Biomedical subjects

I Savic

Publications and source records attributed to I Savic.

30 records · Page 2Linked to original sources

PubMed1997

Pattern of interictal hypometabolism in PET scans with fludeoxyglucose F 18 reflects prior seizure types in patients with mesial temporal lobe seizures.

BACKGROUND: Interictal hypometabolism is routinely used as an indicator of the epileptogenic zone in patients with complex partial seizures (CPSs). However, the regional pattern of hypometabolism varies without obvious reasons, even among patients with identical epileptogenic zones and causes. OBJECTIVE: To investigate whether this pattern may be related to the electroencephalographic and clinical features of the seizure that precedes the positron emission tomographic (PET) scan with fludeoxyglucose F 18. PATIENTS AND METHODS: Fifty-three patients with CPSs were first classified into 4 groups, depending on the features of the seizure that preceded the PET scan (determined from findings from electroencephalography and videotelemetry). In 14 patients, this seizure was focal limbic (characterized by aurae or staring spells); in 18, the CPS was widespread limbic (including automatisms). Ten patients had a CPS with posturing, and 11 had a secondarily generalized CPS. Regions with a hemisphere-normalized concentration of fludeoxyglucose F 18 below the 95% confidence interval of values from 8 control subjects were defined as hypometabolic. The location of these regions was then compared among the 4 groups, and the degree of hypometabolism was related to the time from the seizure to the PET scan with fludeoxyglucose F 18. RESULTS: The hypometabolic area was limited to the epileptogenic zone if the preceding seizure was focal limbic, whereas in patients with widespread limbic seizures, it included one or several additional areas of the limbic cortex (P = .03). Patients with posturing differed from both previous groups by having hypometabolism in the extralimbic frontal lobe (P < .001), and subjects with secondarily generalized seizures differed from all others because of cerebellar (P < .001) and parietal lobe (P < .05) reductions. The time between the seizure and the performance of the PET scan did not correlate with the degree or extent of hypometabolism. CONCLUSIONS: Mechanisms involved in the generation of a seizure that precedes a PET scan with fludeoxyglucose F 18 seem to influence the "interictal" hypometabolic pattern. Therefore, caution should be used when interpreting scans that are preceded by a nonhabitual seizure.

Adolescent↗

PubMed1997

Olfactory bedside test. A simple approach to identify temporo-orbitofrontal dysfunction.

BACKGROUND: Olfactory memory and discrimination are processed by the anteromesial temporal cortex and the orbitofrontal cortex. Both functions may therefore be impaired in limbic epilepsy. METHODS: Twenty-seven patients with mesial temporal lobe seizures (MTLS), 10 patients with neocortical seizures (NS), and 10 matched healthy control subjects underwent evaluation for olfactory quality discrimination (OD) and delayed recognition memory (OM). All patients were referred for presurgical evaluation. The olfactory tests were performed in a same-different paradigm with 10 seconds (OD) and 60 minutes (OM) between presentations of the odors, using the standardized University of Pennsylvania Smell Identification Test. The presentations were monorhinal in the OD and birhinal in the OM tests. The results were related to regional glucose metabolism measured with fludeoxyglucose F 18 positron emission tomography. RESULTS: Patients with MTLS had an impaired OD ipsilateral to the epileptogenic region (P < .001) and a higher total number of errors (including both tests) (P = .002). They also had lower OM scores, but not significantly lower than those of patients with NS (P = .05). The combined OM and OD tests correctly identified patients with MTLS with a sensitivity of 85% and a specificity of 90%, offering a correct lateralization in 74% of patients. Patients with MTLS whose OD was more impaired than OM differed from those with more impaired OM by having a significant hypometabolism not only over the neocortex of the epileptogenic temporal lobe (P = .02) but also in the ipsilateral anterior (P = .008) and orbitofrontal cortex (P = .007) (2-way analysis of variance). CONCLUSIONS: Tests of olfactory function are useful in distinguishing between NS and MTLS. The impairments of OM and OD can be dissociated in pathological states and therefore mediated by different structures.

Adult↗

PubMed1996

Localized cerebellar reductions in benzodiazepine receptor density in human partial epilepsy.

