Fumisuke Matsuo

Placebo‐controlled study of the efficacy and safety of lamotrigine in patients with partial seizures

We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by ≥50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

BACKGROUND Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Atypical herpes simplex encephalitis Clinical, virologic, and neuropathologic evaluation

An atypical form of herpes simplex encephalitis produced by HSV-1 documented in the present article demonstrates that (1) prominent EEG abnormality may correlate with subtle increase in signal intensity on MRI; (2) the disease may start with prominent involvement of the cingulate gyri; and (3) viral infection of the brainstem may cause early onset of severe neurologic dysfunction and coma.

Subarachnoid hemorrhage due to anterior spinal artery aneurysm

This case report describes a 29-year-old man with subarachnoid hemorrhage due to an anterior spinal artery aneurysm. Surgical obliteration of the aneurysm was successful. This is the sixth reported case of an isolated symptomatic aneurysm of a spinal artery.

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.

Magnetoencephalographic spikes not detected by conventional electroencephalography

OBJECTIVE To investigate some of the reasons why magnetoencephalographic (MEG) spikes are at times not apparent in conventional electroencephalograms (EEG) when the data are co-registered, and to explore to what extent modern EEG analysis methods can improve the yield. METHODS Seventy seconds of MEG-EEG co-registration on a 122 channel Neuromag system were studied in a 10-year-old boy with Landau-Kleffner syndrome. Twenty-six EEG channels were originally recorded with a left ear reference. The EEG data were subsequently reformatted (BESA) to a variety of montages for the 10-20 and 10-10 electrode array. A 10 s data epoch was compared in detail for concordance between MEG and EEG spikes. To detect the characteristics of hidden low voltage EEG spikes, MEG spikes were averaged and compared with the concomitant averaged EEG spike. RESULTS While there was an abundance of EEG as well as MEG spikes on the left; definite right-sided spikes were not visible in the EEG. Right hemispheric MEG spikes were, however, plentiful with an average strength of 757 fT. When the individual MEG spikes from the right hemisphere were compared with the corresponding EEG events their amplitude ranged between 24 and 31 microV and were, therefore, indistinguishable from background activity. The majority of them became visible, however, with further sophisticated data analysis. CONCLUSIONS When the relative merits of MEG versus EEG recordings for the detection of epileptogenic spike are investigated the 10-20 system of electrode placement and conventional methods of EEG analysis do not provide optimal data assessment. The use of the 10-10 electrode array combined with modern methods of digital data analysis can provide better concordance with MEG data.

Long-term tolerability of lamotrigine: data from a 6-year continuation study

This open-label, 6-year continuation study of several short-term clinical trials was conducted to assess the long-term tolerability and efficacy of lamotrigine when used as adjunctive therapy or monotherapy for partial seizures in adult patients (> or =16 years) with epilepsy. Study visits occurred every 24 weeks throughout the treatment period. Of the 527 patients enrolled in the long-term continuation study, 508 were exposed to lamotrigine for at least 6 months (including their exposure in the primary clinical study), and 248 were exposed to lamotrigine for at least 5 years. Of the 527 patients, 75 received initial lamotrigine exposure during this study. Investigators judged that overall clinical status at the end of the study or at time of discontinuation (whichever occurred first) was improved moderately or markedly relative to prelamotrigine clinical status for 36% of patients. The most common treatment-emergent adverse events (regardless of suspected cause) were dizziness, diplopia, and headache. The only serious treatment-emergent adverse event occurring at a frequency exceeding 2% was accidental injury (2.7% of patients). Adverse events prompted 28 patients to discontinue from the study. The most common adverse events leading to discontinuation were dizziness (1.3%), headache (0.8%), rash (0.8%), and somnolence (0.6%). All adverse events resolved without sequelae. Lamotrigine administered as monotherapy or adjunctive therapy during a 6-year open-label continuation study was associated with a low incidence of adverse events in adult patients with epilepsy.

Lamotrigine High-Dose Tolerability and Safety in Patients with Epilepsy: A Double-Blind, Placebo-Controlled, Eleven-Week Study

Summary: Purpose: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice‐daily (b.i.d.) dosage regimen of 700 mg/day larnotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses 500 mg/day in patients receiving concomitant enzyme‐inducing antiepileptic drugs (AEDs).

ANTICONVULSANT-INDUCED CUTANEOUS REACTIONS: INCIDENCE, MECHANISMS AND MANAGEMENT

Management of patients receiving anticonvulsant drugs is often a matter of balancing medication efficacy against untoward effects. Cutaneous drug reactions (CDRs) to anticonvulsants are a widely recognised idiosyncratic effect. In spite of almost 60 years’ experience with phenytoin and greater than 80 years’ experience with phenobarbital (phenobarbitone), anticonvulsant-induced CDRs remain one of the most difficult challenges in optimising the care of patients with epilepsy and mood disorders.Epidemiological evaluation is complicated by lack of consensus on reporting and systematic classification of these reactions. Many clinicians choose to discontinue a suspected agent at the first sign of a skin eruption, without confirmation. Time-honoured catalogues are useful for identification of common skin reactions. Broad classification of CDR as mild vs severe reactions seems to aid the clinician in managing the patient.Both immunological and non-immunological factors contribute to CDRs. Immunological mechanisms consist of 4 types (types I through IV reactions). The most serious eruptions result from a type I or type IV immunological process. Non-immunological mechanisms have great variability, but are believed to include activation of effector pathways, as well as the alteration of pharmacodynamic and pharmacokinetic variables. Epidemiological data suggest that non-immunological CDRs are more predominant and largely reflect the incidence of mild CDRs.While there is general agreement about discontinuation of suspected agents, issues pertaining to rechallenge and management of severe life-threatening reactions remain controversial. Of the new anticonvulsants, lamotrigine has received much attention following CDR reports. While rare severe CDRs with lamotrigine have been reported, the drug has been successfully reintroduced without precipitation of CDRs.Severe CDRs require the successful management of fluids, nutrition and infection, and can be best managed in burn centres. Fluid and nutrition balance are typically well controlled with close monitoring of hydration and laboratory values. Prophylactic antibacterial administration is not recommended. Immunosuppressive therapy with corticosteroids to limit the extent of CDRs has received much attention. General recommendations from burn centres suggest this approach may actually promote a negative patient outcome.

Effects of SKF525A, Phenobarbital, Fasting, and Carnitine on the Anticonvulsant Activity and Neurotoxicity of Valproate in Mice

Summary: The anticonvulsant potency of valproate (VPA), as measured by the maximal electroshock seizure model in mice, was improved by pretreatment with the microsomal inhibitor SKF525A and by fasting, but was reduced by chronic phenobarbital pretreatment. Carnitine did not significantly alter the anticonvulsant properties of VPA. These findings suggest that the efficacy of VPA can be improved by factors that alter its metabolic pattern.