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management ❚ Review

Pharmacological management of epilepsy

Carole Brown MSc Clin Pharm, MPS, PIP, PwSI epilepsy

There have been significant advances in the management of epilepsy since the appearance of in 1857. In the last decade, many new drugs have been developed and general understanding of the condition has improved. Here, Pharmacist Epilepsy Practitioner, Carole Brown, considers the current choice of antiepileptic drugs (AEDs), mode of action, newer AEDS, when to start treatment, epilepsy guidelines, adverse effects of AEDs, generic substitution, therapeutic drug monitoring, driving, contraception and bone health.

ong-term antiepileptic drugs (AEDs) remain the main- AEDs exert their effects in a number of ways: Lstay of epilepsy treatment. AEDs eliminate or reduce 1. Modulation of intrinsic membrane conduct- seizure frequency in up to 60–70% of patients.1 Treat- ance, to inhibit excessive firing of neurones, the ment for chronic diseases such as epilepsy means that main targets being sodium and calcium channels, patients often have complex medication regimens to exerting their therapeutic effect by preferential incorporate into their daily routines. AED choice should binding to the inactivated state of the sodium be tailored to individual patient factors that may limit channel, eg , and carbamaz- medication use such as tolerability, treatment adherence epine. Kinetics vary, so binds less and side-effect profile. Non-adherence rates among potently but faster than phenytoin. The drugs pre- patients with epilepsy range from 30–50%.2 Clinicians vent the sustained repetitive firing of neurones so treating epilepsy patients note that non-adherent patients prolong the refractory period. Presynaptic pro- report more difficulty in attaining seizure control than teins modulate release of neurotransmitters patients adherent with their medication. Uncontrolled stored within vesicles; one of these – SV2A – is the seizures lead to major morbidity and mortality, including binding site for .4 physical injury such as head trauma, fractures and burns, 2. Potentiate inhibitory mechanisms – predominately also psychosocial problems such as depression and anxi- GABAergic system – via post-synaptic regulator modula- ety, decreased quality of life and sudden unexpected tion, inhibition of GABA metabolism or blockade of death. The key to compliance with epilepsy medication GABA transport. is concordance, ensuring that patients have a good 3. Inhibit the excitatory mechanisms – predominantly the understanding of the reasons for taking an AED. Inten- glutamatergic system. tional non-adherence can result in poor seizure control. The are by definition a group of disorders Ferrari et al.3 investigated factors associated with rather than a single disease entity, therefore it is not non-adherence in 385 patients with epilepsy. Non- surprising that current AEDs display such a diverse adherence measured by the Morisky–Green test was range of pharmacological actions (see Table 1 [online at 66.2%, a moderate to low result. Non-adherence was www.progressnp.com]).5 higher in men, younger patients and patients with uncontrolled seizures; increasing complexity was also When to start treatment for epilepsy and associated with decreased treatment adherence. The medication selection conclusion was to have strategies to improve adherence Local guidelines – Epilepsy Guidelines, Calderdale in these groups. Less complex treatment regimens may and Huddersfield Foundation Trust (CHFT) 20117 result in better adherence and consequently in better – state that the decision to start AEDs should be seizure control. made by the patient and epilepsy specialist. The An epileptic seizure can be defined as the excessive patient needs to be committed to long-term medica- and synchronous discharge of a group of cortical neu- tion in order to be compliant. Pharmacological rones that leads to a clinically discernible event, epilepsy treatment is guided by NICE guidance 2011 for first- being the repetitive recurrence of seizures. Current med- line AED, adjunctive AEDs and avoidance of AEDs ication treats the symptoms rather than modifying the which may worsen seizures (see Table 2 [online at disease process. www.progressnp.com]). www.progressnp.com Progress in Neurology and Psychiatry March/April 2016 27 Review ❚ Epilepsy management

