Cefaleas primarias con inicio en la infancia y la adolescencia: historia natural y factores pronósticos en una población portuguesa / Primary headache with onset in childhood and adolescence: natural history and prognostic factors in a Portuguese population

Introducción: Las cefaleas son el trastorno neurológico más habitual en la población pediátrica e influyen notablemente en su calidad de vida. La finalidad de este estudio es caracterizar una cohorte de pacientes en seguimiento en una unidad de neurología pediátrica entre el 1 de enero de 2013 y el 31 de diciembre de 2021. Materiales y métodos: Hemos revisado informes médicos y seleccionado a pacientes con cefaleas primarias y un seguimiento mínimo de 12 meses.Resultados: Se incluyó a un total de 226 pacientes, el 54,4% mujeres, con una media de edad al comenzar las cefaleas de 9 ± 3,5 (3,1-16,5) años; el 63,5% eran prepuberales. Se identificó un historial familiar positivo de cefalea en el 76,6% de los casos y factores desencadenantes en el 63,6%. En una primera evaluación clínica, el 45,1% se identificó como migrañas sin aura; el 10,6%, como migrañas con aura; el 3,5%, como cefalea tensional; el 8%, como de tipo mixto (cefalea tensional y migraña); el 1,3%, de otro tipo; y el 31,4% resultó inclasificable. Los pacientes se sometieron a un seguimiento promedio de 2,4 (1,8-3,3) años. El diagnóstico de cefalea tensional se mantuvo estable en el 75% de los pacientes y se solucionó en un 25%; para el 13% de los pacientes con migraña sin aura, el diagnóstico cambió a otro tipo de cefalea, y para el 17,4%, se solucionó; para el 44,4% de los pacientes sin migraña con aura, el diagnóstico cambió por el de otro tipo de cefalea, y para el 11,1%, se resolvió. De las variables estudiadas, sólo la duración del episodio de cefalea tuvo una asociación significativa con la remisión de la cefalea, con una odds ratio de 0,16 (p = 0,03; intervalo de confianza al 95%: 0,032-0,84).Conclusiones: Nuestro estudio muestra que el tipo de cefalea en la población pediátrica cambia con el paso del tiempo, especialmente en los pacientes con migraña con aura. La duración de cada uno de los episodios de cefalea se presentó como un predictor de la remisión de la cefalea con el paso del...(AU)

Introduction: Headaches are the most frequent neurological disorder in the pediatric population, with great impact on quality of life. This study aims to characterize a cohort of patients followed at a pediatric neurology unit between January 1st 2013 and December 31st, 2021. Materials and methods: We reviewed medical records and selected patients with primary headaches and a minimum follow-up of 12 months. Results: A total of 226 patients were included, 54.4% female, with an average age at headache onset of 9 ± 3.5 (3.1-16.5) years; 63.5% were prepubertal. A positive family history of headache was identified in 76.6% of cases and triggers in 63.6%. At first clinical assessment, 45.1% were classified as migraine without aura, 10.6% as migraine with aura, 3.5% tension-type, 8% mixed (tension and migraine), 1.3% other type and 31.4% were unclassifiable. The patients had a median follow-up of 2.4 (1.8-3.3) years. The diagnosis of tension-type headaches remained stable in 75% of the patients and resolved in 25%; 13% of the patients with migraine without aura changed into another type of headache and 17.4% resolved; 44.4% of the patients with migraine with aura turned into another type of headache and 11.1% resolved. Of the variables studied, only duration of headache episode had a significant association with headache remission, with odds ratio 0.16 (p = 0.03; 95% confidence interval: 0.032-0.84).Conclusions: Our study shows that headache type in pediatric population changes over time, especially in those with migraine with aura. The duration of each headache episode was presented as a predictor of headache remission over time.(AU)

Primary headache with onset in childhood and adolescence: natural history and prognostic factors in a Portuguese population. / Cefaleas primarias con inicio en la infancia y la adolescencia: historia natural y factores pronósticos en una población portuguesa.

