The economic burden of tuberous sclerosis complex in the UK: A retrospective cohort study in the Clinical Practice Research Datalink.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder characterized by the development of diverse clinical manifestations. The complexity of this disease is likely to result in substantial challenges and costs in disease management throughout the patient's lifetime. This retrospective database study aims to quantify healthcare resources utilized by TSC patients. METHODS: TSC patients in the Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database were identified between January 1987 and June 2013. Analyses were conducted over the most recent 3-year period of data and stratified by pediatric (< 18) and adult patients. Prescriptions, procedures, diagnostic tests, and healthcare encounters were reported in comparison with a matched comparator cohort. Costs and key economic drivers by primary organ system manifestations were also examined. RESULTS: A total of 286 patients with TSC were identified and consistently reported 2-fold greater resource use than the matched presumably healthy controls. Despite this comparatively greater resource use, half of TSC patients did not record any procedures, and 20% of patients did not record any diagnostic tests; however, inpatient hospitalizations were greater for the TSC cohort (3.1 vs 1.3), but length of stay was comparable. TSC patients had costs totaling £12,681 per patient over the 3-year period, a figure 2.7-fold greater than the total costs in the comparator cohort (£4,777). Costs for patients with specific primary manifestations were even greater, with brain manifestations incurring £22,139 per affected patient. Kidney and nervous system manifestations were the main cost drivers. CONCLUSIONS: The economic burden of TSC and its impact on NHS healthcare resources is mostly attributable to the broad spectrum of manifestations that develop within multiple organ systems. TSC patients may benefit from co-ordinated care based on their requirement for high numbers of healthcare visits across specialties.

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD).

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder characterised by the development of benign growths and diverse clinical manifestations, varying in severity, age at onset and with high clinical burden. AIMS: This longitudinal study aims to describe the broad spectrum of clinical manifestation profiles in a large, representative cohort of TSC patients in the UK in order to better understand disease complexity. METHODS: TSC patients in the Clinical Practice Research Datalink (CPRD) and linked Hospital Episodes Statistics (CPRD-HES) were retrospectively identified between 1987 and 2013. Available history was extracted for each patient and clinical diagnosis, procedure and medication records reviewed. A random selection of patients from the CPRD-HES was used as a Comparator cohort. RESULTS: Three hundred and thirty-four TSC patients with a mean (SD) age of 30.3 (18.6) years were identified (53% female). TSC was diagnosed at mean age 3.2 (4.2) years. Epilepsy and psychiatric manifestations were reported frequently in paediatric (77% and 55%, respectively) and adult patients (66% and 68%, respectively). The prevalence of manifestations in the TSC cohort was markedly higher versus the Comparator cohort. The majority of paediatric (46%) and adult TSC patients (62%) developed clinical manifestations affecting at least three organ systems and forty-nine distinctive organ system manifestation profiles were identified. CONCLUSIONS: TSC patients present with multiple and complex clinical manifestations and profiles that necessitate the co-ordinated action of a multidisciplinary team in order to improve the quality and efficiency of care.

Anti-epileptic drugs and hormonal treatments.

OPINION STATEMENT: Epilepsy and the medications used in its treatment are known to affect the menstrual cycle, aspects of contraception, and bone health in women. Adolescence is an important time to review the diagnosis of both epilepsy and the epilepsy syndrome because of the implications and decisions, which should be made regarding antiepileptic drug (AED) treatment. In girls, once they are on AED therapy, seizure free, and driving, it becomes difficult to change therapy because of the risk of breakthrough seizures and the fact that the new AED may not be as effective as the first. So a treatment choice made in adolescence is often life-long. Therefore, women need to be started on an AED that currently appears to be the most suitable for their seizure type, has a low teratogenic risk, and hopefully does not interact with contraception. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Nonenzyme-inducing AEDs (valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine, and zonisamide) do not show any interactions with the combined oral contraceptive. There are interactions between the combined oral contraceptive and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages >200 mg/day], oxcarbazepine, eslicarbazepine and perampanel [dosages >12 mg/day]) and lamotrigine. Women taking enzyme inducing AEDs should be encouraged to use a method of contraception that is unaffected by their epilepsy medication. Interactions between AEDs and other hormonal therapies are less well studied. Studies have suggested that women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia. No studies have been undertaken looking at preventative therapies for these comorbidities. This article will concentrate on current contraceptive treatment options in patients taking AEDs.

The cardiac model of rehabilitation for reducing cardiovascular risk factors post transient ischaemic attack and stroke: a randomized controlled trial.

