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Biomedical subjects

C Munari

Publications and source records attributed to C Munari.

At least 19 recordsLinked to original sources
PubMed2003

Surgery for drug resistant partial epilepsy in children with focal cortical dysplasia: anatomical-clinical correlations and neurophysiological data in 10 patients.

OBJECTIVE: To analyse a population of children with focal cortical dysplasia operated on for drug resistant partial epilepsy, with emphasis on clinical features, seizure semiology, interictal and ictal EEG and stereo EEG findings, histological and topographical characteristics of the lesions, extension and localisation of cerebral excision, and its postoperative effect on seizure frequency. METHODS: 10 patients were studied, aged between 26 months and 11 years (median 6 years). Magnetic resonance imaging (MRI) abnormalities were unilobar (temporal 3, frontal 2), bilobar (2), or multilobar (1); the two patients with negative MRI suffered from frontal seizures. Presurgical diagnostic steps varied in complexity and invasiveness depending on the anatomical/electrical/clinical features of each patient. In four patients they included only scalp video EEG monitoring, and in six, also invasive recordings using stereotactically implanted intracerebral electrodes. Surgery consisted of corticectomy plus lesionectomy in all cases. RESULTS: 70% of the patients were seizure-free after a minimum postoperative follow up of 25 months. These included three patients with temporal lesions and four of seven patients with other lobar or multilobar extratemporal localisation. One patient had improvement in seizure control. Outcome was poor in multilobar patients, but a class Ia outcome was obtained in one case after partial lesionectomy associated with bilobar corticectomy. All patients showed developmental improvement. CONCLUSIONS: Analysis of the data in these patients allowed the production of an "anatomical-clinical concordance" list, which appeared to be correlated with the diagnostic steps performed. Carrying out a stereo EEG exploration in the most complex cases proved useful in defining the epileptogenic zone in extratemporal and multilobar epilepsies. Stereo EEG recordings facilitated a tailored resection of extralesional cortex.

Cerebral Cortex↗
PubMed2001

Cortical dysplasia: electroclinical, imaging, and neuropathologic study of 13 patients.

PURPOSE: The aim of this study was to correlate the electroclinical and radiologic data with the neuropathologic findings and surgical outcome in epileptic patients with epilepsy and Taylor's focal cortical dysplasia (TFCD) and to characterize further the abnormal intermediate filaments expression in the balloon cell present in the peculiar dysplasia. METHODS: We retrospectively selected 13 TFCD patients who underwent surgery for intractable epilepsy with the aim of removing the magnetic resonance (MR)-detectable lesion and/or the epileptogenic zone defined by stereoelectroencephalographic recordings. The surgical specimens were analyzed by means of routine neuropathologic and immunocytochemical studies. Antisera against different intermediate filaments also were used in serial adjacent sections to evaluate their coexpression in balloon cells. RESULTS: Histopathologic abnormalities typical of TFCD were found not only within the MR-visible lesions but also in most of the epileptogenic zones with no MR signal alterations. Furthermore, the MR-visible lesions contained a high proportion of cells with an abnormal expression of intermediate filament proteins. After a long follow-up, 10 of the patients are now seizure free. CONCLUSIONS: Our findings indicate that highly epileptogenic zones may correspond to tissue alterations not revealed by neuroimaging. Furthermore, the immunocytochemical data show that the dysplastic tissue detected by MR contained high concentrations of cells filled with abnormal intermediate filaments. The detected colocalization of neuronal and glial markers in balloon cells indicates a failure of cellular commitment during development.

Adolescent↗
PubMed2000

Sleep-EEG modulation of interictal epileptiform discharges in adult partial epilepsy: a spectral analysis study.

INTRODUCTION: In order to define accurately the relationship between EEG components (spindles, delta and theta frequencies) and the occurrence of interictal epileptiform discharges (IED) during sleep in partial epilepsy, a correlation study between spike overnight distribution and EEG spectral power time series was performed. METHODS: Eighteen patients (mean age: 24.7+/-5.5 years) affected by partial epilepsy underwent continuous EEG-polysomnography. The temporal series of Slow Wave Activity (SWA), Sigma Activity (SA) and Theta Band (TB), derived from spectral analysis, were obtained from a spike-free and pathologic alteration-free derivation, contralateral to the most active lead, where the IED count was performed. Relationships between SA, SWA and TB and time series of IED were tested by means of correlation techniques after data normalization. RESULTS: Our results revealed a significantly higher correlation between IED and SWA in 12 subjects; a significantly higher correlation between IED and SA in three subjects and a significant correlation with TB in three cases. CONCLUSIONS: Data suggest that in most adult patients with partial epilepsy IED production during sleep is facilitated by the action of synchronizing mechanisms which are active during NREM sleep and lead to the appearance of EEG delta waves. Nevertheless evidence is given of two smaller groups of patients. In one of them IED are more sensitive to the promoting action of the spindle generating mechanism, active during stage 2 of NREM sleep. In the other one the promoting action of TB, characterizing EEG during stage 1 and REM sleep, is evident.

