Ahmad Beydoun

Variability of laser-evoked potentials: attention, arousal and lateralized differences

We recorded laser-evoked potentials (LEPs) from 20 normal subjects by stimulating the skin with pulses from an infrared CO2 laser. The conduction velocity of the peripheral afferent fibers mediating the LEPs averaged 14.9 m/sec. The amplitude of the LEP components correlated significantly with perceived stimulus intensity. During repetitive constant intensity stimulation, the peak-to-peak LEP amplitude decreased 38% during a distraction task and 42% during drowsiness and was absent during stage 2 sleep, indicating a modulation of responsiveness to laser stimulation during distraction and decreased states of arousal. Normative data revealed considerable intersubject variability in LEP latencies and amplitudes. Analysis of intrasubject lateralized (side-to-side) differences revealed that the relative peak-to-peak amplitude was less variable than that of the N or P components. For clinical applications using 3 S.D.s to define the normal range, a lateral interpeak amplitude difference greater than 28% would suggest focal or lateralized sensory abnormality in an individual patient. Vigilance and attentiveness to the stimuli should be monitored during the acquisition of LEPs.

Safety and Efficacy of Two Pregabalin Regimens for Add-on Treatment of Partial Epilepsy

Objective: To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. Methods: A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. Results: Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p ≤ 0.0001) and 44% for pregabalin BID (p ≤ 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p ≤ 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. Conclusions: Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

Oxcarbazepine monotherapy for partial-onset seizures A multicenter, double-blind, clinical trial

Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) 2,400 mg/day versus OXC 300 mg/day monotherapy in patients with medically refractory partial epilepsy. Background: OXC is primarily metabolized by reductase enzymes and, consequently, has a low propensity to inhibit or induce oxidative enzymes and a minimal potential for drug–drug interactions. The efficacy of OXC as monotherapy was shown in several comparative trials in patients with newly diagnosed epilepsy and in hospitalized patients undergoing evaluation for epilepsy surgery. Methods: A multicenter, double-blind, randomized, parallel-group trial design was chosen to assess the antiepileptic efficacy of OXC as monotherapy in a refractory epilepsy patient population. Outpatients aged 12 years or older with inadequately controlled partial seizures, with or without secondarily generalized seizures, were enrolled. Patients finished the trial by completing the double-blind phase or by meeting one of four predefined exit criteria: a twofold increase in partial seizure frequency in any 28-day period relative to baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; occurrence of a single generalized seizure if none occurred during the 6 months prior to randomization; or prolongation or worsening of generalized seizure duration or frequency requiring intervention. Adverse events (AEs), vital signs, and clinical laboratory tests were evaluated. Results: The percentage of patients meeting one of the exit criteria was significantly lower (p < 0.0001) for the OXC 2400 mg/day group (14/34; 41%) than the OXC 300 mg/day group (42/45; 93%). In addition, there was a significant difference in time to exit in favor of the OXC 2400 mg/day group (p = 0.0001). In the intent-to-treat analysis, 12% of patients in the OXC 2400 mg/day group were seizure-free compared with none in the 300 mg/day group. OXC was well-tolerated, with dizziness, fatigue, somnolence, and nausea being the most frequent AEs. Most of these AEs were transient and rated as mild to moderate in intensity. Conclusion: OXC is safe and effective in the treatment of patients with partial epilepsy previously receiving treatment with other antiepileptic drugs. The results of this trial are consistent with previous monotherapy trials with OXC.

Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures

Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug–drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.

Focal Cerebral Magnetic Resonance Changes Associated with Partial Status Epilepticus

Summary: We report 2 patients with transient abnormalities on magnetic resonance imaging (MRI) associated with partial status epilepticus (SE). A man with a 4‐month history of partial seizures had complex partial SE for 9 days, with left temporal maximum on ictal EEG. Left temporal lobe T2 signal was increased on MRI during SE, but cerebral MRI was normal 9 weeks later. A woman with “cryptogenic” temporal lobe epilepsy for 16 years had complex partial SE for 1 week, with right temporal maximum on ictal EEG. T2 Signal was increased over the entire right temporal lobe, extending into the insula, without mass effect, on MRI 1 month after SE ended. Repeat MRI 1 month later showed marked decrease in volume of increased T2 intensity, without gadolinium enhancement, but with mild mass effect over the right anteroinferomesial temporal areas. A gemistocytic astrocytoma was resected. Focal cerebral MRI abnormalities consistent with cerebral edema may be due to partial SE but also may indicate underlying glioma, even in long‐standing partial epilepsy. Focal structural imaging changes consistent with neoplasm should be followed to full resolution after partial SE.

Safety and tolerability of oxcarbazepine in elderly patients with epilepsy.

Despite the high incidence of seizures and epilepsy in the elderly, the tolerability and safety of anticonvulsants are rarely evaluated in this patient population. We compared the safety and tolerability of oxcarbazepine in a cohort of 52 patients aged 65 years and older and a group of 1574 adult patients ranging in age between 18 and 64 years. There was no significant difference between the two groups with respect to premature discontinuation due to adverse events. The four most common adverse events experienced by patients in the elderly group, irrespective of their causal relationship to oxcarbazepine, were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Three patients developed an asymptomatic hyponatremia, with at least one serum sodium level below 125mEq/L. Elderly patients on concomitant natriuretic drugs were significantly more likely to develop serum sodium levels below 135mEq/L. The results indicate that oxcarbazepine is safe to use in elderly patients and that its tolerability in this age group is similar to that of younger adult patients.

Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures

This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).

Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures

Objective: To evaluate the efficacy and safety of oxcarbazepine (OXC) as monotherapy for patients with uncontrolled partial seizures. Methods: A multicenter, double-blind, randomized, parallel-group, dose-controlled monotherapy trial compared OXC at 2400 mg/day with OXC at 300 mg/day in patients with uncontrolled partial-onset seizures previously receiving carbamazepine (CBZ) monotherapy. During a 28-day open-label conversion phase, patients were tapered off CBZ and titrated to OXC 2400 mg/day. After a 56-day open-label baseline phase on OXC 2400 mg/day, patients entered a 126-day double-blind treatment phase in which they were randomized to continue OXC at 2400 mg/day or were down titrated over 6 weeks to OXC at 300 mg/day. Patients met the efficacy endpoint by completing the double-blind treatment phase or by meeting one of four predefined exit criteria. The primary efficacy variable was time to meeting one of the exit criteria. The secondary efficacy variable was the percentage of patients meeting one of the exit criteria in each of the two treatment groups. Results: Of the 143 patients enrolled, 96 were randomized in the double-blind treatment phase. Time to meeting an exit criterion was significantly in favor of the OXC 2400 mg/day group (p = 0.0001). The median time to meeting an exit criterion was 68 days for the OXC 2400 mg/day Group and 28 days for the OXC 300 mg/day Group. In addition, the percentage of patients meeting one of the exit criteria was significantly lower for the OXC 2400 mg/day Group (p = 0.0001). Overall, OXC was well tolerated with the most common adverse events consisting of fatigue, nausea, ataxia, and headache. Conclusion: This trial demonstrated that OXC at 2400 mg/day is well tolerated and efficacious when administered as monotherapy in patients with uncontrolled partial onset seizures.

Laser-evoked cerebral potentials and sensory function in patients with central pain.

&NA; Central pain syndromes (CPS) could be caused by disinhibition of spinothalamic excitability or by other central nervous system (CNS) changes caused by reduced spinothalamic function. To examine these possibilities, we studied 11 patients (ages 51–82 years) with unilateral central pain and with reproducible cerebral evoked vertex potentials in response to cutaneous stimulation of the normal side with pulses from an infra‐red CO2 laser. All patients had normal tactile and kinesthetic sensation; one had slightly decreased vibratory sense bilaterally. All showed, from the unaffected (asymptomatic) side, laser evoked potentials (LEPs) with negative (N) components ranging from 208 to 280 msec peak latency (av: 240 ± 6 SE msec) and peak amplitudes of 1–7 &mgr;V (av: 2.9 ± 0.5 SE &mgr;V), followed, in all but 1 patient, by positive (P) potentials ranging from 288 to 370 msec peak latency (av: 319 ± 7.7 SE msec) with peak amplitudes of 1–7 &mgr;V (2.8 ± 0.5 SE &mgr;V). Laser stimulation of the affected (symptomatic) side in 5 patients evoked LEPs with N‐P interpeak amplitudes that were within 20% of those evoked from the normal side. All but one of these patients had thresholds for warm, heat pain, and deep pain that were normal in comparison with the unaffected side. The excepted patient had the largest N‐P interpeak amplitude asymmetry (18.5%) of this group. Ratings of laser pulse intensity were either symmetrical (n = 2) or increased on the affected side (n = 3) in these patients. In contrast, laser stimulation of the affected side failed to evoke either N or P potentials in 6 patients, all of whom had lateralized increased thresholds for warm, heat pain, or deep pain, or reduced ratings of laser pulse sensation. Although 1 patient had increased ratings of laser pulse sensation, the amplitude of the LEP was always reduced on the side of increased pain or heat threshold in these CPS patients (Fisher exact test: P = 0.015). These results reflect primarily a deficit in spinothalamic tract function and do not suggest excessive CNS responses to synchronous activation of cutaneous heat nociceptors in patients with CPS.

Topical capsaicin selectively attenuates heat pain and A δ fiber-mediated laser-evoked potentials

&NA; Cutaneous stimulation with CO2 laser pulses activates A &dgr; nociceptive afferents and evokes late cerebral potentials (LEPs), the amplitude of which correlates parametrically with the perceived magnitude estimation of laser pulses. Capsaicin is known to desensitize the nociceptive terminals of C fibers. In this double‐blind, vehicle‐controlled experiment, we tested the hypothesis that topical capsaicin would inactivate A &dgr; afferents and lead to an attenuation of the LEPs. Subjects applied capsaicin cream to the dorsum of one hand and vehicle cream to the other 3 times daily for a period of 5 weeks. At weekly intervals before starting, during administration and after discontinuation of capsaicin, LEPs were recorded and psychophysical thresholds and magnitude estimation for several sensory modalities were determined. The results of this study showed that topical capsaicin significantly and reversibly decreased the magnitude estimation of suprathreshold heat pain, laser pulses and amplitude of the LEPs. There was no statistically significant difference in light touch, deep pain and mechanical pain detection thresholds between the capsaicin‐ and vehicle‐treated hands. It indicated that topical capsaicin caused a definite functional and reversible inactivation of A &dgr; nociceptive afferent transmission. The decline in the magnitude estimation of laser pulses concomitantly with the attenuation of LEP amplitudes supports the hypothesis that some A &dgr; afferents mediate noxious heat in humans. These findings demonstrate the usefulness of LEP in the physiological evaluation of nociceptive pathways and its potential usefulness in objectively documenting the effect of pharmacological treatment on pain perception.