P. Van Bogaert

Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET.

Vegetative state (VS) is a condition of abolished awareness with persistence of arousal. Awareness is part of consciousness, which itself is thought to represent an emergent property of cerebral neural networks. Our hypothesis was that part of the neural correlate underlying VS is an altered connectivity, especially between the associative cortices. We assessed regional cerebral glucose metabolism (rCMRGlu) and effective cortical connectivity in four patients in VS by means of statistical parametric mapping and [18F]fluorodeoxyglucose-positron emission tomography. Our data showed a common pattern of impaired rCMRGlu in the prefrontal, premotor, and parietotemporal association areas and posterior cingulate cortex/precuneus in VS. In a next step, we demonstrated that in VS patients various prefrontal and premotor areas have in common that they are less tightly connected with the posterior cingulate cortex than in normal controls. These results provide a strong argument for an alteration of cortical connectivity in VS patients.

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

Statistical parametric mapping of regional glucose metabolism in mesial temporal lobe epilepsy.

We investigated statistical parametric mapping (SPM) use for positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG) data analysis in mesial temporal lobe epilepsy. The study involved 14 patients with temporal lobe epilepsy ultimately treated by anterior temporal lobectomy. Surgical outcome in terms of seizure control was favorable in 12 patients. Two different SPM approaches were designed to analyze each FDG-PET scan: a direct comparison with a control group (n = 27) and a search for significant interhemispheric asymmetry considering the asymmetry existing in the control group. Statistical inference was performed, first, without correction for multiple comparisons (making the hypothesis of temporal hypometabolism) and, second, after correction for multiple comparisons. Search for temporal interhemispheric asymmetry under the hypothesis of temporal hypometabolism was the most reliable SPM approach: hypometabolism was identified on the side chosen for resection in most cases (sensitivity, 71%; specificity, 100%) and was predictive of favorable postsurgical outcome in 90% of the patients. There was no false-positive result within the control group using this approach. After correction for multiple comparisons, SPM also identified in some patients temporal hypermetabolic areas as well as extratemporal cortical and subcortical hypometabolic areas on the side of resection but also on the contralateral side. In a further step, SPM was used for a group analysis of patients with favorable outcome after reversing scans when needed to set an identical lateralization in all patients. This analysis identified multiple ipsilateral temporal and extratemporal hypometabolic regions; when temporal metabolic changes were specifically assessed, the contralateral mesiotemporal region was found hypermetabolic, possibly as a manifestation of compensatory mechanisms in the presence of a unilateral epileptogenic lesion.

Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia

Background: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. Methods: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. Results: Patients with PNKD with MR-1 mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. Conclusions: Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 (MR-1) gene mutations. Other “PNKD-like” families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.

Regional Changes in Glucose Metabolism during Brain Development from the Age of 6 Years

Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) studies of 42 subjects ages 6 to 38 years were analyzed using statistical parametric mapping to identify age-related changes in regional distribution of glucose metabolism adjusted for global activity. Whereas adults were normal volunteers, children had idiopathic epilepsy. We studied polynomial expansions of age to identify nonlinear effects and found that adjusted glucose metabolism varied very significantly in the thalamus and the anterior cingulate cortex and to a lesser degree in the basal ganglia, the mesencephalon, and the insular, posterior cingulate, frontal, and postcentral cortices. Regression plots slowed that the best fit was not linear: adjusted glucose metabolism increased mainly before the age of 25 years and then remained relatively stable. Effects persisted when anti-epileptic drug intake and sleep during the FDG uptake were considered as confounding covariates. To determine if the metabolic changes observed were not due to the epileptic condition of the children, PET data obtained in adults with temporal lobe epilepsy were compared with those in our group of normal adult subjects, resulting in the absence of mapping in the age-related regions. This study suggests that brain maturation from the age of 6 years gives rise to a relative increase of synaptic activities in the thalamus, possibly as a consequence of improved corticothalamic connections. Increased metabolic activity in the anterior cingulate cortex is probably related to these thalamic changes and suggests that the limbic system is involved in the processes of brain maturation.

Regional cerebral glucose metabolism in epilepsies with continuous spikes and waves during sleep.

Background: Epileptic syndromes with continuous spikes and waves during sleep (CSWS) represent a wide spectrum of epileptic conditions associated with cognitive dysfunctions that have the EEG pattern of CSWS as a common feature. Reported are the results of voxel-based analyses of brain glucose metabolism performed in a group of 18 children with CSWS. Methods: Voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (SPM). First, each patient was compared with a control group and the influence of age, epileptic activity, and corticosteroid treatment on metabolic abnormalities was studied. Also, disease-related changes in the contribution of a brain area to the level of metabolic activity in another brain area were investigated using pathophysiologic interactions in groups of patients compared with the control group. Results: Individual SPM analyses identified three metabolic patterns: association of hypermetabolic and hypometabolic areas, hypometabolic areas only, and normal pattern. Age and intensity of awake interictal spiking did not significantly differ in patients showing focal hypermetabolism compared with the other ones. Treatment with corticosteroids was associated with absence of focal hypermetabolism. In the group of patients with hypermetabolic areas, analyses of pathophysiologic interactions showed disease-related altered functional connectivity between the parietal and frontal cortices. Conclusions: Cerebral metabolic patterns are heterogeneous among patients with CSWS. This metabolic heterogeneity could be related to the use of corticosteroid treatment before PET. The parietofrontal altered connectivity observed in patients with hypermetabolism is interpreted as a phenomenon of remote inhibition of the frontal lobes induced by highly epileptogenic and hypermetabolic posterior cortex.