INTRODUCTION: Headaches are the most frequent neurological disorder in the pediatric population, with great impact on quality of life. This study aims to characterize a cohort of patients followed at a pediatric neurology unit between January 1st 2013 and December 31st, 2021. MATERIALS AND METHODS: We reviewed medical records and selected patients with primary headaches and a minimum follow-up of 12 months. RESULTS: A total of 226 patients were included, 54.4% female, with an average age at headache onset of 9 ± 3.5 (3.1-16.5) years; 63.5% were prepubertal. A positive family history of headache was identified in 76.6% of cases and triggers in 63.6%. At first clinical assessment, 45.1% were classified as migraine without aura, 10.6% as migraine with aura, 3.5% tension-type, 8% mixed (tension and migraine), 1.3% other type and 31.4% were unclassifiable. The patients had a median follow-up of 2.4 (1.8-3.3) years. The diagnosis of tension-type headaches remained stable in 75% of the patients and resolved in 25%; 13% of the patients with migraine without aura changed into another type of headache and 17.4% resolved; 44.4% of the patients with migraine with aura turned into another type of headache and 11.1% resolved. Of the variables studied, only duration of headache episode had a significant association with headache remission, with odds ratio 0.16 (p = 0.03; 95% confidence interval: 0.032-0.84). CONCLUSIONS: Our study shows that headache type in pediatric population changes over time, especially in those with migraine with aura. The duration of each headache episode was presented as a predictor of headache remission over time.

TITLE: Cefaleas primarias con inicio en la infancia y la adolescencia: historia natural y factores pronósticos en una población portuguesa.Introducción. Las cefaleas son el trastorno neurológico más habitual en la población pediátrica e influyen notablemente en su calidad de vida. La finalidad de este estudio es caracterizar una cohorte de pacientes en seguimiento en una unidad de neurología pediátrica entre el 1 de enero de 2013 y el 31 de diciembre de 2021. Materiales y métodos. Hemos revisado informes médicos y seleccionado a pacientes con dolores de cabeza primarios y un seguimiento mínimo de 12 meses. Resultados. Se incluyó a un total de 226 pacientes, el 54,4% mujeres, con una media de edad al comenzar las cefaleas de 9 ± 3,5 (3,1-16,5) años; el 63,5% eran prepuberales. Se identificó un historial familiar positivo de cefalea en el 76,6% de los casos y factores desencadenantes en el 63,6%. En una primera evaluación clínica, el 45,1% se identificó como migrañas sin aura; el 10,6%, como migrañas con aura; el 3,5%, como cefalea tensional; el 8%, como de tipo mixto (cefalea tensional y migraña); el 1,3%, de otro tipo; y el 31,4% resultó inclasificable. Los pacientes se sometieron a un seguimiento promedio de 2,4 (1,8-3,3) años. El diagnóstico de cefalea tensional se mantuvo estable en el 75% de los pacientes y se solucionó en un 25%; para el 13% de los pacientes con migraña sin aura, el diagnóstico cambió a otro tipo de cefalea, y para el 17,4%, se solucionó; para el 44,4% de los pacientes sin migraña con aura, el diagnóstico cambió por el de otro tipo de cefalea, y para el 11,1%, se resolvió. De las variables estudiadas, sólo la duración del episodio de cefalea tuvo una asociación significativa con la remisión de la cefalea, con una odds ratio de 0,16 (p = 0,03; intervalo de confianza al 95%: 0,032-0,84). Conclusiones. Nuestro estudio muestra que el tipo de cefalea en la población pediátrica cambia con el paso del tiempo, especialmente en los pacientes con migraña con aura. La duración de cada uno de los episodios de cefalea se presentó como un predictor de la remisión de la cefalea con el paso del tiempo.

[A rare early-onset dystonia (DYT16) in a Portuguese girl]. / Distonia temprana poco frecuente (DYT16) en una niña portuguesa.

TITLE: Distonia temprana poco frecuente (DYT16) en una niña portuguesa.

