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CPD 49: EPILEPSY Biography - Paul Ryan, Community Pharmacist, O'Reilly's Pharmacy, Clonmel; General Practitioner trainee, Cork University Hospital. Paul Ryan has spent the last nine years working in both Community Pharmacy and Hospital Pharmacy. Ryan is particularly interested in Clinical Pharmacy and, after completing a Diploma in the subject, he went on to study medicine. He is currently a GP trainee. By combining these qualifications it has allowed him to be involved in developing and delivering CPD for pharmacists in Ireland. Ryan has worked as a Clinical tutor for eight years, both in the ICCPE and in the IPU academy, as well as the UCC School of Pharmacy at postgraduate level. Ryan started working as a Peer Support Pharmacist for the IIOP in 2014. 1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap

- will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

Epilepsy has multifactorial origins and manifestations and is made up of many types. It is a clinical diagnosis and is based on clinical history and eye witness accounts of the seizure. Primary generalized seizures involve the whole brain and consciousness is lost. Seizures in this category include absence (patient looks blank for a few seconds and does not respond when spoken to), tonic clonic (patients stiffens, loses consciousness and convulses), tonic (patient stiffens and falls), atonic (patient has drop attacks) and myoclonic (patient has rhythmic shock like muscle jerks). Partial seizures involve only part of the brain and consciousness may be altered but not lost. Seizures in this category include simple partial seizure (wide range of symptoms depending on area involved i.e. tingling, twitching, blinking, psychic symptoms). Complex partial seizures occur when the discharge reaches midline and becomes secondarily generalized. Seizures are purely descriptive of events i.e. disturbance of consciousness/behavior/ motor function or sensation and occur in

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Pharmacy management of Epilepsy patients INTRODUCTION

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alcohol withdrawal and hypoglycaemia as well as in epilepsy. People with epilepsy have an increased predisposition to seizures. Depending on the part of the central nervous system involved there are different effects seen. For example, if the motor cortex is involved the patient will have convulsions and if the reticular formation is involved the patient will lose consciousness. Complex seizures are those in which there is loss/altered consciousness and in simple seizures there is no loss of consciousness.   INITIATION OF TREATMENT If a diagnosis of epilepsy is made, treatment with an anti-epileptic drug (AED) is usually recommended, especially if further seizures might cause serious morbidity or mortality. The basis for this advice is a 73% risk of seizure recurrence within four years of two unprovoked seizures1. In some cases treatment may be justified after their first seizure if they are at a higher risk of recurrence as these patients have a slightly better long term outcome with early versus delayed treatment 2.

60 Second Summary Epilepsy is one of the commonest neurological disorders after stroke and it affects approximately 40,000 Irish people. There are many causes and it is classified into different types. People with epilepsy have an increased predisposition to seizures. Seizures are purely descriptive of events and occur in epilepsy as well as other medical conditions. Treatment is usually initiated after a second seizure because there is a 73% risk of seizure recurrence within four years of two unprovoked seizures. There are many factors involved in the medical treatment of epilepsy and this CPD article will mainly focus on initiation of treatment, pharmacology of anti-epileptic medication (AED), tolerability, enzyme induction, therapeutic drug monitoring, drug resistant epilepsy and treatment of certain patient cohorts. A brief discussion on status epilepticus and the role of the pharmacist is also discussed.

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CPD 49: EPILEPSY

DRUG RESISTANT EPILEPSY

ANTIEPILEPTIC DRUG PHARMACOLOGY AEDs suppress the symptoms (seizure) rather than modify the disease process (epileptogenesis) and work by preventing paroxysmal neuronal discharge without affecting normal discharge. Carbamazepine, oxcarbazepine, lamotrigine, valproate and phenytoin bind to the inactivated state of voltage gated Na channels of repetitively firing neurons thus stabilizing neuronal membranes, having a greater block in neurons that have a higher frequency in firing, thus suppressing discharge. Benzodiazepines and phenobarbitone enhance the effect of inhibitory neurotransmitters. WHICH ANTI-EPILEPTIC DRUG TO USE FIRST? Choice of treatment depends on seizure type, age of patient and concurrent/previously tried therapy. There are only a few class 1 trials to compare the efficacy of first line antiepileptics. NICE has produced guidance on how to choose the correct medication3. For instance, carbamazepine and lamotrigine are recommended first-line treatment for focal seizures and sodium valproate is the recommended first-line treatment for generalised tonic–clonic (GTC) seizures (carbamazepine and lamotrigine are also used for GTC seizures). Valproate or ethosuxamide are used in absence seizures and, for myoclonic seizures valproate is used. Valproate and lamotrigine are often used if there is any doubt of seizure type. Formulations of anti-epileptics are not interchangeable and generic substitution should not be employed. TOLERABILITY AND SAFETY OF DRUGS IN NEW ONSET EPILEPSY As the efficacy of many first line anti-epileptics in new onset epilepsy is similar, the tolerability and safety become important considerations when choosing treatment. Sedation and dizziness are common complaints when starting anti-epileptic drugs but usually resolve with time. Sedation is less with the newer anti-

