A kinetic method is described for the estimation of neuroreceptor density as well as the rate constants for association and dissociation of rapidly equilibrating radioligands. The method is exemplified by positron emission tomographic measurements of the human brain using 11C-raclopride, a D 2 dopamine receptor antagonist, and 11C-Ro 15-1788, a benzodiazepine receptor antagonist. Using a linear non iterative algorithm, regional binding characteristics were calculated and displayed pixel by pixel in brain maps. Data from repeated experiments on the same subject with different amounts of the unlabeled ligand were utilized. The binding characteristics were determined according to a two step procedure in which the time course of the free radioligand concentration was estimated from a reference region considered to be free of specific receptor binding sites. Alternative methods to determine the concentration of free radioligand are discussed.

3H-Ro 15-1788, a benzodiazepine receptor antagonist, was injected IV into male and pregnant mice. Autoradiograms were prepared from sagittal sections of animals killed after 30 s to 48 h. In the adult animal there was a rapid and high initial accumulation of radioactivity in the brain as compared to other organs and tissues. The highest accumulation was found in cortical brain areas, such as the olfactory bulb and the frontal cortex. Cerebellar cortex, globus pallidus, amygdala, substantia nigra, colliculus, hippocampus and pons followed in rank order. The rate of decline of radioactivity was highest in the pons and lowest in the olfactory bulb. The initial disappearance of radioactivity from the cerebellum was higher than from the other brain regions. Ro 15-1788 was rapidly eliminated; 4 h after drug administration there was an almost complete clearance of radioactivity from all tissues. After 24 h no trace of activity remained in the animal. The distribution of radioactivity at later time points indicates that metabolites of Ro 15-1788 are eliminated by fecal, urinary and nasal secretion. In the fetus also there was an early accumulation of radioactivity in the central nervous system. The radioactivity in fetal organs was lower than in the mother at all time intervals.

Summary: Purpose : We wished to evaluate the prognostic usefulness of various EEG parameters with respect to remission rates after discontinuation of antiepileptic drug (AED) therapy in children treated for epileptic seizures. Methods : Two hundred forty‐four children with uncomplicated epileptic seizures were randomized to either 1 or 3 years of treatment with AEDs. The treatment was then discontinued in patients who had been seizure‐free during the last 6 months of their allotted time of treatment (n = 154). After treatment discontinuation, the children were followed for at least 2 years. EEG recordings were performed before treatment was initiated and at regular intervals during treatment. Results : The overall relapse rate was 37%. In many children, the amount of epileptiform activity varied considerably between subsequent recordings made during the treatment. The remission rate was slightly higher for children whose last recordings before AED discontinuation were free of epileptiform activity as compared with children in whom such activity was present. However, children who had irregular generalized spike–wave (SW) activity in the recordings made before discontinuation of treatment had a clearly higher relapse rate (67%) both as compared with children without epileptiform activity (33%) and as compared with children with other types of epileptiform activity (33%) in their last EEG recordings before discontinuation. All children treated for only 1 year whose final EEGs displayed generalized irregular SW activity relapsed. Conclusions : We conglude that the presence of epileptiform activity does not in itself necessarily influence prognosis after discontinuation of treatment but that certain types of such activity signal a high risk of relapse.

In order to study the long‐term development of diabetic neuropathy in children with newly diagnosed diabetes mellitus, 144 children were entered in a prospective study of nerve conduction and autonomic nervous function. Neurophysiological recordings of nerve conduction and parasympathetic function (R‐R variations) were made at onset of diabetes and after 2, 5 and 10 years. Low sensory nerve conduction and autonomic dysfunction were found in approximately 25% of the children at onset of diabetes when the patients were not yet in complete remission. During years 0–2, an initial improvement of sensory conduction velocities was found. After 2 years, deteriorations in sensory and motor nerve conduction and autonomic nerve function were common and further deterioration was seen over time. A correlation was found between nerve conduction and glycaemic control.

Purpose: The main purpose of this prospective study was to analyze whether 1 year of treatment was as effective as 3 years with respect to remission rate in children with idiopathic epilepsy.Methods: Treatment for epileptic seizures was started in 207 children aged 2-16 years, They were randomized to treatment for 1 or 3 years. At the end of the predetermined treatment period, 161 children had been seizure-free for 6 months and the treatment could be gradually withdrawn.Results: The overall remission rate in our group of patients was significantly higher (71%) in the group treated for 3 years than in the group treated for 1 year (53%). However, comparison of remission rates between patients with different seizure types showed statistically significant differences in outcome depending on duration of treatment only in children with complex partial seizures (CPS).Conclusions: Our results show that 1 year of treatment can be recommended in children with benign partial epilepsy with rolandic spikes (BECT) and in children with simple partial seizures (SPS) but is clearly insufficient in children with CPS, A proper seizure classification is one important tool, although not sufficient, in offering recommendations concerning the duration of treatment in children with idiopathic epilepsy.

