IRMPD spectroscopy and quantum chemistry calculations on mono- and bi-metallic complexes of acetylacetonate ligands with aluminum, iron, and ruthenium ions.

Metal-ligand cluster ions are structurally characterized by means of gas-phase infrared multiple photon dissociation spectroscopy. The mass-selected complexes consist of one or two metal cations M3+ (M = Al, Fe, or Ru) and two to five anionic bidentate acetylacetonate ligands. Experimental IR spectra are compared with different density functional theory calculations, namely, PBE/TZVP, B3LYP/6-31G*, and M06/6-31+G**. Frequency analysis was also performed at different levels, namely, scaled static harmonic and unscaled static anharmonic, or with ab initio molecular dynamics simulations at the PBE/TZVP level. All methods lead to simulated spectra that fit rather well with experimental data, and the spectral red shifts of several main bands, in the 1200 cm-1-1800 cm-1 range, are sensitive to the strength of the metal-ligand interaction and to the spin state of the ion. Due to the rigidity of those complexes, first principles molecular dynamics calculations provide spectra similar to that produced by static calculations that are already able to catch the main spectral signatures using harmonic calculations at the B3LYP/6-31G* level.

When Should a Brain MRI Be Performed in Children with New-Onset Seizures? Results of a Large Prospective Trial.

BACKGROUND AND PURPOSE: There is a paucity of data regarding the incidence of structural brain lesions in children with new-onset unprovoked seizures. Our aim was to determine the frequencies and types of epileptogenic lesions detected on a dedicated epilepsy protocol MR imaging according to age group, the presence of developmental delay, and the number and types of seizures. MATERIALS AND METHODS: Consecutive children between 6 months and 18 years of age with new-onset unprovoked seizures were included. The frequencies and types of epileptogenic lesions were determined and then stratified according to sex, age groups, the presence of developmental delay, and the number and types of seizures at presentation. Multivariate analysis was used to identify variables significantly associated with the presence of epileptogenic lesions. RESULTS: One thousand children were included. An epileptogenic lesion was identified in 26%, with malformations of cortical development being the most common lesion (32%), followed by hypoxic-ischemic injury (20%) and vascular etiologies (16%). Univariate analysis showed a significant increase in the frequency of epileptogenic lesions with decreasing age, the presence of developmental delay, and the number and types of seizures at presentation. The presence of developmental delay and seizure type at presentation remained significant in a multivariate analysis. CONCLUSIONS: We documented a relatively high rate of epileptogenic lesions in children with new-onset seizures, with the presence of developmental delay and specific seizure types being associated with a higher likelihood of detecting an epileptogenic lesion on neuroimaging. This study fulfills the requirements of the study design recommended by the Practice Committee of the American Academy of Neurology, and we hope that our results will assist the relevant societies and committees in formulating neuroimaging guidelines for children with new-onset seizures.

Biopsy results in a kindred with Lafora disease.

We studied biopsy results in a kindred with the Lafora form of progressive myoclonic epilepsy. Four members of a family with known consanguinity presented as teenagers with seizures, myoclonus, dementia, and ataxia. After the diagnosis was established by brain biopsy in the first patient, many efforts were made to obtain a tissue diagnosis in the three other patients. Lafora bodies were absent in most of the skin biopsy specimens in three patients and in liver biopsy specimens from two patients. In cases of Lafora disease, where a reasonably certain clinical diagnosis can be established, supported by biopsy proof in some family members, repeated biopsy specimens even at advanced stages of the disease may be negative. These findings suggest that negative skin or liver biopsy specimens in patients with progressive myoclonic epilepsy should not exclude the diagnosis of Lafora disease.

Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group.

