CHAPTER 23 The Medical Treatment of Chronic Active Epilepsy Simon Shorvon of adults in an outpatient setting. The special aspects of therapy in children, persons wit h learning disability, and in the elderly are covered elsewhere (Chapters 16 \200\22318). Chronic epilepsy can be de \201 ned as epilepsy in which seizures are still occurring 5 or more years after the initiation of therapy ( 1 ). Therapy in this situation is less likely to be successful than in newly diagnosed epilepsy, and there are several alternative theor ies about why this might be so. It has been suggested, for instance, that the longer epilep sy remains active, the more resistant it becomes to treatment due to the many molecular cha nges that occur in ongo- ing epilepsy. Alternatively, it is possible that the difference is due simply to selection and that patients with chronic epilepsy com- prise the inherently more severe forms of the condition which is unresponsive to therapy from the very start of therapy when com- pared to the milder epilepsies where seizures are controlled at the onset of therapy. Choice of antiepileptic drug therapy in chronic epilepsy In chronic epilepsy, the choice of drug will be usually largely inde- pendent of the cause of epilepsy. This lack of speci \201 city is a striking feature of most adult epilepsies and perhaps is because the antiepi - leptic drugs (AEDs) act mechanistically on the \201 nal physiological pathways of epile ptogenesis, which are similar in many cases what- ever the cause (a concept proposed by Joh n Russell Reynolds and Hughlings Jackson in the 19th century ( 10 )). The overall chance of effecting seizure control is similar for individual drugs, at least in the generality of p artial and secondarily generalized epilepsy, but side effects vary more, and the choice of drugs is often more in \202 u- enced by relative tolerability than ef \201 cacy ( 11 ). T his lack of speci \201 - city applies to tonic \200\223clonic and partial-onset seizures, which are the most common forms of epilepsy in adults, but not to other seizure types, whic h are much less common, nor to the speci \201 c childhood syndromes discussed in Chapter 1 6. The goal of drug therapy in newly diagnosed cases is the com- plete control of seizures, an d this occurs in about 60 \200\22370 % of patients within a few years of the onset of the c ondition ( 2 \200\2236 ). This leaves 30 \200\22340 % of patients who continue to have seiz ures, and thus develop chronic epilepsy. Treatment in chronic epilepsy is more complex and more dif \201 cult than in the newly diagnosed epilepsy. However, long-term seizure contro l in patients with chronic epi- lepsy can be obtained, with skillful treatment, in about 30 % , and it should be further possible to greatly lessen the frequency or sever- ity of sei zures in many of those in whom complete control is not possible. There remain about 10 % of all those developing epilepsy in whom seizures remain severe, frequent, or intractable. Al though small in number, these patients require a high level of medical input. Factors assoc iated with chronicity include: high seizure den- sity prior to commencing treatment, certai n epileptic syndromes, certain aetiologies, the presence of additional learning disability, neuropsychological signs, or neurological signs, psychological dis- turbance ( 6 \200\2238 ). The additional learning disability, psychosocial problems, or other neurological handic aps which coexist with chronic epilepsy can complicate medical therapy further. Chronic epi lepsy can have a major impact on an individual, impacting on personal and domestic life, em ployment, and education ( 9 ). Seizure type and the choice of antiepileptic drugs The usual choices of drugs in different seizure types can be sum- marized under four categories (Table 23.1 ). Generalized tonic \200\223clonic and partial onset seizures A wide range of drugs are licen sed for use in tonic \200\223clonic or partial- onset seizures in chronic epilepsy, whether primarily or secondarily generalized ( 12 \200\22314 ). In almost all randomized controlle d studies, the available AEDs show similar comparative ef \201 cacy ( 11 ). A number of drugs are licensed for use in monotherapy, includ- ing: carbamazepine (best use d in its slow-release formulation), lamotrigine, valproate, levetiracetam, oxcarbazepine, o r topiram- ate ( 15 , 16 ). These drugs are often used as \201 rst-line drugs also in chr onic epilepsy. The other drugs, which are licensed as add-on therapy, are used as second-li ne therapy. The older drugs, phenobar- bital and phenytoin, are also used as \201 rst-lin e therapy in some