CHFT 2011 Guidelines for drug selection for monotherapy: spectrum of activity. The SANAD group comment that Focal and generalised seizures: carbamazepine, lamotrigine, is better tolerated than and more levetiracetam, , sodium valproate efficacious than lamotrigine, and should remain the drug Primary generalised seizures: sodium valproate, of first choice for many patients with generalised and lamotrigine. unclassified epilepsies. However, the potential adverse Uncertain seizure types: sodium valproate, lamotrigine. effects of valproate during pregnancy, mean that the ben- Side-effects and interaction profiles should direct the efits for seizure control in women of childbearing age choice of drug for the individual patient. Elderly patients should be considered very carefully. are particularly sensitive to AED adverse events so low A study by Zeng et al. evaluated the long-term effec- doses are recommended and prescribing drugs with a tiveness of five AEDs – carbamazepine, lamotrigine, high propensity of neurotoxicity should be avoided. oxcarbazepine, topiramate and valproate – for mono- For provoked seizures caused by metabolic distur- therapy of adults with focal epilepsy. The study size was bances or drugs the provocative factor should be cor- 654 patients. Results showed lamotrigine was the most rected or withdrawn; for withdrawal give effective, topiramate less so, oxcarbazepine was more in the short term. AEDs are not indi- effective than valproate but less effective than lamotrigine cated for concussive convulsions. in preventing the first seizure.11 There is a distinction between treatment for primary and secondary generalised tonic-clonic seizures (TCS) as Adverse effects of AEDS some AEDs exacerbate primary generalised TCS but are As a general rule AEDs should be started at a low dose efficacious for secondary generalised seizures. and titrated gradually at doses no higher than recom- mended by the manufacturer. Patients should be warned AED reviews of possible side-effects (see Tables 3 and 4) and given The relative risks and benefits of starting or withholding instructions to seek urgent medical advice if rash, antiepileptic drug treatment in patients with few or infre- bruising or somnolence occur. If there are multiple con- quent seizures are unclear.9 Marson et al. compared the comitant medications, AEDs that do not have drug–drug policies of immediate versus deferred treatment in such interactions are preferred. patients and assessed the effects of these policies on short- hypersensitivity syndrome (AHS), term recurrence and long-term outcomes. The conclu- anhidrosis and hepatic/pancreatic failure occur more sion was that immediate antiepileptic drug treatment often in children than in adults. AHS is a potentially fatal, reduced the occurrence of seizures in the next 1 to 2 but rare, reaction that can manifest as a rash, fever, tender years, but did not affect long-term remission in individu- lymphadenopathy, or eosinophilia. als with single or infrequent seizures. is recommended in NICE guidance The SANAD study (2007) compared the effectiveness 201112 to be prescribed only when other appropriate of carbamazepine, , lamotrigine, oxcarbaze- drug combinations have proved inadequate or have not pine, and topiramate for treatment of partial epilepsy.10 been tolerated. Its use for adjunctive treatment of drug-re- Carbamazepine is widely regarded as first-line drug treat- sistant focal seizures with or without secondary generali- ment for partial-onset seizures. Several newer drugs pos- sation is restricted to adults aged 18 years or older. sess efficacy against these seizure types but previous Patients should be monitored for: QT interval prolonga- randomised controlled trials have failed to inform a tion; changes in vision or retinal pigment, and blue-grey choice between these drugs. The aim was to assess effi- discolouration of nails, lips and skin. The dose should be cacy with regards to longer-term outcomes, quality of life, reduced by 50% in moderate or severe hepatic impair- and health economic outcomes. SANAD was an ment or renal impairment if eGFR is less than 50mL/ unblinded randomised controlled trial in hospital-based min/1.73m2. outpatient clinics in the UK. The study compared seizure is licensed for the adjunctive treatment control, adverse events, psychosocial outcome and costs. of seizures in Lennox–Gastaut syndrome in patients over The authors concluded that lamotrigine was clinically 4 years of age, weight over 30kg. The dose is 200mg twice better than carbamazepine for time-to-treatment failure daily increased in 200mg increments according to outcomes and therefore a cost-effective alternative for response. Main side-effects include nausea, constipation, patients diagnosed with partial-onset seizures. weight loss. Patients who are concerned about hypersen- Valproate is considered a drug of first choice for sitivity syndrome (possibly including rash and fever) patients with generalised-onset seizures, and SANAD should be advised to seek immediate medical attention. notes its broad spectrum of efficacy means it is recom- Its use is restricted to when other AEDs are unsatisfactory. mended for patients with seizures that are difficult to Avoid in severe impairment, careful dose titration in classify. Lamotrigine and topiramate also exhibit a broad mild to moderate impairment.

28 Progress in Neurology and Psychiatry March/April 2016 www.progressnp.com Epilepsy management ❚ Review

AED Adverse reactions Life threatening

Carbamazepine Idiosyncratic (rash), sedation, headache, , nystagmus, AHS, hepatic failure, diplopia, tremor, impotence, hyponatraemia haematological

Clobazam Severe sedation, fatigue, drowsiness, behavioural and None cognitive impairment, restlessness, coordination disturbances. Tolerance and withdrawal syndrome

Clonazepam As for clobazam

Gabapentin Weight gain, peripheral oedema, behavioural changes, Acute pancreatitis, hepatitis, impotence Stevens–Johnson syndrome, acute renal failure

