Pegah Afra

CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite norclozapine steady-state concentration in patients with schizophrenia

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 schizo-phrenia 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.

Duration of complex partial seizures: An intracranial EEG study

Purpose: 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.

Acquired auditory-visual synesthesia: A window to early cross-modal sensory interactions

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.

The Secret “Spice”: An Undetectable Toxic Cause of Seizure

Neurologists and emergency department physicians are frequently involved in the comprehensive evaluation of a first generalized seizure. An important aspect of this evaluation is a detailed history which can identify a provoked seizure secondary to drug toxicity and hence avoid unnecessary treatment with antiepileptic drugs. “Spice” is an umbrella term for a variety of synthetic cannabinoid products whose inhalation has been associated with an increasing number of toxic side effects resulting in emergency department visits. These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use. We report 2 patients with no prior history of neurological disease that experienced their first generalized tonic–clonic seizure after smoking Spice. The mechanism behind the possible proconvulsant effect of synthetic cannabinoids is not known, but it may be due to their effects at the cannabinoid receptor CB1. Although the US Drug Enforcement Administration placed 5 synthetic cannabinoids into schedule 1 for a 12-month period beginning March 2011, new Spice products containing different synthetic cannabinoids continue to emerge. Because synthetic cannabinoids are not detectable on commercial drug screens it is important that neurologists and emergency department physicians consider Spice inhalation in their differential diagnosis of a first generalized seizure.

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance - The U.S. E-37 Trial

The 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.

Therapeutic hypothermia for status epilepticus: A report, historical perspective, and review

Refractory status epilepticus is a disease associated with high morbidity and mortality, which does not always respond to standard treatments, and when they fail, alternative modalities become crucial. Therapeutic hypothermia slows nerve conduction in vitro, and has been shown to abort seizures in animal models. Therapeutic hypothermia has been experimentally used in humans since 1963 for a variety of intracranial pathologies. More recently there have been multiple reports demonstrating the effectiveness of therapeutic hypothermia in treating refractory status epilepticus. We report a case of super-refractory status epilepticus successfully treated with therapeutic hypothermia, complimented by a historical and literature review of this modality. While there is limited evidence, and some risks associated with therapeutic hypothermia, it should be considered as a reasonable and potentially effective treatment option for refractory status epilepticus.

Neurophysiological investigation of idiopathic acquired auditory–visual synesthesia

We present a case of acquired auditory–visual synesthesia and its neurophysiological investigation in a healthy 42-year-old woman. She started experiencing persistent positive and intermittent negative visual phenomena at age 37 followed by auditory–visual synesthesia. Her neurophysiological investigation included video-EEG, fMRI, and MEG. Auditory stimuli (700 Hz, 50 ms duration, 0.5 s ISI) were presented binaurally at 60 db above the hearing threshold in a dark room. The patient had bilateral symmetrical auditory-evoked neuromagnetic responses followed by an occipital-evoked field 16.3 ms later. The activation of occipital cortex following auditory stimuli may represent recruitment of existing cross-modal sensory pathways.

Termination patterns of complex partial seizures: An intracranial EEG study

PURPOSE While seizure onset patterns have been the subject of many reports, there have been few studies of seizure termination. In this study we report the incidence of synchronous and asynchronous termination patterns of partial seizures recorded with intracranial arrays. METHODS Data were collected from patients with intractable complex partial seizures undergoing presurgical evaluations with intracranial electrodes. Patients with seizures originating from mesial temporal and neocortical regions were grouped into three groups based on patterns of seizure termination: synchronous only (So), asynchronous only (Ao), or mixed (S/A, with both synchronous and asynchronous termination patterns). RESULTS 88% of the patients in the MT group had seizures with a synchronous pattern of termination exclusively (38%) or mixed (50%). 82% of the NC group had seizures with synchronous pattern of termination exclusively (52%) or mixed (30%). In the NC group, there was a significant difference of the range of seizure durations between So and Ao groups, with Ao exhibiting higher variability. Seizures with synchronous termination had low variability in both groups. CONCLUSIONS Synchronous seizure termination is a common pattern for complex partials seizures of both mesial temporal or neocortical onset. This may reflect stereotyped network behavior or dynamics at the seizure focus.

False lateralization of seizure onset by scalp EEG in neocortical temporal lobe epilepsy.

False lateralization of ictal onset by scalp EEG has been reported in patients with severe hippocampal sclerosis associated with hemispheric lesions or atrophy. There has been no report of cases of false lateralization by scalp EEG in patients without detectable structural abnormalities on MRI, or in patients with neocortical temporal lobe epilepsy. We report a case of false lateralization of ictal onset by scalp EEG in a patient with neocortical temporal lobe epilepsy and a normal MRI examination, investigated by intracranial EEG recordings. The ictal activity failed to propagate in the ipsilateral temporal lobe, but was strongly propagated to the contralateral temporal lobe resulting in a false lateralization of seizure onset by scalp EEG. It is possible that the poor homolateral propagation and evolution of ictal activity in this patient may be due to a functional rather than structural abnormality of the ipsilateral hippocampus, causing reduced synchrony and amplitude in the ipsilateral temporal cortex.

Partial epilepsy presenting as focal atonic seizure: A case report

A case of atonic seizures localized to the frontal lobe by video-EEG monitoring is reported. The patient is a 38-year-old female with intractable atonic seizures characterized by abrupt onset of facial grimacing and a slow head drop. The onset of atonic seizures was about 6 years before presentation. Video-EEG monitoring showed that her atonic seizures were emanating from the right frontal head region. A high voltage spike and slow wave discharge invariably coincided with the onset of atonic seizures in the patient, similar to the interruption of tonic muscular activity time-locked to a spike on the EEG described in epileptic negative myoclonus; a syndrome associated with epileptic activity in the premotor cortex. Since routine MRI imaging in this patient was normal, diffusion tensor imaging (DTI) was applied to analyze the white matter integrity of the normal-appearing white matter in the frontal lobes of the patient. We compared the fractional anisotropy, parallel diffusivity and perpendicular diffusivity of normal-appearing white matter in the right versus left frontal lobe. Our results showed no significant difference between the two sides. Possible reasons for the normal DTI findings are discussed.