(BQ) Part 2 book “Drugs in use” has contents: Parkinson’s disease, substance misuse, symptom control in palliative care, anticoagulant therapy, colorectal surgery, medicines management, managing medicine risk, dementia, schizophrenia,… and other contents.
18 Epilepsy Ben Dorward Case study and questions Day Miss SL, a 19-year-old student who had recently moved away from home to university, was witnessed ‘having a fit’ by her friends and was taken to the local A&E department The fit had stopped by the time she arrived and Miss SL had no recollection of the event She was sent home from hospital with paracetamol for the resulting headache, and referred to a ‘faints and fits’ clinic at the local neurology department At the neurology clinic she commented that she had been experiencing jerking movements for several years, most notably in the morning, and that these had occasionally led to her dropping her breakfast Her friends had also commented to her that she was prone to daydreaming On questioning she stated that initially she had found the transition to university life quite stressful She admitted to taking full advantage of the social opportunities, and to feeling very tired due to having to get up early for lectures after late nights out The neurologist made a diagnosis of juvenile myoclonic epilepsy (JME) Miss SL was prescribed lamotrigine 25 mg once daily, increasing to 50 mg once daily after 14 days, and was referred to an epilepsy nurse specialist Q1 Q2 Q3 Q4 Q5 Q6 What is epilepsy? Is the history of stress significant? Do you agree with the choice of lamotrigine for Miss SL? Is the dose of lamotrigine appropriate? Outline a pharmaceutical care plan for Miss SL What advice would you offer her if she asked about contraception? What is the role of the epilepsy nurse specialist? Month Miss SL presented a prescription for lamotrigine Her dose was now 50 mg in the morning and 50 mg at night On receiving the 350 D r ug s i n U s e prescription Miss SL commented that the tablets did not look the same as those she was given at the hospital On further questioning you realise she was previously dispensed a generic brand of lamotrigine and the general practitioner (GP) has prescribed the Lamictal brand Q7 Is there a significant difference between the different brands of antiepileptic drugs (AEDs)? Month Miss SL developed a bad chest infection As she was known to be allergic to penicillin (previous urticarial rash to amoxicillin) the GP prescribed ciprofloxacin 500 mg twice daily for days Q8 Is the choice of ciprofloxacin appropriate? Month The lamotrigine dose had been slowly titrated up to 150 mg twice daily but Miss SL was not responding to treatment, and now constantly felt quite tired The myoclonic jerks continued and she had had several further tonic–clonic seizures The frequency of seizures was increasing, and this was particularly noticeable in the 2–3 days before her period Q9 What term is used to describe epilepsy that worsens around the time of menstruation, and how common is it? Q10 What drug treatments are available for this form of epilepsy? After discussion with Miss SL and her epilepsy nurse specialist, the neurologist decided to change the lamotrigine to levetiracetam She was prescribed 250 mg twice daily and instructed to increase the dose to 500 mg twice daily in weeks’ time If she did not experience a reduction in seizure frequency after weeks at 500 mg twice daily, then she was to further increase the dose to 750 mg twice daily At the same time she was instructed to reduce the morning and evening doses of lamotrigine by 50 mg every weeks Q11 Levetiracetam is not licensed as a monotherapy for generalised seizures What is your opinion of the neurologist’s choice? Q12 Levetiracetam is one of the newer AEDs What are the advantages of the newer drugs over the older ones? Month Unfortunately, Miss SL had had to withdraw from her university studies She had become very low in mood but was not keen to take ‘antidepressants’ She had read that St John’s wort can be effective for low mood and came to seek your advice Q13 What advice can you offer about St John’s wort? Epilepsy 351 Q14 If indicated, what is the appropriate drug treatment for depression in people with epilepsy? Month 10 Miss SL experienced a particularly bad cluster of seizures and injured herself on falling She was admitted to a neurological ward for observation and assessment The consultant neurologist prescribed 10 mg of buccal midazolam to be used when required to terminate tonic–clonic seizures lasting longer than minutes Q15 What are the advantages and disadvantages of using buccal midazolam over rectal diazepam? Month 22 Levetiracetam had been