Lacosamide Dizziness, diplopia, can occasionally cause rash None

Lamotrigine Idiosyncratic (rash), insomnia, dizziness, diplopia, headache, AHS, hepatic failure, ataxia, asthenia, blurred vision, may exacerbate myoclonic haematological seizures

Levetiracetam Irritability, behavioural and psychotic changes, asthenia, dizziness, somnolence, headache

Oxcarbazepine Idiosyncratic (rash), headache, dizziness, nausea, somnolence, AHS, haematological ataxia and diplopia, hyponatraemia

Phenobarbital Idiosyncratic (rash), severe drowsiness, sedation, impairment AHS, haematological of cognition and concentration, hyperkinesias and agitation in children, shoulder hand syndrome

Phenytoin Idiosyncratic (rash), ataxia, drowsiness, lethargy, sedation, AHS, hepatic failure, encephalopathy, gingival hyperplasia, hirsutism, dysmorphism, haematological rickets, osteomalacia

Pregabalin Weight gain, , dizziness, somnolence, ataxia, Renal failure, congestive heart confusion failure

Topiramate Somnolence, anorexia, fatigue, nervousness, difficulty with Hepatic failure, anhidrosis concentration / attention, memory impairment, psychomotor slowing, metabolic acidosis, weight loss, language dysfunction, renal calculi, acute angle-closure glaucoma and other ocular effects

Valproate Nausea, vomiting, dyspepsia, weight gain, hair loss Hepatic and pancreatic failure

Zonisamide Idiosyncratic, drowsiness, anorexia, irritability, photosensitivity, AHS, anhidrosis weight loss, renal calculi Table 3. Adverse reactions associated with antiepileptic drugs

Vigabatrin should not be prescribed unless all other life of 20–24 hours, so it can be administered once a day. drug combinations are ineffective or not tolerated. It It has a low potential for drug–drug interactions.13 Effi- should be initiated and supervised by a specialist. About cacy and safety have been assessed in four randomised one-third of patients treated with have suffered clinical trials: patients with improvements over 50% visual field defects. Prominent behavioural side effects ranged between 17–43%. Adverse effects were mild to have occurred in some patients. moderate – commonly dizziness, somnolence, diplopia, abnormal co-ordination, blurred vision, vertigo. A study Newer AEDs to evaluate eslicarbazepine, at doses between 400mg and Eslicarbazepine is licensed for adjunctive treatment in 1200mg in stroke patients over a 2-year period, found that adults with focal seizures. Its mechanism of action is hyponatraemia developed in four out of 32 patients, and blockade of the voltage-gated . The active was symptomatic in three patients. Hyponatraemia symp- metabolite has a linear pharmacokinetic profile, a half- toms can be subtle and delayed, therefore monitoring of www.progressnp.com Progress in Neurology and Psychiatry March/April 2016 29 Review ❚ Epilepsy management

AED Adverse reactions Precautions

Eslicarbazepine Gastrointestinal disturbances, dizziness, drowsiness, headache, Rash; avoid in severe renal impaired coordination, tremor, visual disturbances impairment

Perampanel Nausea, changes in appetite, weight increase, aggression, Avoid in severe hepatic failure dizziness, drowsiness and moderate or severe renal failure

Primidone See , also nausea, visual disturbances Reduce dose in hepatic impairment may precipitate coma

Tiagabine Diarrhoea, dizziness, tiredness, tremor, emotional lability, Avoid in acute porphyria, avoid abrupt withdrawal

Table 4. Adverse effects associated with AEDs used as adjunctive therapy, second or third line