Conventional (visual) analysis of EMG was compared to a computerized quantitative method (turns/amplitude). Ten patients with a clinical history of peripheral nerve lesion were examined in order to investigate whether quantitative analysis of EMG increased the diagnostic sensitivity of peripheral nerve lesions to the laryngeal muscles. Quantitative analysis either agreed with conventional analysis or resulted in false negative diagnosis compared to conventional analysis. Thus, conventional analysis turned out to be more sensitive to neurogenic damage than the quantitative method. EMG results were compared to clinical findings.

An index based on 12 electrophysiological parameters (conduction velocities, F-latencies, and amplitudes) was constructed to obtain an overall estimation of peripheral nerve conduction. The index was expressed as the mean deviation (in SD) compared to controls standardized for age or height. The stability of the index was tested by repeated examinations during intervals of several months in healthy subjects. The use of a compound index enabled detection of slight impairments of nerve conduction. The relatively low interrecording variability of the index makes it suitable to follow the progression of a polyneuropathy.

Eighteen patients with long-standing insulin-dependent (type 1) diabetes mellitus and polyneuropathy were studied after combined pancreatic and renal transplantation. Repeated tests were performed on peripheral nerve function (electroneurography) and on autonomic function (R-R test) 6 mo and 1, 2, and 4 yr after the transplantation. Eighteen diabetic patients with only a kidney graft served as controls. After initial improvement of nerve conduction in both groups, probably caused by the elimination of uremia, further improvement was seen only in the euglycemic pancreas-graft recipients. Improvement of autonomic (parasympathetic) function was slight after 48 mo and was similar in both groups.

CNS conduction and autonomic nervous function were investigated in 15 patients with HMSN I. Central motor conduction time (CMCT) was estimated with magnetic brain stimulation and electrical nerve root stimulation. Somatosensory evoked potential (SEP) and visual evoked potential (VEP) were used for assessment of central sensory and visual conduction. Autonomic effector organ functions were assessed with the R-R variation test for parasympathetic function, and the sympathetic skin response test (SSR) for skin sympathetic sudomotor activity. Five of the patients had prolonged CMCT. Central sensory conduction was normal in 3, and slightly prolonged in 1 of the patients, but could not be estimated in 11 due to lack of response from the cervical recording. VEP was abnormal in 2 patients. R-R variations during normal breathing were low in 8 of 15 patients, and low also during deep breathing in 1 of 15. The SSR test was pathological in 5 of 15 patients. Thus, impaired central conduction and/or autonomic dysfunction was not an uncommon finding in patients with HMSN I.

We have studied the fate of diabetic neuropathy and autonomic function in 13 patients with long standing Type 1 (insulin-dependent) diabetes mellitus following combined pancreas and kidney transplantation. Fifteen diabetic patients with a kidney graft only served as controls. After initial improvement of the neuropathy in both groups, probably caused by the elimination of uraemia, a continuous improvement during the 48 months study was seen in the euglycaemic pancreas graft recipients only. Autonomic (parasympathetic) function improved only slightly and to a similar extent in both groups.

In vitro autoradiography of a 11C-labelled ligand, Ro 15–1788, was used in saturation experiments in order to quantify benzodiazepine receptor binding in whole human brain hemisphere cryo-sections. A special incubation chamber was developed with the aim of performing standardized quantitative studies with short-lived positron emitting isotopes. 11C-labelled ligand binding was studied in temporal cortex, cerebellum, white matter and pons incubated in vitro. White matter, lacking benzodiazepine receptor binding, was used as an estimate of nonspecific binding, for calculation of specific binding. Saturability of binding was demonstrated in the neocortical and cerebellar regions. Radioactivity counting of incubated adjacent tissue sections was done as a control. Computerized densitometry of the autoradiograms gave similar results as the tissue counting. A comparison with in vivo saturation experiments using the same 11C-labelled ligand and positron emission tomography in healthy human subjects also gave binding characteristics of the same magnitude. The 11C-autoradiograms showed a good spatial resolution (about 180 μm). 11C-autoradiography with suitable radioligands should be a valuable technique of screening the distribution and characteristics of neuroreceptors in the human brain. This quantitative method will provide the PET investigator with preliminary binding data, and may thus supply valuable information concerning positioning in PET and concerning significant regions of interest.

