Marilisa M. Guerreiro

A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy

In many countries oxcarbazepine (OXC) has been registered for use as first-line and add-on treatment for patients with partial seizures with or without secondarily generalized seizures (PS) and generalized tonic-clonic seizures without partial onset (GTCS). Its use as monotherapy in children and adolescents with newly diagnosed epilepsy was investigated in this double-blind, randomized, parallel-group comparison with phenytoin (PHT). A total of 193 patients aged 5-18 years with either PS or GTCS were enrolled. After a retrospective baseline assessment, patients were randomized to OXC or PHT in a 1:1 ratio. The double-blind treatment phase comprised two periods: an 8-week flexible titration period; followed by 48 weeks maintenance treatment. In the efficacy analyses, there were no statistically significant differences between OXC and PHT. Forty-nine (61%) patients in the OXC group and 46 (60%) in the PHT group were seizure-free during the maintenance period. In total, 24 patients in the OXC group discontinued treatment prematurely (two for tolerability reasons) compared with 34 in the PHT group (14 for tolerability reasons). The number of premature discontinuations due to adverse experiences was statistically significantly lower in the OXC group than in the PHT group. Moreover, the odds of an individual discontinuing prematurely (regardless of reason) were almost twice as high in the PHT group. This trial provides further support for the efficacy and safety of OXC as first-line treatment in children and adolescents with PS and GTCS. In addition, the results show that OXC in these patients has significant advantages over PHT in terms of tolerability and treatment retention.

Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment

Two familial X‐linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X‐linked transmission. On the other hand, the pedigrees of 2 families ruled out X‐linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X‐linked syndrome of cortical maldevelopment. Ann Neurol 2000;48:39–48

Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy

Objective: To describe the clinical, genetic and MR characteristics of patients with familial mesial temporal lobe epilepsy (MTLE). Design/Methods: The familial occurrence of MTLE was identified by a systematic search of family history of seizures in patients followed in the authors’ epilepsy clinic. All probands and, whenever possible, other affected family members underwent EEG and MR investigations. Results: Twenty-two unrelated families with at least two individuals with MTLE were identified by clinical and EEG findings. Ninety-eight individuals with history of seizures were evaluated. Sixty-eight patients fulfilled the diagnostic criteria for MTLE. MRI was performed in 84 patients, and showed hippocampal atrophy with increased T2 signal in 48 (57%). The distribution of hippocampal atrophy according to the seizure outcome groups was 6 of 13 patients (46%) with seizure remission, 16 of 31 (51%) with good seizure control under medication, and all 16 patients with refractory MTLE. Hippocampal atrophy was found also in patients that did not fulfill the criteria for MTLE: 3 of 10 (30%) patients with febrile seizure alone, 6 of 10 (60%) patients with recurrent generalized tonic-clonic seizures, and 1 of 4 (25%) patients with a single partial seizure. Conclusion: Familial MTLE is a clinically heterogeneous syndrome. Hippocampal atrophy was observed in 57% of patients, including those with benign course or seizure remission, indicating that the relationship between hippocampal atrophy and severity of epilepsy might be more complex than previously suspected. In addition, these findings indicate the presence of a strong genetic component determining the development of mesial temporal sclerosis in these families.

Voxel-based morphometry in patients with idiopathic generalized epilepsies.

Idiopathic generalized epilepsies (IGE) are a group of frequent age-related epilepsy syndromes. IGE are clinically characterized by generalized tonic-clonic, myoclonic and absence seizures. According to predominant seizure type and age of onset, IGE are divided in subsyndromes: childhood absence and juvenile absence epilepsy (AE), juvenile myoclonic epilepsy (JME) and generalized tonic-clonic seizures on awakening (GTCS). The limits between these subsyndromes are not well defined, supporting the existence of only one major syndrome. Visual assessment of routine magnetic resonance imaging (MRI) in patients with IGE is normal. MRI voxel-based morphometry (VBM) uses automatically segmented gray and white matter for comparisons, eliminating the investigator bias. We used VBM to study 120 individuals (47 controls, 44 with JME, 24 with AE and 15 with GTCS) to investigate the presence of subtle structural abnormalities in IGE subsyndromes. VBM was performed searching for abnormalities on gray matter concentration (GMC) between patients groups and controls. Compared to controls, JME presented increased GMC in frontobasal region and AE showed increased GMC in the superior mesiofrontal region. The GTCS group did not differ from controls. There were no areas of reduced GMC with the statistical level selected. Region of interest analysis showed increased GMC in the anterior portion of the thalamus in patients with absence seizures. Our results support subtle GMC abnormalities in patients with JME and AE when compared to controls. These findings suggest the existence of different patterns of cortical abnormalities in IGE subsyndromes.

Voxel-based morphometry reveals excess gray matter concentration in patients with focal cortical dysplasia.

Summary:  Purpose: Many patients with focal cortical dysplasia (FCD) continue to have seizures after surgical treatment. The usual explanation for the poor surgical outcome is the presence of residual dysplastic tissue missed by the preoperative neuroimaging investigation and therefore not resected during surgery. We apply a voxel‐based morphometry (VBM) analysis to the magnetic resonance imaging (MRI) scans from patients with epilepsy and visually detected FCD to investigate whether (a) VBM is able to detect gray‐matter concentration (GMC) abnormalities in patients with FCD, and (b) whether the extent of GMC abnormalities in the brain of these patients differs from the regions observed by using visual inspection.