BACKGROUND: Previous studies suggest that the morphological substrate for cerebellar dysfunction is destruction of Purkinje cells, but disagree on whether this is caused by seizure- or drug-related toxicity. The benzodiazepine (BZ) receptor antagonist flumazenil tagged with carbon 11 is a sensitive marker of Purkinje cells. OBJECTIVE: To investigate whether cerebellar dysfunction in partial epilepsy is related to seizures through cerebrocerebellar connections. DESIGN: Positron emission tomography with [11C] flumazenil was conducted in 5 patients with frontal lobe seizures, 12 patients with mesial temporal lobe seizures, and 7 healthy men. Eight patients also had [18F]-fluorodeoxyglucose positron emission tomography. Cerebellar regions of interest were delineated using magnetic resonance imaging and a computerized anatomical brain atlas, and the epileptogenic regions were determined with a multimethod assessment. RESULTS: Patients with frontal lobe seizures had a significantly reduced BZ receptor density in the anterior cerebellum contralateral to the seizure onset region (P < or = .001), 2-way repeated-measure analysis of variance). Patients with mesial temporal lobe seizures had reductions in the ipsilateral (posterior and anterior) cerebellum (P < or = .001 for both). No significant asymmetries were found in regional glucose metabolism. CONCLUSIONS: The observed distribution of BZ receptor reductions is congruent with animal experiments showing tht frontal lobe projections to the cerebellum are crossed, whereas projections from mesial temporal loe are predominantly ipsilateral. The results thus indicate a functional relation with seizures and may reflect excitotoxic lesions or specific changes in the gamma-aminobutyric BZ system.

Adult↗

PubMed1996

Cortical benzodiazepine receptor changes are related to frequency of partial seizures: a positron emission tomography study.

Measurements of benzodiazepine (BZD) receptor density with positron emission tomography (PET) are a promising method of identifying and localizing epileptogenic regions. We investigated whether the pattern of BZD receptor changes depends on seizure frequency, studying 19 patients with matching seizure semiology but different rates of seizure occurrence, using [11C]flumazenil as the ligand. All patients had partial epilepsy and normal magnetic resonance imaging (MRI) of the brain. The visually determined PET focus, characterized by reduced BZD receptor density, corresponded to the epileptogenic focus/seizure onset region in all patients. The degree of BZD receptor reduction showed a positive correlation with seizure frequency. Patients with daily seizures differed from those with fewer seizures in two aspects: (a) the degree and extent of BZD receptor reduction was more pronounced, and (b) BZD receptors were also reduced in the primary projection areas of the focus. Flumazenil-PET reliably identifies epileptogenic brain regions in patients with partial seizures. In addition, flumazenil-PET can distinguish patients with frequent seizures. The method therefore is not only suitable for noninvasive localization of the seizure focus, but also may provide a biochemical marker of epileptogenicity.

Adult↗

PubMed1996

Localized cerebellar hypometabolism in patients with complex partial seizures.

PURPOSE: We sought to determine the cause of cerebellar dysfunction in epilepsy and whether this dysfunction was directly related to seizures. METHODS: Cerebellar metabolism was evaluated in 48 patients with a well-defined region of seizure onset and with corresponding hypometabolism. Regions of interest (ROI) were drawn according to a standardized template. If the ROI/nonepileptogenic cortex count rate ratio was outside the 95% confidence interval (CI) of controls, the ROI was defined as abnormal. The ratios from cerebellar hemispheres (defined as ipsi- or contralateral to the seizure onset region), were compared among controls (n = 8); patients who had seizure onsets and corresponding hypometabolism mesially in a temporal lobe (patient group 1, n = 19); patients whose seizures had onset mesially in a temporal lobe but spread rapidly to the ipsilateral frontal lobe and who had hypometabolism both in the affected temporal lobe and frontal lobe (patient group 2, n = 23); and patients who had seizure onsets and corresponding hypometabolism in the frontal lobe (patient group 3, n = 6). RESULTS: Significant hypometabolism was noted in the contralateral cerebellum of patients in group 2 and 3 [p = 0.007 and p = 0.008, respectively; two-way analysis of variance (ANOVA)]. In contrast, patients in group 1 tended to have lower values in the ipsilateral cerebellum (p = 0.057). CONCLUSIONS: The observed cerebellar changes are consistent with animal data showing that cerebellar connections to frontal lobes are numerous and crossed, whereas the connections to mesial temporal lobes are less abundant, bilateral, with an ipsilateral predominance. The difference between the two groups of patients with mesial temporal seizures suggests that cerebellar dysfunction in partial epilepsy, at least to a certain extent, is related to mechanisms involved in seizure generation and spread.

