Gholam K. Motamedi

Epilepsy and cognition

Patients with epilepsy are more prone to cognitive and behavioral deficits. Epilepsy per se may induce or exacerbate an underlying cognitive impairment, a variety of factors contribute to such deficits, i.e., underlying neuropathology, seizure type, age of onset, psychosocial problems, and treatment side effects. Epilepsy treatment may offset the cognitive and behavioral impairments by stopping or decreasing the seizures, but it may also induce untoward effects on cognition and behavior. The neurocognitive burden of epilepsy may even start through in utero exposure to medications. Epilepsy surgery can also induce certain cognitive deficits, although in most cases this can be minimized. Clinicians should consider cognitive side effect profiles of antiepileptic medications, particularly in extreme age groups. While no effective treatments are available for cognitive and behavioral impairments in epilepsy, comprehensive pretreatment evaluation and meticulous selection of antiepileptic drugs or surgical approach may minimize such untoward effects.

Optimizing parameters for terminating cortical afterdischarges with pulse stimulation.

Summary:  Purpose: We previously reported that brief pulses of electrical stimulation (BPSs) can terminate afterdischarges (ADs) during cortical stimulation. We investigated conditions under which BPS is more likely to suppress ADs.

Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam.

Background: The relative effects of levetiracetam (LEV) and carbamazepine (CBZ) on cognitive and neurophysiologic measures are uncertain. Methods: The effects of LEV and CBZ were compared in healthy adults using a randomized, double-blind, two-period crossover design. Outcome measures included 11 standard neuropsychological tests and the score from a cognitive-neurophysiologic test of attention and memory. Evaluations were conducted at screening, baseline pre-drug treatment, end of each maintenance phase (4 weeks), and end of each washout period after drug treatment. Results: A total of 28 adults (17 women) with mean age of 33 years (range 18 to 51) completed the study. Mean maintenance doses (±SD) were CBZ = 564 mg/day (110) and LEV = 2,000 mg/day (0). CBZ was adjusted to mid-range therapeutic level. Mean serum levels (±SD) were CBZ = 7.5 mcg/mL (1.5) and LEV = 32.2 mcg/mL (11.2). An overall composite score including all measures revealed worse effects for CBZ compared to LEV (p ≤ 0.001) in the primary analysis and for CBZ (p ≤ 0.001) and LEV (p ≤ 0.05) compared to non-drug in secondary analyses. Across the 34 individual variables, CBZ was worse than LEV on 44% (15/34); none favored CBZ. Compared to the non-drug average, CBZ was worse for 76% (26/34), and LEV was worse for 12% (4 of 34). Sensitivity and specificity of standard neuropsychological tests and the cognitive-neurophysiologic test were determined to direct future studies; detection was most accurate by the cognitive-neurophysiologic test. Conclusions: Levetiracetam produces fewer untoward neuropsychological and neurophysiologic effects than carbamazepine in monotherapy at the dosages and timeframes employed in this study.

Antiepileptic drugs and memory

Impaired memory is among the most common complaints of patients with epilepsy. Multiple factors contribute to memory impairment in patients with epilepsy. Thus, delineation of the effects of antiepileptic drugs (AEDs) on memory in clinical populations faces methodological difficulties. Further, subjective perception of memory problems by patients is influenced by mood. However, there is evidence from animal and healthy volunteer studies supporting an independent potential for AEDs to impair memory. Differential AED effects on memory have been observed, and AED effects may interact with focal brain lesions. Memory impairment from AEDs is a greater concern at the age extremes, although the effects of AEDs, especially the newer agents, have not been thoroughly studied in these populations. Well-controlled studies are needed to understand the underlying mechanisms and to further delineate the magnitude and relative effects of AEDs on memory.

