Plans, designs, and analyses for clinical trials of anti-cocaine medications: where we are today. NIDA/VA/SU Working Group on Design and Analysis.

Increased interest in addiction psychopharmacology has raised unique methodologic issues in the design, conduct, and analysis of outcomes in clinical trials of therapeutic agents for drug dependence. This article summarizes issues raised at a meeting in Palo Alto, California, on November 4, 1996, that was sponsored by the Medication Development Division of the National Institute on Drug Abuse and the Department of Veterans Affairs Cooperative Studies Program to discuss the methodologic issues in clinical trials of cocaine pharmacotherapy.

Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.

We evaluated the efficacy and safety of gabapentin administered as monotherapy in an 8-day, randomized, double-blind, dose-controlled, parallel-group, multicenter study comparing dosages of 300 and 3,600 mg/d gabapentin in 82 hospitalized patients whose antiepileptic medications had been discontinued for seizure monitoring. Seizures under study were complex partial seizures with or without secondary generalization. Patients exited the study if they experienced a protocol-defined exit event indicating lack of efficacy. Time to exit was significantly longer (p = 0.0001) and completion rate was significantly higher (53% versus 17%; p = 0.002) for patients receiving 3,600 mg/d gabapentin. Gabapentin was well tolerated by patients in both dosage groups, and no patients exited the study due to adverse events, despite rapid initiation of full dose within 24 hours. These results demonstrate that gabapentin has anticonvulsant activity and is well tolerated when administered as monotherapy in patients with refractory partial seizures.

Gabapentin in generalized seizures.

The efficacy of gabapentin (Neurontin), in generalized seizures was evaluated in this 14 week, double-blind, placebo-controlled, parallel-group, add-on, multicenter study. A total of 129 patients with refractory generalized seizures were randomized to receive either placebo or 1200 mg/day gabapentin as add-on therapy. Patients received their standard regimens of antiepileptic drugs (AEDs) during a 12 week baseline period, and gabapentin or placebo was added-on in the subsequent 14 week evaluation period. Results of both an intent-to-treat (ITT) and evaluable-patient analyses showed that gabapentin provided greater reduction in the frequency of generalized tonic-clonic seizures than did placebo; however, the differences between treatments were not statistically significant. Gabapentin did not affect the frequency of absence or myoclonic seizures. Adverse events were reported by 67% of gabapentin-treated patients and by 56% of placebo-treated patients. The most frequently occurring adverse events among patients receiving gabapentin were somnolence, fatigue, and dizziness. Gabapentin is well tolerated by patients with generalized seizures. The results of this study show a trend toward an effect of gabapentin in reducing the frequency of generalized tonic-clonic seizures and suggest that further exploration of high dose gabapentin in generalized epilepsy is warranted.

The dynamics of metabolic change following seizures as measured by positron emission tomography with fludeoxyglucose F 18.

OBJECTIVE: To examine the time course of alterations in glucose metabolism in relation to the interval from the last seizure, focus laterality, seizure frequency, and seizure type. DESIGN: Metabolic study with the use of positron emission tomography with fludeoxyglucose F 18. Blinded scan evaluation with use of a standard template. Multivariate regression analysis of positron emission tomographic data. SETTING: National Institutes of Health Clinical Center, Bethesda, Md. PATIENTS: Thirty-two adults with intractable partial epilepsy and lateralized seizure onset documented by video-electroencephalographic monitoring. MAIN OUTCOME MEASURE: Normalized metabolic rate for glucose ipsilateral and contralateral to the epileptic focus. RESULTS: The most dramatic changes occurred in inferior temporal regions; the midtemporal region was affected as well. Effects lasting 48 hours were found after both simple and complex partial seizures. The time course was different for the two types of seizures. The inferior temporal metabolic rate ipsilateral to the focus increased compared with the interictal rate during the 24-hour period following simple partial seizures; a nadir occurred in the second 24 hours. The rate then rose to an intermediate level after 48 hours. The relative to an intermediate level after 48 hours. The relative regional increase in ipsilateral metabolism following complex partial seizures persisted for 48 hours before falling. CONCLUSION: The brain may take longer than 24 hours after a partial seizure to return to its baseline state.

Gabapentin as add-on therapy for refractory partial epilepsy: results of five placebo-controlled trials.

