Changing trends in antiepileptic drug prescribing in girls of child-bearing potential.

OBJECTIVE: To characterize trends in prescribing carbamazepine (CBZ), sodium valproate (VPA) and lamotrigine (LTG) in adolescent females in the UK and to examine possible reasons for changing trends. DESIGN: Population-based observational study. SETTING: UK General Practice Research Database between 1 January 1993 and 31 December 2006. PATIENTS: 12-18-year-old subjects who were issued >or=1 CBZ, VPA or LTG prescription. MAIN OUTCOME MEASURES: Prescribing prevalences stratified by age, gender and antiepileptic drug. RESULTS: 5417 patients (47.6% females) were prescribed 147 111 prescriptions for CBZ (34.5%), VPA (38.6%) or LTG (26.9%). The prevalence of LTG prescribing in females increased from 0.08 (95% CI 0.04 to 0.12) to 0.80 (95% CI 0.70 to 0.89) per 1000 female population. Conversely, the prevalence in females of CBZ and VPA prescribing significantly decreased from 1.00 (95% CI 0.85 to 1.15) to 0.51 (95% CI 0.44 to 0.58) and from 0.94 (95% CI 0.80 to 1.09) to 0.63 (95% CI 0.55 to 0.72), respectively. This 10-fold rise in LTG prescribing in females is much higher than the fivefold rise in males from 0.09 (95% CI 0.05 to 0.14) to 0.47 (95% CI 0.40 to 0.54) per 1000 male population. CONCLUSION: The practice of prescribing antiepileptic drugs in adolescents has changed gradually over the last decade. More females aged 12-18 years are prescribed LTG than CBZ or VPA and the increase is much greater than for males. The increase in LTG prescribing mirrors a corresponding decrease in both VPA and CBZ. Concerns about potential problems to offspring appear to be affecting prescription trends in adolescent females of child-bearing potential.

Seizure-related injuries in a group of young people with epilepsy wearing protective helmets: incidence, types and circumstances.

PURPOSE: To provide information on the incidence, types and circumstances of injuries sustained in a group of young people with epilepsy using protective helmets. METHODS: Thirty-three residential students (21 M, 12 F, age range 5-21, mean 14.5 years) attending a special epilepsy centre over 1 year were provided with helmets. The types of protective measures, seizure frequency, types of injuries, circumstances and outcome were recorded. RESULTS: Fourteen thousand seven hundred and fifty-one seizures were recorded in the 33 patients, which resulted in 59 injuries. The seizure-related injury risk was 4/1000 seizures. Scalp and facial bruises were the commonest injury (51%). Additional protective measures, such as bed guards and padding of dinner tables and sinks, were used for 57% of these students. Helmets were in use in 46% of the accidents; 68% of these accidents resulted in facial or scalp injuries, which required medical attention in 48%. Helmets were not in use in 41% of accidents; 57% of these accidents resulted in facial or scalp injuries, which required medical attention in 36%. Data on wearing of helmets in the accidents were unavailable in 13%. CONCLUSIONS: Injuries continue to occur despite the use of helmets. Changes to the helmet design and modifications to suit the seizure type may improve the protection offered by helmets.

Safety, tolerability, and pharmacokinetics of remacemide in children.

Eleven patients (nine males, two females), 9-14 years of age, received adjunctive therapy with remacemide in an open ascending-dose study at two residential centers in the United Kingdom. Children taking enzyme-inducing drugs were given remacemide twice daily, starting at approximately 4 mg/kg per day and doubling the dose at two weekly intervals to a target dose of approximately 16 mg/kg per day. Children not taking enzyme-inducing drugs (n = 5) received half of these doses. After the dose-escalation phase, remacemide was slowly withdrawn over 2 weeks except in two children who, because of apparent benefit, entered a continuation phase. Remacemide generally was well tolerated in doses up to 13.5 mg/kg per day. Adverse events were similar to those reported in adults, with central nervous system and gastrointestinal events being the most common. One patient died after a suspected seizure, which was unlikely to have been related to remacemide treatment. No adverse effects on neuropsychologic functioning were observed; effects on vital signs and laboratory variables were not clinically significant. The pharmacokinetic profile for remacemide and its desglycinyl metabolite in children is similar to that seen in adult patients. Plasma concentrations of remacemide and the desglycinyl metabolite are reduced in the presence of concomitant antiepileptic drugs with hepatic enzyme-inducing activity.