Neuroradiologic findings in leptomeningeal carcinomatosis: the value interest of gadolinium-enhanced MRI

SummaryFour patients with leptomeningeal metastases documented by neuroradiological examinations are reported. All had central nervous system or systemic neoplasms and showed clinical signs of carcinomatous meningitis. Gadolinium-enhanced MRI (Gd-MRI) disclosed for each patient pathological foci, allowing delineation of the extent of meningeal disease. Although non-specific, these findings, combined with the clinical context and CSF analysis, may lead to a rapid diagnosis and treatment of carcinomatous meningitis, even when malignant cells are not detected in the cerebrospinal fluid.

Maturation of Thalamic Radiations between 34 and 41 Weeks' Gestation: A Combined Voxel- Based Study and Probabilistic Tractography with Diffusion Tensor Imaging

BACKGROUND AND PURPOSE: This study aimed to investigate brain maturation along gestational age with diffusion tensor imaging in healthy preterm and term neonates. Therefore, a voxel-based study of fractional anisotropy (FA) and mean diffusivity (Dav) was performed to reveal the brain regions experiencing microstructural changes with age. With tractography, the authors intended to identify which fiber tracts were included in these significant voxels. MATERIALS AND METHODS: There were 22 healthy preterm and 6 healthy term infants who underwent MR imaging between 34 and 41 weeks of gestation. A statistical parametric approach was used to evidence the effect of age on regional distribution of FA and Dav values. The fiber tracts suspected to be included in the significant clusters of voxels were identified with neuroanatomy and tractography atlases, reconstructed with probabilistic tractography, and superimposed on the parametric maps. RESULTS: Parametric analysis showed that FA increases with age in the subcortical projections from the frontal (motor and premotor areas) and parietal cortices, the centrum semiovale, the anterior and posterior arms of the internal capsules, the optic radiations, the corpus callosum, and the thalami (P < .05, corrected). Superimposition of the parametric maps on tractography showed that the corticospinal tract (CST); the callosal radiations (CR); and the superior, anterior, and posterior thalamic radiations were included in the significant voxels. No statistically significant results were found for Dav maps. CONCLUSIONS: These results highlight that, besides the already-evidenced FA increase in the CST and CR, the thalami and the thalamic radiations experience microstructural changes in the early development of the human brain.

Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q10 deficiency.

SummaryThe cardiofaciocutaneous (CFC) syndrome is characterized by congenital heart defect, developmental delay, peculiar facial appearance with bitemporal constriction, prominent forehead, downslanting palpebral fissures, curly sparse hair and abnormalities of the skin. CFC syndrome phenotypically overlaps with Noonan and Costello syndromes. Mutations of several genes (PTPN11, HRAS, KRAS, BRAF, MEK1 and MEK2), involved in the mitogen-activated protein kinase (MAPK) pathway, have been identified in CFC–Costello–Noonan patients. Coenzyme Q10 (CoQ10), a lipophilic molecule present in all cell membranes, functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. CoQ10 deficiency is a rare treatable mitochondrial disorder with various neurological (cerebellar ataxia, myopathy, epilepsy, mental retardation) and extraneurological (cardiomyopathy, nephropathy) signs that are responsive to CoQ10 supplementation. We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency. Her psychomotor development was severely impaired, hindered by muscular hypotonia and ataxia, both improving remarkably after CoQ10 treatment. This case suggests that there is a functional connection between the MAPK pathway and the mitochondria. This could be through the phosphorylation of a nuclear receptor essential for CoQ10 biosynthesis. Another hypothesis is that K-Ras, one of the proteins composing the MAPK pathway, might be recruited into the mitochondria to promote apoptosis. This case highlights that CoQ10 might contribute to the pathogenesis of CFC syndrome.

Impact of focal interictal epileptiform discharges on behaviour and cognition in children

It is hypothesised that focal interictal epileptiform discharges (IED) may exert a deleterious effect on behaviour and cognition in children. This hypothesis is supported by the abnormally high prevalence of IED in several developmental disorders, like specific language impairment, and of cognitive and behavioural deficits in epileptic children after excluding confounding factors such as underlying structural brain lesions, drug effects, or the occurrence of frequent or prolonged epileptic seizures. Neurophysiological and functional neuroimaging evidence suggests that IED may impact cognition through either transient effects on brain processing mechanisms, or through more long-lasting effects leading to prolonged inhibition of brain areas distant from but connected with the epileptic focus (i.e. remote inhibition effect). Sustained IED may also impair sleep-related learning consolidation processes. Nowadays, the benefits of anti-epileptic treatment aimed at reducing IED are not established except in specific situations like epileptic encephalopathies with continuous spike and waves during slow-wave sleep. Well-designed pharmacological studies are still necessary to address this issue.