Epilepsy

Epilepsy Search date November 2005 Anthony Marson and Sridharan Ramaratnam QUESTIONS What are the benefits and risks of starting antiepileptic drug treatment following a single seizure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 What are the effects of monotherapy in newly diagnosed partial epilepsy? . . . . . . . . . . . . .4 What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 What are the effects of additional treatments in people with drug resistant partial epilepsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...0 Which people in remission from seizures are at risk of relapse on withdrawal of drug treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 What are the effects of behavioural and psychological treatments for people with epilepsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...0 What are the effects of surgery in people with drug resistant temporal lobe epilepsy? . . . .15 INTERVENTIONS TREATING SINGLE SEIZURES Trade off between benefits and harms Antiepileptic drugs after a single seizure . . .3 PARTIAL EPILEPSY: MONOTHERAPY Beneficial Carbamazepine* . . . . . . . . . . . . . . . . . . .4 Phenobarbital* . . . . . . . . . . . . . . . . . . . .5 Phenytoin* . . . . . . . . . . . . . . . . . . . . . . .6 Sodium valproate*. . . . . . . . . . . . . . . . . .6 GENERALISED EPILEPSY: MONOTHERAPY Beneficial Carbamazepine* . . . . . . . . . . . . . . . . . . .7 Phenobarbital* . . . . . . . . . . . . . . . . . . . .8 Phenytoin* . . . . . . . . . . . . . . . . . . . . . . .8 Sodium valproate*. . . . . . . . . . . . . . . . . .9 TREATING DRUG RESISTANT PARTIAL EPILEPSY Beneficial Addition of second line drugs (gabapentin, levetiracetam, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, or zonisamide). . . . . . . . . . . . . . . . . . . . .9 DRUG WITHDRAWAL AND RELAPSE Trade off between benefits and harms Antiepileptic drug withdrawal for people in remission . . . . . . . . . . . . . . . . . . . . .10 BEHAVIOURAL AND PSYCHOLOGICAL TREATMENTS Likely to be beneficial Educational programmes . . . . . . . . . . . .13 Unknown effectiveness Biofeedback . . . . . . . . . . . . . . . . . . . . .12 Cognitive behavioural therapy . . . . . . . . .12 Family counselling . . . . . . . . . . . . . . . . .14 Relaxation plus behavioural modification therapy . . . . . . . . . . . . . . . . . . . . . . .14 Relaxation therapy . . . . . . . . . . . . . . . . .11 Yoga . . . . . . . . . . . . . . . . . . . . . . . . . .11 SURGERY IN PEOPLE WITH DRUG RESISTANT TEMPORAL LOBE EPILEPSY Beneficial Temporal lobectomy* . . . . . . . . . . . . . . .15 Likely to be beneficial Amygdalohippocampectomy*. . . . . . . . . .16 Vagus nerve stimulation as adjunctive therapy for partial seizures New. . . . . . . . . . .16 Unknown effectiveness Lesionectomy . . . . . . . . . . . . . . . . . . . .16 To be covered in future updates Treatment of drug resistant generalised epilepsy *Categorisation based on consensus. See glossary� main/1201_new 01/11/06 N eurologicaldisorders Clin Evid 2006;15:1–3. BMJ Publishing Group Ltd 2006 1 Key Messages • During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission. • After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects and their long term benefit is unknown. • Carbamazepine, phenobarbital, phenytoin and sodium valproate are widely considered to be effective in controlling seizures in partial or in newly diagnosed generalised (tonic clonic) epilepsy, but we found no RCTs comparing them with placebo and a placebo controlled trial would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs; carbamazepine is considered to be the drug of choice for partial epilepsy. Adding second line drugs to usual treatment reduces seizure frequency in people with drug resistant partial epilepsy, but increases adverse effects such as dizziness and somnolence. We don’t know if any one is more likely to reduce seizures compared with the others. • In people who have been seizure free for at least 2 years on treatment, almost 60% of those who withdraw from antiepileptic treatment will remain seizure free, compared with almost 80% of people who continue treatment. • Educational programmes may reduce seizure frequency and improve psychosocial functioning in people with epilepsy, but we don’t know whether other behavioural of psychological treatments are beneficial. • There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in people with drug resistant temporal lobe epilepsy, but they can cause neurological adverse effects. • High level vagus nerve stimulation may reduce seizure frequency in people with drug resistant partial seizures, but it may cause hoarseness and dyspnoea, and long term effects are unknown. • CAUTION: Vigabatrin, which may be used as second line treatment, causes concentric visual field abnormalities which are probably irreversible in about 40% of people. DEFINITION Epilepsy is a group of disorders rather than a single disease. Seizures can be classified by type as partial or focal (categorised as simple partial, complex partial, and secondary generalised tonic clonic seizures) or generalised (categorised as generalised tonic clonic, absence, myoclonic, tonic, and atonic� seizures).1 A person is considered to have epilepsy if they have had two or more unprovoked seizures. INCIDENCE/ PREVALENCE Epilepsy is common, with an estimated prevalence in the developed world of 5–10/1000, and an annual incidence of 50/100 000 people.2 About 3% of people will be given a diagnosis of epilepsy at some time in their lives.3 AETIOLOGY/ RISK FACTORS Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving the brain. The causes/risk factors include birth/neonatal injuries, congenital or metabolic disorders, head injuries, tumours, infections of the brain or meninges, genetic defects, degenerative disease of the brain, cerebrovascular disease, or demyelinating disease. Epilepsy can be classified by cause.1 Idiopathic generalised epilepsies (such as juvenile myoclonic epilepsy or childhood absence epilepsy) are largely genetic. Symptomatic epilepsies result from a known cerebral abnormality; for example, temporal lobe epilepsy may result from a congenital defect, mesial temporal sclerosis, or a tumour. Cryptogenic epilepsies are those that cannot be classified as idiopathic or symptomatic. PROGNOSIS About 60% of untreated people have no further seizures during the 2 years after their first seizure.4 For most people with epilepsy the prognosis is good. About 70% go into remission, defined as being seizure free for 5 years on or off treatment. This leaves 20–30% who develop chronic epilepsy, which is often treated with multiple antiepileptic drugs.5 AIMS OF INTERVENTION To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; to improve quality of life; in people in remission, to withdraw antiepileptic drugs without causing seizure recurrence; to minimise adverse effects of treatment. main/1201_new 01/11/06 Epilepsy N eu ro lo gi ca ld is or de rs  BMJ Publishing Group Ltd 20062 OUTCOMES For treatment after a single seizure: Time to subsequent seizures, time to achieve remission, proportion of people achieving remission. For treatment of newly diagnosed epilepsy: Retention on allocated treatment or time to withdrawal of allocated treatment, time to remission, time to first seizure after treatment. For treatment of drug resistant epilepsy: Percentage reduction in seizure frequency, proportion of responders (response defined as ≥ 50% reduction in seizure frequency). For drug withdrawal: Time to seizure recurrence. For behavioural treatments: Improvement in quality of life, reduction in anxiety, depression, and fear of seizures; coping or adjustment to epilepsy (assessed by validated measures). METHODS Clinical Evidence search and appraisal November 2005. QUESTION What are the benefits and risks of starting antiepileptic drug treatment following a single seizure? OPTION ANTIEPILEPTIC DRUGS AFTER A SINGLE SEIZURE Four RCTs found that treatment following a single seizure with antiepileptic drugs reduced seizure recurrence at 1–3 years compared with no treatment or placebo. One RCT in people with one or more seizures found that immediate treatment with antiepileptic drugs increased the time to first and second subsequent seizure, and reduced the time to achieve 2 year remission of seizures compared with no treatment. However, we found no evidence that treatment alters long term prognosis. Long term antiepileptic drug treatment is potentially harmful. Benefits: We found no systematic review. We found five RCTs.6–10 The first RCT compared immediate treatment after a first unprovoked seizure versus no immediate treatment.6 People were randomised within 7 days of their first tonic clonic seizure�. The RCT found that there were half as many second seizures with immediate treatment compared with no immediate treatment at 2 years (419 people, 44% women, 27% aged < 16 years, 66% aged 16–60 years, 7% aged > 60 years; AR for relapse: 24% with immediate treatment v 42% with no immediate treatment; HR 0.5, 95% CI 0.3 to 0.6). However, no significant difference was found in the proportion of people achieving a 2 year remission in seizures (AR 60% with immediate treatment v 68% with no immediate treatment; RR 0.82, 95% CI 0.64 to 1.03; RR adjusted for time of starting treatment 0.96, 95% CI 0.77 to 1.22). People who had 2 seizure free years after a relapse were included in the 2 year remission figures; this