Roy G. Beran

Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures.

The results of a multicentre, randomised, double-blind, placebo controlled, crossover trial of lamotrigine as add-on therapy in patients with partial seizures poorly controlled by established antiepileptic drugs (AEDs) are presented. The study consisted of two 12 week treatment periods each followed by a four week washout period. During the lamotrigine treatment phase, patients received 150 mg or 300 mg daily dose depending on their concomitant AEDs to achieve concentrations in the range 1-3 mg/L. Forty one patients were entered at four centres and all patients entered completed the study. There was a highly significant (p < 0.001) decrease in total seizure counts on lamotrigine compared with placebo. Overall, 22% of patients experienced at least a 50% reduction in the total numbers of all seizures types on lamotrigine, compared with none on placebo. When the total numbers of partial seizures (simple and complex partial) were analysed there was also a significant (p < 0.05) reduction in seizure counts on lamotrigine compared with placebo. When total numbers of secondarily generalised seizures were compared the trend for a reduction in this seizure type did not achieve significance (0.05 < p < 0.1). Concomitant AED plasma concentrations were virtually unchanged. It is concluded that lamotrigine is an effective AED in the treatment of therapy-resistant partial seizures.

Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study.

Objective: To compare efficacy and safety of gabapentin (GPT) versus placebo for prophylaxis of chronic daily headache (CDH) (headache at least 15 days/month of greater than 4 hours duration over preceding 6 months). Methods: This is a multicenter randomized placebo-controlled crossover study. After 4-week baseline, subjects, aged 18 to 65, were randomized to GPT 2,400 mg/day or placebo. There was 2 weeks titration, 6-week stable dosage, and 1 week washout period between treatment arms. The primary efficacy measure was the difference between the percentage of headache-free days per treatment period. Secondary efficacy measures included headache duration and severity, degree of disability, associated symptoms, concomitant medications, Visual Analogue Scale (VAS) scores, and quality of life (QOL). Results: A total of 133 patients were enrolled (41 men, 92 women, mean age 43 years). All were eligible for safety analysis. Ninety-five received sufficient treatment to allow evaluation of efficacy. There was a 9.1% difference in headache-free rates favoring GPT over placebo (p = 0.0005). Benefits for GPT were also demonstrated for headache-free days/month (p = 0.0005), severity (p = 0.03), VAS (p = 0.0006), headache-associated symptoms of nausea (p = 0.03) and photophobia/phonophobia (p = 0.04), disability affecting normal activities (p = 0.02), attacks requiring bed rest (p = 0.001), and QOL related to bodily function (p = 0.01), health/vitality (p = 0.0001), social function (p = 0.006), and health transition (p = 0.0002). Reduction in headache days/month was seen across the spectrum of prerandomization headache frequencies. Conclusion: Gabapentin represents a therapeutic option for chronic daily headache.

Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.

Summary: Purpose: Lamotrigine (LTG) is recognised as effective add‐on therapy for focal epilepsies, but this is the first double‐blind, placebo‐controlled, crossover study in treatmentresistant generalised epilepsy.

Aggressive behaviour in intellectually challenged patients with epilepsy treated with Lamotrigine

Summary: Purpose: Lamotrigine (LTG) is a valuable addition to the medical management of epilepsy with wide spectrum of efficacy and good outcomes for quality of life. We report the emergence of a syndrome of aggressive behavior provoked by LTG in patients with epilepsy and intellectual challenge.

Review of the legal obligations of the doctor to discuss Sudden Unexplained Death in Epilepsy (SUDEP)--a cohort controlled comparative cross-matched study in an outpatient epilepsy clinic.

INTRODUCTION Acknowledging informed consent and warning of material risk, the present study examined the current debate regarding early discussion of Sudden Unexplained Death in Epilepsy (SUDEP). It sought to confirm the profile of those prone to SUDEP and to determine the basis for disclosure to patients. METHODS Patients with SUDEP attending an Australian outpatient epilepsy clinic between 1985 and 2000 were compared to an age, gender and epilepsy type cross-matched control group to ascertain risk factors for SUDEP and similarities to published parameters. These were evaluated as the basis for actions in negligence for either disclosure or failure to disclose. RESULTS Twenty-one SUDEP patients were identified: aged 18-70 years; the majority had localisation-related epilepsy (13:8, 62%); male to female ratio was 3:1; and 15/21 used polypharmacy, compared with 8/21 controls (P = 0.02951). Handedness, alcohol use or deterioration of epilepsy were unrelated. DISCUSSION This population mirrored the literature and confirmed an absence of risk factors amenable to modification. As discussion of SUDEP with males with localisation-related epilepsy on polypharmacy could not alter outcome it is unlikely that failure to disclose could be causal and hence successful in an action for negligence. Conversely, disclosure, in the absence of the patient seeking the information, may causally adversely affect quality of life hence providing successful action in negligence. Duty of care dictates open and frank discussion with those seeking the information. Thus, each case must be managed individually and doctors are advised to document the decision-making process.