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)

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine-3 (M3G) and morphine-6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half-life of morphine was 4.2 h (95% CI 3.6-4.8) the mean volume of distribution was 4.1 l kg-1 (95% CI 2.9-5.4) and the mean plasma clearance was 11.4 ml min-1 kg-1 (95% CI 8.1-14.7). The mean oral bioavailability was 101% (95% CI 56-147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half-life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.

Positron emission tomography (PET) is a brain imaging technique which is at least 1000 times more sensitive than nuclear magnetic resonance (NMR). Today NMR can produce images of structures of the brain, but whether or not functional NMR will become clinically relevant still has to be proven. PET can give information about functional events in the brain of individual living patients. In PET, probes are used to study brain function. These probes are introduced into the central nervous system by intravenous injection, having been selected to follow and participate in the various aspects of biochemical processes in the brain that are to be studied. The probes are ordinary organic molecules which can be followed when labelled with a specific type of isotope called a positron emitting isotope. Ordinary radioactive isotopes cannot be used since the radiation from such isotopes does not pass through the skull bone. But positrons, the particles which are released from disintegrating positron emitting isotopes, can be recorded because when they collide with electrons in the tissue, gamma radiation is produced by the annihilation of antimatter and matter. The gamma radiation moves from the inside of the brain out toward the detection devices, which can be placed in rings around the head. Thus, PET is a technique by which the emission of gamma radiation from compounds labeled with specific isotopes is studied. These isotopes also have the advantage of being short-lived.

The 11C‐labelled benzodiazepine antagonist Ro 15–1788 (flumazenil) and positron emission tomography (PET) were used to determine quantitative characteristics of benzodiazepine receptor binding in the neocortex of healthy young men. Saturating doses of unlabelled flumazenil administered i.v., before or together with the ligand‐reduced 11C‐flumazenil accumulation in the neocortex by about 90 per cent. Saturating doses of unlabelled flumazenil had little effect on the accumulation of radioactivity in the benzodiazepine receptor‐poor regions such as pons or white matter. By giving graded doses of unlabelled flumazenil together with the tracer, saturation isotherms were obtained allowing the calculation of receptor density (Bmax) and equilibrium dissociation constant (Kd) values on the basis of certain assumptions Bmax values were in the order of 90 pmol/g and Kd values in the order of 10 nM in the neocortex. Scatchard and Hill plots of the radioactivity data indicated that 11C‐flumazenil binds to saturable sites of a homogeneous population. The data indicate that intravenous doses of 1 or 2 mg flumazenil result in a benzodiazepine receptor occupancy of about 50 per cent. The method described should be useful for studying regional differences in benzodiazepine receptor characteristics in the living human brain in healthy subjects and neuropsychiatric disorders, and also in relation to treatment with drugs interacting with benzodiazepine receptors.

The effects of 2 and 5 days of total parenteral nutrition (TPN; 70 g amino-acids, 100 g fat, 150 g glucose) on carbohydrate, fat and amino-acid levels and on cerebral function were investigated in 10 patients with alcoholic cirrhosis and 7 age-matched healthy controls. The results were compared to those after a standardised oral diet.

The metabolic fate of the benzodiazepine antagonist RO 15‐1788 labelled with 11C was studied in plasma from human subjects after intravenous administration in connection with positron emission tomography. Ro 15–1788 and its metabolites were separated by thin‐layer chromatography and the radioactivity in the different compounds was determined. 11C‐Ro 15–1788 was extensively and rapidly metabolised to the corresponding free acid. At 36 minutes after administration only 50% of the radioactivity in plasma represented unchanged compound.

Visual evoked potentials (VEP) have been suggested to be of value in the diagnosis of subclinical and mild hepatic encephalopathy. In the present study, a comparison between VEP and four psychometric tests (number connection test A and B, digit symbol and word memory test) was periormed in 42 cirrhotic patients, 17 of whom had clinical signs of encephalopathy. The results were compared to sex- and age-matched healthy controls. The VEP latencies for P2 (the second positive wave) and N3 (the third negative wave) were 11% and 26% longer (P < 0.01–0.001) in the patients than in the controls. Moreover, the latencies for N2 (the second negative wave) and P2 were longer in the encephalopathic as compared to the non-encephalopathic patients (P < 0.05). There was a significant correlation between the latencies for N2 and number connection tests A and B and digit symbol test. However, of the patients with clinical encephalopathy, less than half had VEP latencies longer then the mean ± 2 S.D. above those for the controls. In contrast, none of the encephalopathic patients had normal results on the psychometric tests. This study demonstrates that although statistically significant differences exist between groups of cirrhotic patients and controls, VEP is not a reliable tool for the diagnosis of encephalopathy in the individual patient.