Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. METHODS: The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. RESULTS: Median percent reduction was -28.7% for placebo, -38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and -42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: -13.3%; 1200 mg: -34.5%, P = 0.02; 2400 mg: -52.7%, P = 0.006) in the North American study site cluster. A concentration-response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals. CONCLUSIONS: Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC.

Rank-related maternal effects of androgens on behaviour in wild spotted hyaenas.

Within any hierarchical society, an individual's social rank can have profound effects on its health and reproductive success, and rank-related variation in these traits is often mediated by variation in endocrine function. Maternal effects mediated by prenatal hormone exposure are potentially important for non-genetic inheritance of phenotypic traits related to social rank, and thus for shaping individual variation in behaviour and social structure. Here we show that androgen concentrations in wild female spotted hyaenas (Crocuta crocuta) are higher during late gestation in dominant females than in subordinate females. Furthermore, both male and female cubs born to mothers with high concentrations of androgens in late pregnancy exhibit higher rates of aggression and mounting behaviour than cubs born to mothers with lower androgen concentrations. Both behaviours are strongly affected in other mammals by organizational effects of androgens, and both have important effects on fitness in hyaenas. Therefore, our results suggest that rank-related maternal effects of prenatal androgen exposure can adaptively influence offspring phenotype in mammals, as has previously been shown to occur in birds. They also suggest an organizational mechanism for the development of female dominance and aggressiveness in spotted hyaenas, traits that may offset the costs of extreme virilization.

A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Vigabatrin Protocol 024 Investigative Cohort.

This study compared the efficacy and tolerability of vigabatrin 3/day as add-on therapy with that of placebo in patients with focal epilepsy whose complex partial seizures were difficult to control with established antiepilepsy drug therapy. We enrolled 203 patients; 182 (90 placebo; 92 vigabatrin) received drug therapy under double-blind conditions. We increased the daily dosage to 2.5 g/day during a 4-week titration segment and maintained it at 3 g/day during the 12-week maintenance segment. By analyses we found a statistically significant lower frequency of seizures (complex seizures plus partial seizures secondarily generalized) at the end of the study for patients receiving vigabatrin than for those receiving placebo. The median monthly frequency was reduced by three seizures per 28 days in the placebo group (baseline, 8.3; end of study, 7.5) (p = 0.0002). Therapeutic success (a 50% reduction from baseline in mean monthly seizure frequency) was attained in 40 of the vigabatrin patients (43%) compared with 17 of those treated with placebo (19%) (p < 0.001). Vigabatrin significantly increased the mean number of seizure-free days per 28 days (2.2 days) compared with placebo (0.5 days) (p = 0.0024). Mean trough serum vigabatrin concentration during therapy was 8.6 +/- 7.7 micrograms/ml. The oral clearance of vigabatrin was determined to be 7.8 L/hr, and the elimination half-life was 8.4 hours. No clinically important changes in MRI, evoked potential, or other laboratory tests were noted during vigabatrin treatment. The results of this study indicate that 3 g/day vigabatrin is more effective than placebo as add-on therapy. Vigabatrin was well tolerated, compliance was high with twice-daily administration, and therapy did not result in clinically relevant drug interactions.

The syndrome of frontal lobe epilepsy: characteristics and surgical management.

We reviewed the historical features, preoperative diagnostic evaluation, operative procedure, and surgical outcome in 16 patients with refractory frontal lobe epilepsy. Clinical expression of the epilepsy varied widely, particularly with respect to seizure characteristics, although high monthly seizure frequency and absence of a risk factor for epilepsy before age 5 occurred more often than in reported in temporal lobe epilepsy patients. Seizures often caused early bilateral movements, were brief, and lacked oroalimentary automatisms and a prolonged postictal state. Both the interictal and ictal scalp EEGs had relatively poor sensitivity and specificity and often either contained no epileptiform abnormalities or were misleading. MRI usually identified structural lesions when these were present, although it was negative in two patients with tumors. In the absence of an MRI lesion, intracranial EEG usually identified the area to be resected, although it too provided misleading information in one case. Surgical procedures consisted of focal resections with or without anterior corpus callosotomy, or of corpus callosotomy alone. Nearly all patients improved after surgery, with a majority (67%) becoming seizure-free (average follow-up, 46 months). Preoperative seizure frequency correlated with seizure relief after surgery, as did age of seizure onset, whereas presence of tumor did not. We conclude that frontal lobe epilepsy warrants aggressive investigation and that surgical treatment often can be successful.