OBJECTIVE: To evaluate the feasibility and effectiveness of a standard National Health Service cardiac rehabilitation programme on risk factor reduction for patients after a minor stroke and transient ischaemic attack. DESIGN: Single-blind randomized controlled trial. SETTING: Cardiac rehabilitation classes. SUBJECTS: Twenty-four patients. INTERVENTION: All participants received standard care. In addition, the intervention group undertook an eight-week cardiac rehabilitation programme consisting of weekly exercise and education classes. OUTCOME MEASURES: Cardiovascular disease risk score; lipid profiles; resting blood pressure; C-reactive protein (measured with a high sensitive assay) and fibrinogen levels; blood glucose; obesity; physical activity levels; subjective health status (SF-36); Hospital Anxiety and Depression Scale. RESULTS: Group comparison with independent t-tests showed a significantly greater improvement in the cardiovascular disease risk score for participants in the intervention group compared to standard care (intervention 25.7 ± 22.8 to 23.15 ± 18.3, control 25.03 ± 15.4 to 27.12 ± 16.1, t = -1.81, P < 0.05). There were also significant improvements for the intervention group in activity levels (intervention 9.41 ± 7.7 to 8.08 ± 5.7, control 14.50 ± 5.5 to 9.83 ± 6.6, t = -2.00, P < 0.05) and the SF-36 domains of physical functioning (intervention 70 ± 24.6 to 75.4 ± 11.1, control 90.00 ± 12.4 to 83.16 ± 17.3, t = -2.72, P < 0.05) and mental health (intervention 84 ± 40 to 92 ± 40, control 88.00 ± 60 to 84 ± 44, z = -2.06, P < 0.05). CONCLUSION: The results suggest that standard cardiac rehabilitation programmes are a feasible and effective means of reducing the risk of future cardiovascular events for patients after minor stroke and transient ischaemic attack.

Managing epilepsy in women of childbearing age.

Epilepsy affects the menstrual cycle, aspects of contraception, fertility, pregnancy and bone health in women. It is common for seizure frequency to vary throughout the menstrual cycle. In ovulatory cycles, two peaks can be seen around the time of ovulation and in the few days before menstruation. In anovulatory cycles, there is an increase in seizures during the second half of the menstrual cycle. There is also an increase in polycystic ovaries and hyperandrogenism associated with valproate therapy. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Non-enzyme-inducing antiepileptic drugs (AEDs) [valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine and zonisamide] do not show any interactions with the combined oral contraceptive (OC). There are interactions between the combined OC and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages>200 mg/day], oxcarbazepine) and lamotrigine. Pre-conception counselling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be informed about issues relating to the future pregnancy, including methods and consequences of prenatal screening, fertility, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labour, breast feeding and care of a child. During pregnancy, the lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate and lamotrigine is particularly teratogenic. Most pregnancies in women with epilepsy are without complications, and the majority of infants are delivered healthy with no increased risk of obstetric complications in women. There is no medical reason why a woman with epilepsy cannot breastfeed her child. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. Studies have suggested that women with epilepsy are at increased risk of fractures, osteoporosis and osteomalacia. No studies have been undertaken looking at preventative therapies for these co-morbidities.

Care in people 60 years of age and over with chronic or recently diagnosed epilepsy: a note review in United Kingdom general practice.

AIM: To ascertain present United Kingdom (UK) management processes for epilepsy in older people. METHOD: This was a general practice notes review of people being treated for epilepsy 60 years and over. RESULTS: The cohort of 110 was from six practices. Seizure frequency in older people with epilepsy appears lower than in general; 75% are seizure free. This compares with 40-60% of people in other general practice note reviews and audits, where age is not a factor. Out of the people still having seizures over half have less than one seizure per month. Monotherapy rates are similar to the population in general. Nobody was taking more than two AEDs. There is evidence of new AED use, especially lamotrigine; it is the most commonly prescribed AED in those diagnosed in later life. Geriatricians appear to receive virtually no referrals for the diagnosis of epilepsy. General physicians, psychiatrists and neurologists receive many more. Geriatricians and general physicians appear never to follow up older people with epilepsy; GPs following up 91%, and neurologists and specialist nurses 9%. CONCLUSIONS: Seizure frequency in older people with epilepsy is generally low. Geriatricians appear to receive virtually no referrals for the diagnosis or management of epilepsy in older people. Follow up is mainly undertaken by GPs. Although lamotrigine has a difficult dosing schedule, which may be confusing for some older people, its use is high perhaps reflecting recent guidelines and evidence. These results may be peculiar to the geographical area used, so other work is needed to confirm or refute these findings.