Cerebellum↗

PubMed1995

[11C]flumazenil positron emission tomography visualizes frontal epileptogenic regions.

Presently available noninvasive methods correctly localize epileptogenic regions in only approximately 50% of patients with frontal lobe epilepsy (FLE). Earlier studies have shown that temporal lobe epileptogenic regions may be identified readily by positron emission tomography (PET) measurements of regional benzodiazepine (BZD) receptor binding. We tested the specific applicability of this method in patients with FLE. Six patients with frontal partial seizures and 7 healthy men were investigated with PET and the BZD receptor ligand [11C]flumazenil. All patients had magnetic resonance (MR) brain scans. The independent assessment of seizure-onset region was based on seizure semiology, intra- and extracranial EEG and, in 4 cases, also on [18F]fluorodeoxyglucose (FDG)-PET. The epileptic focus/seizure-generating region was correctly identified by [11C]flumazenil PET in all patients. This region was characterized by a significant reduction in BZD receptor density. The area with reduced BZD receptor density was better delimited than the corresponding hypometabolic region, which was observed in 50% of patients investigated with [18F]FDG-PET. MRI was normal in 5 patients. Visualization of BZD receptors with [11C]flumazenil PET appears to be a promising approach for noninvasive identification of frontal lobe epileptogenic regions.

Adult↗

PubMed1994

In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy.

Electrophysiological data suggest that an abnormal oscillatory pattern of discharge in cortical and thalamic neurons may be the major mechanism underlying primary generalised epilepsy. No neurochemical or anatomical substrate for this theory has hitherto been demonstrated in humans and the pathophysiology of primary generalised epilepsy remains unknown. By means of PET and the benzodiazepine (BZ) ligand [11C]flumazenil it has been previously shown that the BZ receptor density is reduced in the epileptic foci of patients with partial epilepsy. In the present study the method was further developed and used in a comparative analysis of cortical, cerebellar, and subcortical BZ receptor binding in patients with primary generalised tonic and clonic seizures (n = 8), and healthy controls (n = 8). Patients with generalised seizures had an increased BZ receptor density in the cerebellar nuclei (p = 0.006) and decreased density in the thalamus (p = 0.003). No significant changes were seen in the cerebral and cerebellar cortex or in the basal ganglia. The observed alterations suggest that the gamma-amino-butyric acid (GABA)-BZ system may be affected in the cerebello-thalamocortical loop of patients with generalised epilepsy and indicate possible targets for selective pharmacological treatment.

Adult↗

PubMed1993

Comparison of [11C]flumazenil and [18F]FDG as PET markers of epileptic foci.

Recent PET results indicate that the benzodiazepine (BZ) receptor density measured with the BZ receptor antagonist [11C]flumazenil is reduced in human epileptic foci. The present study examines the applicability of this finding in the presurgical investigation of patients with intractable partial epilepsy. In eight patients, the PET measurements were performed after injection of the BZ receptor antagonist [11C]flumazenil and [2-18F]2-deoxy-2-fluoro-D-glucose ([18F]FDG)--a tracer for measurements of the rate of regional glucose metabolism. The focus localising ability of the two PET tracers was examined using extra--and intracranial EEG recordings as reference. The focus was first determined visually on the PET images obtained after a bolus injection of each of the PET tracers. Its anatomical localisation and spatial delimitation was then evaluated for each patient with a computerised anatomical brain atlas. [11C]flumazenil was found to be a more sensitive and accurate focus localiser than [18F]FDG. This observation was valid both for quantified and non-quantified images. In the preoperative diagnosis of epileptic foci, the PET measurements of BZ receptors may be a suitable and, in some cases, superior method to the generally used "[18F]FDG-PET" method.

