B. Sadzot

Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-d-glucose method

Using the [18F]fluorodeoxyglucose method and positron emission tomography, we studied cerebral glucose utilization during sleep and wakefulness in 11 young normal subjects. Each of them was studied at least thrice: during wakefulness, slow wave sleep (SWS) and rapid eye movement sleep (REMS), at 1 week intervals. Four stage 3-4 SWS and 4 REMS fulfilled the steady state conditions of the model. The control population consisted of 9 normal age-matched subjects studied twice during wakefulness at, at least, 1 week intervals. Under these conditions, the average difference between the first and the second cerebral glucose metabolic rates (CMRGlu was: -7.91 +/- 15.46%, which does not differ significantly from zero (P = 0.13). During SWS, a significant decrease in CMRGlu was observed as compared to wakefulness (mean difference: -43.80 +/- 14.10%, P less than 0.01). All brain regions were equally affected but thalamic nuclei had significantly lower glucose utilization than the average cortex. During REMS, the CMRGlu were as high as during wakefulness (mean difference: 4.30 +/- 7.40%, P = 0.35). The metabolic pattern during REMS appeared more heterogeneous than at wake. An activation of left temporal and occipital areas is suggested. It is hypothetized that energy requirements for maintaining membrane polarity are reduced during SWS because of a decreased rate of synaptic events. During REMS, cerebral glucose utilization is similar to that of wakefulness, presumably because of reactivated neurotransmission and increased need for ion gradients maintenance.

Is 11C-flumazenil PET superior to 18FDG PET and 123I-iomazenil SPECT in presurgical evaluation of temporal lobe epilepsy?

OBJECTIVE: To determine the contribution of 18FDG PET, 11C-flumazenil PET, and 123I-iomazenil SPECT to the presurgical evaluation of patients with medically intractable complex partial seizures. METHODS: Presurgical evaluation was performed in 23 patients, who were considered candidates for temporal lobe resective surgery (14 females and nine males with a median age of 34 (range 13 to 50) years). The presurgical diagnosis was based on seizure semiology as demonstrated with ictal video recording, ictal and interictal scalp EEG recordings, and MRI. RESULTS: Eighteen patients had convergent findings in clinical semiology, interictal and ictal EEG with scalp and sphenoidal electrodes, and MRI that warranted surgery without depth EEG (DEEG). In five patients with insufficient precision of localisation, DEEG with intracerebral and subdural electrodes was performed. MRI showed abnormalities in 22 out of 23 patients. Of these 22, 18 had mesial temporal sclerosis. This was limited to the mesial temporal lobe in four and more widespread in the temporal lobe in 14 patients. In one patient only enlargement of the temporal horn was found and in three others only white matter lesions were detected. 18FDG PET showed a large area of glucose hypometabolism in the epileptogenic temporal lobe, with an extension outside the temporal lobe in 10 of 23 patients. Only in one of these patients DEEG showed extratemporal abnormalities that were concordant with a significant extratemporal extension of hypometabolism in 18FDG PET. 18FDG PET was compared with the results of scalp EEG: in none of the patients was an anterior temporal ictal onset in scalp EEG related to a maximum hypometabolism in the mesial temporal area. By contrast, the region of abnormality indicated by 11C-flumazenil PET was much more restricted, also when compared with DEEG findings. Extension of abnormality outside the lobe of surgery was seen in only two patients with 11C-flumazenil and was less pronounced compared with the intratemporal abnormality. Both 18FDG PET and 11C-flumazenil PET reliably indicated the epileptogenic temporal lobe. Thus these techniques provide valuable support for the presurgical diagnosis, especially in patients with non-lesional MRI or non-lateralising or localising scalp EEG recordings. In those patients in whom phase 1 presurgical evaluation on the basis of classic methods does not allow a localisation of the epileptogenic area, PET studies may provide valuable information for the strategy of the implantation of intracranial electrodes for DEEG. Previous studies have suggested that 11C-flumazenil binding has a closer spatial relationship with the zone of ictal onset than the area of glucose hypometabolism, but this study suggests rather that the decrease in the 11C-flumazenil binding simply reflects a loss of neurons expressing the benzodiazepine-GABA receptor. 11C-flumazenil PET did not prove to be superior to 18FDG PET. CONCLUSION: In 21 patients sufficient material was obtained at surgery for a pathological examination. In 17 mesial temporal sclerosis, in one an oligodendroglioma grade B, in another a vascular malformation and in two patients no abnormalities were found. Although all 21 patients with pathological abnormality showed hypometabolic zones with 18FDG PET and a decreased uptake in 11C-flumazenil binding, there was no strong correlation between pathological diagnosis and functional abnormal areas in PET. Grading of medial temporal sclerosis according to the Wyler criteria showed no correlation with the degree of hypometabolism in either 18FDG or 11C-flumazenil PET. The interictal 123I-iomazenil SPECT technique was highly inaccurate in localising the lobe of surgery.

Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]Altanserin : results in young normal controls

Changes in serotonin-2 receptors have been demonstrated in brain autopsy material from patients with various neurodegenerative and affective disorders. It would be desirable to locate a ligand for the study of these receptors in vivo with positron emission tomography (PET). Altanserin is a 4-benzoylpiperidine derivative with a high affinity and selectivity for S2 receptors in vitro. Dynamic PET studies were carried out in nine normal volunteers with high-specific activity (376–1,680 mCi/μmol) [18F]altanserin. Arterial blood samples were obtained and the plasma time–activity curves were corrected for the presence of labeled metabolites. Thirty minutes after injection, selective retention of the radioligand was observed in cortical areas, while the cerebellum, caudate, and thalamus had low radioactivity levels. Specific binding reached a plateau between 30 and 65 min postinjection at 1.8% of the injected dose/L of brain and then decreased, indicating the reversibility of the binding. The total/nonspecific binding ratio reached 2.6 for times between 50 and 70 min postinjection. The graphical analysis proposed by Logan et al. allowed us to estimate the binding potential (Bmax/KD). Pretreatment with ketanserin was given to three volunteers and brain activity remained uniformly low. An additional study in one volunteer showed that [18F]altanserin can be displaced from the receptors by large doses of ketanserin. At the end of the study, unchanged altanserin was 57% of the total plasma activity. These results suggest that [18F]altanserin is selective for S2 receptors in vivo as it is in vitro. They indicate that [18F]altanserin is suitable for imaging and quantifying S2 receptors with PET in humans.

Comparison of [11C]Diprenorphine and [11C]Carfentanil Binding to Opiate Receptors in Humans by Positron Emission Tomography:

The kinetics and regional distribution of [11C]carfentanil, a μ-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at ∼40 min, whereas [11C]diprenorphine showed a linear increase until ∼60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of μ-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-μ sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the μ sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the δ- and κ-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace μ, δ, and κ subtypes, will help offset these limitations.

PET studies of patients with partial epilepsy: visual interpretation vs. semi-quantification/quantification

One of the advantages of PET is to allow for precise regional measurements of radioactive tracers in slices of brain. Furthermore, complex compartment modelling methods have been designed to transform the regional radioactive concentrations into biological units. The question is often raised whether quantification of PET studies is necessary in clinical practice. In epileptology, the regional biochemical changes associated with temporal lobe epilepsy are easily detected by experienced eyes and quantification is not required for diagnosis purposes. By contrast, inter‐patient or inter‐population comparisons can only be performed if regional measures have been obtained; if the PET method has been previously validated, simple measurements (regional activity) are sufficient and (kinetic) compartmental modelling is not necessary in routine.

Quantitative Analysis of 18/FDG-PET in the Presurgical Evaluation of Patients Suffering from Refractory Partial Epilepsy

CT, MRI, 18/FDG-PET and Depth. EEG, performed with subdural and depth electrodes were part of the presurgical evaluation in 22 patients. Statistical analysis of 18/FDG-PET was performed to compare cerebral utilization of glucose to that of normal age matched controls. The findings of CT, MRI, and quantitative analysis of PET are compared with those of ictal Depth. EEG. A positive correlation between CT and Depth. EEG was obtained in 23% of the patients and between MRI and Depth. EEG. in 50%. For both imaging techniques a negative correlation was found in 5%. Regional abnormalities were found with quantified PET in 95% of the patients and were concordant with Depth. EEG. for side of onset in 77% of the patients and for lobe of onset in 59%. A possibly false localising PET result for lobe of onset was obtained in 8 patients (36%). Limitations of PET were most apparent in patients with regional mesiolimbic or bilateral seizure onset. A favourable outcome of surgery was associated usually with positive convergence of both methods. PET may be a valuable contribution to the research and management of partial complex epilepsy, but at present cannot be considered a reliable alternative to invasive EEG methods in patients without clear unilateral focus localization on surface EEG.