gradually titrated upwards to a dose of 1500 mg twice daily and her seizures had become well controlled Miss SL had started a career in accounting and met a partner They had discussed starting a family and wanted to know more about how Miss SL’s epilepsy would affect this Q16 What are the issues concerning pregnancy in women with epilepsy? Q17 What drug should epileptic women who wish to become pregnant take, and at what dose? Answers What is epilepsy? A1 Epilepsy is a neurological disorder characterised by a tendency towards epileptic seizures An epileptic seizure is the result of abnormal electrical activity in the brain The manifestation of an epileptic seizure depends on the area of the brain affected by the abnormal electrical activity There are two main seizure types: (a) (b) Generalised seizures are a result of electrical activity spreading through the entire cerebral cortex They can be secondary to a focal seizure or idiopathic (see below) Absence, myoclonic and tonic– clonic (grand mal) seizures are forms of generalised seizure Partial (focal) seizures are a result of a localised electrical disturbance and are often the result of functional changes caused by brain tumours or congenital structural abnormalities such as focal cortical dysplasia Partial seizures can be further subdivided into simple– partial and complex–partial, based on whether there is an impairment of consciousness (complex–partial) or not (simple–partial) 352 D r ug s i n U s e There are a large number of epilepsy syndromes that can be characterised by the pattern of seizure type, age of onset and response to drug treatment Many of the generalised epilepsy syndromes have a genetic basis The diagnosis of epilepsy is largely a clinical one An accurate eyewitness account of the seizures is one of the most useful pieces of information in making a diagnosis JME is a form of idiopathic generalised epilepsy and is one of the most common epilepsy syndromes It is characterised by myoclonic jerks and generalised tonic–clonic seizures, often shortly after waking Many patients also have absence seizures People with JME can be photosensitive, i.e myoclonic and tonic–clonic seizures can be precipitated by flashing or flickering light Is the history of stress significant? A2 Tiredness and a lack of sleep can increase the number of seizures, particularly myoclonic seizures in JME Also, a significant number of people presenting to a neurology clinic with possible epilepsy will be diagnosed with non-epileptic attack disorder (NEAD) Such seizures can be called non-epileptic seizures, pseudoseizures, functional seizures, or non-organic seizures, and although they can look very much like epileptic seizures, during an attack an electroencephalogram (EEG) will show no abnormal electrical brain activity This is one of the reasons why it is very important that a person with suspected epilepsy should be referred to a suitably trained neurologist NEAD can often be a reaction to stress To complicate matters further, some patients with epilepsy may have non-epileptic as well as epileptic seizures There is no specific drug treatment for NEAD Do you agree with the choice of lamotrigine for Miss SL? A3 (a) (b) Sodium valproate and lamotrigine are considered first-line treatments for JME; however, sodium valproate is no longer recommended as a first-line treatment in women of childbearing potential, for a number of reasons: Teratogenicity There is a 2–3% incidence of fetal abnormalities among the general population The UK Epilepsy and Pregnancy Register (see A16b) records a major malformation rate of 5.9% for babies born to mothers treated with sodium valproate during pregnancy Side-effects can include weight gain, hair loss and menstrual disturbances, all of which are particularly undesirable in young women The SANAD trial was a large-scale practice-based randomised controlled Epilepsy 353 trial comparing the long-term outcomes of the newer antiepileptic drugs (AEDs) against the older ones One arm of the study compared valproate to lamotrigine in the treatment of generalised epilepsy syndromes and concluded that sodium valproate was more effective but lamotrigine was better tolerated Overall, sodium valproate was the most cost-effective treatment for generalised epilepsy It is generally recommended that preventative drug treatment for epilepsy should only be considered after a person experiences a second seizure, but in certain epilepsy syndromes treatment may be warranted before a second seizure occurs Miss SL’s history indicates she had already experienced absence and myoclonic seizures prior to her presentation at A&E Many people diagnosed with JME will require lifelong