Deletion of the GABAA Receptor α1 Subunit Increases Tonic GABAA Receptor Current: A Role for GABA Uptake Transporters

The loss of more than half the number of GABAA receptors yet lack of pronounced phenotype in mice lacking the gene for the GABAA α1 subunit is somewhat paradoxical. We explored the role of tonic GABAA receptor-mediated current as a target of compensatory regulation in the α1 knock-out (−/−) mice. A 62% increase of tonic current was observed in the cerebellar granule cells (CGCs) of α1−/− compared with wild-type (+/+) mice along with a 67% increase of baseline current variance. Examination of whole-cell currents evoked by low concentrations of GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol suggested no upregulation of α6 and δ subunit-containing GABAA receptors in the α1−/−, confirming previous biochemical studies. Single-channel current openings were on average 32% shorter in the α1−/− neurons. Single-channel conductance and frequency of opening were not different between genotypes. Tonic current induced by application of the GABA transporter GAT-1 blocker NO711 (1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride) was significantly larger in the α1−/−, suggesting an increase of ambient GABA concentration. Experiments done with a known concentration of extracellular GABA complemented by a series of biochemical experiments revealed a reduction of GAT activity in α1−/− without an identifiable reduction of GAT-1 or GAT-3 protein. We report increased tonic GABAA receptor-mediated current in the α1−/− CGCs as a novel compensatory mechanism. Our data establish a role for GABA transporters as regulators of neuronal excitability in this and relevant models and examine other tonic conductance-regulating mechanisms responsible for the adaptive response of the cerebellar network to a deletion of a major synaptic GABAA receptor subunit.

Wavelet-crosscorrelation analysis can help predict whether bursts of pulse stimulation will terminate afterdischarges

OBJECTIVE Extraoperative cortical localizing stimulation (LS) is a standard clinical tool used to assess brain function before epilepsy surgery. However, LS can produce unwanted afterdischarges (ADs). We previously have shown that brief pulses of electrical stimulation (BPS) can terminate ADs caused by cortical stimulation. Our objective was to assess whether wavelet-crosscorrelation analysis could help predict the conditions under which BPS would be most likely to terminate ADs. METHODS We used wavelet-crosscorrelation analysis to get wavelet-correlation coefficients (WCC), and determine time lag (TL) and absolute value of TL (ATL) between two electrodes. For Analysis-1, we compared WCC and ATL in epoch 1 which was before LS, epoch 2 which was after LS but before BPS, and epoch 3 which was after BPS. For Analysis 2, we compared WCC and ATL during epoch 1 under 4 conditions: epochs when ADs subsequently terminated within 2 s after the end of BPS (1A), terminated within 2-5 s (1B), did not terminate within 5 s (1C), and when ADs did not appear (1D). RESULTS We found that BPS efficacy in terminating ADs was predicted by (1) low correlation and (2) slow propagation speed between electrode pairs in the 2-10 s period before stimulation. CONCLUSIONS Wavelet-crosscorrelation analysis can help predict conditions during which BPS can abort ADs. It is possible that similar analyses could help predict when BPS or other interventions could abort clinical seizures.

Termination of epileptiform activity by cooling in rat hippocampal slice epilepsy models

Cooling has been shown to terminate experimentally induced epileptiform activity in models of epilepsy without causing injury to the cooled brain, suggesting that cooling could represent an approach to seizure control in intractable focal epilepsies. Here we sought to determine the most effective way to apply cooling to abort spontaneous epileptiform discharges in in vitro brain slice models. We induced spontaneous epileptiform activity in rat brain slices by exposure to 4-aminopyridine (4-AP), 4-AP plus bicuculline, and Mg(2+)-free artificial CSF (aCSF) at 28-34 degrees C. Extracellular field recordings were made at hippocampal or neocortical sites. Slice temperature was reduced by perfusion with cold aCSF. Rapid cooling at rates of 2-5 degrees C/s was compared to cooling at slower rates of 0.1-1 degrees C/s. Cooling at both rates reversibly aborted epileptiform discharges in all three models and at all recording sites. With rapid cooling, small temperature drops were highly effective in terminating discharges, an effect that was sustained for as long as the reduced temperature level was maintained. In contrast, slow cooling required much larger temperature drops to inhibit discharges. With slow cooling, absolute temperature drops to 21-22 degrees C caused a 90% reduction in event frequency, but cooling to 14-15 degrees C was required to terminate discharges. We conclude that rapid cooling as effectively aborts discharges in in vitro epilepsy models as does slow cooling, but the magnitude of the temperature change required is less. Practical devices to inhibit seizure activity may only need to induce small temperature drops, if the cooling can be applied sufficiently rapidly.