Adult↗
PubMed2000

Inhibitory circuits in human dysplastic tissue.

PURPOSE: Different types of epilepsies and seizures depend on the nature and location of the primary disturbance and are presumably mediated by different physiopathological mechanisms. We immunocytochemically investigated possible changes in the inhibitory-aminobutyric acid (GABA)ergic system in specimens taken from four patients who underwent surgery for intractable epilepsy and presented two different types of focal cortical dysplasia in the temporal lobe. METHODS: The patients were selected on the basis of electroclinical, imaging, and routine neuropathological data: two had Taylor focal dysplasia, and two had non-Taylor dysplasia (microdysgenesia). The study was performed using antibodies against parvalbumin (PV), glutamic acid decarboxylase (GAD), and GABA-transporter 1 (GAT1). RESULTS: In the patients with Taylor dysplasia, laminar disorganization of the cortex was associated with the presence of giant neurons and ballooned cells; there was a reduced number of PV-positive neurons and terminals, the giant neurons were surrounded by clusters of PV- and GAD-positive terminals, and there was an overall reduction in GAT1. Despite the presence of cortical laminar disorganization, no giant or ballooned cells were found in the patients with non-Taylor microdysgenesia; there was a marked decrease in PV and GAD immunoreactive elements, with a patchy distribution of GAD and GAT1 immunoreactivity but no clustering of PV and GAD terminals. CONCLUSIONS: These results suggest that the two forms of cortical dysplasia are characterized by different and selective morphofunctional alterations in the GABAergic system.

Adult↗
PubMed2000

Epilepsy surgery: guidelines for minimum standard equipment and organization.

These guidelines, developed by the Study Group on Functional Neurosurgery of the Italian Society of Neurosurgery, concern the minimum standard equipment and organization required to a center dealing with the surgical treatment of epilepsy. They include the general criteria for patient selection, the main presurgical diagnostic procedures able to define seizure characteristics and concomitant brain abnormalities, the standard surgical procedures utilized. "Cryptogenetic" as well as "symptomatic" epilepsies are considered. Recommendations are also provided for correct result assessment and follow-up evaluation. Guidelines presented here reflect a multidisciplinary consensus and expert opinion, based on scientific evidence and current clinical experience.

Epilepsy↗
PubMed1999

Presurgical strategies and epilepsy surgery in children: comparison of literature and personal experiences.

We reviewed 41 studies on epilepsy surgery in 1645 children and adolescents. The available data vary greatly from one paper to another, particularly as regards the age of the patients included, selection criteria, presurgical methodology, and the type of surgical intervention. Moreover, the surgical results are classified according to very different criteria. Our experience in Grenoble concerning 55 children (age < or = 16 years; postoperative follow-up > 18 months) is discussed in the light of data in the literature. The need is stressed for a consensus on the type of information that must be supplied by well-detailed studies on homogeneous groups of epilepsy surgery patients.

Adolescent↗
PubMed1999

Selective block of rat and human neocortex GABA(B) receptors regulating somatostatin release by a GABA(B) antagonist endowed with cognition enhancing activity.

Previously, we have shown that presynaptic GABA(B) receptors regulating the release of various transmitters from CNS terminals can be differentially blocked by GABA(B) antagonists suggesting the existence of pharmacologically distinct GABA(B) receptor subtypes. We here examined the ability of CGP 36742 [(3-aminopropyl)n-butylphosphinic acid], a selective GABA(B) antagonist endowed with cognition enhancing activity, to block release-regulating GABA(B) receptors. In particular, CGP 36742 was tested against the inhibition of the depolarization-evoked release of GABA, glutamate, cholecystokinin and somatostatin produced by (-)baclofen in rat and human neocortex axon terminals. CGP 36742 potently antagonized (IC50 = 0.14 microM) the inhibition by (-)baclofen of somatostatin release from superfused rat neocortex synaptosomes. In contrast, the effects of (-)baclofen on GABA, glutamate and cholecystokinin release were insensitive to CGP 36742, at concentrations of up to 100 microM. In human neocortex synaptosomes CGP 36742 exhibited a pattern of selectivity identical to that in rat synaptosomes, although the antagonist was at least 10-fold less potent in human than in rat brain. CGP 36742 is the first compound displaying great selectivity for the GABA(B) presynaptic receptors regulating somatostatin release. Considering the proposed implication of the neuropeptide in cognitive processes, disinhibition of somatostatin release merits consideration as one of the mechanisms possibly involved in the behavioral activity of CGP 36742.