coun- tries. A number of comparative studies have been carried out, but n o one \201 rst- or second-line drug has been found to be consistently This chapter focuses on the principles of drug therapy in chronic epilepsy, although it mus t be emphasized that drug therapy is only part of a treatment strategy which should also in clude counseling, lifestyle manipulation and avoidance of provoking factors, and non-pharma cological therapy. These are discussed elsewhere in this volume (Chapter 12). The chapter a lso focuses on the therapy oxford textbook of epilepsy and epileptic seizures 254 Table 23.1 Antiepileptic drugs in different seizure types Seizure type Drugs which show ef \201 cacy Drugs which may worsen seizures Partial seizures, secondarily generalized tonic \200\223clonic seizures, primary generalize d tonic \200\223clonic seizures First-line AEDs: carbamazepine (best used in its slow-release formulation), lamotrigine, va lproate, levetiracetam, oxcarbazepine, topiramate Second-line AEDs: acetazolamide, clobazam , clonazepam, gabapentin, lacosamide, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, vigabatrin, zonisamide Absence seizures (typical absence) First-line AEDs: ethosuximide, lamotrigine, levetiracetam, valproate Second-line AEDs: acet azolamide, clobazam, clonazepam, phenobarbital, topiramate, Carbamazepine, gabapentin, oxcarbazepine, tiagabine, vigabatrin Myoclonic seizures First-line AEDs: lamotrigine, levetiracetam, valproate Second-line AEDs: clobazam, clonazep am, phenobarbital, piracetam, topiramate Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine, vigabatrin Atypical absence, tonic and atonic seizures First-line AEDs: lamotrigine, levetiracetam, topiramate, ru \201 namide, valproate. Zonisa mide. Second-line AEDs: acetazolamide, clobazam, clonazepam, phenobarbital, phenytoin, prim idone Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine, vigabatrin (List based on author \200\231s preference.) progressive myoclonic epilepsy or in the focal epilepsies is more dif \201 cult to treat, and drug combinations may be necessary. superior or inferior in terms of seizure control. The most striking \201 nding from all t hese studies is the similarity, not the difference, in responder rates on treatment with th e various AEDs. However, the similarity in overall antiepileptic effects hides important in dividual differences, both in side-effects and in ef \201 cacy, and there are many patient s who fail to respond to one drug but who do respond to another. It is therefore usual, and indeed logical, to rotate a patient through trials of treatment with all appropriate thera pies ( 17 ). Piracetam is an unusual drug which is uniquely effective in myo- clonus and which has no ef fect in other types of epilepsy. High doses are required, but the drug is well tolerated. I t is most used in the treatment of myoclonus in the progressive myoclonic epilepsy syndrome s. Some drugs exacerbate absence or myoclonic seizures in the gen- eralized epilepsies, or ind eed precipitate myoclonus for the \201 rst time in susceptible patients. Phenytoin has be en reported to worsen the myoclonus in the Lafora body disease, and carbamazepine, oxcarbaz epine, and phenytoin can aggravate myoclonus in juvenile myoclonic epilepsy. In idiopathic generalized epilepsy (IGE) there is a clinical impres- sion that valproate is a better choice than carbamazepine for \201 rst- line therapy of tonic \200\223clonic se izures ( 18 ). However, there is little, if any, conclusive evidence to support this propos ition; and indeed most well-conducted studies show little difference in ef \201 cacy betwe en any of the major AEDs. However, myoclonus and/or absence seizures which often coexist wi th tonic \200\223clonic seizures in IGE do respond well to valproate or levetiracetam, and are frequently worsened by carbamazepine or oxcarbazepine. In partial-onset sei- zures, it is also frequently stated that carbamazepine is more effec- tive than valproate, but again there is little or no de \201 nitive evidence of such a difference, and in chronic epileps y, either drug can be highly effective. Atypical absence, atonic, and tonic seizures These seizure types occur in the context of th e Lennox \200\223Gastaut syndrome or the other severe epileptic encephalopathies. The drug treatment is essentially similar for each, although full control of seizures is usually not possible. Valproate or lamotrigine are rec- ommended by most as \201 rst-choice drugs. T raditional alternatives are the benzodiazepine drugs (e.g. clobazam or clonazepam), acetazo lamide, phenobarbital, or primidone. Levetiracetam has promise