included people in the no immediate treatment group who started treatment after having a second seizure. The second RCT compared immediate treatment (carbamazepine, or sodium valproate if carbamazepine not tolerated) versus no treatment.7 The RCT found that immediate treatment significantly reduced the risk of relapse over 3 years of follow up (91 people aged 18–50 years, presenting to hospital within 24 hours of a first unprovoked seizure; AR of recurrent epileptic attack after 36months: 10/45 [22%] with immediate treatment v 29/42 [71%] with no treatment; P < 0.05). The third RCT compared immediate treatment with carbamazepine versus no treatment.8 The RCT found that immediate treatment signifi- cantly reduced the risk of relapse over 12 months (31 children presenting within 1 month of a first unprovoked afebrile seizure; AR of recurrent unprovoked seizure: 2/14 [14%] with immediate treatment v 9/17 [53%] with no treatment; P = 0.03). The fourth RCT compared immediate treatment with sodium valproate versus placebo (see com- ment below).9 It found that sodium valproate reduced the number of people experienc- ing a recurrent seizure over 12 months, but the significance of this reduction was not assessed (228 adults aged 16–79 presenting within 2 weeks after their first seizure; seizure recurrence: 5/113 [4.4%] with sodium valproate v 63/115 [54.8%] with placebo; significance assessment not performed). The fifth RCT compared immediate versus deferred antiepileptic drug treatment in people with one (56%) or more (44%) previous unprovoked seizures (see comment below).10 It found that immediate treat- ment increased time to first and second subsequent seizure (1443 people aged over 1 month old with a history of at least one unprovoked seizure; HR for first seizure: 1.4, main/1201_new 01/11/06 Epilepsy N eurologicaldisorders  BMJ Publishing Group Ltd 2006 3 95% CI 1.2 to 1.7; HR for second seizure: 1.3, 95% CI 1.1 to 1.6). Immediate treatment reduced the time to achieve 2 year remission of seizures (P = 0.023). However, at 5 years there was no difference in the proportion of people who had been seizure free for between 3 and 5 years (76% with immediate treatment v 77% with deferred treatment; ARR 0.2%, 95% CI –5.5% to +5.8%). Harms: The adverse effects of antiepileptic drugs are well known and include idiosyncratic reactions, teratogenesis, and cognitive effects. Interim analysis in the first RCT found that 14/204 (7%) of participants discontinued antiepileptic drug treatment owing to adverse events (not further specified).11 No information on adverse events was reported in the final analyses.6 The second RCT did not report on adverse events.7 In the third RCT 4/16 (25%) of children discontinued carbamazepine owing to adverse effects (somno- lence or allergic rash).8 The fourth RCT reported the following adverse effects of sodium valproate: gastrointestinal effects (3/113 [2.7%] with sodium valproate v 1/115 [0.9%] with placebo); weight gain (5/113 [4.4%] with sodium valproate v 1/115 [0.9%] with placebo); loss of hair (2/113 [1.8%] with sodium valproate v 0/115 [0%] with placebo; significance assessments not performed).9 In the fifth RCT people in the immediate treatment group were more likely to report at least one adverse event, including depression, dizziness, and gastrointestinal symptoms (AR for at least one adverse event: 270/685 [39%] with immediate treatment v 214/721 [31%] with deferred treatment; ARI 8.6%, 95% CI 3.6% to 13.6%).10 Comment: The fifth RCT had a pragmatic design and included participants who had experienced one (56% participants) or more (44% participants) seizures where both the participant and the clinician were uncertain about the need for immediate antiepileptic drug treat- ment.10 This RCT therefore addresses the same clinical question as RCTs purely in people with single seizures with respect to the balance of benefits and risks of initiating antiepileptic therapy. Although treatment allocation was not explicitly described in the fourth study, Clinical Evidence authors have confirmed that allocation was random.9 QUESTION What are the effects of monotherapy in newly diagnosed partial epilepsy? OPTION CARBAMAZEPINE We found no placebo controlled RCTs of carbamazepine used as monotherapy in people with partial epilepsy, but widespread consensus holds that it is effective and placebo controlled trials would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs in terms of seizure control; carbamazepine is considered to be the drug of choice for partial epilepsy. Systematic reviews found that phenobarbital was more likely to be withdrawn than carbamazepine. Benefits: Carbamazepine versus placebo: We found no systematic review or RCTs (see