Adult↗
PubMed1999

Pharmacological diversity between native human 5-HT1B and 5-HT1D receptors sited on different neurons and involved in different functions.

The releases of [3H]5-hydroxytryptamine ([3H]5-HT) and of endogenous glutamic acid and their modulation through presynaptic h5-HT1B autoreceptors and h5-HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [3H]5-HT was antagonized by the 5-HT1B/5-HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5-HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5-HT1B receptor ligand SB-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 microM, was unable to interact with the h5-HT1D heteroreceptor. The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate was antagonized by the h5-HT1D receptor ligand BRL-15572; added in the absence of 5-HT the compound was without effect. BRL-15572 (1 microM) was unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. The selective 5-HT1A receptor antagonist (+)-WAY 100135, previously found to be an agonist at the h5-HT1D heteroreceptor regulating glutamate release, could not interact with the h5-HT1B autoreceptor when added at 1 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.

Adult↗
PubMed1999

Native human neocortex release-regulating dopamine D2 type autoreceptors are dopamine D2 subtype.

Dopamine (DA) autoreceptors expressed at DA nerve terminals regulate DA release. Considerable evidence has indicated that, in rodents, these autoreceptors belong to the D2 type of the DA receptor family, which, in turn, comprises the D2, D3 and D4 subtypes. We investigated here, for the first time, the subclassification of native human DA autoreceptors by studying the release of [3H]DA evoked by electrical stimulation in fresh human neocortical slices. The results have been compared with those obtained in three animal systems: rat neocortical and striatal slices and rat mesencephalic neuronal cultures. In human neocortical slices, the D2/D3 receptor agonist quinpirole (1 nM-10 microM) inhibited tritium release with a calculated EC50 of 17 nM and a maximal inhibition of approximately 75% reached at 1 microM. In the presence of the D2/D3 receptor antagonist (-)-sulpiride (0.1 and 1 microM), the concentration-response curve of quinpirole was shifted to the right, and the apparent pA2 mean value was 8.5 (8.14-8.77); on the other hand, the inhibitory effects of quinpirole were not affected by the D3 receptor-selective antagonist [7-N,N-dipropylamino-5,6,7, 8-tetrahydro-naphtho(2,3b) dihydro,2,3-furane] (S 14297) and the D4 receptor-selective antagonist 3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo [2,3-b]pyridine (L-745,870) (0.01-1 microM in each case). Superimposable results have been obtained when the release was elicited from rat striatal slices or dopamine mesencephalic neurons in culture, whereas quantitative differences emerged in the case of rat cortical slices. It is concluded that in human brain, as well as in rat brain, the release of DA in the terminal region of midbrain dopaminergic neurons is regulated through autoreceptors of the D2 subtype.

Adult↗
PubMed1999

An H(2) (15)O-PET study of cerebral blood flow changes during focal epileptic discharges induced by intracerebral electrical stimulation.