Behavioural effects of the new anticonvulsants.

Of the 9 new anticonvulsants that have been marketed recently in the UK or US, a number appear to have either adverse or beneficial effects on behaviour. There is now a considerable database of information, in terms of the number of patients treated and/or the number of published reports, on vigabatrin, lamotrigine, gabapentin and topiramate. Oxcarbazepine has been available in some centres for several years and there is extensive experience with the drug in Scandinavia. It appears that the profile of adverse and beneficial effects is similar to that of carbamazepine. Behavioural effects have probably been greatest with vigabatrin, with psychosis, depression and other behavioural problems recorded, but the use of this drug has been limited because of the concern about visual field constriction. The cognitive and behavioural effects of topiramate have caused concern, but these may be much less of a problem if lower starting dosages and escalation rates are used. Psychosis and depression have been associated with topiramate, as they have with another carbonic anhydrase inhibiting drug, zonisamide. Although zonisamide has been used for many years in Japan and Korea, experience elsewhere with this drug is currently very limited. Gabapentin seems to be less associated with adverse behavioural effects than some of the other new anticonvulsant drugs. The reports of behavioural disturbance with gabapentin in children may be related to dose escalation. Behavioural disturbance as a direct result of lamotrigine seems to be uncommon, although indirect effects on behaviour, through the so-called 'release phenomenon' from improved seizure control and consequent ability to misbehave, can occur. Positive behavioural effects have been described with several of the new anticonvulsants, particularly gabapentin, lamotrigine and oxcarbazepine; all of these drugs may have mood-levelling effects that could be of value in treating affective disorders. The information on tiagabine and levetiracetam is too limited to allow any firm conclusions to be drawn with regard to positive or negative behavioural effects. When interpreting reports of behavioural changes with anticonvulsants, it is important to avoid attributing the effect to the drug when one or more of the other multiple causes of behavioural disturbance in people with epilepsy may be responsible or when an indirect effect such as 'forced normalisation' may be the cause. Many of the published studies are retrospective and unblinded rather than double-blind, placebo-controlled, prospective trials, implying that much of the data must be interpreted with caution at this stage.

Methsuximide reduces valproic acid serum levels.

The authors investigated whether methsuximide affects serum levels of valproic acid. Pre-morning-dose serum valproic acid levels were measured in 17 patients (12 male, 5 female; age range, 8-19; mean, 14.5 years) who either started or stopped taking methsuximide but whose dose of valproate and other medication remained unchanged. Four of these patients both started and stopped taking methsuximide. For the whole group the mean valproic acid level (+/- standard error) while not taking methsuximide was 81.9 +/- 5.3 mg/L and while taking methsuximide was 55.7 +/- 4.3 mg/L. The difference between the means was highly significant (paired t test, p < 0.001). The mean valproic acid serum level before taking methsuximide was 85.4 +/- 4.5 mg/L (14 patients), which decreased to 58.2 +/- 4.8 mg/L while taking methsuximide (difference highly significant, p < 0.001). In the eight patients who stopped taking methsuximide the mean serum level increased from 49.8 +/- 7.5 mg/L to 71.7 +/- 8.5 mg/L (difference significant p = 0.025). Because methsuximide reduces valproic acid serum levels, it may be necessary to increase the valproate dose when methsuximide is added or reduce the valproate dose when methsuximide therapy stops, to avoid loss of seizure control or valproate toxicity respectively.

Is generic prescribing acceptable in epilepsy?