comment below). Carbamazepine versus other antiepileptic drugs: We found three systematic reviews comparing carbamazepine versus sodium valproate, phenobarbital, and phenytoin.12–14 The first systematic review (search date 2005, 5 RCTs, 1265 people, of whom 830 had partial epilepsy and 395 had generalised epilepsy, aged 3–83 years, ≥ 47% men, follow up < 5 years) compared carbamazepine versus sodium valproate.12 The systematic review included a meta-analysis of the subgroup of people with partial epilepsy. Carbamazepine significantly increased 12 month remission com- pared with sodium valproate and reduced the risk of first seizure (HR > 1 for an event that is more likely with sodium valproate; remission: HR 0.82, 95% CI 0.67 to 1.00; first seizure: HR 1.22, 95% CI 1.04 to 1.44). A test for statistical interaction between treatment and epilepsy type (partial versus generalised) was performed and was significant for time to first seizure but not for time to 12 month remission. These subgroup analyses must therefore be treated with caution. The second systematic review (search date 2004, 4 RCTs, 680 people aged 2–68 years, of whom 523 had partial epilepsy, ≥ 52% men) compared carbamazepine versus phenobarbital.13 For people with partial epilepsy it found no significant difference in remission during the next 12 months (HR > 1 for an event more likely on phenobarbital; HR 1.03, 95% CI 0.72 to 1.49). However, it found that phenobarbital significantly increased time to first seizure main/1201_new 01/11/06 Epilepsy N eu ro lo gi ca ld is or de rs  BMJ Publishing Group Ltd 20064 compared with carbamazepine (HR > 1 for an event more likely on phenobarbital; HR 0.71, 95% CI 0.55 to 0.91). The third systematic review (search date 2005, 3 RCTs, 552 adults and children, of whom 431 had partial epilepsy, ≥ 47% men) compared carbamazepine versus phenytoin.14 The review did not present results separately for people with partial epilepsy. Overall, it found no significant difference between car- bamazepine and phenytoin for treatment withdrawal, first seizure, or 12 month remis- sion (treatment withdrawal: HR 0.97, 95% CI 0.74 to 1.28; first seizure: HR 0.91, 95% CI 0.74 to 1.12; time to 12 month remission: HR 1.00, 95% CI 0.78 to 1.29). Harms: Carbamazepine versus placebo: We found no systematic review or RCTs. Carbamazepine versus other antiepileptic drugs: The first review found no signifi- cant difference in treatment withdrawal between carbamazepine and sodium valproate (HR > 1 for an event that is more likely with sodium valproate; HR 1.00, 95% CI 0.79 to 1.26).12 The second review found that carbamazepine was significantly less likely to be withdrawn than phenobarbital (HR > 1 for an event more likely on phenobarbital; HR 1.60, 95% CI 1.18 to 2.17).13 Comment: Placebo controlled trials of carbamazepine would now be considered unethical. The meta-analysis provides weak evidence in support of the consensus view to use carbamazepine as the drug of choice in people with partial epilepsy.12 The systematic reviews did not present results separately in children and adults.12–14 OPTION PHENOBARBITAL We found no placebo controlled RCTs of phenobarbital used as monotherapy in people with partial epilepsy, but widespread consensus holds that it is effective and placebo controlled trials would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs in terms of seizure control. Systematic reviews found that phenobarbital was more likely to be withdrawn than phenytoin or carbamazepine. Benefits: Phenobarbital versus placebo:We found no systematic review or RCTs (see comment below). Phenobarbital versus other antiepileptic drugs: We found two systematic reviews comparing phenobarbital versus carbamazepine and phenytoin.13,15 The first systematic review (search date 2004, 3 RCTs, 599 people with partial or generalised epilepsy, aged 3–77 years, ≥ 43% men) compared phenobarbital versus phenytoin,15 but it did not undertake subgroup analyses for people with partial or generalised epilepsy. Overall, it found no significant difference in 12 month remission or first seizure (HR > 1 for an event more likely with phenobarbital; 12 month remission: HR 0.93, 95% CI 0.70 to 1.23; first seizure: HR 0.84, 95% CI 0.68 to 1.05). The second systematic review (search date 2004, 4 RCTs, 680 people aged 2–68 years, of whom 523 had partial epilepsy, ≥ 52% men) compared carbamazepine versus phenobarbital.13 For people with partial epilepsy it found no significant difference in remission during the next 12 months (HR > 1 for an event more likely on phenobarbital; HR 1.03, 95% CI 0.72 to 1.49). However, it found that phenobarbital significantly increased time to first seizure compared with carbamazepine (HR