Frank M. C. Besag

International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy

In order to address the major impact on quality of life and epilepsy management caused by associated neuropsychiatric conditions, an international consensus group of epileptologists met with the aim of developing clear evidence‐based and practice‐based statements to provide guidance on the management of these conditions. Using a Delphi process, this group prioritized a list of key management areas. These included: depression, anxiety, psychotic disorders, nonepileptic seizures, cognitive dysfunction, antiepileptic drug (AED)–related neurobehavioral disorders, suicidality, disorders in children and adolescents, disorders in children with intellectual disability, and epilepsy surgery. Clinical practice statements were developed for each area and consensus reached among members of the group. The assessment and management of these conditions needs to combine knowledge of psychiatric disorders, knowledge of the impact of epilepsy and its treatment on psychopathology, and an ability to deliver care within epilepsy services. The aim of these statements is to provide guidance on quality care for people with epilepsy that have a range of neuropsychiatric disorders.

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.

Childhood epilepsy in relation to mental handicap and behavioural disorders

Epidemiological studies indicate that there is a high rate of mental retardation and behavioural problems in children with epilepsy. In some cases both the epilepsy and the mental retardation will have a common cause, such as a metabolic disorder or brain trauma. However, in other children, the epilepsy itself may cause either temporary or permanent learning problems. When permanent learning disability can be prevented it is important to treat the epilepsy early and effectively. Children with specific learning difficulties and memory problems can benefit greatly from appropriate management. There are many causes of behavioural disturbance in children with epilepsy. These causes include the epilepsy itself, treatment of the epilepsy, reactions to the epilepsy, associated brain damage/dysfunction and causes that are equally applicable to children who do not have epilepsy. Identifying the cause or causes in each child allows rational management to be provided. Antiepileptic treatment with medication or surgery can either improve the situation or make matters worse. The treatment should be tailored to the needs of the individual child. If surgery is required, there is a strong argument for performing this early in life, both to allow the greatest opportunity for brain plasticity and also to allow the child full benefit from the important developmental and educational years, without the problems that can be associated with the epilepsy. Skilled management of children with epilepsy who have mental retardation and/or behavioural problems can be very rewarding both for the family and for the professionals involved.

Beneficial and Adverse Psychotropic Effects of Antiepileptic Drugs in Patients with Epilepsy

Antiepileptic drugs (AEDs) can have both beneficial and adverse psychotropic effects. They act on neurotransmitter systems, neuronal ion permeability and other targets, although the exact mechanisms are not generally fully elucidated. A systematic review of the literature reveals evidence for both positive and negative effects on depression, anxiety, aggression, psychosis and sleep in patients with epilepsy. Topiramate, vigabatrin, levetiracetam, tiagabine and zonisamide have been associated primarily with adverse psychotropic effects, whilst gabapentin, pregabalin, lacosamide and lamotrigine, in particular, have demonstrated a more beneficial psychotropic profile, especially with regard to affective symptoms. This review, however, identifies specific methodological issues with studies that have reported on the psychotropic effects of AEDs, suggesting that some of the findings might be inconclusive or unreliable because of confounding factors, particularly the presence of psychiatric history. More rigorous double-blind, randomized, placebo-controlled trials on larger numbers of patients with epilepsy, with clear inclusion/exclusion criteria, that are specifically designed to investigate psychotropic changes are more likely to produce results that inform clinical practice and direct future research.

Behavioural effects of the newer antiepileptic drugs: an update

The negative and positive effects of the nine newer antiepileptic drugs that have received a product licence in the UK or in the US are reviewed. The importance of avoiding misinterpretation of the data because of confounding factors such as alternative psychosis, the release phenomenon or drug interactions is emphasised. Vigabatrin has been associated with both psychosis and depression. Due to the concentric visual field defects that may occur with vigabatrin, its use is now limited, although it remains the drug of choice for infantile spasms. Lamotrigine seems to be largely associated with improvement rather than deterioration of mood and behaviour. It may have a role in treating affective disorder. Gabapentin probably has relatively little effect on behaviour but may exacerbate behavioural problems in some children with pre-existing difficulties. Topiramate may precipitate both psychosis and depression, but these are less likely to occur if the currently recommended lower starting doses, escalation rates and target doses are used. The data for tiagabine are limited, but there is no clear evidence for psychosis or depression being caused by this drug. Oxcarbazepine may be of value in treating mood disorder, but the information is very limited. There are few reports of behavioural disturbances with levetiracetam, but the data suggest that there is no significant increase in psychosis or depression. There are some reports of psychosis and other behavioural disturbances with felbamate, but the use of this drug is limited by the serious adverse effects of hepatotoxicity and aplastic anaemia. There is some evidence for psychosis with zonisamide, but there is also a suggestion that this drug may be of benefit in treating psychiatric disorders. Careful individual assessment of each patient should enable the clinician to determine whether the medication or some other factor is responsible for any behavioural disturbance.