There is considerable debate about the role of generic prescribing for people with epilepsy. The arguments go beyond simple considerations of cost on one hand and the possibility of toxicity or loss of seizure control on the other. The concepts of bioavailability and bioequivalence require further consideration. The measures that are currently used may not apply equally well to all situations. For example, additional measures may be needed for controlled-release preparations and in the other special cases. There is an extensive literature on the bioequivalence of various phenytoin preparations. This anticonvulsant drug is poorly soluble in water, has nonlinear kinetics and has a narrow therapeutic range, implying that problems with bioequivalence are likely to occur. This is borne out by clinical experience. There are a few published investigations on carbamazepine. The systematic studies, on the whole, fail to show major differences in bioequivalence between the various formulations. There is sparse information on the comparison between generic and proprietary formulations of other anticonvulsant drugs. Whatever arguments might be put forward supporting brand name or generic prescribing, there are strong reasons for recommending tight control on the consistency of anticonvulsant drugs, both generic and proprietary. There is also a strong case for ensuring that the physician who signs the prescription remains in control of the situation and that any decisions that the physician makes should be based on accurate and reliable information.

Successful re-introduction of lamotrigine after initial rash.

The aim of this study was to determine whether lamotrigine can be re-introduced safely and with a benefit in young people who previously had a mild rash associated with the first introduction of this drug. In the first 150 young people (5-19 years old) treated with lamotrigine in a special centre for epilepsy, seven developed a mild rash soon after starting the drug. In none of these cases was the rash severe, nor was there any mucous membrane involvement. The lamotrigine was stopped immediately when the rash was identified and was subsequently re-introduced, using a special very-low-dose-escalation regime, starting with 0.1 mg /day total daily dose, after periods ranging from 47 to 236 days. It was possible to re-introduce the lamotrigine without recurrence of persistent rash and without any adverse effects in all seven cases. The re-introduction of lamotrigine was associated with improvement in five of the seven cases. It is recommended that lamotrigine is stopped as soon as any rash attributable to the drug develops but it may be possible to re-introduce the drug after mild rash using a very-slow-dose-escalation regime, with a benefit in at least some cases.

Methsuximide lowers lamotrigine blood levels: A pharmacokinetic antiepileptic drug interaction.

PURPOSE: To determine whether methsuximide (MSM) affects lamotrigine (LTG) blood levels and whether any change is of clinical significance. METHODS: LTG serum levels in 16 patients taking MSM were compared with those before starting or after stopping the MSM. The 16 patients, (11 boys, five girls) were young people (mean age, 15.5 years; range, 9-19 years) with a variety of seizure types and syndromes. In six cases, LTG levels were available both before MSM was started and after it was stopped. RESULTS: The mean LTG serum concentration before starting or after stopping MSM was 13.4 mg/L, and the mean level while taking MSM was 6.3 mg/L. This difference was highly significant (p < 0.0005, paired t test). MSM lowered the LTG serum concentration in every case, with a mean decrease of 53% (range, 36-72%). In some patients this led to a deterioration in seizure control when MSM was added or an improvement in seizure control after MSM was stopped. CONCLUSIONS: Although MSM is a valuable add-on, broad-spectrum drug when used in combination with LTG, adjustment of the LTG dose may be necessary when MSM is started or stopped, to allow for the fact that MSM lowers LTG blood levels.

Lamotrigine-associated rash: risk/benefit considerations in adults and children.

PURPOSE: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add-on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice. METHODS: The panel of experts reviewed all published and unpublished data related to the incidence and risk factors for serious rash with LTG. RESULTS: An allergic skin reaction occurs in approximately 10% of patients, usually in the first 8 weeks. Rashes leading to hospitalization, including Stevens-Johnson syndrome and hypersensitivity syndrome, occurred in approximately one of 300 adults and one of 100 children in clinical trials and appeared to be increased with overrapid titration when starting therapy and with concurrent valproate (VPA). CONCLUSIONS: Recommendations are made for both minimizing the likelihood of serious rash and for management of rash in patients taking LTG. Risk of serious rash may possibly be lessened by strict adherence to manufacturer's dosing guidelines, particularly in patients who are at higher risk: those on concurrent VPA and in the pediatric population.

Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial.