Problems that mothers' with epilepsy experience when caring for their children.

Women with epilepsy who were service users of Epilepsy Action in the United Kingdom (UK) completed a questionnaire on the risks of caring for their baby and whether they were provided with useful information on fulfilling their caring role (Epilepsy Action is the trading name of the British Epilepsy Association a major UK charity for those with epilepsy). The cohort of 84 all reported some problems. The following were rated as being the most problematic; caring for their baby outside the home and bathing, whereas breastfeeding was rated as much less problematic. Some problems were rated as severe, which meant some babies were put at undue risk. Approximately 50% had been provided with information about caring and managing risk. Eighty-six percent found this information useful. The main conclusion is that more extensive, well-planned research is needed on this topic. There is virtually nothing in the academic literature to guide practice and this is needed. Present guidelines tend only to cover what the women rate as less problematic, e.g. breastfeeding, whereas what they rate highly problematic is often not covered. This needs attention in updates.

Best practice guidelines for the management of women with epilepsy.

Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST FEEDING: All women with epilepsy should be encouraged to breastfeed their babies. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. THE CARE OF CHILDREN OF MOTHERS WITH EPILEPSY: Although there is much anxiety about the possible risks to a child from the mother's epilepsy, there is little published evidence. The risk of the child being harmed depends on the type of seizure and its severity and frequency, and this risk is probably small if time is taken to train mothers and caregivers in safety precautions. MENOPAUSE: During menopause, about 40% of women report worsening of their seizure disorder, 27% improve, and a third had no change. Hormone replacement therapy is significantly associated with an increase in seizure frequency during menopause, and this is more likely in women with a history of catamenial epilepsy. BONE HEALTH: Women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia.

An audit of lamotrigine, levetiracetam and topiramate usage for epilepsy in a district general hospital.

The aim of this audit was to ascertain outcomes for people who had taken or who were still taking three "new generation" broad-spectrum antiepileptic drugs (AEDs), namely lamotrigine, levetiracetam and topiramate. Thirteen percent of people became seizure free and approximately, one-third had a reduction of greater than 50% in their seizures. Two-thirds of people were still taking their audit AED. In addition, approximately one-third of people with a learning disability derived substantial benefit, although the rate of seizure freedom was lower. All three AEDs were most successful at treating primary generalised epilepsy and least successful with symptomatic generalised epilepsy. With some reservations the data suggests that levetiracetam and topiramate are the most efficacious AEDs, but topiramate is the least well tolerated. These results mean consideration of a "general prescribing policy" is important when using and choosing these AEDs. We conclude that lamotrigine, levetiracetam and topiramate are useful additions to the armamentarium of AEDs.

Patient and physician reactions to generic antiepileptic substitution in the treatment of epilepsy.

BACKGROUND: The clinical and economic consequences of generic antiepileptic drug (AED) substitution are not yet fully understood. This article provides a broad perspective of generic AED substitution in five countries. METHODS: Two cross-sectional telephone-based surveys (patient and physician) were undertaken in Canada, the United Kingdom, France, Germany, and Spain. A total of 1409 interviews, 974 patients and 435 physicians, were completed. RESULTS: Across all countries studied, patients and physicians alike have elevated concerns about the safety and efficacy of generic AEDs as compared with drugs for acute care. CONCLUSION: There is an opposition to generic substitution by both patients and physicians, especially with concern over increased breakthrough seizure risk. Further evidence is required to understand how costs and effects of generic AED substitution affect patient welfare.

Safety profile of levetiracetam.

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Implementing good practice in epilepsy care.

Examples of evidence-based guidelines for epilepsy care exist. However, guidelines are of little use if they are not recognised, implemented and supported. The object of this study was to establish the degree to which good practice guidelines for epilepsy have been implemented and to identify positive and negative factors that affect their implementation. Semi-structured questionnaires were sent to 750 randomly selected health professionals working in primary and secondary care in England. The sample comprised nurses (200), adult consultants (including learning disability consultants) (300), paediatric consultants (150) and general practitioners (100). Aspects of good practice are being implemented in some areas, but not generally, therefore service provision is likely to remain fragmented until this is addressed. Professionals have been prevented from successful implementation of guidelines to sustain good practice due to a number of factors, most notably lack of time, workload, competing priorities and staffing levels. Factors that have promoted and encouraged the successful adoption and application of good practice include inputs from epilepsy specialist nurses (ESNs), appropriate, timely and accessible professional development opportunities and the support and enthusiasm of colleagues.