Efficacy and safety of levetiracetam in clinical practice: Results of the SKATE™ trial from Belgium and The Netherlands

OBJECTIVE Aim of the study was to assess the efficacy and safety of levetiracetam as add-on treatment in patients with partial-onset epilepsy in clinical practice. METHODS In this observational, multi-centre study patients were treated with levetiracetam for 16 weeks. From a starting dose of 1000 mg/day, dose levels were adjusted at 2-weekly intervals in 1000-mg steps, to a maximum of 3000 mg/day, based on seizure control and tolerance. Analysis of efficacy was based on reduction in seizure frequency relative to baseline, 50% and 100% responder rates (for partial seizures and all seizure types combined) and percentage of patients using levetiracetam at the end of the study. Analysis of safety was based on occurrence of adverse events. RESULTS The present analysis concerns the results of patients recruited in Belgium and The Netherlands. Of the 251 patients included in the study, 86.9% completed 16 weeks of treatment. Reduction in frequency of partial-onset seizures was 62.2%, with 19.3% of the patients becoming seizure free and 56.6% having a reduction in seizure frequency of > or = 50%. These percentages were more or less the same when calculated for all seizure types combined. Tolerance of levetiracetam treatment was good, with most adverse events being only mild to moderate in severity, and only 10.0% of the adverse events leading to discontinuation from the study. Asthenia, somnolence, dizziness and headache were the most frequently reported adverse events. CONCLUSION Levetiracetam is effective and safe as add-on treatment for partial-onset seizures in clinical practice.

Detection and quantification of opiate receptors in Man by positron emission tomography. Potential applications to the study of pain

Opiate receptors in the brain are the target of endogenous opioids and of exogenous synthetic opiates. It is well established that these receptors play a major role in the modulation of pain perception. With positron emission tomography (PET) and the appropriate radioligands, it is now possible to image and quantify neuroreceptors in vivo. We used 11C-diprenorphine and the extremely potent mu opiate receptor agonist 11C-carfentanil to image the distribution of opiate receptors in the human brain and to quantify their density, affinity, and occupancy. Several important methodological aspects of the in vivo opiate receptor labeling with PET in relation to the study of pain are considered in this paper. Monitoring receptor occupancy by opiate drugs as a function of pain relief has the potential to reveal better ways to treat pain.

Is positron emission tomography a useful tool for studying migraine

Despite the high prevalence of migraine in the population, the pathophysiology of this condition remains poorly understood. Vascular changes have been postulated. With positron emission tomography and various radiotracers, it is possible to have a non-invasive access to a number of parameters of interest in migraine research. These are presented and discussed in this article. PET has great potential for answering some basic questions concerning the physiological or biochemical changes that can occur during and between migraine attacks. Few studies have been published, however, probably because of (i) limitations inherent to the technique and (ii) problems in study design.

Zerebrale Funktionen bei hirngeschädigten Patienten. Was bedeuten Koma

ZusammenfassungKomatöse, „Vegatative-state-“ (VS-), „Minimally-conscious-state-“ (MCS-) oder Locked-in-Patienten stellen ein Problem für die Diagnose, Prognose, Behandlung und tägliche Betreuung auf der Intensivstation dar. Am Patientenbett ist die Evaluation möglicher kognitiver Funktionen schwierig, weil willentliche Bewegungen möglicherweise sehr gering, unregelmäßig oder für die Patienten schnell erschöpfend sind. Funktionelle neurologische Bildgebungsverfahren können die klinische Einschätzung von Patienten mit veränderten Bewusstseinszuständen nicht ersetzen. Dennoch kann objektiv beschrieben werden, wie stark die zerebrale Aktivität und ihre regionale Verteilung in Ruhe und unter Stimulation vom Normalzustand abweichen. Durch Quantifizierung der Gehirnaktivität können Patienten differenziert werden, die sich manchmal nur durch ein kurzes und unvollständiges Blinzeln voneinander unterscheiden. Nach unserer Meinung werden Positronenemissionstomographie (PET) und die künftige Nutzung von „functional magnetic resonance imaging“ (fMRI) unser Verständnis schwer hirngeschädigter Patienten substanziell erweitern.AbstractComatose, vegetative, minimally conscious or locked-in patients represent a problem in terms of diagnosis, prognosis, treatment and everyday management at the intensive care unit. The evaluation of possible cognitive functions in these patients is difficult because voluntary movements may be very small, inconsistent and easily exhausted. Functional neuroimaging cannot replace the clinical assessment of patients with altered states of consciousness. Nevertheless, it can describe objectively how deviant from normal the cerebral activity is and its regional distribution at rest and under various conditions of stimulation. The quantification of brain activity differentiates patients who sometimes only differ by a brief and incomplete blink of an eye. In the present paper, we will first try to define consciousness as it can be assessed at the patient’s bedside. We then review the major clinical entities of altered states of consciousness encountered in the intensive care unit. Finally, we discuss the functional neuroanatomy of these conditions as assessed by positron emission tomography (PET) scanning.