Occupational outcome after temporal lobectomy for refractory epilepsy.

We evaluated employment after temporal lobectomy for refractory epilepsy in 86 patients (3.5 to 8 years of follow-up). Seventy-three patients qualified for the work force before and after surgery. Unemployment rates declined after surgery (18 patients [25%] unemployed before surgery, eight patients [11%] unemployed after surgery), and underemployment also tended to diminish. Improvement in occupational status related strongly to the degree of postoperative seizure relief. Seizure-free patients fared better (no unemployment, little underemployment) than patients with some seizure-free years and some years with seizures after surgery, whose high underemployment level persisted. Patients with seizures in each year after surgery fared worst (despite reduced seizure frequency), with increased unemployment after surgery. Age at surgery also influenced vocational outcome in patients who were unemployed before surgery. Historical, educational, cognitive, and behavioral measures did not correlate with vocational outcome. Employment gains came slowly; unemployed patients took up to 6 years to obtain work after surgery. Of 13 students at the time of surgery, 11 have graduated and nine are now employed. We conclude that seizures play a large role in limiting employment, and that by alleviating seizures, temporal lobectomy improves employability in people with refractory epilepsy. Surgery thereby provides benefit to individuals with epilepsy by increasing financial independence and to society by reducing unemployment.

Seizures in temporal lobe epilepsy: I. Reliability of scalp/sphenoidal ictal recording.

We determined both (1) the reliability (reproducibility) of seizure onset location in patients with temporal lobe recorded with extracranial EEG and (2) if interictal spike (IIS) location influences that reliability. EEGs were recorded with the 10-20 system and sphenoidal electrodes. Between 1985 and 1993, 166 patients with suspected temporal lobe epilepsy were eligible for inclusion with a total of 734 seizures recorded. Each seizure onset was classified as either localized, lateralized, or nonlocalized. Individual patients were then grouped according to interictal spike location (i.e., unilateral, bilateral, or none) as well as by ictal onset reproducibility patterns (i.e., concordant, semiconcordant, conflicting, or nonlocalized) based on each patient's monitoring session. Seizure onset location was reproducible in 68% of the cases and variable patterns of seizure onset were seen in 32% of patients. Patients with unilateral IIS (68%) were more likely to have consistent ictal onset patterns than patients with bilateral IIS (27%). The first seizure more often predicted subsequent seizure onset patterns when it was localized than when it was nonlocalized. Of 18 patients with conflicting temporal lobe seizures, up to four seizures were necessary to detect independent bilateral temporal lobe seizures.

Predictors of outcome after anterior temporal lobectomy: the intracarotid amobarbital test.

The intracarotid amobarbital test (IAT) examines hemispheric memory and language. We set out to determine whether memory performance on the IAT correlated with seizure relief after anterior temporal lobectomy in 117 patients with refractory epilepsy. The IAT assessed recognition memory performance for nine items with correction for false-positive recognitions. We then compared performance of one hemisphere with that of the other, defining a correctly lateralized memory deficit as worse performance when using the hemisphere containing the operated temporal lobe than when using the other hemisphere. The analysis included concurrent factors that might also affect outcome, such as age at first risk for epilepsy, presence or absence of tumor, and Full Scale IQ. A discriminant function analysis demonstrated that patients with a correctly lateralized memory deficit on the IAT had an increased probability of being seizure-free following surgery after controlling for other predictors. The performance of the nonoperated temporal lobe related to outcome, although less strongly. The magnitude of the difference in performance between the two hemispheres and the performance of the operated hemisphere did not relate to outcome. Patients who became seizure-free had an earlier age at first risk than did those with persistent seizures, and tumor presence weakly correlated with postoperative outcome. IQ did not correlate with outcome. We conclude that the IAT predicts seizure relief after anterior temporal lobectomy independent of other known risk factors we examined.

A noninvasive protocol for anterior temporal lobectomy.