Esclerosis tuberosa: caracterización clínica e intento de correlación fenotipo/genotipo / Tuberous sclerosis: Clinical characteristics and their relationship to genotype/phenotype

INTRODUCCIÓN: La esclerosis tuberosa (ET) es una enfermedad de afectación multisistémica y gran variabilidad fenotípica. Están identificados 2 genes involved en la génesis de la enfermedad: TSC1 y TSC2. OBJETIVOS: Caracterizar clínicamente a los pacientes con ET seguidos en Neurología Pediátrica de un hospital de tercer nivel durante los últimos 10 años y correlacionar el genotipo con la gravedad de la clínica neurológica y los estudios de imagen. PACIENTES Y MÉTODOS: Estudio retrospectivo descriptivo, mediante consulta de la historia clínica y evaluación de las resonancias magnéticas (RM) de pacientes con ET. RESULTADOS: Se estudiaron 35 casos, con una mediana de edad, al diagnóstico, de 10 meses. En el 91,4% se registraron crisis epilépticas, con un predominio de espasmos epilépticos a la presentación. Más del 50% tenía deterioro cognitivo y el 49% trastornos de conducta. Se sometieron a estudio genético 24 ni˜nos con predominio de mutaciones TSC2 (58,3%). De los 11 casos de epilepsia refractaria, 6 tenían mutación del gen TSC2. De los 8 pacientes con déficit cognitivo moderado a grave, se identificaron 5 mutaciones TSC2. Se revisaron 26 RM y en el 76,9% se observó una afectación completa de los lóbulos cerebrales, lo que refleja una gran cantidad de lesiones. De los enfermos con mutaciones TSC2 y RM realizada, todos tenían alta carga de lesión y 5 epilepsia refractaria. DISCUSIÓN: En nuestra muestra, nos encontramos con un alto porcentaje de mutaciones en el gen TSC2. Esta mutación está asociada a un peor pronóstico neurológico, con crisis más farmacorresistentes y un atraso cognitivo más severo

INTRODUCTION: Tuberous sclerosis (TS) is an inherited disorder with multisystemic involvement and a high phenotypic variability. There are two genes that cause this condition: TSC1 and TSC2. OBJECTIVES: Our goal was to clinically characterize patients with TS followed up in the Pediatric Neurology Clinic of a tertiary hospital during the last 10 years, and correlate the genotype with the severity of neurological manifestations and imaging studies. PATIENTS AND METHODS: Retrospective analysis of patients with TS, including review of medical records and available MRI imaging. RESULTS: We studied 35 cases with a median age at diagnosis of ten months. Seizures were the first manifestation in 91.4% of cases, with a predominance of epileptic spasms. Over 50% had cognitive impairment and 49% behavioral disorders. A genetic study was performed on 24 children, and TSC2 mutations identified in 58.3% of them. Of the 11 cases of refractory epilepsy, six had the TSC2 gene mutation. In the group of eight patients with moderate/severe cognitive deficits, five had TSC2 mutations. We reviewed 26 MRI scans, in which it was observed that 76.9% had diffuse involvement of cerebral lobes, which reflects a greater burden of injury. Of the patients who had an MRI scan performed and had TSC2 mutations, all had a high tuber load, and5 of them had refractory epilepsy. DISCUSSION: In our sample we observe a high percentage of mutations in the TSC2 gene. This mutation carries a worse neurological prognosis, with drug-resistant epilepsy and a more severe cognitive impairme

[Tuberous sclerosis: clinical characteristics and their relationship to genotype/phenotype]. / Esclerosis tuberosa: caracterización clínica e intento de correlación fenotipo/genotipo.