serum sodium in patients taking eslicarbazepine is rec- is an orally active, non-competitive gluta- ommended, especially in the elderly.14 mate receptor antagonist. It demonstrates novel pharma- Levetiracetam monotherapy outcomes from an epi- cology and is the first licensed drug that specifically and lepsy clinic were studied in 228 patients, 70.6% of whom selectively inhibits the AMPA-type of glutamate receptor. had partial-onset seizures, 25.9% had idiopathic general- Perampanel is licensed for adjunctive treatment of par- ised epilepsies and 3.5% unclassified GTCS.15 Seizure tial-onset seizures, with or without secondary generalised freedom was achieved in around half of patients on a seizures, in patients with epilepsy aged 12 years and older. median dose levetiracetam of 1000mg/day. This was It is administered orally, once daily, typically at bedtime.19 more likely to occur in those taking the drug as first mon- is used as an adjunctive treatment for focal otherapy and in those with fewer than five pre-treatment seizures with or without secondary generalisation not seizures. The drug was withdrawn in 16.2% of patients; controlled by other AEDs. (Around 30% of seizures are 50% of these developed neuropsychiatric symptoms, eg resistant to treatment.) The use of tiagabine should be depression, mood swings, irritability, depression. avoided in absence, myoclonic, tonic and atonic seizures is a unique functionalised amino acid due to risk of seizure exacerbation. It has a favourable specifically synthesised for use as an AED. It was approved safety profile. The suggested titration is in 5mg incre- in 2008 as adjunctive therapy for partial-onset seizures ments to minimise CNS-related side effects. It should not with or without secondary generalisation, and restricted be used in patients with severely impaired liver function. for specialist use in refractory epilepsy in people with epi- The are unaffected in patients with lepsy aged over 16 years. Its mechanism of action is to renal impairment or renal failure.20 increase slow inactivation of the voltage-gated sodium Topiramate is an effective antiepileptic drug given channels.16 The pharmacological response to lacosamide alone or as adjunctive treatment in generalised ton- differs from sodium-channel blocking AEDs.8 The drug ic-clonic seizures or focal seizures without secondary gen- does not interact with other AEDs, and its anticonvulsant eralisation. It is also licensed for prophylaxis of migraine. effect is possibly antagonised by MAOIs and tricyclic-re- The drug has two unusual non-neurological side effects lated , mefloquine, antipsychotics and – urolithiasis and body weight loss.21 It is recommended orlistat. There is a risk of PR interval prolongation, and it to ensure adequate hydration, especially when undertak- is contraindicated in second or third degree AV block.17 ing strenuous activity or in a warm environment. A study comparing efficacy and safety of lacosamide in , first approved in 1989, is a benzisoxaz- 118 paediatric and adult patients with uncontrolled epi- ole derivative with a unique chemical structure, predict- lepsy, showed lacosamide was well tolerated in adults as able dose-dependent pharmacokinetics and multiple in previous trials, adverse events occurring at a low fre- complementary mechanisms of action. There have quency, related to the nervous and gastrointestinal sys- been over two million patient years of experience of tems, included dizziness, headache, nausea, diplopia and zonisamide for treatment of epilepsy and it has Interna- somnolence, with dyspepsia onset occurring during the tional League Against Epilepsy (ILAE) level A evidence titration period.18 The discontinuation rate due to for efficacy/effectiveness as initial monotherapy for side-effects was 8.5%. A 50% seizure reduction was adults with partial-onset seizures. It is not known to be reported in 33–41% of patients receiving lacosamide associated with clinically significant drug–drug interac- 200mg–600mg a day. There was a 50% responder rate in tions.22 Zonisamide displays predictable dose-depend- adults with refractory epilepsy. ent pharmacokinetics, a half-life of 60 hours allowing