Gabapentin (GBP, Neurontin), a new antiepileptic drug (AED) with a novel mechanism of action, exhibits low acute toxicity in mice, rats, and monkeys, and is not teratogenic. GBP pharmacokinetics are simple and predictable; GBP is eliminated by urinary excretion, is not protein-bound or metabolized, does not induce or inhibit hepatic enzymes, and does not interact with other AEDs. In five placebo-controlled, double-blind studies of GBP as add-on therapy, 307 patients with refractory partial seizures received placebo and 485 received GBP dosages of 600, 900, 1,200, or 1,800 mg/day for 12 weeks following a 12-week baseline. Seizure frequency, as measured by response ratio and responder rate, was improved for patients receiving GBP compared with placebo; differences were statistically significant in two of the three large, multicenter studies. Adverse events occurred in 76% of GBP-treated patients, compared with 57% of placebo-treated patients. No serious adverse events were consistently attributable to GBP therapy. Changes in clinical laboratory values were not considered clinically important. GBP represents a significant addition to the armamentarium of AEDs available for treatment of patients with epilepsy.

Temporal lobectomy for uncontrolled seizures: the role of positron emission tomography.

We evaluated the role of positron emission tomography (PET) with [18F]deoxyglucose (FDG) (FDG-PET) for planning surgery in 53 patients who had temporal lobectomy for uncontrolled seizures at National Institutes of Health from 1981 to 1990. Investigators blinded to PET data used results of telemetered video-electroencephalographic ictal monitoring and other standard criteria to decide whether subdural electrodes (22 patients, i.e., the "invasive" group) should be implanted or surgery performed. PET scans were analyzed using a standard regional template. Mean lateral but not mesial temporal asymmetry was significantly higher in patients who became seizure free (p < 0.03). Patients with > or = 15% hypometabolism were significantly more likely to be seizure free in the entire study population and the invasive subgroup. Visual identification of hypometabolism was less accurate. When a clear temporal ictal surface electroencephalographic focus was present, FDG-PET provided less additional information. FDG-PET may be particularly valuable if the surface electroencephalographic scan is nonlocalizing. In addition to helping to identify the seizure focus, it may allow limitation of invasive electrode placement to those necessary for functional mapping. When PET is used to identify epileptic foci, quantitative measurements of asymmetry should be made.

Comparison of PET measurements of cerebral blood flow and glucose metabolism for the localization of human epileptic foci.

We compared the relative sensitivity of two interictal PET techniques, bolus injection of [15O] labeled water for estimation of cerebral blood flow (H2(15)O CBF-PET), and 18F 2-deoxyglucose (18FDG-PET) for cerebral glucose metabolism (CMRglc), and T2-weighted magnetic resonance imaging, in 28 patients with medically intractable complex partial seizures undergoing evaluation for surgery. There were statistically significant associations between lateralization by 18FDG-PET, and MRI, but not H2(15)O CBF-PET, and lateralization of the epileptic focus as defined by scalp-sphenoidal ictal EEG. Fifteen patients had surgery or subdural electrodes. 18FDG-PET was more closely associated with a good outcome than H2(15)O CBF-PET, which, in addition, showed hypoperfusion contralateral to the epileptic temporal lobe in several cases. H2(15)O sensitivity may have been reduced by technical factors, but 18FDG-PET appears to be more specific for localization of epileptic zones.

PET imaging of opiate receptor binding in human epilepsy using [18F]cyclofoxy.

We used [18F]cyclofoxy (CF), a potent opiate antagonist with affinity for mu and kappa receptors, and the Scanditronix PC1024-7B PET scanner to study 14 patients with complex partial seizures (CPS), and 14 normal controls. Epileptic foci were localized by prolonged EEG-video monitoring. EEG was recorded continuously during each scan. Immediately before CF administration, [15O]labeled water was used to measure cerebral blood flow, and showed hypoperfusion ipsilateral to the EEG focus. Blood samples (corrected for radiolabeled metabolites) and tissue time-activity data were acquired over 90 min following bolus CF injection. Anatomic regions were outlined directly on the PET images. A kinetic model was used to derive the total volume of distribution (Vt) in each brain region. Specific binding (Vs) was determined by substracting non-specific binding (Vt) measured in a receptor-poor brain region (occipital cortex). Regions with high Vs included mesial temporal lobes, thalamus, basal ganglia, and frontal cortex. Individual patients appeared to have higher binding in temporal lobe ipsilateral to the EEG focus, but there was no asymmetry for the patients as a group in mean Vt or Vs in anterior mesial, posterior mesial, anterior lateral, posterior lateral temporal cortex, thalamus, basal ganglia, or, for Vt, in regions of low specific binding: occipital lobe, parietal lobe, cerebellum.

