The patient did not receive any specific treatment and showed a normal progressive evolution that lasted 1 / to 2 years and a very slow regression that lasted for a more prolonged time than expected (the 3 hemangiomas have not completely disappeared yet), although all 3 have been asymptomatic. MRI of the brain did not disclose a hemangioblastoma of the cerebellum or any other vascular lesion of the brain. Mental development of this girl was in the borderline range, as is commonly seen in Pascual-Castroviejo II syndrome (P-CIIS)/PHACE syndrome and in NF1, 2 syndromes which have not been reported to be associated in the same patient previously.

Persistence of the stapedial artery associated with facial hemangioma: a case report.

We report on a girl with a left facial hemangioma and absence of the right ear and canal who also showed absence of the left vertebral and anterior cerebral arteries (ipsilateral to the facial hemangioma), and absence of the external carotid artery and presence of stapedial artery on the right side (contralateral to the facial hemangioma and ipsilateral to the auditory organ malformation). Persistence of the stapedial artery may be related to the facial hemangioma or with the hemifacial hypoplasia with similar possibilities. This is the first case to the best of our knowledge of the association between P-CIIS and a persistent stapedial artery.

[Subependymal giant cell astrocytoma in tuberous sclerosis complex. A presentation of eight paediatric patients]. / Astrocitoma subependimario de células gigantes en el complejo de esclerosis tuberosa. Presentación de ocho pacientes infantiles.

OBJECTIVE: Presentation of 8 patients with subependymal giant-cell astrocytomas (SGCA) associated with tuberous sclerosis complex (TSC). MATERIAL AND METHODS: There are 8 patients, 6 males and 2 females with TSC, who presented with the tumour between the neonatal period and 24 years. RESULTS: All patients showed bilateral hypersignalised areas in zones close to the foramen of Monro. Three of the patients were admitted urgently due to blindness and increased intracranial pressure. Incomplete removal of the tumour has always been bad solution as it resulted in the death of the patient (in one case) or further surgery operation in the short term. Only one patient developed the tumour suddenly from pre-existing subependymal nodules from the childhood and they had to be removed at 24 years of age. By contrast, 32 patients with TSC and images of subependymal nodules whose CT or MR progress was followed up for between 10 and 30 years did not develop a tumour. One patient had to be operated four times over 20 years. CONCLUSIONS: SGCA associated with TSC is a severe complication which as likely to develop and careful monitoring is required from neonatal age with periodicclinical and imaging studies in order to avoid its irreversible complications. Hydrocephaly, blindness and even the death can be the main consequences. Reintervention of the recurrent tumour is often necessary.

Association of cutaneous red-to-purple hemangiomas with leptomeningeal hemangiomas. a clinical study of two patients.

Cutaneous hemangioma is a benign vascular tumor of infancy with an initial proliferating period that appears between 1 to 2 weeks of life, extends during 18 months to 2 years of life, and then slowly regresses during several years until it disappears completely. They are characterized by endothelial cell proliferation followed by diminishing hyperplasia and progressive fibrosis. Vascular malformations are present at birth, grow commensurately with the child, and are characterized histologically by a normal rate of endothelial cell turnover, flat endothelium, thin (normal) basal membrane and normal mast cells. These cutaneous anomalies are commonly associated with cerebellar malformations, main cerebral arteries anomalies, congenital cardiac anomalies and/or coarctation of the aorta and persistence of embryonic arteries. Cutaneous hemangiomas can be associated with intracranial or extracranial hemangiomas that regress at the same time as the cutaneous hemangiomas. Cutaneous hemangiomas may show different types of color. Cutaneous red-to-purple hemangiomas are uncommon and their bright-red color is evident from the first weeks of life and remains unaltered until the hemangioma disappears. The intracranial angiographic studies in our series of more than 50 cases with facial hemangioma showed that patients with red-to-purple hemangiomas are commonly associated with localized leptomeningeal hemangiomas either in the ipsilateral or contralateral side. These leptomingeal hemangiomas were visualized only by MR enhanced with gadolinium. Involution of the cutaneous and leptomeningeal hemangiomas seems to occur simultaneously as in other types of external and internal hemangiomas.

Congenital and evolving vascular disorders associated with cutaneous hemangiomas: case report.

Conventional arteriography in an 11-month-old boy with cardiopathy, aortic arch coarctation and haemangiomas showed the absence of the right internal carotid and vertebral arteries, hypertrophy of the right external carotid artery, with enlargement of the internal maxillary and ophthalmic arteries that supplied the right cerebral hemisphere. An MRI study showed an infarcted area in the posterior zone of the left cerebral hemisphere vascularised by the middle cerebral artery that was caused by a thrombosis during a severe bout of gastroenteritis. MRA studies performed at 16 and 23 years of age revealed progressive narrowing of the left carotid and vertebral arteries, persistence of the proatlantal and trigeminal arteries, and poor cerebral vascularisation that, at adult age, was entirely supplied through collateral arteries, branches of both external carotids, the presence of unilateral duplication of the vertebral arteries and ascending pharyngeal artery.