Partial epileptic seizures are known to cause a focal increase in cerebral blood flow (CBF). However, quantified studies of ictal CBF changes under intracranial EEG control are still needed to assess the relationships in time and space between CBF changes and electrical discharges. Ten patients undergoing an intracerebral stereotaxic EEG (stereo-EEG) investigation for epilepsy surgery were prospectively studied for local perfusion changes. These were measured by H(2)(15)O-PET during 12 subclinical or mild symptomatic focal epileptic discharges induced by intracerebral electrical stimulation of the hippocampus (eight), amygdala (two), temporal pole (one) and fusiform gyrus (one). This study aimed to assess whether a significant focal blood flow change reflected the geographical extent of the underlying coincident epileptic discharge, as measured by this method at seizure onset. No significant CBF change was observed on test-retest at rest or during ineffective electrical stimulations outside the epileptogenic area. Compared with the resting condition, a significant focal perfusion increase of 16-55% occurred during eight discharges, there was no CBF change in three and a significant CBF decrease in one. Ictal CBF increases were mostly associated with low-voltage fast activity, but their magnitude had no obvious link with the duration of the discharge (range 8-106 s). Regional analysis of ictal PET was performed in 10 anatomical areas during each of the 12 discharges. Of all the 120 regions, 59 were not explored by intracerebral electrodes and 14 (24%) of these demonstrated ictal CBF changes. In 43 of the 61 regions explored by stereo-EEG (70.5%), PET and depth EEG findings converged, showing either a CBF change in a discharging area or no CBF change in a region unaffected by the discharge. Areas of increased CBF indicated an underlying epileptic discharge in almost 100% of the cases. Conversely, of the 18 regions showing discrepancies between intracerebral recordings and PET data, 17 were discharging regions showing no ictal CBF changes. Thus, a focal CBF increase, when detected at the seizure onset concomitantly with the initial low-voltage fast activity, was a reliable marker of an underlying epileptic discharge. It emphasizes the importance of injecting blood-flow tracers as soon as possible after detection of the discharge in routine clinical studies, even at a subclinical stage of the seizure. However, the extent of significant ictal CBF changes can be more restricted than that of the electrical discharge, thus limiting the reliability of ictal CBF images for outlining the contours of a tailored cortectomy.

Adult↗
PubMed1999

Ictal bradycardia in a patient with a hypothalamic hamartoma: a stereo-EEG study.

Little is known about bradycardia and cardiac asystole which occur during partial epileptic seizures, especially whether they relate to ictal involvement of well-defined cortical areas. Several reports based on simultaneous electrocardiographic and intracranial depth electroencephalographic monitoring have shown that either the fronto-orbital cortex or the amygdalohippocampal complex could be responsible for such cardiac variations. We performed stereo-EEG recordings in a patient with refractory localization-related epilepsy associated with a hypothalamic hamartoma. We found that other cortical areas, such as the frontocentral region and the temporal neocortex, can contribute to the genesis of ictal bradyarrhythmia. Second, the lesion per se, although located within the hypothalamus, is not involved with this phenomenon.

Adult↗
PubMed1999

Taylor's cortical dysplasia: a confocal and ultrastructural immunohistochemical study.

In the present report we describe the neuropathological characteristics of tissue surgically resected from three patients affected by intractable epilepsy secondary to cortical dysplasia. Common features, suggestive of a focal cortical dysplasia of Taylor, were observed in all specimens. Immunocytochemical procedures were performed using neuronal and glial markers and the sections were observed at light traditional and confocal microscopes. This part of the investigation pointed out: 1. cortical laminar disruption; 2. very large neurons displaying a pyramidal or round shape; 3. ballooned cells; 4. decrease of calcium binding proteins immunoreactivity; 5. abnormal nets of parvalbumin- and glutamic acid decarboxylase-positive puncta around giant neurons but not around ballooned cells. Ultrastructural investigation on the same material provided evidence of a high concentration of neurofilaments in giant neurons and of glial intermediate filaments in ballooned cells. In addition, immunolabeled GABAergic terminals clustered around giant neurons were not found to establish synapses on their cell bodies. The present data, derived from a limited sample of patients but showing very consistent features, suggest that in Taylor's type of cortical dysplasia a disturbance of migratory events could be paralleled by a disruption of cell differentiation and maturation and by an impairment of synaptogenesis. This latter mechanism seemed to affect especially the inhibitory elements, and could account for the hyperexcitability of this tissue and thus for the high epileptogenicity of Taylor's dysplasia.

Adult↗
PubMed1999

Activity of putative cognition enhancers in kynurenate test performed with human neocortex slices.