We report the results of a protocol for choosing candidates for temporal lobectomy using a standard battery of objective tests without intracranial electrodes. We assigned each test a level of importance, and an algorithm was used to determine whether temporal lobectomy could be performed. Fifty-one patients (total pool, 103 patients) met protocol requirements and had an anterior temporal lobectomy with a mean follow-up of 39.4 months (range, 21 to 64 months), most remaining on anticonvulsant therapy. Eighty percent are seizure free, 12% have less than 3 seizures per year or only nocturnal seizures, and 8% have greater than 80% reduction in seizure frequency. One-third of patients who failed protocol criteria did not have temporal lobe seizures when studied with intracranial electrodes. We analyzed and modified the algorithm after comparing these patients with others who were poor candidates for temporal lobectomy. We conclude that this protocol is effective and recommend using such an objective algorithm.

Hemispheric asymmetries in arousal affect outcome of the intracarotid amobarbital test.

OBJECTIVE: To evaluate changes in arousal and their impact on memory performance during the intracarotid amobarbital test (IAT). METHODS: Along with memory measures, level of arousal was evaluated through clinical ratings and nonverbal self-ratings in epilepsy patients undergoing IAT before anterior temporal lobectomy. RESULTS: Irrespective of seizure focus, left-sided amobarbital injection resulted in decreased objective and subjective arousal more often than right-side injection. Impaired objective arousal was greater when the left hemisphere was injected second, because of the presumed additive effects of systemic amobarbital residual from the first injection. Decreased objective arousal was related to poorer performance on memory testing following left-hemisphere injection. CONCLUSIONS: The IAT, as practiced in most centers, is biased, so patients with right temporal lobe seizure focus are more likely to "pass" the test, whereas patients with left seizure focus are more likely to "fail" the test. The significant impact of changes in arousal on memory testing needs to be considered when using IAT results to select patients for temporal lobectomy.

Functional MRI lateralization of memory in temporal lobe epilepsy.

OBJECTIVE: To determine the feasibility of using functional magnetic resonance imaging (fMRI) to detect asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy (TLE). BACKGROUND: Assessment of mesial temporal lobe function is a critical aspect of the preoperative evaluation for epilepsy surgery, both for predicting postoperative memory deficits and for seizure lateralization. fMRI offers several potential advantages over the current gold standard, intracarotid amobarbital testing (IAT). fMRI has already been successfully applied to language lateralization in TLE. METHODS: fMRI was carried out in eight normal subjects and 10 consecutively recruited patients with TLE undergoing preoperative evaluation for epilepsy surgery. A complex visual scene encoding task known to activate mesial temporal structures was used during fMRI. Asymmetry ratios for mesial temporal activation were calculated, using regions of interest defined in normals. Patient findings were compared with the results of IAT performed as part of routine clinical evaluation. RESULTS: Task activation was nearly symmetric in normal subjects, whereas in patients with TLE, significant asymmetries were observed. In all nine patients in whom the IAT result was interpretable, memory asymmetry by fMRI concurred with the findings of IAT including two patients with paradoxical IAT memory lateralization ipsilateral to seizure focus. CONCLUSIONS: fMRI can be used to detect asymmetries in memory activation in patients with TLE. Because fMRI studies are noninvasive and provide excellent spatial resolution for functional activation, these preliminary results suggest a promising role for fMRI in improving the preoperative evaluation for epilepsy surgery.

Ventricular asystole during vagus nerve stimulation for epilepsy in humans.

Electrical stimulation of the vagus nerve, a recently available option for patients with refractory epilepsy, has demonstrated safety and efficacy. We report four patients with refractory epilepsy who experienced ventricular asystole intraoperatively during initial testing for implantation of the vagus nerve stimulator. Acute intraoperative vagus nerve stimulation may create ventricular asystole in humans. Extracorporeal cervical vagus nerve stimulation testing with continuous EKG monitoring intraoperatively before generator implantation is warranted.

The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy.