drug treatment Is the dose of lamotrigine appropriate? A4 Yes It is very important to adhere to the recommending starting regimen for lamotrigine, which depends on whether it is prescribed as monotherapy or in combination with other antiepileptics Rapid dose escalation is associated with the development of rash, including cases of toxic epidermal necrolysis and Stevens–Johnson syndrome, which are severe, potentially fatal hypersensitivity reactions For this reason, people started on lamotrigine should be counselled to seek medical attention immediately if they develop a rash Lamotrigine is metabolised hepatically by glucuronidation The enzymeinducing AEDs, which include carbamazepine and phenytoin, can accelerate the metabolism of lamotrigine, whereas sodium valproate inhibits lamotrigine glucuronidation It is therefore very important to check the patient’s concomitant medication to ensure the dose is appropriate, as the starting dose and titration regimen are dependent on whether lamotrigine is prescribed as monotherapy, in combination with sodium valproate, or in combination with enzyme-inducing AEDs Outline a pharmaceutical care plan for Miss SL What advice would you offer her if she asked about contraception? A5 The pharmaceutical care plan should ensure that her treatment is prescribed at an appropriate dose, monitored correctly, and that Miss SL receives all the information she needs about her treatment Checks should be made on whether Miss SL is taking any other medicines, particularly oral contraception Before offering specific counselling to Miss SL it is important to check whether or not she is taking any other medication Concomitant therapy may affect the starting dose of lamotrigine (see A4 and below) 354 (a) D r ug s i n U s e Monitoring It is not necessary to monitor serum levels of lamotrigine, and therapeutic dose monitoring generally has limited applications in monitoring AED therapy Other monitoring includes: i(i) (ii) (b) Response to treatment: patients may keep a seizure diary For adverse effects, especially rash Women taking oral contraception should be advised to report any breakthrough vaginal bleeding, as this suggests contraception is inadequate Contraception Although lamotrigine is not an enzyme-inducing drug, recent evidence suggests it can reduce levels of progestogens and women taking lamotrigine need to be aware that oral contraceptives may not be fully effective In addition, combined oral contraceptives can reduce lamotrigine levels Starting or stopping an oral contraceptive may thus require adjustment of the lamotrigine dose The Summary of Product Characteristics recommends that women’s contraceptive needs should be reviewed if lamotrigine is to be prescribed, and they should be advised to use effective alternative non-hormonal contraception The efficacy of oral contraceptives is also reduced in women taking the enzyme-inducing antiepileptics phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone and topiramate, all of which enhance metabolism of the female sex hormones The following recommendations are made for oral contraception in women taking enzyme-inducing AEDs: ii(i) Enzyme-inducing AEDs are likely to render progesterone-only contraceptives ineffective i(ii) Women wishing to take combined oral contraceptives should start on a daily ethinylestradiol dosage of at least 50 micrograms In practice this can be achieved by doubling the dose of preparations containing 30 micrograms of ethinylestradiol (iii) If breakthrough bleeding occurs then the daily ethinylestradiol dose can be further increased to 75 or 100 micrograms An alternative option is to consider taking three consecutive pill packets without a break, followed by a 4-day break, rather than the usual (‘tri-cycling’) Non-hormonal methods of contraception may also be considered (c) General counselling points that should be covered with Miss SL include: Epilepsy 355 iii(i) Explaining the name of the drug and the aim of treatment, i.e to prevent and hopefully stop further seizures The drug may not have an instant effect, and the dose will be gradually increased to minimise the risk of side-effects ii(ii) Lamotrigine needs to be taken regularly at the same time of the day and evenly spaced out during the day, i.e take each dose approximately 12 hours apart for a twice-daily regimen Written information is also beneficial for people with complicated treatment regimens, and for those with epilepsy who have learning difficulties i(iii) The potential side-effects of lamotrigine should be explained, including the importance of reporting any new rash Gastrointestinal side-effects such as nausea can occur, as well as tiredness and