in these types of epilepsy o n an anecdotal level but formal studies are limited. Phenytoin may be useful for tonic seiz ures, but may exacerbate atonic seizures. Topiramate and zonisamide have been shown to be e ffective in various open and controlled studies. Generalized absence seizures Generalized absence seizures occur only in the syndrome of IGE . Valproate is the commonest \201 rst choice AED. Other drugs which can be used as \201 rst-line therapy, but which have less reliable effects are levetiracetam, lamotrigine, top iramate, zonisamide, and the benzodiazepines. Ethosuximide is another highly effective drug but is largely ineffective in controlling generalized tonic \200\223clonic seizures, which often coexist with absence seizures. Table 23.2 Epilepsies in which myoclonus is part of the phenotype \227\206 Idiopathic generalized epilepsy (IGE) \227\206 Benign myoclonic epilepsy syndrom es of childhood \227\206 Severe epilepsy syndromes of childhood and epileptic encephalopat hies \227\206 Progressive myoclonic epilepsies (PMEs) \227\206 Focal epilepsies in the ce ntral cortex \227\206 Symptomatic focal epilepsies (particularly those due to mitochondria l Myoclonic seizures Myoclonus occurs in various clinical settings (Table 23.2 ). The myoclon us in IGE is generally well controlled on single drug therapy with valproate which is the d rug of \201 rst choice. Where valproate is inappropriate or ineffective, other agents whi ch can be used are levetiracetam, lamotrigine, topiramate, zonisamide, and the benzo- diaze pines. The myoclonus in the symptomatic generalized, disease, inherited or acquired metabolic disease, infections, drug and toxins) Derived from Shorvon ( 14 ). CHAPTER 23 the medical treatment of chronic active epilepsy 255 dosing frequencies, cost, and such factors as risks in pregnancy In Table 23.3 are some exa mples of factors which commonly in \202 u- ence the use of some drugs. Felbamate also has a powerful effect in atypical absence, tonic, and atonic seizures, and t he drug still has a useful place in refractory cases where other medication has failed. Ru \201 namide is also useful in the various seizure types in the Lennox \200\223Gastaut synd rome and is licensed only for this indication. Although large fortunes have been sunk into pharmacogenetics, no genetic predisposition has been identi \201 ed in any situation which helps predict who will respond and who will no t to any speci \201 c drug. Given the heterogeneity of epilepsy and the importance of envi ronmental factors, this is perhaps not surprising. Prescribing patterns also vary depending on other factors such marketing pres- sures, the medical system, teaching, and information sources and there are surprisingly large differences in the relative use of drugs in diffe rent countries. Drugs which exacerbate seizures Carbamazepine and oxcarbazepine are frequently reported to exac- erbate atypical absence and tonic seizures. Tiagabine can dramati- cally worsen atypi cal absence seizures, resulting sometimes in a rather characteristic non-convulsive status epilepticus. It is proba- ble that gabapentin, pregabalin, and vigabatrin have similar effe cts. Benzodiazepine can exacerbate tonic seizures, and occasionally precipitate tonic statu s epilepticus. All drugs can occasionally worsen seizures, emphasizing the individual natur e of response. Side effects The side effects of AEDs are a major factor in \202 uencing drug choice, not least because the ef \201 cacy of different drugs, in population terms shows little differ ence ( 19 ). Each drug has a speci \201 c side- effect pro \201 le and these are outlined in more detail in Chapter 26. However, the following side effects are those which are most fre- quently in \202 uence drug choice: Tailoring drugs to different patient pro \201 les In spite of the lack of differentiation between drugs in the regula- tory trials, it is clear in routine clinical practice that the re are quali- tative differences, in their antiepileptic potency, their side effects, and t heir tolerability. The art of good epilepsy therapy is to tailor a drug to individual patie nt needs. People differ, for instance, in their willingness to risk speci \201 c side effe cts (e.g. weight gain). Preferences will depend on age, gender, comorbidity, co-medication and 1. Weight gain \200\224 and those who are overweight might be keener to try topiramate or zonisamide which both typically result in weight loss, rather than gabapentin, pregabalin o r valproate which typically result in weight gain. Table 23.3 Tailoring antiepileptic drugs in partial-onset epilepsy to patient characteristi