Adult↗

PubMed1991

Feasibility of reversing benzodiazepine tolerance with flumazenil.

To examine whether the benzodiazepine antagonist flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures, the antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated. Electroencephalographic studies in 6 patients with partial and 6 with generalised seizures showed that flumazenil had a short (20 min) non-dose-dependent suppressant effect on epileptic discharges in those with partial seizures. Receptor occupancy studies in 12 patients showed that 1.5 mg flumazenil given intravenously occupied 55% receptors, whereas 15 mg occupied nearly all receptors. When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil, they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.

Adult↗

PubMed1990

Recent advances in psychiatric brain imaging.

The characterization of neuroreceptor functions in the living human brain has hitherto been hampered by the lack of techniques useful for the measurement of physiologic events within the human brain in vivo. Recent developments in positron emission tomography (PET) has allowed the quantitative tracing of intravenously administered molecules within tissue compartments of the brain. Using ligands binding with high affinity to cerebral neuroreceptors it has been possible to examine not only the distribution but also some quantitative aspects of brain neuroreceptors in living human subjects by the PET technique. By the selection of highly selective ligands for different receptor systems and by labeling them with positron emitting isotopes as 11C or 18F, methods have been developed for the characterization of receptor subtypes for the endogenous ligands dopamine, serotonin, opiates, acetylcholine, glutamate and GABA. The present communication describes the use of 11C-SCH 23390 and 11C-raclopride for the analysis of D1 and D2 dopamine receptors, the benzodiazepine (BZ) antagonist 11C-Ro 15-1788 for benzodiazepine receptors and 11C-nicotine for nicotine receptors. Specificity of binding was verified by using active and inactive stereoenantiomers of the ligands. After the intravenous administration of the ligands quantitative aspects of the receptor binding was calculated using models according to equilibrium or dynamic approaches. Bmax and Kd values for D2 dopamine and BZ receptors could be determined in the brain of healthy human subjects and patients with neuropsychiatric disorders. No alteration of D2 dopamine receptors in the major basal ganglia were found in drug naive schizophrenic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzazepines↗

PubMed1988

In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci.

Ten patients with partial epilepsy and five healthy controls had positron emission tomography (PET) of the brain after intravenous administration of the 11C-labelled benzodiazepine (BZ) receptor ligand 'Ro-15 1788'. In all ten patients BZ receptor binding was significantly lower in the epileptic focus than in the contralateral homotopic reference region and the remaining neocortex. No asymmetries in BZ receptor binding were observed between homotopic reference regions in the controls or the non-epileptic regions of patients. These results demonstrate the potential of the BZ receptor as a biochemical marker for display of epileptic foci by PET, and also strengthen the hypothesis that inhibitory mechanisms are disturbed in the epileptic focus.

Adult↗

PubMedDate not supplied

Cortical benzodiazepine receptor binding in patients with generalized and partial epilepsy.

Impaired cortical inhibition may be involved in epileptogenic mechanisms. In a positron-emission tomography (PET) study, we demonstrated a reduction of the cortical benzodiazepine (BZD) receptor density in the epileptic foci of patients with partial epileptic seizures. In the present study, we used the same method in 10 patients with primary generalized epilepsy to determine whether an altered BZD receptor binding could also be demonstrated in this patient group. The [11C]-labeled BZD receptor antagonist Ro 15-1788 was used as ligand. Receptor affinities and densities were calculated in various cortical regions and then compared with the values from corresponding "nonepileptic" regions in the previously examined partial epilepsy patients. Focal alterations of the BZD receptor density or affinity were not demonstrated in patients with generalized epilepsy. This patient group had a slight tendency toward lower mean cortical BZD receptor density, however, as compared with corresponding values from 10 patients with partial epilepsy. Our results strongly suggest that a focal alteration of cortical inhibition is not a prominent feature of human generalized epilepsy. The observed tendency toward lower mean cortical BZD receptor density may be a consequence of diffusely impaired cortical inhibition. Further investigations of this issue are therefore indicated.

Adult↗