INTRODUCTION: Tuberous sclerosis (TS) is an inherited disorder with multisystemic involvement and a high phenotypic variability. There are two genes that cause this condition: TSC1 and TSC2. OBJECTIVES: Our goal was to clinically characterize patients with TS followed up in the Pediatric Neurology Clinic of a tertiary hospital during the last 10 years, and correlate the genotype with the severity of neurological manifestations and imaging studies. PATIENTS AND METHODS: Retrospective analysis of patients with TS, including review of medical records and available MRI imaging. RESULTS: We studied 35 cases with a median age at diagnosis of ten months. Seizures were the first manifestation in 91.4% of cases, with a predominance of epileptic spasms. Over 50% had cognitive impairment and 49% behavioral disorders. A genetic study was performed on 24 children, and TSC2 mutations identified in 58.3% of them. Of the 11 cases of refractory epilepsy, six had the TSC2 gene mutation. In the group of eight patients with moderate/severe cognitive deficits, five had TSC2 mutations. We reviewed 26 MRI scans, in which it was observed that 76.9% had diffuse involvement of cerebral lobes, which reflects a greater burden of injury. Of the patients who had an MRI scan performed and had TSC2 mutations, all had a high tuber load, and5 of them had refractory epilepsy. DISCUSSION: In our sample we observe a high percentage of mutations in the TSC2 gene. This mutation carries a worse neurological prognosis, with drug-resistant epilepsy and a more severe cognitive impairment.

Síndrome de Sturge-Weber: variabilidad clínica y de neuroimagen / Sturge-Weber syndrome -clinical and neuroimaging variability

El síndrome de Sturge-Weber es un síndrome neurocutáneo raro cuya gravedad está determinada por el grado de afectación cerebral y el control de la epilepsia. Los autores describen y analizan las características clínicas y de neuroimagen de este síndrome, a través de un estudio retrospectivo de 13 pacientes (8 niñas; con edad en la primera consulta entre los 15 días y los 9 años). Doce presentaban angioma facial y una atriquia en la zona de afectación cerebral. Se diagnosticó epilepsia en 6 casos, hemiplejía en 4, retraso psicomotor en 7 y glaucoma en 4 casos. Se encontraron alteraciones cerebrales en 10 niños, 3 sin sintomatología neurológica. La clínica presentada es variable y no siempre hay relación entre la gravedad clínica y las anomalías de neuroimagen, que pueden aparecer hasta en ausencia de síntomas neurológicos(AU)

Sturge Weber Syndrome is a rare neurocutaneous syndrome in which the severity is determined by degree of brain involvement and control of epilepsy. The authors describe and analyse clinical and imaging features of this syndrome, through a retrospective study of 13 patients (8 girls; aged between 15 days and 9 years at first visit). Twelve had facial angioma and one had atrichia corresponding to the area of brain involvement. Epilepsy was diagnosed in 6 cases, hemiplegia in 4, psychomotor delay in 7, and glaucoma in 4. Cerebral abnormalities were found in 10 children, 3 without neurological symptoms. The clinical signs and symptoms vary and there is not always a relationship between the severity of the clinical and neuroimaging abnormalities, which may occur even in the absence of neurological symptoms(AU)

[Sturge-Weber syndrome -clinical and neuroimaging variability]. / Síndrome de Sturge-Weber: variabilidad clínica y de neuroimagen.

Sturge Weber Syndrome is a rare neurocutaneous syndrome in which the severity is determined by degree of brain involvement and control of epilepsy. The authors describe and analyse clinical and imaging features of this syndrome, through a retrospective study of 13 patients (8 girls; aged between 15 days and 9 years at first visit). Twelve had facial angioma and one had atrichia corresponding to the area of brain involvement. Epilepsy was diagnosed in 6 cases, hemiplegia in 4, psychomotor delay in 7, and glaucoma in 4. Cerebral abnormalities were found in 10 children, 3 without neurological symptoms. The clinical signs and symptoms vary and there is not always a relationship between the severity of the clinical and neuroimaging abnormalities, which may occur even in the absence of neurological symptoms.

Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment.

BACKGROUND: Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis. PATIENTS AND METHODS: We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy. RESULTS: CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels. CONCLUSION: Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.

Neurodegeneration associated with genetic defects in phospholipase A(2).

OBJECTIVE: Mutations in the gene encoding phospholipase A(2) group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A(2). METHODS: We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations. RESULTS: Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations. CONCLUSION: Defects in phospholipase A(2) lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A(2) suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.

Stereotypies in Rett syndrome: analysis of 83 patients with and without detected MECP2 mutations.