epileptics. Valproate can cause weight gain. Carbamazepine can cause bone marrow failure so be alert for symptoms of anaemia, bruising and infection. Lamotrigine can cause a rash in 12% of patients, typically within the first 8 weeks of treatment, leading to withdrawal in 3% of patients. To reduce the risk of side effects, the doses should be started low and slowly titrated upwards (usually symptom led) and, if seizures are still taking place titrate up to maximum dose. ENZYME INDUCTION Strong hepatic enzyme inducers include phenytoin, phenobarbitone and primidone and weak hepatic enzyme inducers include carbamazepine, oxcarbazepine and topiramate. People on long term enzyme induction should be screened for osteoporosis and sexual dysfunction. Over the counter dietary supplements or herbal preparations like Gingko Biloba or St Johns wort can interact with antiepileptic medications that are metabolized by the liver. THERAPEUTIC DRUG MONITORING There is no evidence that routine blood level monitoring is beneficial unless to confirm suspected non adherence, evaluate unexplained toxicity or evaluate uncontrolled seizures in individual cases 4. If there is a previous blood level to compare at a time of good control, a level may help in this circumstance to see whether there has been a significant drop at a time of poor seizure control. The general rule is to ‘treat the patient not the level’. Many patients obtain freedom from seizures with concentrations below the therapeutic range while some tolerate and require concentrations above the range. Seizure control and development of adverse effects usually determine the dose. An exception to this is phenytoin, for which monitoring is strongly recommended, particularly at concentrations above 20mg/L because of the non-linear saturation dose kinetics (in which small changes in dose lead to large rises in plasma level) 4.

Half of patients with new onset focal or generalized seizures as internationally defined 5 become free from seizures while taking the first appropriately selected anti epileptic drug 6. 70-80% of patients with new onset epilepsy have complete seizure control with anti-epileptics available today; however up to 30% of patients have drug resistant epilepsy 7. Any patient in whom at least 2 trials of adequately selected and dosed anti-epileptic drugs have not brought sustained remission fulfils the ILAE criteria for drug resistant epilepsy 8. The mechanisms underlying drug resistant epilepsy are still not fully understood 9. It is interesting that a history of depression and a high frequency of seizures before treatment onset have been associated with drug resistance10. There is no class 1 evidence to show superior efficacy of any AED for treating drug resistant epilepsy11. WHAT IF THE FIRST DRUG FAILS TO INDUCE SEIZURE REMISSION? Two main options exist for patients who continue to have seizures despite taking the first chosen anti-epileptic; combination therapy (add-on therapy) or alternative monotherapy (substitution) 12.  Most doctors prefer add on treatment with small increases in dose because it prevents the possibility of breakthrough seizures after discontinuation of the first drug. Substitution is preferable for patients who suffer intolerable side effects from the first drug. There is no evidence that it is more beneficial to take  more than two drugs at any time, therefore keep drug combinations to two maximum where possible. TREATMENT OF CERTAIN POPULATION COHORTS Older people As there are lower glomerular filtration rates in this patient cohort, the doses of renally excreted drugs should be reduced. There is also a change in body fat, albumin and cytochrome P450 and hyponatraemia secondary to oxcarbazepine may be more common 13. Older people are also more likely to be on medication which increases the possibility of drug interactions. Mono therapy with an anti-epileptic that is well tolerated and has low possibility of drug interactions, such as lamotrigine, gabapentin 14 or low dose topiramate, is preferable. Women There is a higher incidence of bone fracture in people with epilepsy (particularly women) compared to the general population because they can break a bone during a seizure, as well as the use of anti-epileptic drugs (especially enzyme inducing ones) which increase the risk 15. Enzyme inducing drugs were shown to independently increase the risk of fracture in the Womens Health Initiative study 16. The