Developmental language disorder associated with polymicrogyria

Background Subtle disorders of neuronal migration occur in the brains of some dyslexic patients who presented developmental language disorder (DLD) during early childhood. Objective To investigate a possible neuroanatomical substrate based on neuroimaging evaluation in children with DLD. Methods The authors obtained psychological assessment, language evaluation, neurologic examination, and neuroimaging investigation. Inclusion criteria were as follows: children should be at least 4 years of age; primary complaint of language delay; normal hearing; IQ >70; and an informed consent form signed by parents or guardians. Exclusion criteria were severe motor and cognitive handicap. ResultsFifteen children met all inclusion criteria. Ages ranged from 4 to 14 years and 11 were boys. Six patients presented diffuse polymicrogyria (PMG) around the entire extent of the sylvian fissure on MRI, and they had severe clinical manifestation of DLD: they did not speak at all or had mixed phonologic–syntactic deficit syndrome. Six children presented PMG restricted to the posterior aspects of the parietal regions, and they had a milder form of DLD: mainly phonologic programming deficit syndrome. The other three children had different imaging findings. Conclusions Developmental language disorder can be associated with polymicrogyria and the clinical manifestation varies according to the extension of cortical abnormality. A subtle form of posterior parietal polymicrogyria presenting as developmental language disorder is a mild form of perisylvian syndrome.

Specific language impairment: linguistic and neurobiological aspects

Specific language impairment (SLI) occurs when children present language maturation, at least 12 months behind their chronological age in the absence of sensory or intellectual deficits, pervasive developmental disorders, evident cerebral damage, and adequate social and emotional conditions. The aim of this study was to classify a group of children according to the subtypes of SLI and to correlate clinical manifestations with cortical abnormalities. Seventeen children with SLI were evaluated. Language assessment was based on standardized test (Peabody) and a non-standardized protocol, which included phonological, syntactical, semantical, pragmatical and lexical aspects of language. All children, except one, had abnormal MRI. Thirteen children presented perisylvian polymicrogyria. The MRI findings in the remaining three patients were: right frontal polymicrogyria, bilateral fronto-parietal atrophy, and hypogenesis of corpus callosum with Chiari I. The data show that patients with posterior cortical involvement tended to present milder form of SLI (no sign of articulatory or bucofacial praxis disturbance), while diffuse polymicrogyric perisylvian cortex usually was seen in patients who presented severe clinical manifestation, mainly phonological-syntactic deficit. In conclusion, SLI may be associated with perisylvian polymicrogyria and clinical manifestation may vary according to the extent of cortical anomaly.

MRI volumetry shows increased anterior thalamic volumes in patients with absence seizures

The interaction between thalamus and cortex appears to be critical to the pathophysiology of idiopathic generalized epilepsies (IGEs). The objective of this study was to investigate thalamic volumes of a group of patients with IGEs using high-resolution MRI. Thalamic segmentation was performed by the same rater, who was unaware of the diagnosis. Thalamic volumes were divided into anterior half and posterior half. One hundred forty-seven patients were scanned (71 with juvenile myoclonic epilepsy, 49 with generalized tonic-clonic seizures only, and 27 with absence epilepsy). Subgroup analyses with corrections for multiple comparisons showed that, when compared with those of controls, anterior thalamic volumes were increased in patients with absence epilepsy and juvenile myoclonic epilepsy with absence seizures, but not in patients with generalized tonic-clonic seizures only and juvenile myoclonic epilepsy without absence seizures. Our results demonstrated that the anterior thalamus is structurally different in patients with IGEs and absence seizures as compared with patients with IGEs without absence seizures.

Brain Single Photon Emission Computed Tomography Imaging in Landau-Kleffner Syndrome

Summary: Five right–handed children with Landau‐Kleffner syndrome (LKS) who had disease onset between the ages of 3 and 9 years were studied with EEG and single‐photon emission computed tomography (SPECT) before and, in four cases, after 6 months of corticosteroid treatment. EEG findings included both focal and generalized spikes as well as spike‐wave discharges with bilateral temporal predominance. These increased markedly during sleep in 1 child, and continuous spike‐and‐wave complexes appeared during slow‐wave sleep in another patient. Neuropsychological testing demonstrated verbal auditory agnosia. Magnetic resonance imaging (MRI) was performed in 4 children and was normal. Brain SPECT imaging demonstrated abnormal perfusion in the left temporal lobe in all patients. The response to corticosteroid therapy was mixed. Our findings reinforce the concept that LKS is a functional disease affecting the language‐dominant brain areas. We conclude that SPECT imaging may be of diagnostic assistance in the evaluation of this syndrome of unknown etiology.

Processamento auditivo e SPECT em crianças com dislexia

Dichotic listening (DL) was evaluated in 36 children with: verbal dichotic listening test, alternating dissilable dichotic test and non-verbal dichotic listening test. Children were separated into two groups: experimental group with 18 dyslexic children and control group with 18 normal children. Both groups were comparable in gender, laterality and social-economic level. All dyslexic children underwent neuroimaging exam (SPECT). Our data showed that there was a statistical difference between both groups in all DL tests. Abnormal SPECT findings were seen in 50% of the dyslexic children, hypoperfusion of the left temporal lobe being the most frequent abnormality. We conclude that dyslexic children present an impairment of central neurologic processing that may be detected by DL tests, and by functional imaging exam, such as SPECT, as well.