cs (based on preferences from the author \200\231s clinical practice) Patient characteristics Drugs that are particularly suitable Drugs that should be particularly avoided Patients with severe partial-onset seizures Clobazam, carbamazepine, lacosamide, levetiracetam, oxcarbazepine, phenytoin, topiramate, z onisamide Gabapentin, lamotrigine, valproate Patients who wish particularly to avoid cosmetic effects Phenobarbital, phenytoin, primidone, valproate (for its effects on hair) Patients with prominent anxiety Clobazam (and other benzodiazepines), carbamazepine, gabapentin, phenobarbital, pregabalin, valproate Levetiracetam Patients with prominent depression Carbamazepine, lamotrigine, valproate Levetiracetam, vigabatrin, phenobarbital Patients with renal stones Acetazolamide topiramate, zonisamide, Patients with migraine Topiramate, valproate Patients with the need to lose weight (or not to gain weight) Topiramate, zonisamide Gabapentin, pregabalin, valproate Patients with foreign tissue lesional epilepsy (e.g. tumor) Carbamazepine, clobazam, levetiracetam, oxcarbazepine, phenytoin, tiagabine Patients with hyponatraemia Carbamazepine, oxcarbazepine, Patients at particular risk from allergy Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate, vigabatrin Acetazolamide, carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, zonisamide Patients at particular risk of heart disease Carbamazepine, lacosamide, lamotrigine, oxcarbazepine Patients at risk from osteoporosis Gabapentin, levetiracetam, pregabalin Phenobarbital, phenytoin Patients in whom the risk of hepatic enzyme interactions have to be avoided (e.g. those co- mediated with antibiotics, immunosuppressive drugs, oncological drugs, antipsychotics, etc. ) Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate, vigabatrin Derived from Shorvon ( 14 ). oxford textbook of epilepsy and epileptic seizures 256 Drug resistance The concept has recently arisen that some epilepsy is inherently \200\230d rug resistant \200\231. Indeed, the International League Against Epilepsy has even proposed a standardized de \201 nition of drug-resistant epilepsy \200\224 epilepsy which remains active despite trials of at least two appropriately selected antiepileptic drugs ( 23 ). T wo predomi- nant theories have been cited to explain resistance: that this is due to geneti c changes in enzymes which transportation drugs across the blood \200\223brain barrier (not ably p-glycoprotein coded by the ABCB1 gene) or in drug-target proteins (for instance, the gamma- aminobutyric acid (GABA) receptor). However, as not all drugs are transported by the same enzymes, or indeed any transporter enzymes at all, and as different drugs act at diff erent targets or multiple targets, the concept of universal drug resistance due to such gen etic variation is untenable. Furthermore, other factors are associated with resistance, inc luding the nature of the underlying etiology, the cerebral position and size of a structura l etiology such as a tumor, the syndrome, the severity, or duration of epi- lepsy, presence of associated handicap, environmental and provok- ing factors, hepatic enzyme induction, d rug dosage, receptor upregulation, and so on. Also, as discussed in the following section, many patients attain good periods of remission after more than two drugs have proved ineffe ctive. For all these reasons, a unitary concept of drug-resistance, at least to this author , seems an illusory one. Epilepsy is too heterogenous a condition, and its treatment also t oo various, for this concept to have any meaningful validity. 2. Psychological effects the patient \200\231s affective and psychological states are impor tant considerations in drug choice. Some drugs, notably valproate and carbamazepine tend to stabilize mood. Levetiracetam tends to cause anxiety and agitation, and particu- larly so in patients already anxious or agitated. Phenobarbital and the benzodiazepines tend to exac erbate depression and sedation. 3. Teratogenicity \200\224 in women planning to embark on pregnancy, valproate is relative ly contraindicated and only carbamazepine and lamotrigine, and possibly levetiracetam, have proven rela- tive safety. 4. Cosmetic effects \200\224 phenytoin and barbiturate are associated with long-term cosme tic effects not shared with other antiepi- leptics. Valproate can cause hair loss. 5. Cognitive impairment \200\224 some drugs, notably topiramate, zonisamide, pregabalin, a nd phenobarbital, have reputations for being more likely to result in sedation or cognitive impairment than other drugs. 