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.

Clinical guidelines for the management of epilepsy in adults with an intellectual disability

Clinical guidelines exist for the treatment of chronic epilepsy and epilepsy in women (2). This publication provides guidance for the clinician investigating and managing epilepsy in adults who have an intellectual disability as defined by an Intelligence Quotient (IQ) of less than 70, onset in the developmental period and difficulties with adaptive functioning.

Use of selective serotonin reuptake inhibitors in children and adolescents.

Depression is a serious condition, associated with considerable morbidity and mortality; selective serotonin reuptake inhibitors (SSRIs) were commonly used in its treatment in child and adolescent psychiatry until recently. In the wake of the recent UK Committee on Safety of Medicines (CSM) advice, we conducted a rapid review of current available information on SSRIs and suicidality (suicidal ideation, self-harm and suicide attempt) in children and adolescents from clinical trials and epidemiological studies. There is insufficient safety information from the randomised controlled trials to confirm a definite association between SSRIs and suicidality. Furthermore, analysis of suicide and antidepressant prescribing trends in three countries and a large case-control study do not support the hypothesis that there is a link between use of SSRIs and death caused by suicide. Regulatory agencies and the media should have strict guidelines for the management of information relating to the treatment of this condition so that clinicians can make properly informed decisions.We suggest clinical guidelines for managing depression in children and adolescents. SSRIs should not be considered for use as first-line treatment in mild or moderate depression of childhood, where psychological interventions such as cognitive behaviour therapy or interpersonal therapy are the mainstay. SSRIs should be considered when there is severe depression that does not respond to psychological interventions; when the child is suicidal and is admitted as an inpatient, is severely depressed or has bipolar depression despite adequate doses of mood-stabilisation agents; or when the child or family prefers pharmacotherapy to psychological interventions and gives informed consent. Local bodies of clinicians or peer groups should agree protocols and acceptable guidelines, taking into consideration the type of patients being assessed, the availability of nonpharmacological intervention, and the benefit-risk ratio of the pharmacological intervention. It is important that parents (and patients when possible) be given accurate information regarding the current controversy over SSRI prescribing. More research into the use of SSRIs in childhood depression is urgently required.

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 ⩾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.

Mortality Rates and Causes of Death in Children with Epilepsy Prescribed Antiepileptic Drugs A Retrospective Cohort Study using the UK General Practice Research Database

Background: Patients with epilepsy, including children, have an increased risk of mortality compared with the general population. Antiepileptic drugs (AEDs) were the most frequent class of drugs reported in a study looking at fatal suspected adverse drug reactions in children in the UK.Objective: The objective of the study was to identify cases and causes of death in a paediatric patient cohort prescribed AEDs with an associated epilepsy diagnosis.Methods: This was a retrospective cohort study supplemented with general practitioner-completed questionnaires, post-mortem reports and death certificates. The setting was UK primary care practices contributing to the General Practice Research Database. Participants were children and adolescents aged 0–18 years prescribed AEDs between 1993 and 2005. Causality assessment was undertaken by a consensus panel comprising paediatric specialists in neuropathology, neurology, neuropsychiatry, paediatric epilepsy, pharmacoepidemiology and pharmacy to determine crude mortality rate (CMR) and standardized mortality ratios (SMRs), and the likelihood of an association between AED(s) and the event of death.Results: There were 6190 subjects in the cohort (contributing 26 890 person-years of data), of whom 151 died. Median age at death was 8.0 years. CMR was 56.2 per 10000 person-years and the SMR was 22.4 (95% CI 18.9, 26.2). The majority of deceased subjects had severe underlying disorders. Death was attributable to epilepsy in 18 subjects; in 9 the cause of death was sudden unexpected death in epilepsy (SUDEP) [3.3 per 10 000 person-years (95% CI 1.5, 6.4)]. AEDs were probably (n = 2) or possibly (n = 3) associated causally with death in five subjects. Two status epilepticus deaths were associated causally with AED withdrawal.Conclusions: Children prescribed AEDs have an increased risk of mortality relative to the general population. Most of the deaths were in children with serious underlying disorders. A small number of SUDEP cases were identified. AEDs are not a major cause of death but in a small proportion of cases, a causal relationship between death and AEDs could not be excluded.