headache As with many AEDs, particularly the older drugs, lamotrigine is associated with a risk of haematological toxicity and patients should be advised to seek medical advice if they develop symptoms suggestive of anaemia (fatigue, breathlessness etc); low platelets (bruising or bleeding); or infection (because of potential neutropenia) i(iv) Miss SL needs to ensure her medication does not run out and that doses are not missed, and needs to know where to get further supplies In some parts of the UK shared care protocols for epilepsy exist where hospitals are responsible for supplying newly prescribed medication until the patient is stabilised on the new treatment Omission of doses or sudden discontinuation of AEDs can lead to worsening seizures, possibly status epilepticus, and are thought to be a factor associated with sudden unexplained death in epilepsy (SUDEP) This term is used when people with epilepsy die suddenly and no obvious cause is found at post mortem The exact cause of SUDEP is not yet known ii(v) Depending on where they live, people with epilepsy may be entitled to claim exemption from prescription charges i(vi) If Miss SL has a driving licence then she must be advised that she should contact the Driver & Vehicle Licensing Authority (DVLA) Current UK regulations state that a person can apply for a driving licence when they have been completely free of seizures for year, or have had a pattern of sleep seizures only for years (vii) Miss SL could be advised of local and national support groups for patients with epilepsy 356 D r ug s i n U s e In developed countries with ready access to AEDs the overall prognosis for people with epilepsy is good: up to 70% will have their seizures controlled with drug treatment What is the role of the epilepsy nurse specialist? A6 Epilepsy clinical nurse specialists perform a vital role in providing practical and emotional support to people with epilepsy and their carers They may be based in hospital or primary care settings, and can be very useful contacts for patient-specific medication enquiries Is there a significant difference between the different brands of AEDs? A7 Generic versions of medicines are often significantly cheaper than branded ones Although the prescribing of generic medicines is recommended to reduce drug costs, this practice is somewhat controversial in relation to the prescribing of AEDs; however, Miss SL can be reassured if the neurologist and GP feel it is acceptable to switch brands, her response to lamotrigine therapy should not be affected The pharmacist has an important role in listening to patients’ concerns about the appearance of their tablets and providing reassurance when appropriate Many of the older AEDs, such as carbamazepine and phenobarbital, have narrow therapeutic indices In the case of phenytoin, its metabolism is saturable This means that small dose increases, such as those caused by a switch to a slightly more bioavailable formulation, may produce a disproportionate increase in the serum concentration of drug and result in toxicity There are published case reports and series describing loss of, or worsening, seizure control or side-effects after switching to an alternative brand of AED The newer AEDs generally have more predictable pharmacokinetics and broader therapeutic indices In the case of generic lamotrigine the UK Department of Health has advised that there is no compelling evidence to suggest that swapping to a generic alternative will have an adverse clinical outcome More research is required into brand switching of AEDs to identify patient groups who may be at risk In testing generic medicines, the European Agency for the Evaluation of Medicinal Products (EMEA) stipulates that to prove bioequivalence between a generic and branded medicinal product, the bioavailability must be within 80% and 125% The pharmacokinetic parameters used for comparison include the maximal concentration (Cmax) and area under the curve (AUC) A potential variation of up to 25% may seem significant, but the limits of 80% and 125% are statistical Epilepsy 357 ones: they represent the 90% confidence intervals when calculating the ratios of pharmacokinetic parameters between the generic and the branded medicinal product There are some limitations of bioequivalence studies: (a) (b) Bioequivalence studies are usually performed in young healthy volunteers who are taking no other, potentially interacting, drugs Extrapolating results from studies in healthy volunteers to an elderly population with comorbidities and concomitant drug therapy, or to paediatric populations, may not be accurate The studies compare generic medicines to their branded equivalent