BACKGROUND: Convulsive status epilepticus is the most common neurological medical emergency and has high morbidity and mortality. Early treatment before admission to hospital is best with an effective medication that can be administered safely. We aimed to find out whether there are differences in efficacy and adverse events between buccal administration of liquid midazolam and rectal administration of liquid diazepam in the acute treatment of seizures. METHODS: At a residential school with on-site medical facilities 42 young people with severe epilepsy were enrolled. Continuous seizures of more than 5 min duration were randomly treated with buccal midazolam or rectal diazepam. If the seizure did not stop within 10 min additional medication chosen by the attending physician was administered. We monitored oxygen saturation and blood pressure for 30 min after treatment. The main outcome measures were efficacy, time from arrival of the nurse to drug administration, time from drug administration to end of seizure, and incidence of adverse cardiorespiratory events. FINDINGS: Buccal midazolam was used to treat 40 seizures in 14 students, and rectal diazepam 39 seizures in 14 students. Midazolam stopped 30 (75%) of 40 seizures and diazepam 23 (59%) of 39 (p=0.16). The median time from arrival of the nurse to administration of medication was 2 min. Time from administration to end of seizure did not differ significantly between the two treatments. No clinically important adverse cardiorespiratory events were identified in the two groups. Buccal midazolam was universally acceptable to the nursing and care staff. INTERPRETATION: Buccal midazolam is at least as effective as rectal diazepam in the acute treatment of seizures. Administration via the mouth is more socially acceptable and convenient and may become the preferred treatment for long seizures that occur outside hospital.

Treatment of photosensitive epilepsy using coloured glasses.

A recently introduced optometric technique, colorimetry, enables the perceptual effects of ophthalmic tints to be evaluated subjectively, optimized, and then prescribed in tinted spectacles. The new technique is beneficial in reducing visual stress in patients with dyslexia and migraine. We describe an open trial designed to ascertain: (1) whether the colorimetry assessment, as it is now given, is safe for the investigation of photosensitive patients in optometry clinics where colorimetry equipment is most readily available, but where EEG control is not practical; (2) what proportion of patients with photosensitive epilepsy is likely to benefit to the extent already described in individual cases; (3) whether a tint selected by colorimetry could be shown to reduce the incidence of paroxysmal epileptiform EEG activity in response to flicker and patterns, thereby validating the subjective methods and corroborating the reported seizure reduction. Twenty-four females and nine males (aged 12-43 years) took part. All the patients had suffered visually-provoked seizures, had exhibited a photoparoxysmal response on at least one previous EEG recording, and had received a diagnosis of photosensitive epilepsy. Twenty-two were currently experiencing seizures. A further EEG was recorded in all except seven cases: a routine resting record, followed by hyperventilation. Colorimetry was performed after hyperventilation and before photic stimulation. Twenty-three (70%) reported beneficial effects during colorimetry and were prescribed glasses. There was a preponderance of lenses with a rose or purple colour, in contrast to patients with dyslexia. Seventeen of the 23 patients were available at follow-up, an average of 2.4 years later. Thirteen (57%) reported benefits, and said they were still using the lenses. In six of the 13 the benefits were pronounced, including a reduction of dizziness from fluorescent lighting, elimination of aura when using computer screens etc. Only in three cases was there a reduction in seizures that could reasonably be attributed to the use of lenses; in two of these cases no medications were prescribed, and in the third the medications remained unchanged for four years, two before and two after the introduction of the glasses. In an additional four cases a reduction in seizures was observed but medication had been changed. There was a modest reduction in EEG photosensitivity with the coloured lenses but also to an equivalent or lesser extent with grey in all of the eight patients examined in this way. One patient had seizures during colorimetry, but the seizures were not accompanied by scalp EEG changes.

Exercise induced steroid dependent dystonia, ataxia, and alternating hemiplegia associated with epilepsy.