Therapeutic brain hypothermia, its mechanisms of action, and its prospects as a treatment for epilepsy

Cooling the core body temperature to 32–35°C, is almost standard practice for conditions such as cardiac arrest in adults, and perinatal hypoxic ischemic encephalopathy in neonates. Limited clinical data, and more extensive animal experiments, indicate that hypothermia could help control seizures, and could be applied directly to the brain using implantable devices. These data have fostered further research to evaluate whether cooling would be a viable means to treat refractory epilepsy. Although the effect of temperature on cellular physiology has long been recognized, with possibly dual effects on pyramidal cells and interneurons, the exact mechanisms underlying its beneficial effects, in particular in epilepsy, are yet to be discovered. This article reviews currently available clinical and laboratory data with a focus on cellular mechanisms of action and prospects of hypothermia as a treatment for intractable seizures.

The effect of levetiracetam monotherapy on subjective sleep quality and objective sleep parameters in patients with epilepsy: Compared with the effect of carbamazepine-CR monotherapy

PURPOSE There is relatively little known about the effects of new antiepileptic drugs (AEDs) on sleep. This study was done to evaluate the effect of levetiracetam (LEV) on subjective sleep quality and sleep architecture in patients with epilepsy, and the results were compared with the effects of carbamazepine-CR (CBZ-CR). METHODS This is a longitudinal randomized controlled trial using two different treatments, LEV (1000 mg/day) or CBZ-CR (400mg/day). Thirty-one subjects (16 LEV and 15 CBZ-CR) had partial epilepsy and were tested with an overnight polysomnography (PSG) with full 10-20 electrodes. Sleep questionnaires and National Hospital Seizure severity Scale (NHS3) were evaluated. PSG and the questionnaires were repeated after 4-6 weeks of treatment. RESULTS In the LEV group, when treatment PSG findings were compared with baseline, there was a significant increase in sleep efficiency (p=0.039) but no changes in subjective sleep parameters. In the CBZ-CR group, there was a significant increase in the percentage of slow wave sleep (p=0.038) while other sleep parameters were not significantly changed after treatment. There were no significant differences in effects on sleep between the LEV and CBZ-CR groups. CONCLUSION LEV may increase sleep efficiency without major effects on sleep structure with an overall effect on sleep parameters comparable to CBZ-CR.

Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

Hypothermia can terminate epileptiform discharges in vitro and in vivo epilepsy models. Hypothermia is becoming a standard treatment for brain injury in infants with perinatal hypoxic ischemic encephalopathy, and it is gaining ground as a potential treatment in patients with drug resistant epilepsy. However, the exact mechanism of action of cooling the brain tissue is unclear. We have studied the 4-aminopyridine model of epilepsy in mice using single- and dual-patch clamp and perforated multi-electrode array recordings from the hippocampus and cortex. Cooling consistently terminated 4-aminopyridine induced epileptiform-like discharges in hippocampal neurons and increased input resistance that was not mimicked by transient receptor potential channel antagonists. Dual-patch clamp recordings showed significant synchrony between distant CA1 and CA3 pyramidal neurons, but less so between the pyramidal neurons and interneurons. In CA1 and CA3 neurons, hypothermia blocked rhythmic action potential discharges and disrupted their synchrony; however, in interneurons, hypothermia blocked rhythmic discharges without abolishing action potentials. In parallel, multi-electrode array recordings showed that synchronized discharges were disrupted by hypothermia, whereas multi-unit activity was unaffected. The differential effect of cooling on transmitting or secreting γ-aminobutyric acid interneurons might disrupt normal network synchrony, aborting the epileptiform discharges. Moreover, the persistence of action potential firing in interneurons would have additional antiepileptic effects through tonic γ-aminobutyric acid release.