30 Progress in Neurology and Psychiatry March/April 2016 www.progressnp.com Epilepsy management ❚ Review

once or twice daily administration. The most frequently Epilepsy medicine Daily dose Approximate risk % risk reported adverse effects are somnolence, dizziness and anorexia/ weight loss.23 Carbamazepine Any Two in a hundred 2.4 Lamotrigine Below 400mg Two in a hundred 2.4 On the horizon was filed for approval to treat partial- Lamotrigine Above 400mg Six in a hundred 5.9 onset seizures in epilepsy patients over 16 years old, sup- Valproate Above 1100mg Ten in a hundred 10.7 ported by data from phase III studies. In January 2016 the European commission licensed brivaracetam as adjunc- Table 5. Risk of major congenital malformations associated with epilepsy medicine monotherapy29 tive therapy for adult epilepsy patients with uncontrolled partial-onset seizures. Special populations The drug shows high water solubility and modest lipo- Pregnancy philicity. No dose adjustment is required for renal impair- The UK Epilepsy and Pregnancy Register was set up to ment, and for patients with hepatic impairment a starting find out more about having epilepsy and taking epilepsy dose of 50mg/day may be considered.24 The dose range medicines during pregnancy (Table 5).27 is 50mg to 200mg/day taken twice daily. It is a highly The teratogenic risk associated with sodium val- selective, reversible, high affinity synaptic vesicle protein proate is higher than with other AEDs both as mono- 2A (SV2A) ligand with higher potency at the binding site and polytherapy. The teratogenic effect of sodium than levetiracetam. Dizziness and somnolence are very valproate is dose dependent and greatest for daily doses common side- effects; common side-effects include >1100mg. High congenital malformation (CM) rates decreased appetite, irritability and . associated with prenatal sodium valproate exposure are more likely to be related to the total daily dose rather Therapeutic drug monitoring (TDM) than peak serum concentrations. Prescribing con- The pharmacokinetics of AEDs vary, resulting in wide trolled-release sodium valproate or administering it in differences in the plasma steady-state concentration in multiple divided doses does not reduce the risk of con- patients receiving the same dose. This variability will genital malformations.28 affect the degree of pharmacological response, as the In a Drug Safety Update published on 17 February concentration of the drug in plasma is in equilibrium 2016, the Medicines and Healthcare products Regulatory with that in the brain. Toxic effects will correlate with the Agency (MHRA) says that children exposed to valproate plasma level rather than the prescribed dose. However, in utero are at high risk of developmental disorder in up therapeutic decisions must be based on evaluation of clin- to 30–40% of cases and congenital malformations in up ical response rather than plasma drug measurements to 10% of cases.29 Valproate is associated with a dose-de- alone.25 Therapeutic ranges for AEDs represent the pendent risk of abnormal pregnancy outcomes whether range at which most patients respond. If a patient is well taken alone or in combination with other medicines. controlled at a subtherapeutic level then there is no need This prompted a review of all women of childbearing age to increase the dose. The type and severity of epilepsy taking valproate to ensure that they were using effective affect the response to any given plasma drug concentra- contraception and that they were informed of the risks tion.26 It is proposed that any concentration up to the associated with valproate during pregnancy and the need upper limit should be considered potentially therapeutic. for regular review of treatment. Pharmacodynamic tolerance is seen with the benzodiaz- epines and . Therapeutic and/or toxic effects Elderly may diminish over time despite stable concentrations in In elderly patients all AEDs are introduced with caution, the blood due to adaption mechanisms. The develop- and health-care professionals need to remain vigilant to ment of pharmacodynamic tolerance to the increased sedation, confusion and mental sedation. Phar- effects of benzodiazepines in patients on chronic macokinetic factors are diminished, of these creatinine treatment means they tolerate concentrations which clearance is the most significant. The general advice ‘start would be toxic if prescribed acutely to a patient. The low go slow’ is particularly relevant in the elderly. AEDs therapeutic efficacy of their chronic treatment is cause drowsiness and co-ordination problems in the often limited by diminished efficacy. With phenobar- elderly, which can lead to falls and fractures. bital, tolerance to sedative effects does not entail a simultaneous loss in anticonvulsant activity. The value Practical considerations of TDM is greatest for phenytoin for which the rela- Interactions tionship between plasma concentration and effect is Enzyme induction is the main cause of drug-drug inter- relatively consistent. actions for AEDs. The effect is to increase the rate of www.progressnp.com Progress in Neurology and Psychiatry March/April 2016 31 Review ❚ Epilepsy management