Some cognition enhancers were previously shown to potently prevent antagonism of the N-methyl-D-aspartate (NMDA)-evoked release of norepinephrine (NE) brought about in slices of rat hippocampus by kynurenic acid, an endogenous NMDA receptor blocker. We have examined the impact of putative nootropic agents in the kynurenate test performed with slices of human cerebral cortex from patients undergoing neurosurgery. In slices of human neocortex, local application of NMDA evoked release of [3H]NE; the effect of NMDA was antagonized by several NMDA receptor antagonists, including kynurenic acid. The antagonism of the NMDA-evoked [3H]NE release produced by 300 microM kynurenate was potently (EC50 <10 microM) prevented by most of the nootropics tested, including aniracetam, oxiracetam, D-cycloserine, and the glutamate analog CR 2249 (but not its enantiomer CR 2361). Nicotine or tacrine (up to 10 microM) did not show any effect in the kynurenate test. Nicotine (30-100 microM) itself increased the release of [3H]NE; interestingly, the nicotine-evoked overflow was blocked not only by the nicotin receptor antagonist mecamylamine but also by NMDA receptor antagonists, suggesting an indirect mechanism mediated by glutamate/aspartate release. To conclude, the similarities between the data obtained here with human neocortex slices and those previously obtained in the rat indicate that the kynurenate test performed with rat brain slices may represent a useful biochemical assay to study cognition-enhancing drugs.

Excitatory Amino Acid Agonists↗
PubMed1999

Research perspectives in cortical dysplasia and associated epilepsies.

Our understanding of cortical alterations and related epilepsies has grown enormously in the last decade thanks to the explosion of basic information from laboratory neuroscience combined with advances in diagnostic tools, therapeutic approaches and surgical techniques. In the present paper, we briefly review the most important advances in these fields from the point of view of the clinician concerned with cortical malformation-related epilepsies. We propose that a highly effective way forward, expected not only to widen knowledge of the basic mechanisms of seizure generation, but also to improved the management of patients, would be to promote interdisciplinary research programmes on resected human cortex that involve neurosurgeons, neurologists and laboratory neuroscientists.

Cerebral Cortex↗
PubMed1998

Immunocytochemical investigation on dysplastic human tissue from epileptic patients.

In this report we describe three patients with developmental cortical abnormalities (generally referred as cortical dysplasia), revealed by MRI and operated on for intractable epilepsy. Tissue, removed for strictly therapeutic reasons, was defined as the epileptogenic area by electroclinical data and stereo EEG (SEEG) recordings. Tissue samples were processed initially for histology, and selected sections were further processed for immunocytochemical investigation in order to determine whether the region of cortical dysplasia was co-extensive with the epileptogenic area. In two patients with nodular heterotopia, disorganized aggregates of neurons (as revealed by neuronal cytoskeletal markers) were found within the nodules. Both pyramidal and local circuit neurons were present in the nodules, but no reactive gliosis was present. When nodules reached the cortex, the cortical layers were disrupted. In the patient with localized cortical dysplasia, a complete disorganization of the cortical lamination was found, and numerous neurons were also present in the white matter. Disoriented pyramidal neurons weakly labelled with cytoskeletal neuronal markers were also present but no cytomegalic cells were found. One of the patients with nodular heterotopia underwent only partial resection of both the 'epileptogenic area' and of the lesion; this patient still presents with seizures. The other patient with nodular heterotopia is seizure-free after a complete lesionectomy and excision of the epileptogenic area. The third patient, with focal cortical dysplasia, had two surgeries; she became seizure-free only after the excision of the epileptogenic area detected by SEEG recording. The present data suggest that the dysplastic areas identified by MRI should not be considered as the only place of origin of the ictal discharges. From the neuropathological point of view, the focal cortical dysplasia can be considered as a pure form of migrational disorder. However, the presence of large aggregates of neurons interspersed within the white matter, in the subcortical nodular heterotopia, suggests that a defect of neuronal migration could be associated with an exuberant production of neuroblasts and/or a disruption of mechanisms for naturally occurring cell death.

Cerebral Cortex↗
PubMed1997

Neuropsychological study during video-EEG recording of successive partial seizures of right temporo-central origin.

A 15-year-old, right-handed boy underwent video-EEG study as a first step in presurgical evaluation for a severe drug-resistant right temporo-central epilepsy. He was monitored while performing neuropsychological tests over a 67-minute period during which 23 brief seizures were recorded. Despite his right-handedness, both inter-ictal and ictal verbal performances were impaired. Analysis of the relationships between the characteristics of the EEG and the neuropsychological results revealed that a worsening in cognitive performances correlated with an increase in inter-ictal abnormalities, particularly when subclinical paroxysms were present; that the cognitive tasks executed peri-ictally were correctly performed in almost 50% of the cases; and that the error rate was higher when a task was presented during or immediately after a seizure rather than before its onset. A Wada test, performed on the basis of the cognitive results, demonstrated right hemisphere dominance for language. Our observations underline the importance of neuropsychological testing in presurgical procedures, and suggest that it should be performed peri-ictally whenever possible.

Adolescent↗