The associations between epilepsy and depressive illness in secondary care.

BACKGROUND: The association between epilepsy and depressive illness has long been established. However, though various explanations-psychosocial and anatomical-have been proposed findings from studies are inconsistent and often contradictory. AIMS: This study aimed to compare the features of those people with epilepsy seen in a secondary care setting who developed a depressive illness with those that did not. METHOD: Information regarding the patient's epilepsy, history and presence of depressive illness and perceived social functioning was gathered from case notes, questionnaire and patient interview. RESULTS: The experience of a depressive episode was associated with the presence of a right sided lesion, attacks occurring more than once each month, diagnosis made in adulthood and a perceived marked effect of the epilepsy on mobility and social activity. CONCLUSION: These findings are not all consistent with work already carried out in this field. However, they do point to a multifactorial aetiology of depressive illness in this group as is the case in the general population. Possible explanations for frequently contradictory findings are discussed.

Epilepsy and pregnancy.

Pregnancies in women with epilepsy are high risk and need careful management by both the medical and obstetric teams due to the increased incidence of complications and adverse outcomes of pregnancy. By the time a pregnant woman with epilepsy presents, the foetus is virtually fully formed and the opportunity for altering drug treatment has passed. Women need to be counselled and told to seek advice about their anticonvulsant therapy should they wish to become pregnant. All major anticonvulsant drugs are teratogenic but the main risk to the developing foetus appears to be when the mother is on polytherapy especially if sodium valproate forms part of the combination. Folate supplements (5 mg) before conception are advisable. There appears to be a minor but significant increased risk of maternal complications in women with epilepsy such as hyperemesis gravidarum, pre-eclampsia and eclampsia, vaginal bleeding and premature labour. In the majority of women seizure control will not alter during pregnancy. Oral vitamin K should be given to the mother receiving enzyme-inducing antiepileptic drugs. POST-NATAL INFANT DEVELOPMENT: There is an increased risk of prematurity (9-11%), stillbirth, neonatal and perinatal death, haemorrhagic disease of the newborn, low Apgar scores and low birth weight (7-10%). BREAST FEEDING: Virtually all the anticonvulsant drugs are excreted in breast milk in low concentrations. Feeding difficulties, irritability and lethargy can occur. However, the benefits of breast feeding usually far outweigh any minor risks to the baby.

The associations between epilepsy and depressive illness in secondary care.

BACKGROUND: The association between epilepsy and depressive illness has long been established. However, though various explanations-psychosocial and anatomical-have been proposed findings from studies are inconsistent and often contradictory. AIMS: This study aimed to compare the features of those people with epilepsy seen in a secondary care setting who developed a depressive illness with those that did not. METHOD: Information regarding the patient's epilepsy, history and presence of depressive illness and perceived social functioning was gathered from case notes, questionnaire and patient interview. RESULTS: The experience of a depressive episode was associated with the presence of a right-sided lesion, attacks occurring more than once each month, diagnosis made in adulthood and a perceived marked effect of the epilepsy on mobility and social activity. CONCLUSION: These findings are not all consistent with work already carried out in this field. However, they do point to a multifactorial aetiology of depressive illness in this group as is the case in the general population. Possible explanations for frequently contradictory findings are discussed.

Interactions between antiepileptic drugs and hormonal contraception.

An interaction between antiepileptic drugs (AEDs) and the combined oral contraceptive pill was first proposed when the dose of estradiol in the oral contraceptive pill was reduced from 100 to 50 microg. There was a higher incidence of breakthrough bleeding and contraceptive failure among women with epilepsy compared with women in general. Since then, interaction studies have been undertaken to look for possible interactions between AEDs and the combined oral contraceptive pill. Phenobarbital (phenobarbitone), phenytoin, carbamazepine, oxcarbazepine, felbamate and topiramate have been shown to increase the metabolism of ethinylestradiol and progestogens. Therefore, if a women is on one of the AEDs and wishes to take the oral contraceptive pill, she will need to take a preparation containing at least 50 microg of ethinylestradiol. Levonorgestrel implants are contraindicated in women receiving these AEDs because of cases of contraceptive failure. It is recommended that medroxyprogesterone injections be given every 10 rather than 12 weeks to women who are receiving AEDs that induce hepatic microsomal enzymes. There are no interactions between the combined oral contraceptive pill, progesterone-only pill, medroxyprogesterone injections or levonorgestrel implants and the AEDs valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide and the benzodiazepines. Therefore, normal dose contraceptive preparations can be used in patients receiving these AEDs.