ObjectivesThe Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3‐5‐day Epilepsy Monitoring Unit (EMU) stay and long‐ term clinical outcomes of the device stimulating in all modes.Materials and MethodsThe E‐37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR® in subjects with drug‐resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events.ResultsTwenty implanted subjects (ages 21–69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six‐months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3).ConclusionsThe Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

SUMMARYPurpose: The dynamics of partial seizures originating from neocortical and mesial temporal regions are thought to differ, yet there are no quantitative comparative studies. The studies reported here investigate the duration of complex partial seizures in these populations using analyses of seizures recorded from intracranial arrays. Methods: Data were collected from patients undergoing presurgical evaluation with intracranial electrodes. Seizure duration was defined as the time of earliest sustained ictal activity until the termination either in all electrodes (global duration, GD), or at the onset area (focal duration, FD). Patients were divided into three groups: mesial temporal lobe epilepsy (MTLE), neocortical temporal lobe epilepsy (NCTLE), and neocortical extratemporal lobe epilepsy (NCXTLE). Results: Complex partial seizure durations were significantly longer in the MTLE group compared to the NCXTLE group. Median GD for MTLE was 106 s, and for NCXTLE was 78 s. There were no significant differences between seizure durations when comparing MTLE group to NCTLE group, or comparing NCTLE group to NCXTLE group. In the MTLE group, patients with bilateral recording arrays had significantly longer median seizure durations (GD and FD) than those sampled with unilateral arrays. Conclusions: In this select group of patients there is a significant difference between the duration of complex partial seizures of mesial temporal and neocortical extratemporal origin with mesial temporal complex partial seizures being longer. This may result from a number of possibilities including the bilateral propagation of some mesial temporal seizures and differences in ictal generators of the underlying networks.

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Synesthesia is experienced when sensory stimulation of one sensory modality elicits an involuntary sensation in another sensory modality. Auditory-visual synesthesia occurs when auditory stimuli elicit visual sensations. It has developmental, induced and acquired varieties. The acquired variety has been reported in association with deafferentation of the visual system as well as temporal lobe pathology with intact visual pathways. The induced variety has been reported in experimental and post-surgical blindfolding, as well as intake of hallucinogenic or psychedelics. Although in humans there is no known anatomical pathway connecting auditory areas to primary and/or early visual association areas, there is imaging and neurophysiologic evidence to the presence of early cross modal interactions between the auditory and visual sensory pathways. Synesthesia may be a window of opportunity to study these cross modal interactions. Here we review the existing literature in the acquired and induced auditory-visual synesthesias and discuss the possible neural mechanisms.