Phenotypic heterogeneity in hypertrophic cardiomyopathy (HC) makes definitive diagnosis difficult, particularly during family screening. We studied the electrocardiogram (ECG) as a potential initial screening test in patients with HC. Using accepted diagnostic criteria, we examined the ECGs and echocardiograms of 159 patients with a confirmed clinical or genetic diagnosis of HC. An abnormal ECG was found in 154 patients (97%) while only 146 (92%) showed an abnormal echocardiogram. Of the former, 9 patients (6%) had normal echocardiograms and had been diagnosed on the basis of identification of a mutation in the beta myosin heavy chain gene (n = 8) or obligate carrier status (n = 1). Only 1 of these 9 patients was under age 20, the time at which hypertrophy is normally expressed on the echocardiogram. The remaining 5 patients (3%) without ECG abnormality consisted of 1 patient with an echocardiogram clearly diagnostic of HC and 4 clinically normal patients (aged 13, 24, 29, and 33 years) with normal echocardiograms who had been diagnosed by mutation identification (n = 3) or obligate carrier status (n = 1). Thus only these latter 4 patients (3%) would not have been diagnosed as having HC based on an abnormal ECG and/or abnormal echocardiogram. Screening relatives for HC by ECG criteria alone detects all those whom an echocardiogram will diagnose. While echocardiography aids in the specificity of HC diagnosis, the ECG, within the context of a family with a proven case of HC, is a more sensitive marker of the disease. It is therefore both a cost-effective and useful tool for screening those to proceed to echocardiography.

Prenatal alcohol and stress interact to attenuate ejaculatory behavior, but not serum testosterone or LH in adult male rats.

Restraint stress reduced blood alcohol levels in pregnant rats given a liquid alcohol diet. The male offspring prenatally exposed to both stress and alcohol failed to ejaculate spontaneously, although they copulated normally following exogenous testosterone (T) administration. Males prenatally exposed only to alcohol or only to stress showed no behavioral deficits. Adult serum T and luteinizing hormone levels were normal in both of the fetal alcohol exposed male groups. It appears that the androgen threshold for ejaculatory behavior is elevated in males prenatally exposed to alcohol plus stress and cannot be realized with normal testosterone titers, but it can be attained with exogenous hormone administration. Presumably the alcohol and stress combination interfered with ontogenetic patterns of T needed to fully masculinize the fetal nervous system.

Detection of mesial temporal lobe hypoperfusion in patients with temporal lobe epilepsy by use of arterial spin labeled perfusion MR imaging.

BACKGROUND AND PURPOSE: Interictal hypometabolism has lateralizing value in cases of temporal lobe epilepsy and positive predictive value for seizure-free outcome after surgery to treat epilepsy. Alterations in regional cerebral metabolism can also be inferred from measurements of regional cerebral perfusion. The purpose of this study was to determine the feasibility of detecting cerebral blood flow (CBF) asymmetries in the mesial temporal lobes using continuous arterial spin labeling perfusion MR imaging, which is a noninvasive method for calculating regional CBF. METHODS: Twelve patients with medically refractory temporal lobe epilepsy who underwent preoperative evaluation for temporal lobectomy and 12 normal control participants were studied retrospectively. Absolute and normalized mesial temporal CBF measurements were compared between the patient and control groups. Lateralization based on a perfusion asymmetry index was compared with metabolic ((18)[F]-fluorodeoxyglucose positron emission tomography) and hippocampal volumetric asymmetry indices and with clinical lateralization. RESULTS: Mesial temporal CBF was more asymmetric in patients with temporal lobe epilepsy than in normal control participants, although asymmetric mesial temporal CBF was also found in normal participants, with the left side dominant. Ipsilateral mesial temporal CBF was significantly decreased compared with contralateral mesial temporal CBF in patients with temporal lobe epilepsy. Global CBF measurements were significantly decreased in patients compared with control participants. Asymmetry in mesial temporal blood flow in patients persisted after normalization to global CBF. Lateralization using continuous arterial spin labeling perfusion MR imaging asymmetry index significantly correlated with lateralization based on (18)[F]-fluorodeoxyglucose positron emission tomography hypometabolism, hippocampal volumes, and clinical evaluation. CONCLUSION: Continuous arterial spin labeling perfusion MR imaging can detect interictal asymmetries in mesial temporal lobe perfusion in patients with temporal lobe epilepsy. This technique is readily combined with routine structural assessment and potentially offers an inexpensive and noninvasive means of screening for asymmetries in interictal mesial temporal lobe function.

Proof of efficacy trials: endpoints.

Seizure frequency data are difficult to work with because they are so variable both between and within patients. Seizures can come in clusters, thereby adding to the variation in seizure frequency. Also, seizure frequency data are non-parametric in nature, making them difficult to analyze by some statistical techniques without transforming them. Therefore, to improve data analysis in proof of efficacy studies, manipulations of seizure frequency are commonly used, such as the proportion of responders above an arbitrary threshold, or the response ratio. Other useful endpoints are time to nth seizure, number of seizure-free days, proportion of seizure-free patients, and assessment of seizure severity using rating scales. The choice of endpoint(s) will depend upon the design of the study.