This is the first randomized, double-blind, parallel-group, multicenter trial that evaluated the efficacy of divalproex sodium monotherapy by comparing seizure frequency in 143 patients with poorly controlled partial epilepsy randomly assigned to high (80 to 150 micrograms/mL; 555 to 1,040 mumol/L) or low (25 to 50 micrograms/mL; 175 to 345 mumol/L) plasma valproate groups. There was a statistically significant reduction from baseline in the 8-week frequency of complex partial (p = 0.001) and secondarily generalized tonic-clonic seizures (p = 0.018) for patients in the high, compared with the low, plasma valproate group. Compared with baseline, there was a 30% median reduction in complex partial seizures for patients in the high group and a 19% increase for those in the low group. The median reduction for secondarily generalized tonic-clonic seizures was 70% for patients in the high group compared with a 22% increase in the low group. Adverse events that occurred significantly more frequently in the high group included tremors, thrombocytopenia, alopecia, asthenia, diarrhea, vomiting, and anorexia. This study demonstrates the efficacy of divalproex sodium as monotherapy for the treatment of partial-onset seizures and supports its role as one of the first-line antiepileptic drug treatments for patients with partial epilepsy.

Correlation of evoked potential and MRI findings in Wilson's disease.

We recorded brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials to median nerve stimulation (MSEPs) within 10 days of brain MRI in 20 patients with Wilson's disease (WD). MRI was abnormal in 90% of patients, demonstrating symmetric striatum and brainstem lesions with or without thalamic lesions. MSEPs were abnormal in 65% of patients, usually showing bilaterally prolonged N/P13-N20 latencies. BAEPs were abnormal in 40%, most often with bilateral prolongation of the III-V latency. The III-V and N/P13-N20 interpeak latencies correlated significantly with the severity of MRI lesions in the caudal pons, rostral pons, and caudal midbrain. Our results indicate that subclinical sensory dysfunction is common in WD, and that auditory and somatosensory pathways are most severely affected at the brainstem level. Both the localization and severity of evoked potential abnormalities correspond closely to the morphologic changes in the pons and caudal midbrain shown by MRI.

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.

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.

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. The US Gabapentin Study Group 82/83.

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%).

Pain-related laser-evoked potentials in awake monkeys: identification of components, behavioral correlates and drug effects.

Cutaneous stimulation with CO2 laser pulses activates small diameter sensory afferents and evokes a pain-related potential best recorded from the vertex (Cz) of humans. We report here the first successful recording of pain-related laser evoked potentials (LEPs) from awake monkeys. Laser pulses with stimulus intensities adjusted to the lowest level giving reproducible cerebral responses were delivered to the shaved tail of three awake African green monkeys. The proximal and distal tail were stimulated to calculate the conduction velocity of the activated fibers. The effects of subcutaneous injections of morphine and cocaine on the LEPs were evaluated. The results indicate that reproducible LEPs, with a morphology similar to those obtained from humans, can be recorded from the awake monkey. The calculated conduction velocity of the activated fibers averaged 8.7 m/s, which is in the range of A delta fibers. Following subcutaneous morphine injections, the LEPs disappeared and were quickly restored to their baseline amplitude following administration of naloxone. Cocaine administered subcutaneously led to a significant attenuation of LEP amplitudes without producing behavioral sedation. These findings suggest that the LEPs recorded from monkeys represent analgesic-sensitive, nociceptive-related potentials similar to those recorded from humans.

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

Cutaneous stimulation with CO2 laser pulses activates A delta of 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 delta 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 delta 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 delta 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.

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

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 microV (av: 2.9 +/- 0.5 SE microV), 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 microV (2.8 +/- 0.5 SE microV). 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.

Measuring the coherence of intracranial electroencephalograms.

OBJECTIVE: Previous coherence studies of human intracranial electroencephalograms (EEGs) can be faulted on two methodological issues: (1) coherence estimates in a majority were formed from a very small number of independent sample spectra, and (2) the statistical significance of coherence estimates was either not reported or was poorly evaluated. Coherence estimator performance may be poor when a small number of independent sample spectra are employed, and the coupling of poor estimation and statistical testing can result in inaccuracy in the measurement of coherence. The performance characteristics of the coherence estimator and statistical testing of coherence estimates are described in this manuscript. METHODS: The bias, variance, probability density functions, and confidence intervals of the estimate of magnitude squared coherence (MSC); and power analysis for the test of zero MSC were developed from the exact analytic form of the probability density function of the estimate of MSC for Gaussian random processes. The coherence of a single epoch of background EEG, recorded from a patient with intractable seizures, was evaluated with different parameter values to aid in the exposition of the concepts developed here. RESULTS: The statistical characteristics of WOSA coherence estimates are a function of a single estimator parameter, the number of independent sample spectra employed in the estimation. Bias and variance are high, confidence intervals may be large, and the probability of Type II errors is high if a small number of independent sample spectra are employed. A considerable improvement in measurement accuracy is possible with careful selection of estimator parameter values. CONCLUSIONS: Coherence measurement accuracy can be improved over previous applications by attention to estimator performance and accurate statistical testing of coherence estimates.