metabolism of the affected drug causing a reduction in reduction in blood can cause plasma level and a potential reduction in the misinterpretation of total concentration. therapeutic response. Different AEDs vary considerably in their characteris- Interactions between AEDs are subject to individual tics, which influence the risk, if switching between differ- variability: primarily they are pharmacokinetic, although ent manufacturers’ medicines, of causing adverse effects pharmacodynamic interactions can also have some clin- or loss of seizure control. AEDs with nonlinear pharma- ical impact. A marked elevation of a low AED plasma cokinetics, such as phenytoin, mean that slight differ- concentration may improve seizure control or therapeu- ences between different versions of the same drug such tic response, whereas a small elevation of a near toxic as particle size or dissolution rate may lead to significant plasma level of drug may precipitate toxicity. So although differences in . The bioequivalence for a small change in blood level of AED may have little clin- most AEDs has not been evaluated in patients with epi- ical effect in the majority of patients there may be a pro- lepsy or in special populations such as the elderly or those found effect in some patients.30 on polytherapy.31 Bioequivalence of a generic drug is An important objective of AED treatment is to mini- established by comparing pharmacokinetic parameters mise the risks of drug interactions, both with AEDs and relating to the active ingredient, which must not vary concomitant medication. For example, the addition of between 80% and 125% after single/repeated adminis- lamotrigine to patients already on valproate is a risk factor tration of both products. Theoretically, plasma drug lev- for development of skin rash, however, there is no risk if els could be up to 45% lower than another generic, valproate is introduced to lamotrigine. Valproate inhibits however, plasma drug levels usually vary by only 5–7%.32 the metabolism of lamotrigine; drug levels can be The bioequivalence of drugs varies from patient to increased two-fold, a consequence of inhibition of lamo- patient, which may or may not correspond to the average trigine metabolism through UGT1A4 glucuronidation. therapeutic range of the drug.33 During combination therapy valproic acid synergistically Recent problems in the supply chain for community enhances the antiepileptic activity (partial and general- pharmacy have caused shortages of particular brands; ised seizures) and toxicity of lamotrigine, a consequence explanation of the problem by the prescriber can allay of a pharmacodynamic interaction. the potential caused by a switch of a branded generic if the AED is in category 2 or 3. Category 1 con- Generic substitution of AEDs tains phenytoin capsules, which are manufactured by a Generic substitution is cost effective for many medica- sole manufacturer – Flynn pharmaceuticals. There is a tions, however, in the case of AEDs two parameters, the choice of brands for carbamazepine, and it is important bioavailability and secondly the drug’s therapeutic to maintain continuity between secondary and primary range, need to be considered (see Table 6). The solu- care. Different preparations of carbamazepine vary in bility of phenytoin in gastrointestinal fluids appears to bioavailability, so it is prudent to avoid changing the be the main reason for the variation in bioavailability formulation. of different formulations. Monitoring blood levels can be useful; however, caution is needed in patients with Drugs and driving low albumin or renal failure as the consequent Recent legislation from March 2015 states that it is illegal to drive if unfit to do so as a result of taking legal or illegal MHRA / CHM: Three risk-based Drugs drugs. 35 The restrictions include medicines prescribed categories: for epilepsy such as and . The 1. Maintain continuity of a specific Phenytoin, carbamazepine, upper plasma levels of the drugs specified in the legisla- manufacturer’s product phenobarbitone, tion are: clonazepam 50ug/L and diazepam 550ug/L. Patients should be advised about the new regulations, 2. The need for continued supply of Valproate, lamotrigine, and reassured that if they take their medicines in accord- a particular manufacturer’s product perampanel, retigabine, ance with the prescription and they not subject to seda- should be based on clinical judgement rufinamide, clobazam, tive or cognitive side-effects then driving is permissible. and consultation with the patient and/ clonazepam, oxcarbazepine, These medications are often taken at night as they can or carer, taking into account seizure eslicarbazepine, zonisamide, have sedating side-effects. However, in some patients the frequency and treatment history topiramate sedative effects may still be apparent the next day. Cau- 3. It is usually unnecessary to maintain Levetiracetam, lacosamide, tion is needed if clonazepam is withdrawn as it can cause continuity of brand unless there tiagabine, gabapentin, rebound insomnia. Patients would be able to raise a stat- are specific concerns such as patient , , utory medical defence providing the drug was lawfully anxiety vigabatrin prescribed for medical purposes and taken in accordance Table 6. Classification of risk of switching between different manufacturers for AEDs34 with the advice of the prescriber. 32 Progress in Neurology and Psychiatry March/April 2016 www.progressnp.com Epilepsy management ❚ Review