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CPD 49: EPILEPSY

Womens Health Initiative study concluded that attention to fall prevention is particularly important in postmenopausal women who use anti-epileptic medication. Anti-epileptic medication - and in particular enzyme inducing ones - have been shown to decrease bone mineral density and alter bone metabolism. One mechanism is by inducing cytochrome P, which accelerates metabolism of vitamin D to polar inactive metabolites17. Risedronate plus calcium and vitamin D has been shown to prevent the occurrence of new fractures in males with a higher risk of fractures18.

topiramate and oxcarbazepine will be increased and dose adjustment will have to be made to reduce the risk of breakthrough seizures19 . The risk of continued use of sodium valproate to the unborn child especially should be discussed, being aware that higher doses of sodium valproate (more than 800mg/day) and polytherapy, particularly with sodium valproate, are associated with higher risk. 5mg of folic acid should be given to all women of child bearing potential. There is limited information on the risks to the unborn child associated with newer drugs.

Pregnant women and neonates

BREAST MILK

Two out of three women with epilepsy who become pregnant remain seizure free throughout pregnancy. However, anti-epileptic drug dosages may need to be adjusted, particularly if seizures occur in the first trimester. A woman who is planning to get pregnant should be given accurate information with regard to the risks of AEDs and pregnancy, particularly the possible effects on the unborn child. As there is an increased glomerular filtration rate during pregnancy, the clearance of lamotrigine and possibly levetiracetam,

Primidone and levetiracetam pass into breast milk in amounts that may be clinically important unlike valproate, phenytoin, phenobarbital and carbamazepine 20.

quality of life and lead to an increased suicide rate. Before considering starting a patient on an anti-depressant, look to see if they are on phenobarbital, vigabatrin, tiagabine, clobazam, topiramate or levetiracetam as these can all induce depressive symptoms in patients with epilepsy. It must also be taken into consideration that, if carbamazepine, valproate or lamotrigine are discontinued it may precipitate depression as these all have mood stabilizing properties. Sertraline, fluoxetine and citalopram are 3 antidepressants where there is limited evidence of benefit for depressed patients with epilepsy 22. As there are minor pharmacokinetic interactions with escitalopram and citalopram these should be considered first line drugs followed by sertraline. Fluoxetine and paroxetine interfere with CYP450 so, when these are used the anti-epileptic drug doses may need to be adjusted.

PATIENTS WITH CO-MORBIDITIES

STATUS EPILEPTICUS

There is double the lifetime community based prevalence of depression, suicidal ideation and generalized anxiety disorder in patients with epilepsy compared to the general population 21. This is very significant as both depression and anxiety affect the

The International League Against Epilepsy (ILAE) defined status epilepticus more than 20 years ago as being a single epileptic seizure of >30 minutes duration or a series of epileptic seizures during which function is not regained

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CPD 49: EPILEPSY

between ictal events in a 30 minute period 23. Because of the clinical urgency in treating generalized convulsive status epilepticus (GCSE), however, a 30 minute definition is neither practical nor appropriate in clinical practice. Once seizures have continued for more than a few minutes, treatment should begin and an ambulance should be called. Considering the need for rapid evaluation and intervention in GCSE, an accepted operational definition of status epilepticus is ≥5 minutes of continuous seizures, or ≥2 discrete seizures between which there is incomplete recovery of consciousness. Buccal midazolam or rectal diazepam are used first line. In early status epilepticus buccal midazolam is a key option as a randomized controlled trial showed that it achieved seizure cessation in 8 minutes compared with 15 minutes for rectal diazepam, with no difference in the rates of respiratory depression 24. In established status, epilepticus options include intravenous valproate, levetiracetam, phenytoin and phenobarbital. In refractory status, epilepticus midazolam, thiopentone and propofol are possible options. STOPPING ANTI-EPILEPTICS The decision to stop anti-epileptics should be based on the risk of seizure recurrence after discontinuation (which is twice as high overall in the 2 years after discontinuation) and continuing to take them. The risk of recurrence of seizures when patients stop taking anti-epileptics is as high as 34% with a wide range of 12-66% 25. If the patient is seizure-free for more than 2 years, this implies a 60% chance of persistent remission in certain epilepsies. Factors which favour this include no previous unsuccessful attempts at withdrawal, control easily achieved on a low dose of 1 drug, normal neurological examination and electroencephalogram, primary generalized epilepsy (except juvenile myoclonic epilepsy) and benign syndromes. There is a greater risk of seizure recurrence off anti-epileptic drugs if the patient is over 16 years, on more than 1 anti-epileptic, previously had seizures after starting drug treatment, history of generalized tonic-clonic seizures or history of myoclonic seizures. The revised ILAE definition of epilepsy states that ‘Epilepsy is considered to be resolved for individuals who either had an age dependent epilepsy syndrome but are now past the applicable age or those who remained seizure-free for the last 10 years and off anti-seizure medications for at least the last 5 years’. Factors to be taken into account when a patient is being counselled about discontinuation include driving, pregnancy, work and family. It is also worth considering that, if other seizures were to occur, it may cause embarrassment for the patient as well as causing loss of the drivers’ license or rarely seizure related death. If the anti-epileptic drug was to be restarted, this does not guarantee immediate or sustained resumption of seizure control. The patient might still be anxious to discontinue due to drug related side effects and drug interactions and, if so, a slow tapering discontinuing schedule