Psychosocial stress and urinary cortisol excretion in marmoset monkeys (Callithrix kuhli).

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the hallmarks of the physiological responses to psychosocial stressors. The most common method of assessing HPA function is via the measurement of plasma cortisol levels. However, venipuncture involves capture and restraint, which can modify HPA function. We validated a noninvasive procedure for monitoring HPA responses to stressors by measuring excretion of free urinary cortisol. Samples collected throughout the day displayed marked circadian variation, with low cortisol values in first-void samples, followed by a mid-morning peak in cortisol excretion. Concentrations of excreted cortisol declined throughout the day. Exposing marmosets to mild and moderate stressors (11 h isolation in a small cage and manual restraint) increased excreted cortisol concentrations in a dose-dependent fashion: isolation in a small cage led to elevated cortisol in afternoon samples, while manual restraint and isolation produced elevated cortisol in both morning and afternoon samples. The marmoset HPA is differentially sensitive to rather subtle variations in stressors, and these results show that urinary cortisol excretion is a valid and sensitive index of the HPA response to these stressors.

Telemetered temperature monitoring in preweanling Mongolian gerbils (Meriones unguiculatus).

Like most small mammals, Mongolian gerbils (Meriones unguiculatus) are born without the ability to maintain core body temperature (Tb). Breeding adults, juvenile alloparents, nest materials, and other litter mates probably contribute to the maintenance of core body temperature in neonates, but the relative role of each factor is unknown. We developed a procedure allowing biotransmitters to be implanted into 9-day-old pups for use with a radiotelemetry system. Experiment 1 demonstrated the development of thermoregulatory capacity over postpartum days 11, 15, and 19. Pups at 11 days of age lacked thermoregulatory capacity, and maintained Tb only slightly above the ambient temperature (15 degrees C) of the testing environment. The transition from poikilothermy to homeothermy was clearly accomplished by day 19, with pups maintaining Tb of 35.8 +/- 0.2 degrees C for at least 100 min. Experiment 2 measured Tb in 11- and 12-day-old pups during a thermal challenge (15 degrees C) in the presence of nest materials, litter mates, or both. Pups provided with either nest materials, litter mates, or both maintained higher Tb during a 40-min test than those without these resources. Our methodology minimizes disruptions and the thermal consequences associated with other invasive (rectal probe thermistors) and noninvasive (e.g., infrared thermography) procedures.

Relation between food preference and food-elicited vocalizations in golden lion tamarins (Leontopithecus rosalia).

We report the results of 2 studies on food-elicited vocalizations in golden lion tamarins (Leontopithecus rosalia). First, we investigated the preferences of 10 golden lion tamarins for 6 foods. Tamarins prefer mealworms and raisins significantly more than apple, egg, carrot, or marmoset diet. Food preference rank was significantly and positively correlated with the rank of latency to choose a particular food. Second, we investigated the relation between food preference and 15 vocal parameters measured from the calls emitted by 5 tamarins to a subset of the foods. Only 1 parameter was significantly correlated with food preference across animals. Within-subjects multivariate analysis of variance showed that the vocalizations to foods are significantly different. Our results support an hypothesis that food-elicited vocalizations vary in ways that correspond to the caller's preference but not in a manner that labels food type.

Patterns of social preference across different social contexts in golden lion tamarins (Leontopithecus rosalia).

We investigated the role of mutual and circumstantial factors in maintaining exclusive social relationships in a New World primate. Four breeding pairs of golden lion tamarins (Leontopithecus rosalia rosalia) were allowed to interact with their mate or an unfamiliar, opposite-sex adult in each of 4 different social contexts: in view of the mate, out of the mate's view, with only the mate present, and with only the unfamiliar animal present. Males and females were in proximity to, approached, and sniffed their mates significantly more often than they did unfamiliar tamarins. These behaviors suggest a preference for the familiar mate. However, when mates were absent, tamarins demonstrated significantly higher levels of approach and sniffs toward unfamiliar animals. These patterns of behavior indicate that circumstantial factors, such as social context, may regulate social interactions between paired tamarins and unfamiliar, opposite-sex conspecifics.