Driving regulations say that a person who suffers from CHFT guidelines for vitamin D deficiency in primary epilepsy may qualify for a group 1 licence if she or he has care mention AEDs (including enzyme inducers pheny- been free from any epileptic attack for one year. toin, phenobarbital, primidone, and carbamazepine, as A person who has suffered from a single unprovoked well as valproate, an enzyme inhibitor) as a risk factor for epileptic seizure will qualify for a licence if he or she has vitamin deficiency. Vitamin D status is assessed if been free from further attacks for a 6-month period, pro- 25-hydroxyvitamin D (25-(OH) D) is deficient – defined vided that there are no further clinical factors or investi- as a plasma level less than 30nmol/L. In such cases high- gations that may suggest an unacceptably high risk of a dose vitamin D is indicated – 40 000 units for 7 weeks (as further seizure occurring, in which case they cannot drive 20 000 unit capsules, two per week; 40 000 unit capsule for 12 months. A person who has suffered an epileptic once a week, or calciferol oral solution). The NICE clin- attack whilst asleep must also refrain from driving from 1 ical guideline for management of epilepsy (2012) recom- year from the date of the attack, unless they have had an mends monitoring vitamin D, calcium and alkaline attack whilst asleep more than 3 years ago and have not phosphatase every 2 to 5 years for patients taking had any awake attacks since that sleep attack. enzyme-inducing AEDs. During epilepsy reviews advice Any change or dose reduction of AED by the physi- on diet and weight-bearing exercise should be given for cian means the licence is revoked for 12 months as per the prevention of vitamin D deficiency, along with advice epilepsy regulations but re-application can be earlier about over-the-counter vitamin D supplements. Certain once treatment has been reinstated for 6 months and as supplements are gelatine free, so suitable for vegetarians. long as there have been no further seizures in the 6-month period after recommencing treatment. Contraception The effectiveness of combined oral contraceptives, pro- Bone health gesterone-only oral contraceptives, contraceptive It is increasingly recognised that epilepsy patients are at patches and vaginal rings can be considerably reduced increased risk of osteopenia and osteoporosis. However, by AEDs that induce liver enzymes. Lamotrigine con- there are numerous confounders and much of the work centrations are halved through glucuronidation induc- has been conducted in refractory patients or those in tion by COCPs containing ethinylestradiol/ long-term care. A cross-sectional study showed that levonorgestrel. Health-care professionals should warn patients with epilepsy have lower bone mineral density patients about this and be aware that lamotrigine dosing (BMD) and vitamin D levels. Multiple AEDs, enzyme-in- may need to be altered accordingly if these medications ducing AEDs and generalised seizures were all are used together. This effect is negated when lamotrig- associated factors.36 ine is prescribed with sodium valproate, which inhibits There have been reports of decreased BMD, osteope- lamotrigine glucuronidation. nia, osteoporosis and fractures and bone- Levonorgestrel-containing IUDs can be safely used related sequelae with patients on long-term therapy with with AEDs. carbamazepine, eslicarbazepine, oxcarbazepine, pheny- toin, phenobarbital and sodium valproate. AEDs are Depression and epilepsy thought to affect bone health through disturbance of Antidepressants can have a slight effect on the seizure mineral metabolism and acceleration of bone turnover threshold, however, rational use of medi- mechanisms. Osteomalacia is a rare effect of primidone. cation can improve quality of life for patients with epi- Chronic metabolic acidosis associated with topiramate lepsy.39 Research from three studies with SSRIs showed and zonisamide increases the risk of renal stone forma- no significant increase in seizure frequency. Existing evi- tion and may potentially lead to osteopenia. The effect of dence on effectiveness of antidepressants in treating topiramate on bone-related sequelae has not been sys- depressive symptoms associated with epilepsy is very lim- tematically investigated; there is insufficient evidence for ited.40 Further clinical trials in large cohorts of patients levetiracetam. Lamotrigine does not appear to be associ- are required to better inform treatment policy in the ated with effects on bone. future. Anxiety and depression are common in patients The MHRA highlighted the effects on bone and with epilepsy; an antidepressant that has the minimum advised that long-term treatment with phenytoin, effect on the seizure threshold should be selected. For carbamazepine, primidone and sodium valproate are example, the SSRIs and have a associated with decreased bone mineral density, which minimal effect on seizures unless taken in high doses. may lead to osteopenia, osteoporosis and increased frac- Several AEDs also function as mood stabilisers,41 tures, particularly in those patients immobilised for long which means that some patients may be managed on one periods, have inadequate sun exposure or inadequate drug; this applies also to some patients also diagnosed dietary calcium intake.37 with non-epileptic attack disorder (NEAD). Common www.progressnp.com Progress in Neurology and Psychiatry March/April 2016 33 Review ❚ Epilepsy management

AEDs are categorised into 4 categories depending on risk38 Category 1: No restriction for use of the contraceptive method Category 2: Where the advantages of using the method generally outweigh the theoretical or proven risks Category 3: Theoretical or proven risks generally outweigh advantages of using the method. Not recommended unless other more appropriate methods are not available or acceptable Category 4: Represents an unacceptable health risk if the contraceptive method is used

Anticonvulsants Category -only Category Combined oral Pill (POP) contraceptive

Phenytoin, carbamazepine, 3 Effectiveness POP 3 Minimum 50mcg eslicarbazepine, phenobarbitone, reduced, consistent ethinylestradiol primidone, topiramate, use of condoms oxcarbazepine, higher doses of recommended topiramate and perampanel