may be undertaken. Antiepileptic drugs are continued for at least 1-2 years after epilepsy surgery. Use of these drugs in this setting led to the old name anti-convulsants (convulsions after surgery). ROLE OF THE PHARMACIST It is very important that good communication exists between all healthcare professionals involved, as well as the patient and their carers so the treatment plans are clear. Written evidence-based information about epilepsy should be given to the patients. We, as pharmacists are ideally placed to identify non-adherence to medication as well as identifying medication-related side effects. We can also advise on the use of non-prescribed medications and supplements, as well as advising doctors on the best treatment available for a particular patient. When reviewing prescriptions, look at the dose and see if there have been any changes in dose, is the prescription slow release or plain? Be mindful of drug interactions and remember generic substitution is not advised. Factors involved in patient counselling include side effects, compliance (need for memory aids), work and pregnancy. In summary, pharmacists have a huge role in the effective management of epilepsy and, as patient advocates, through clear communication between all the parties involved. Sources of information: Websites www.epilepsy.ie www.epilepsyresearch.org.uk www.epilepsy.org.uk REFERENCES: 1. Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:429-34. 2. Kim LG, Johnson TL, Marson AG, Chadwick DW; MRC MESS Study group.Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results from the mess trial. Lancet Neurol 2006;5:317-22. 3. NICE. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. January 2012. NICE CG137. 4. Schmidt D. Drug treatment of epilepsy: options and limitations. Epilepsy Behav 2009;15:56-65. 5. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. 6. Sillanpää M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 2006;129:617-24. 7. Cockerell OC, Johnson AL, Sander JW, Shorvon SD. Prognosis of epilepsy:a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a

prospective population-based study. Epilepsia 1997;38:31-46. 8. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-77. 9. Löscher W, Brandt C. Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 2010;62:668-700. 10. Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res 2007;75:192-6. 11. Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 2011;52:657-78. 12. Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005;7:S1-64. 13. Robertson MM, Trimble MR. The treatment of depression in patients with epilepsy. A doubleblind trial. J Affect Disord 1985;9:127-36. 14. Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868-73. 15. Pack A. Bone health in people with epilepsy: is it impaired and what are the risk factors? Seizure 2008;17:181-6. 16. Carbone LD, Johnson KC, Robbins J, Larson JC, Curb JD, Watson K, et al. Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the women’s health initiative (WHI). J Bone Miner Res 2010;25:873-81. 17. Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 2013;54:11-27. 18. Lazzari AA, Dussault PM, Thakore-James M, Gagnon D, Baker E, Davis SA, et al. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy—antiepileptic drug and osteoporosis prevention trial. Epilepsia 2013; published online 6 Sep. 19. Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al; EURAP Study Group. Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry. Epilepsia 2013;54:1621-7. 20. Meador KJ, Loring DW. Risks of in utero exposure to valproate. JAMA 2013;309:1730-1 21. Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48:2336-44. 22. Noe KH, Locke DE, Sirven JI. Treatment of depression in patients with epilepsy. Curr Treat Options Neurol 2011;13:371-9. 23. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia. 1993;34(4):592. 24. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366:205-10. 25. Schmidt D, Löscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience. Acta Neurol Scand 2005;111:291-300.

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Cpd 49 epilepsy  
Cpd 49 epilepsy  
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