Cerebral metabolism and depression in patients with complex partial seizures.

Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

Effect of valproate on human cerebral glucose metabolism.

We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had two positron-emission tomography (PET) scans with 18F-2-deoxyglucose (FDG), with, and without, VPA (mean level 52 mg/dl, range 30-127 mg/dl). Patients continued carbamazepine (CBZ) for both scans: serum concentrations were not significantly changed by VPA (CBZ range 5.4-12 mg/dl). Seven patients had the "without-VPA" scan first. Mean interval between PET scans was 75 days. Global CMRglc was decreased by 22% by addition of VPA (7.2 +/- 1.8 mg/100 g/min without VPA, 5.6 +/- 1.1 g/min with VPA, p less than 0.05, corrected). Thirteen regions of interest (ROIs) were analyzed in each hemisphere in each PET scan. Metabolic rates were significantly lower in 15 of 26 ROIs with VPA (p less than 0.05, corrected). VPA depresses cerebral metabolism to a greater degree than do CBZ and phenytoin (PHT) but less than does phenobarbital (PB). The metabolic effect may be related to the mechanism of action and have neuropsychological implications.

Cerebral activation during speech discrimination in temporal lobe epilepsy.

Eight patients with uncontrolled complex partial seizures underwent positron emission tomography with 18-fluoro-2-deoxyglucose both at rest and during an auditory order discrimination task using speech syllables. Eight age-matched controls were scanned under identical conditions; an additional 18 normal subjects were scanned only at rest. No consistent task-related changes were seen in control subjects. For the 3 patients with left temporal epileptogenic foci, left inferior temporal lobe hypometabolism was more evident during the activated than during the resting scan. Activation procedures may augment the diagnostic yield of metabolic scanning in epilepsy.

Congenital mirror movements. Abnormal organization of motor pathways in two patients.

We studied 2 patients with congenital mirror movements by means of various neurophysiological and metabolic techniques, including mapping of motor evoked potentials to transcranial electrical and magnetic stimulation, premovement and somatosensory evoked potentials, kinematics of voluntary movements, muscle reflexes, and positron emission tomography (PET). Abnormalities in maps of motor and premovement potentials and in PET scans were consistent with a bilateral representation of hand muscles in the motor cortex, the existence of physiologically active connections capable of conducting fast efferent volleys from the motor cortex to ipsilateral muscles, the presence of mirror EMG activity in either hand with intended voluntary movement of the other hand, the absence of mirrored EMG responses from wrist flexors and extensors to mechanical perturbation of the contralateral wrist, and normal scalp distribution of somatosensory evoked potentials to right and left median nerve stimulation. Our findings are consistent with aberrant organization of motor representation areas and corticospinal pathways with ipsilateral as well as contralateral control of voluntary movement.

Neuroendocrinology and limbic epilepsy: relationships to psychopathology, seizure variables, and neuropsychological function.

Correlations were sought among neuroendocrine, psychopathologic, neuropsychological, and seizure variables in 16 male patients with limbic epilepsy. Plasma prolactin and luteinizing hormone levels were directly correlated with seizure frequency. Plasma prolactin was inversely correlated with thought disorder. Post hoc findings included a strong direct correlation between total plasma testosterone levels and aggression. These relationships may help to elucidate mechanisms related to interictal symptomatology in patients with limbic epilepsy.

Psychopathology and limbic epilepsy: relationship to seizure variables and neuropsychological function.

Correlations were sought among psychopathologic, neuropsychological, and seizure variables in 21 patients with limbic epilepsy. Observer-based assessments, such as the Bear-Fedio Inventory, and self-report assessments of psychopathology were used. Self-reported psychotic experiences were associated with increased seizure frequency. Increased religiosity was noted in patients whose epileptic focus included the left side. Increased neuropsychological impairment was associated with several measures of psychopathology, including those related to thought disorder, psychoticism, and affective disturbance.

Sporadic Creutzfeldt-Jakob disease in two coworkers.

We report the coincidence of pathologically confirmed sporadic CJD in two unrelated schoolteachers who shared a school wing for 9 months. The first developed ataxia, tremulousness, and dementia 5 months after his last contact with his colleague. Diagnosis of CJD was made 2 months later by brain biopsy. Eight months later, the second teacher developed similar symptoms and died after 9 months. Whether this unique coincidence reflects mere chance or some form of direct viral transmission is unknown. Continued epidemiologic surveillance for any future "coincidence" is warranted.