6. Comorbidities \200\224 these may in \202 uence drug choice, depending on the system involved and the therapies employed. Pharmacokinetics and drug interactions The pharmacokinetics of individual drugs influences choice. Parameters such as the T max , the half life, the absorption, the mode of metabolis m and excretion, the diurnal variation of levels, and the effect of comorbid conditions suc h as renal or hepatic disease can be clinically important. Drug interactions can have a str ong in \202 uence of drug choice ( 20 , 21 ). A treatment protocol in chronic epilepsy Recent studies have shown that a systematic approa ch to the AED therapy of chronic patients can result in seizure freedom in about 30 % of ca ses and signi \201 cant improvement in a further 50 % . Taking a nihilistic view (that not hing can be done to improve seizure con- trol in chronic epilepsy) is a common mistake whic h consigns many patients to lifelong disability. When \201 rst seeing a patient with chro nic uncontrolled epilepsy, a two-stage procedure should be adopted: \201 rst, assessment and second, a treatment plan should be devised ( 14 , 24 ) (Table 23.4 ). Evidence for comparative ef \201 cacy in chronic epilepsy \200\224 meta-analysis of regul atory drug trials The US Food and Drug Administration has mandated that all new candidate A EDs must demonstrate superior ef \201 cacy to a compara- tor in a clinical trial, not just simple equivalence. From the clinical (in contrast to the regulatory) perspective, this ha s had one serious disadvantage \200\224 all new drugs have been compared, in the rand- omi zed clinical trials, primarily with placebo, rather than with each other. Thus, the trials do not individually give much information to the clinician about the relative bene \201 ts of individual drugs. One way around this problem has been to perform meta-analyzes of tria ls, and to use meta-analytical statistical methods to compare and contrast the effectivenes s of individual drugs trialed against placebo ( 13 ). Such analyzes have obvious and well-k nown disad- vantages, but potentially provide the best information available for making dru g choice. However, in the published meta-analyzes all licensed drugs were found to be stati stically superior to placebo (and indeed it is on this basis that they are licensed), and a lthough there were sometimes nearly twofold differences between the mean odds ratios of sei zure control for different drugs, the con \201 dence intervals were wide and overlap, and thus these differences between drugs were not statistically signi \201 cant. One criticism of this method of analysis is that drugs are being compared at the dosages used in the cli nical trials, and that higher doses of the seemingly less effec- tive drugs might produce b etter results, and it remains true that the regulatory trials and the meta-analysis provide only very limited information about the true utility of a licensed drug in routine clinica l practice. Table 23.4 Two-stage approach to therapy in chronic active epilepsy Assessment \227\206 Review diagnosis and etiology (history, EEG, imaging) \227\206 Classify seizures and syndrome \227\206 Review compliance \227\206 Review drug history (including dose, le ngth of therapy, and reasons for discontinuation): \226 Which drugs were useful in the past? \226 Which drugs were not u seful in the past? \226 Which drugs have not been used in the past? \227\206 Review precipitants and non-pharmacological factors Treatment plan \227\206 Document proposed sequence of AEDs to \200\230trial \200\231 \227\206 Decide th e duration of drug \200\230trials \200\231 \227\206 Decide which background medication to continue and to withdraw \227\206 Consider non-pharmacological measures (lifestyle, alter native therapy, etc.) \227\206 Consider surgical therapy \227\206 Recognize the limitatio ns of therapy \227\206 Provide information on these to patient CHAPTER 23 the medical treatment of chronic active epilepsy 257 Assessment The assessment of all patients presenting with chronic epilepsy should consider the following points: explained in advance to the patient to maintain con \201 dence and compliance. Ideally, ea ch antiepileptic should be tried in a reason- able dose added to a baseline drug regimen \200\224 usually one or two other AEDs \200\224 and as the drug is added, withdrawal or ch ange in dose of other drugs may be needed. Thus decisions have to be made about: which drug s to trial and in what sequence, and which drugs to retain as a baseline regime; which drug s to withdraw; the dura- tion of each treatment trial. Review the diagnosis of epilepsy In up to 20 % of patients referred to specialized clinics because of