Melatonin Response in Active Epilepsy

Summary: Urinary excretion of 6‐sulfatoxymelatonin (aMT.6S), the hepatic metabolite of melatonin, was measured for three consecutive 8‐h intervals, beginning at 0600 h, in 30 patients with untreated active epilepsy and in 19 healthy subjects. Excretion of aMT.6S in a 24‐h period in patients with active epilepsy was 77.3 ± 55 nmol (median 68.0, range 8.7–280 nmol), significantly higher (p < 0.05) than that of healthy subjects (49.1 ± 14 nmol, median 49.0, range 19.7–68.0 nmol). Sequential 8‐h urinary aMT.6S excretion rates in patients with active epilepsy were 2.45 ± 2.8 nmol/h (0600–1400 h), 0.83 ± 0.5 nmol (1400–2200 h) and 6.38 ± 5.0 nmol/h (2200–0600 h) as compared with 1.43 ± 0.8, 1.10 ± 0.8 and 3.81 ± 1.3 nmol/h, respectively, in healthy subjects. Analysis of variance (ANOVA) indicated that the difference in total output resulted from greater nocturnal excretion (F= 5.58, p = 0.018). Melatonin production in untreated patients with active epilepsy is increased and has a circadian pattern with a phase difference as compared with that of normal subjects.

Interface of epilepsy and sleep disorders

Obstructive sleep apnoea was first brought to prominence by Henri Gastaut, a French epileptologist. Since that time the interface between epilepsy and sleep disorders has received less attention than might be justified, recognizing that sleep deprivation is a poignant provocateur for seizures. Sleep deprivation is often used as a diagnostic procedure during electroencephalography (EEG) when waking EEG has failed to demonstrate abnormality. Patients referred to an outpatient neurological clinic for evaluation of possible seizures in whom sleep disorder was suspected, either due to snoring during the EEG or based on history, were evaluated with all-night diagnostic polysomnography (PSG) and appropriate intervention administered as indicated. Patient and seizure demography, sleep disorder and response to therapy were reviewed and the interface explored. Fifty patients aged between 10 and 83 years underwent PSG. Approximately half were diagnosed with epilepsy and almost three-quarters had sleep disorders sufficiently intrusive to require therapy (either continuous positive air pressure (CPAP) or medication). With co-existence of epilepsy and sleep disorders, proper management of sleep disorders provided significant benefit for seizure control. Snoring during EEG recordings could alert to the possibility of a sleep disorder even with epilepsy diagnosed. Where both epilepsy and sleep disorder coexist appropriate management of the sleep disorder improves control of the epilepsy.

The absorption of gabapentin following high dose escalation

Gabapentins (GBP) is structurally similar to GABA yet its mode of action remains uncertain. It is water-soluble and GI tract absorption occurs via the L-amino acid transport system in the proximal small bowel. It has been suggested that this transportation is capacity limited, thus decreasing GBP bioavailability at higher doses. GBP is not protein bound, therefore, salivary levels might be expected to be similar to those in serum; also the drug does not induce hepatic enzymes and is excreted unmetabolised by the kidney. Within the dose-range normally prescribed, it is devoid of pharmacokinetic (PK) drug interactions with all other anti-epileptic drugs. This study assesses two things in patients with epilepsy: (a) bioavailability of higher doses of GBP (1200-4800 mg per day), and (b) the influence of high dose GBP on between-dose serum concentrations of co-prescribed anti-epileptic drugs. After stabilising at each dosage, a sequence of serum and saliva samples were collected within the dosage interval; GBP and co-medication concentrations were determined and the results subjected to PK modelling. Meaned results from 10 patients indicate that GBP continues to be absorbed in a reasonably linear manner relative to dose up to 4800 mg per day. The study also shows that GBP is transported into saliva, however, salivary concentrations are only 5-10% of those in plasma. Furthermore, the results indicate that GBP, in higher than recommended doses, did not change plasma concentrations of lamotrigine, carbamazepine, carbamazepine-epoxide, vigabatrin, primidone, phenobarbitone or phenytoin when added to treatment. It is concluded that larger than recommended doses of GBP can be efficiently absorbed by some patients and also that GBP plasma levels do not fluctuate greatly between dosage intervals, therefore, twice daily dosage is a possibility.

Cross‐Reactive Skin Eruption with Both Carbamazepine and Oxcarbazepine

Summary: Oxcarbazepine (OCBZ), a 10‐keto derivative of carbamazepine (CBZ) has been reported to have a similar range of efficacy and fewer unwanted effects than CBZ since it is a prodrug for the monohydroxy derivative (MHD). A cross‐reactivity of only 1 in 4 has been reported between OCBZ and CBZ. For these reasons, we tried OCBZ with 3 consecutive patients with poorly controlled epilepsy who had had a therapeutic response to CBZ but in whom CBZ was discontinued because of serious skin reaction. Each patient had a similar skin response after exposure to only 600–900 mg OCBZ, which suggests a need to practice caution when substituting OCBZ for CBZ in patients known to have serious skin reaction to CBZ.

Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study.

PURPOSE To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice. METHODS All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated. RESULTS Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000 mg/day, 9.5% receiving 2000 mg/day, and 1.2% receiving 1000 mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (> or = 50% reduction from baseline in weekly seizure frequency) over the treatment period; two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%). CONCLUSION Levetiracetam as add-on therapy at doses up to 3000 mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.