BACKGROUND: Hand stereotypies are considered a hallmark of Rett syndrome (RTT) and are usually described as symmetric movements at the midline. However, related pathologies may show the same type of involuntary movement. Furthermore, patients with RTT also have stereotypies with other localizations that are less well characterized. METHODS: We analyzed stereotypies in 83 patients with RTT, 53 with and 30 without a mutation detected in the MECP2 gene. Patients were observed and videotaped always by the same pediatric neurologist. Stereotypies were classified, and data were submitted to statistical analysis for comparison of mutation-positive and -negative patients and analysis of their evolution with the disease. RESULTS: All the patients showed hand stereotypies that coincided with or preceded the loss of purposeful hand movements in 62% of the patients with MECP2 mutations. The hair pulling stereotypy was more frequent in the group with detected mutations, whereas hand washing was not. Hand gaze was absent in all RTT patients with MECP2 mutations. Patients with MECP2 mutations also had more varied stereotypies, and the number of stereotypies displayed by each patient decreased significantly with age in this group. In all patients, stereotypies other than manual tended to disappear with the evolution of the disease. CONCLUSIONS: Although symmetric midline hand stereotypies were not specific to patients with an MECP2 mutation, some of the other stereotypies seemed to be more characteristic of this group. In patients younger than 10 years and meeting the necessary diagnostic criteria of Rett syndrome, the association of hand stereotypies without hand gaze, bruxism, and two or more of the other stereotypies seemed to be highly indicative of the presence of an MECP2 mutation.

Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.

We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.

[The identification of multiple thrombophilic risk factors in an infant with cerebrovascular accident]. / Múltiples factores de riesgo trombofílicos identificados en un lactante con accidente vascular cerebral.

INTRODUCTION: Neonatal stroke (NNS) incidence appears to be increasing over the last years. This is believed to be a consequence of diagnostic accuracy rather than a real amplification of this entity. Nowadays, NNS incidence is estimated to be 1:4000 full newborns. CASE REPORT: Child with left middle cerebral artery territory infarction in which several thromboembolic risk factors were documented both in the child (neonatal sepsis and factor V Leiden) and his mother (lupus anticoagulant, pre-eclampsy and factor V Leiden). CONCLUSIONS: This case supports the increasing evidence in recent reports that association of multiple prothrombotic risk factors (maternal and foetal) is present in NNS genesis. This way the authors agree that wide prothrombotic study may be of crucial interest in identifying subjacent thrombophilic disease, even when an exogenous risk factor is present.

One year of Lamivudine therapy for portuguese patients with chronic hepatitis B.

OBJECTIVE: To assess the efficacy of lamivudine treatment on hepatitis B e antigen (HBeAg) and/or hepatitis B surface antigen (HBsAg) seroconversion, on other virological and serological markers of response including hepatitis B virus (HBV) DNA and serum aminotransferases, and the safety of lamivudine treatment in hepatitis B patients. PATIENTS: This phase III open-label study evaluated the virological and biochemical response to lamivudine in 70 Portuguese patients with HBeAg positive chronic hepatitis B. Patients were treated with lamivudine 100mg once daily for 12 months. METHODS: Antiviral activity was assessed by measuring alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels at all protocol visits, and hepatitis B serology and HBV DNA were performed at baseline and at month 12 visits. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: The primary endpoint was virological response at month 12, defined as loss of detectable HBeAg from serum with a reduction of HBV DNA to undetectable levels, and this was observed in 19/69 (27.5%) of patients. Almost half of the patients were HBV DNA negative by this time. Mean ALT values decreased steadily during treatment and by 12 months 61% of patients had values within the normal range. HBeAg seroconversion (HBeAg negative, HBeAb positive) was achieved in 27.9% of patients by 12 months, although all patients remained HBsAg positive. CONCLUSION: Lamivudine was well tolerated and the incidence of adverse events was similar to those reported in previous studies. Lamivudine treatment resulted in virological and biochemical improvements in HBeAg positive chronic hepatitis B patients, with HBeAg seroconversion in one-third of patients.