José Paulo Monteiro

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.

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.

Memory functioning in children with epilepsy: frontal lobe epilepsy, childhood absence epilepsy, and benign epilepsy with centrotemporal spikes.

Specific cognitive deficits have been identified in children with epilepsy irrespective of results on intelligence tests. Memory deficits are traditionally attributed to temporal lobe epilepsy, whereas the impact of frontal lobe epilepsy on memory functions has remained controversial. The aim of this study was the examination of memory abilities in other childhood common epilepsy syndromes (frontal lobe epilepsy (FLE), childhood absence epilepsy (CAE), and benign epilepsy with centrotemporal spikes (BECTS)) and the influence of epilepsy-related variables. Memory was examined in 90 children with epilepsy (each epilepsy group consisted of 30 children), aged 6–15, and compared with 30 control children. Children with FLE showed significant deficits in verbal and visual memory. In addition, type of epilepsy, earlier age at epilepsy onset, and longer active duration of epilepsy were associated with memory problems. Seizure frequency and treatment, however, did not influence memory performance. This study indicates that children with FLE show greater risk of developing memory deficits than children with CAE or BECTS, thus highlighting the importance of assessing also memory functions in frontal lobe epilepsy.

Rett syndrome with and without detected MECP2 mutations: An attempt to redefine phenotypes

BACKGROUND The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. PATIENTS AND METHODS We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. RESULTS Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. CONCLUSION A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.

Intellectual functioning in children with epilepsy: Frontal lobe epilepsy, childhood absence epilepsy and benign epilepsy with centro-temporal spikes

PURPOSE The purpose of our study is to describe intellectual functioning in three common childhood epilepsy syndromes - frontal lobe epilepsy (FLE), childhood absence epilepsy (CAE) and benign epilepsy with centro-temporal spikes (BECTS). And also to determine the influence of epilepsy related variables, type of epilepsy, age at epilepsy onset, duration and frequency of epilepsy, and treatment on the scores. METHODS Intellectual functioning was examined in a group of 90 children with epilepsy (30 FLE, 30 CAE, 30 BECTS), aged 6-15 years, and compared with a control group (30). All subjects obtained a Full Scale IQ ≥ 70 and they were receiving no more than two antiepileptic medications. Participants completed the Wechsler Intelligence Scale for Children - Third Edition. The impact of epilepsy related variables (type of epilepsy, age at epilepsy onset, duration of epilepsy, seizure frequency and anti-epileptic drugs) on intellectual functioning was examined. RESULTS Children with FLE scored significantly worse than controls on WISC-III Verbal IQ, Full Scale IQ and Processing Speed Index. There was a trend for children with FLE to have lower intelligence scores than CAE and BECTS groups. Linear regression analysis showed no effect for age at onset, frequency of seizures and treatment. Type of epilepsy and duration of epilepsy were the best indicators of intellectual functioning. CONCLUSION It is crucial that children with FLE and those with a longer active duration of epilepsy are closely monitored to allow the early identification and evaluation of cognitive problems, in order to establish adequate and timely school intervention plans.

Transient idiopathic dystonia in infancy

Aim:  Review of transient idiopathic dystonia cases to improve knowledge on this entity, in relation to frequency, characterization and evolution.

Chickenpox and stroke in children: case studies and literature review

Postvaricella cerebral arteriopathy (PVCA) presents with acute haemiparesis and/or haemidistonia, caused by ischaemic lesions of internal capsule and/or basal ganglia, related to stenosis of proximal middle and/or anterior cerebral arteries. Anti‐aggregant drugs are recommended to prevent thrombus expansion and recurrent stroke, but neurologic outcome is usually good regardless of the therapeutic approach.

Unilateral optic neuritis as a presentation of neurobrucellosis.

Neurobrucellosis manifesting as optic neuritis is a rare disease in childhood. We report a case of neurobrucellosis in a 11 year old girl leading to visual impairment and headache. Physical examination revealed mild oedema of right tibiotarsic joint and optic neuritis. Investigations showed CSF pleocytosis and a Brucella serum agglutination titer of 1/640. Complete reversal of the symptoms was observed after appropriate antibiotic treatment. To our knowledge only four cases of neurobrucellosis manifesting with visual impairment in childhood are previously reported in literature.

Ketogenic Diet for Refractory Epilepsy in Children-An Institutional Experience

Introduction: Ketogenic diet consists in a adequate protein diet (1 qram/kg), low in carbohydrates and rich in lipids, which induces a prolonged state of ketosis that modifies the cerebral energetic metabolism. This study aims to characterize the children with refractory epilepsy treated with ketogenic diet, enrolled in a Child Development Center in Portugal. It intends to evaluate the efficacy and tolerability of the diet and to identify in which epilepsy syndromes and etiologies the diet is effective. Methods: Retrospective analysis of the cases of refractory epilepsy treated with ketogenic diet. Results: Sixteen children were included, eleven boys. The mean age of seizures onset was 13,9 months (0-72 months) and of ketogenic diet onset was 4,4 years (5 months-16 years). At the end of the first month, 62,5% had a seizure reduction of more than 50%. The efficacy reached 43,8% at the end of third month and 31,3% at the end of the sixth month. In 31,3% there was a reduction of the number of anti-epileptic drugs and 56,3% had an improvement in the behavior/ cognition. The diet was more effective in infantile spasms, Lennox-Gastaut and Dravet syndromes and genetic and structural epilepsies, particularly in malformations of the cortical development. The mean time to a clinical response was 1,4 months. The diet had a good tolerability, with side effects only in 31,2%, none with clinical severity. Conclusion: In this study, ketogenic diet has proven to be safe and effective and should be considered in children with severe and refractory epilepsies.

A Distinct Phenotype in a Novel ATP1A3 Mutation: Connecting the Two Ends of a Spectrum

Alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, arreflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome are phenotypic distinct entities that share mutations on a common gene, the ATP1A3, that encodes the a3 subunit of the Na/K-ATPases. RDP symptoms start abruptly (hours to days), in previously healthy adolescents or young adults, with dystonia with a rostrocaudal pattern and parkinsonism. Symptoms are usually triggered by emotional or physical stress and do not respond to levodopa. The ictal phase is followed by a chronic maintenance of acquired symptoms that rarely relapse. AHC usually begins within the first 6 months of life, triggered by physical and emotional stress, with sudden and transient episodes of hemiplegia combined with other paroxysmal symptoms, such as dystonia, nystagmus, autonomic disturbances, and seizures. Falling asleep can relieve symptoms. Nonparoxysmal symptoms ensue over the years. Developmental delay and intellectual disability are the most common, followed by dysarthria, ataxia, and choreoathetosis. Flunarizine may reduce the frequency of plegic attacks and motor deterioration. CAPOS syndrome is a symmetric ataxic encephalopathy of childhood recently associated with a mutation of ATP1A3 (c.2452G>A). As with RDP and AHC, it has an acute onset and physical stress as a trigger. Optic atrophy and sensorineural hearing loss are distinct chronic features.