This paper describes a 20 year old woman with a new combination of neurological impairments in which the motor phenomena were responsive to corticosteroid treatment. She had lifelong moderate learning impairment. A variable ataxia with cerebellar characteristics was present from early life, with early severe exacerbation when seizures were uncontrolled. Atypical absence and simple and complex partial seizures were present from the first year of life and EEG abnormalities were maximal in the right parietal region, concordant with a mild non-specific abnormality of the white matter in the region of the trigone. Episodes of alternating hemiplegia occurred from 11 years, unassociated with seizures. Exercise induced dystonia occurred from the age of 5. After 10-20 minutes walking, her right foot would turn in and the right leg would stiffen, followed by the left and by falling and inability to get up for several minutes. Prednisolone improved her ataxia and was associated with cessation of both seizures and exercise induced dystonia. This adds a new syndrome to the corticosteroid responsive motor disorders associated with epilepsy.

Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction?

PURPOSE: To determine whether the toxicity that occurs in some patients when lamotrigine (LTG) is added to carbamazepine (CBZ) is the result of either a pharmacokinetic or a pharmacodynamic interaction. METHODS: Escalating LTG doses were added to ongoing CBZ treatment in 47 patients. All patients had blood samples collected for drug concentration measurement, including the epoxide metabolite of CBZ, before starting LTG treatment and after stabilising at each dose escalation. Patients also were examined for signs of toxicity. RESULTS: After LTG was introduced, nine patients demonstrated clinical signs of CNS toxicity, mainly diplopia and dizziness. There was no significant (p = 0.05) change in the serum concentrations of either CBZ or its epoxide metabolite when LTG was added either to the group as a whole or to the nine patients who experienced adverse CNS effects. LTG serum concentrations also were below the level at which the common signs of LTG toxicity, such as nausea, vomiting, or unsteadiness, are more likely to occur. In seven of the nine patients who exhibited CNS toxicity, CBZ serum concentrations were >8 mg/L on LTG introduction. CONCLUSIONS: Toxicity is more likely to occur when LTG is added to CBZ if the initial CBZ level is high, typically >8 mg/L. This appears to be the result of a pharmacodynamic interaction. A reduction of CBZ dose usually resolves the toxicity, allowing the LTG dose to be escalated to maximal effect. It is not usually necessary to stop either drug.

Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics.

PURPOSE: To determine whether buccal/sublingual administration of midazolam (MDL) would lead to detectable venous concentrations and EEG changes in 10 healthy volunteers. METHODS: The study consisted of an open-label and a double-blind phases. Subjects held 10 mg MDL in 2 ml peppermint-flavored fluid or peppermint-flavored placebo in their mouth for 5 min and then spat it out. Cardiorespiratory and EEG monitoring was performed in all subjects. RESULTS: Venous MDL concentrations measured on 10 occasions from 5 to 600 min after administration showed a rapid increase for the first 20-30 min. However, changes in the 8- to 30-Hz frequencies identified by spectral analysis of the EEG showed changes in < or = 5-10 min in test but not in control subjects--more rapid than were expected from the venous absorption data. There were no significant adverse effects. CONCLUSIONS: Our data provide direct evidence of the speed of cerebral effect of a drug. Our results suggest that the buccal/sublingual route of administration should be tested in emergency treatment of seizures as an alternative to the rectal route, over which it has clear practical advantages.

Lamotrigine in the treatment of epilepsy in people with intellectual disability.

Information about the mechanism of action and pharmacology of lamotrigine is summarized. A brief review of the literature on the use of this drug in people with intellectual disability is followed by a suggested framework for evaluating antiepileptic drugs in this population. The role of lamotrigine is systematically examined against the suggested framework. This leads to the conclusion that lamotrigine is a very favourable drug for treating epilepsy in people with intellectual disability because it has a broad spectrum of action, is effective in treating subtle seizures, shows no loss of effect with time, is not usually sedative, does not produce difficult-to-manage adverse effects, appears to have no direct adverse behavioural effects and is available in a range of 'patient friendly' preparations. However, it is important to use the drug wisely. This implies starting with low doses of lamotrigine and escalating the dose slowly to avoid adverse effects, especially rash, and being aware of drug interactions which could cause difficulty, including the prolongation of half-life with valproate, the pharmacodynamic interaction when it is added to carbamazepine and the pharmacokinetic interactions of lamotrigine with a number of antiepileptic drugs.