Lamotrigine 1 No interactions with 3 Minimum 30mcg POP ethinylestradiol

Box: UK medical eligibility criteria for contraceptive use by the Faculty of sexual & reproductive health care, College of Obstetricians & Gynaecologists side-effects of medication, such as drowsiness, can lower with learning disabilities including their careers. It is the seizure threshold in susceptible patients. Tricyclic ensured that written protocols are in place for epilepsy antidepressants may require downward dose adjustment patients prescribed rescue medication and carers given if concurrently administered with AEDs metabolised by appropriate training. The pharmacist with a special cytochrome P-450. In the case of phenytoin and carba- interest in epilepsy (PwSI) implements clinical care mazepine this can lead to unintended toxicity from the plans in primary care agreed with the consultant neu- antidepressant. rologists and general practitioner; these are discussed Educating patients with epilepsy, their families and with the patient and carers. carers can reduce stigma associated with the condition. Provision of information about AEDs and epilepsy should Conclusion be clearly written, easy to understand and culturally rele- The treatment of epilepsy has been transformed vant. Epilepsy Action and the National Society for Epi- since the serendipitous discovery of phenobarbital in lepsy are excellent sources of information for epilepsy. 1912, both in the spectrum of medication available Good seizure control improves quality of life for patients and improved knowledge of how best to use AEDs. with epilepsy. Improving access to specialist information, as pro- vided by the PwSI epilepsy service in primary care, Models of care encouraging adherence to medication combined A structured management system for epilepsy has been with a rational combination of AED and concomitant established in primary care in Calderdale. As with other medication, minimising side-effects and addressing chronic diseases, an annual review is desirable. The any modifiable risk factors and addressing psychoso- shared management system identifies all patients with cial issues can serve to optimise care for the patients epilepsy, records demographic data and validates the with epilepsy. classification of seizures and syndromes. This advises monitoring seizure frequency, aiming to improve con- References, Tables 1 and 2 are online only, available free to trol by adjustments to medication, minimising side-ef- view on the Progress in Neurology and Psychiatry website fects of medication and drug interactions. Drug therapy www.progressnp.com is tailored to the individual to optimise quality of life and avoid toxicity. Therapeutic drug monitoring is con- Ms Brown is the Pharmacist Epilepsy Practitioner ducted where indicated and routine blood tests are for Calderdale. done as per NICE guidance. Where structured with- drawal from medication is appropriate it is facilitated Declaration of interests with patient consent and clinical support from neurol- No conflicts of interest were declared. ogists. Discussion of lifestyle interventions and dissemi- nation of information to help improve quality of life for Acknowledgement patients with epilepsy is an important aspect of care. My thanks to Dr James Ward, GPwSI neurology, for Women’s issues are addressed and the needs of patients his comments on this article.

34 Progress in Neurology and Psychiatry March/April 2016 www.progressnp.com Epilepsy management ❚ Review

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www.progressnp.com Progress in Neurology and Psychiatry March/April 2016 34a Review ❚ Epilepsy management

Blockage / inhibition of Blockage / inhibition Blockage / inhibition Potentiates inhibitory Reduces excitatory neuronal voltage-operated of neuronal calcium of neuronal potassium transmission transmission sodium channels channels channels

Carbamazepine ***

Lamotrigine *** Lamotrigine*

Oxcarbazepine*** Oxcarbazepine* Oxcarbazepine*

Phenytoin ***

Topiramate** Topiramate** Topiramate** Topiramate**

Valproate* Valproate* Valproate** Valproate*

Zonisamide** Zonisamide**

Levetiracetam* Levetiracetam* Levetiracetam*

Phenobarbital* Phenobarbitone*** Phenobarbitone*

Ethosuximide***

Tiagabine***

Gabapentin* Gabapentin* Gabapentin**

Benzodiazepine***

Felbamate** ** Felbamate** Felbamate**

Vigabatrin***

***primary action, **probable action, *possible action

Table 1. Proposed mechanisms of antiepileptic drug (AED) action5,6

34b Progress in Neurology and Psychiatry March/April 2016 www.progressnp.com Epilepsy management ❚ Review

Seizure type First-line AEDs Adjunctive AEDs Other AEDs that may Do not offer AEDs be considered on (may worsen seizures) referral to tertiary care

Generalised tonic-clonic Carbamazepine, Clobazam, lamotrigine, (If there are absence lamotrigine, levetiracetam, sodium or myoclonic seizures, oxcarbazepine, sodium valproate, topiramate or if juvenile myoclonic valproate epilepsy suspected) carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine , vigabatrin

Tonic or atonic Sodium valproate Lamotrigine Rufinamide, topiramate Carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine, vigabatrin

Absence Ethosuximide, lamotrigine, Ethosuximide, Clobazam, clonazepam, Carbamazepine, sodium valproate lamotrigine, sodium levetiracetam, gabapentin, valproate topiramate, zonisamide oxcarbazepine, phenytoin, pregabalin, tiagabine, vigabatrin

Myoclonic Levetiracetam, sodium Levetiracetam, sodium Clobazam, clonazepam, Carbamazepine, valproate, topiramate valproate, topiramate piracetam, zonisamide gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, vigabatrin

Focal Carbamazepine, Carbamazepine, Eslicarbazepine lamotrigine, levetiracetam, clobazam, gabapentin, acetate, lacosamide, oxcarbazepine, sodium lamotrigine, phenobarbital, valproate levetiracetam, phenytoin, pregabalin oxcarbazepine, sodium tiagabine, vigabatrin, valproate, topiramate zonisamide

Prolonged or repeated Buccal seizures and convulsive Rectal diazepam in the Intravenous community

Table 2. AED options by seizure type recommended by NICE8

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