Safety and efficacy of oxcarbazepine: results of randomized, double-blind trials.

Oxcarbazepine is approved as monotherapy and adjunctive therapy for partial seizures with and without secondarily generalized seizures in adults and as adjunctive therapy for partial-onset seizures in children aged 4-16 years. The clinical development of oxcarbazepine is different from the newer antiepileptic drugs (AEDs) in the extent and concordance of results across clinical trials. The safety and efficacy of oxcarbazepine was evaluated in adjunctive therapy trials, in comparative monotherapy trials with classic AEDs in adults and children with newly diagnosed epilepsy, in monotherapy therapeutic failure design trials in patients with refractory partial seizures, and in trigeminal neuralgia and affective disorder. The results of oxcarbazepine in treating epilepsy are discussed.

Gabapentin: pharmacokinetics, efficacy, and safety.

Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half-life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset.

Pitfalls of EEG interpretation in epilepsy.

Electroencephalogram remains the single most valuable investigation in patients with known or suspected seizure disorders. Errors made in the interpretation of electroencephalogram studies are common and have significant consequences for the patient. This article presents a logical approach to the analysis of electroencephalograms, illustrating the principle pitfalls in each step of this analysis.

Seizure disorders of aging: differential diagnosis and patient management.

The incidence of seizures increases significantly after age 60, mainly because of an associated rise in the prevalence of such etiologies as stroke, brain tumors, and toxic-metabolic disturbances, including alcohol or drug misuse and diabetes. The differential diagnosis must rule out transient ischemic attacks, syncope, and psychiatric disorders, among other conditions. Treatment is based on the underlying cause. Seizures caused by toxic-metabolic disturbances are treated by correcting the underlying condition. Those with other etiologies require single-drug therapy with an anticonvulsant, such as phenytoin, valproic acid, or carbamazepine.

Asymptomatic brain magnetic resonance imaging abnormalities in splenectomized adults with thalassemia intermedia.

BACKGROUND: A high incidence of thrombotic events in thalassemia intermedia (TI) patients led to the identification of a hypercoagulable state. Brain involvement has not been widely studied in TI, although limited reports confirm a low incidence of overt stroke and high incidence of silent brain infarcts. PATIENTS/METHODS: This was a prospective study conducted on 30 adult, splenectomized TI patients. Patients were screened for absence of neurological signs or symptoms, and stroke-related risk factors. Patient charts were reviewed for demographics, duration since splenectomy, and any history of transfusion therapy. Blood samples were obtained for complete blood counts and serum ferritin. Direct determination of liver iron concentration (LIC) was performed by R2 magnetic resonance imaging (MRI). Brain MRI was performed on all patients, looking for ischemic lesions and/or atrophy. RESULTS: The mean age of patients was 32.1 +/- 11 years (range, 18-54 years), with a male to female ratio of 13:17. Eighteen patients (60%) had evidence of one or more white matter lesions (WMLs) on brain MRI, all involving the subcortical white matter. Fourteen patients had evidence of multiple WMLs, with a mean of 5 +/- 10 lesions (range, 2 to > 40 lesions). The vast majority of patients (94%) had small (< 0.5 cm) to medium (0.5-1.5 cm) WMLs, with only one patient showing evidence of a large (> 1.5 cm) WML. Eleven patients (37%) had mild cerebral atrophy. On multivariate analysis only age and transfusion history were independently and significantly associated with the occurrence of zero, single or multiple WMLs. CONCLUSION: WMLs and brain atrophy are a common finding in adult, splenectomized, TI patients. Increasing age and transfusion naivety are associated with a higher incidence and multiplicity of lesions.