[Neurofibromatosis type 2 (NF2). Study of 7 patients]. / Neurofibromatosis tipo 2 (NF2). Estudio de 7 pacientes.

OBJECTIVE: The aim of this paper is to present the cases of 7 young children and young adult with type 2 neurofibromatosis (NF2). MATERIAL AND METHODS: Seven patients, 5 females and 2 males, aged 2 to 33 years, were studied by intracranial and spinal magnetic resonance (MRI) and clinically. In 5 patients, the symptoms because around the time of the diagnosis while 2 patients, who had no previous symptoms, were diagnosed by MRI after undergoing the test because a parent had been diagnosed of NF2 by MRI. RESULTS: All 7 patients had bilateral vestibular schwannomas (VS) and only two had no associated intracranial and/or spinal tumors. Four patients had intracranial meningiomas, mainly located in the lesser wing of the temporal fossa and in the falx, and 5 had spinal cord tumors (ependymomas and meningiomas). An attempt to made to remove the VS in all but one case, however, it was not possible to remove completely the tumors in any case. Deafness was the common sequel in all operated cases, associated with permanent bilateral facial paralysis in one and unilateral facial parenthesis in another. CONCLUSION: A comparison of our series of NF1 and NF2 cases shows that the ratio of NF2:NF1 in childhood is approximately 1:100, and that the clinical features of NF2 are considerably more severe than in NF1.

[Segmental neurofibromatosis in children. Presentation of 43 patients]. / Neurofibromatosis segmentaria en niños. Presentación de 43 pacientes.

INTRODUCTION: It is known as segmental neurofibromatosis type 1 (NF1) a type of NF1 characterized by the features circumscribed to one or more body cutaneous and/or subcutaneous segments. This entity is recognized from recently and it is related with somatic mosaicism. PATIENTS AND METHODS: 43 patients (29 females and 14 males) with ages below 16 years were retrospectively studied. Image study of the affected region of the body was performed in all patients to discard a subjacent organic disease, and a neurofibroma was histologically demonstrated in some cases. Somatic or gonosomal mosaicism was not investigated in any of the patients. RESULTS: Only 8 patients showed cutaneous lesion--7 with café-au-lait spots (3 of freckles type, 4 of large spots, of which, 3 were bilateral and 1 unilateral ) and 1 presented neurofibromas-. The other cases (81%) had cutaneous lesion with subjacent lesion (neurofibromas and bone dysplasia in most cases). The subcutaneous lesions were seen in all parts of the body without a preferent location. In cases with only cutaneous lesion, the clinical features were seen on the trunk skin. CONCLUSION: Segmental NF1 is considered to be the result of a somatic or gonosomal mosaicism and still is underdiagnosed. Features of segmental NF1 can be found in as many regions of the body as NF1 without mosaicism. The types of segmental NF1 that were seen less frequently in this series were those with only cutaneous features (café-au-lait spots and neurofibromas). Types with subcutaneous features that involved subjacent organs were seen in 81% of patients. Familial patients, with NF1 or segmental NF1 was shown in 15 patients (35%) and bilateral lesion in 4 cases (9.3%).

[Neurofibromatosis type 1 and optic pathway gliomas. A series of 80 patients]. / Neurofibromatosis tipo 1 y gliomas de vías ópticas. Una serie de 80 pacientes.

PATIENTS AND METHODS: From a series of 530 patients with neurofibromatosis type 1 (NF1), we performed a retrospective assessment of the long-term neurologic, visual, neuroimaging and evolution of 80 patients (15%) with optic pathway gliomas (OPG). All the 80 patients, 58 (72.5%) females and 22 (27.5%) males were diagnosed during childhood (below age 16 years), range 13 months to 15 years (average: 4.6 years). RESULTS: Image studies showed the distribution of the lesions among optic nerves, chiasm, tracts and radiations demonstrated that only 25% of the tumors involved only one optic nerve and 11.5% were located only in the chiasm, while 40% involved one or both optic nerves and chiasm, tracts and radiations. Two patients showed pilocytic astrocytoma in the histological study. Late diagnosis (after 7 years of age) of OPG was made in three patients and late progression was evident in three others who required surgical resection, radiotherapy or chemotherapy. CONCLUSIONS: All patients were diagnosed during childhood (below 16 years of age). Incidence was double in girls than in boys. Despite the apparent tumoral agressivity of the magnetic resonance and magnetic resonance spectroscopy images, histological findings corresponded to benign pilocytic astrocytoma. Some tumors follow the growth after 7 years. Continued monitoring of patients with NF1 into adulthood is advisable.

Segmental neurofibromatosis type 1 (NF1) associated with Cobb syndrome: case report.

We present a 3-month-old girl who showed segmental NF1 and Cobb syndrome. She has a cutaneous vascular malformation located on the middle T (4)-T (6) region superimposed on a giant cutaneous café-au-lait spot. Magnetic resonance arteriography (MRA) revealed bilateral renal artery stenosis, extensive hypertrophy of the spinal epidural venous plexus, coarctation and tubular hypoplasia of the aortic arch and proximal portion of descending aorta. To the best of our knowledge the association of both neurocutaneous disorders has not being previously described.