but not against other generic brands One AED commonly associated with prescribing and administration errors is modified-release carbamazepine, which is often prescribed for epilepsy and has several advantages over the standard tablet formulations, such as less fluctuation in plasma levels, thereby reducing sideeffects and improving seizure control; and twice-daily administration, which may encourage patient adherence Pharmacists should actively clarify prescriptions for twice-daily regimens of carbamazepine if the modified-release formulation is not prescribed Occasionally, however, in patients exquisitely sensitive to carbamazepine, the modified-release tablets are prescribed three times a day Is the choice of ciprofloxacin appropriate? A8 No Ciprofloxacin is a quinolone antibiotic associated with an approximately 1% risk of seizures Quinolone antibiotics are thought to inhibit membrane receptor binding of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) A macrolide antibiotic such as erythromycin would be appropriate for Miss SL However, it is important to remember that erythromycin is a strong inhibitor of the cytochrome P450 3A4 isoenzyme and can interact with a number of the older, hepatically metabolised AEDs, notably carbamazepine Concomitant erythromycin therapy can increase carbamazepine levels resulting in intoxication What term is used to describe epilepsy that worsens around the time of menstruation, and how common is it? A9 Catamenial epilepsy affects approximately 10% of women of childbearing age The definition of catamenial epilepsy is not an exact one, but around 10% of women with epilepsy experience a worsening of seizures around the 358 D r ug s i n U s e time of menstruation Seizures may also worsen mid-cycle, around the time of ovulation Catamenial seizures are thought to result from the changing levels of sex hormones that occur throughout the menstrual cycle, in particular the reduction of serum progesterone prior to the onset of menstruation What drug treatments are available for this form of epilepsy? A10 Clobazam, a benzodiazepine, is often prescribed in short courses for catamenial epilepsy Clobazam at a dose between and 30 mg/day (sometimes higher in refractory cases) may be prescribed to be taken on the days it is anticipated that seizures will be worse Clobazam is prescribed in addition to the patient’s regular AEDs Acetazolamide has also been used intermittently for catamenial epilepsy This is a relatively fast-acting antiepileptic that can be initiated at a therapeutic dose Its use is based on expert opinion Levetiracetam is not licensed as a monotherapy for generalised seizures What is your opinion of the neurologist’s choice? A11 AEDs are sometimes prescribed outside of their licence indications, and levetiracetam monotherapy is a reasonable choice for Miss SL The use of leveiracetam as monotherapy is reasonable in this patient Sodium valproate is not an ideal therapeutic option because of its adverse effect profile and teratogenicity risk Carbamazapine can exacerbate myoclonic and absence seizures Topiramate and zomisamide are other therapeutic options for JME There are a number of reasons for prescribing outside licensed indications These include: (a) (b) Exceeding the maximum dose recommended in the Summary of Product Characteristics The general principle when prescribing AEDs is to start at a low dose to minimise adverse effects and then increase the dose until seizures are controlled or side-effects become unacceptable For many AEDs central nervous system (CNS) sideeffects such as drowsiness and somnolence are dose related and become the limiting factor in dose escalation Many of the more severe side-effects of hepatic and haematological toxicity are idiosyncratic reactions, and the incidence is not related to the drug dose; rash from lamotrigine is an exception to this Prescribing for an indication not listed in the Summary of Product Characteristics, e.g for use as monotherapy when it is licensed as an adjunctive therapy only Most of the newer AEDs gained marketing ... Dep r es si o n 395 taking it Venlafaxine can also cause increases in serum cholesterol, particularly following prolonged use Again, in susceptible patients routine monitoring may be advisable... medication adherence in Parkinson’s disease Mov Disord 20 05; 20 : 15 02? ??1507 Hibble JP Long-term studies of dopamine agonists Neurology 20 02; 58: S 42? ??S50 National Institute for Health and Clinical Excellence... 20 07; 356: 29 –38 Singh N, Pillay, Choonara Y Advances in the treatment of Parkinson’s disease Prog Neurobiol 20 07; 81: 29 –44 Thanvi B, Lo N, Robinson T Levodopa-induced dyskinesia in Parkinson’s