apparent chronic epilepsy, the seizures are not predominately epileptic in origi n. Misdiagnosis arises most commonly in relation to psychogenic seizures, re \202 ex synco pe, and cardiac arrhythmia. A detailed eye-witness account of the attacks therefore should be obtained and will usually be diagnostic. A series of normal electroencephalogram (EEG) r esults should alert one to the possi- bility that the attacks are non-epileptic, although t his is not an infallible rule. An invaluable aid to diagnosis can be the viewing of a recor ding of the attack made by home video or on a mobile phone. The treatment plan can take a number of months to complete, requiring patience and tenacity , and the procedure should be explained in advance to the patient to maintain con \201 den ce and compliance. This needs the expenditure of time and effort by the doctor, who should be available throughout for guidance and reassurance. Perseverance brings rewards, however, and the reso- lute will, following this protocol, become established on effective long-ter m therapy. The effectiveness of this approach was shown in one study in which a total of 265 drug addi tions were studied in 155 adult patients with chronic epilepsy (de \201 ned as epilepsy ac tive at least 5 years after and initiation of therapy) ( 17 ). Other therapy was varied (an d some drugs withdrawn) according to normal clinic practice. If one drug addition was ineff ective, another would be tried. Of the 155 patients, the study found that after one, two, o r three drug additions, 28 % overall were rendered seizure free by this protocol of active medication change. Sixteen per cent of all drug additions resulted in seizure freedom (de \201 ned as seizure freedom at last follow-up for 12 months or longer), and a 50 \200\22399 % seizure reduction occurred in a further 21 % . Establish etiology The cause of the epilepsy must be established. This is important as spec i \201 c cerebral conditions may require therapy in their own right, and also because prog nosis and response to therapy are strongly in \202 uenced by the underlying cause. This ma y require MRI scan- ning and/or other investigations. A high-quality MRI scan is a mandator y test in a patient with chronic epilepsy without a known cause. Classify seizure type and syndrome Knowledge of the syndrome and seizure type guides the ch oice of medication and other therapies. Accurate seizure and syndrome classi \201 cation r equires a detailed clinical history and EEG. Choice of drug to trial and to retain as the baseline regimen The drugs should be selected from those which have either not been previously used in optimal doses or which have been u sed and did prove helpful. Rational choices therefore depend on a well- documented history of previous drug therapy. A most important element of the treatment plan is to decide the \200\230batting order \200\231 of drug trials and this will depend on seizure type, side ef fects, inter- actions, the patient pro \201 le, personal preference and other factors. The new drugs added to a regimen should be introduced slowly. This results in better tolerabil ity. It is usual to aim initially for a low maintenance dose and then to titrate upwards de pending on response, but in severe epilepsy, higher doses are often required right away. Review previous treatment history The response to an AED is, generally speaking, relatively consistent over time. A knowledge of the previous treatment history is there- fore vital t o the formulation of a rational treatment plan. This part of the history is often overlooke d. Review compliance Erratic compliance can be a reason for poor seizure control. A drug walle t, \201 lled up for the whole week, can be of great assistance for patients who often for get to take the medication. Treatment plan A key step in the successful treatment of chronic epilepsy is the developmen t of a prospective treatment plan. This should be based on the assessment, and the plan sho uld be documented in medical records and discussed with the patient. Choice of drugs to withdraw and the drug withdrawal process Drugs which should be considere d for withdrawal are those which have been given in the past in an adequate trial at optima l doses and which were either ineffective or caused unacceptable side effects. Drug withdra wal needs care, and should be carried out in a gradual step-wise fashion. The sudden reduct ion in dose of an AED can result in a severe worsening of seizures or in status epilepticus . Only one drug should be withdrawn at a time. If the withdrawal period is likely to be dif \201 cult, the dangers can be reduced by cover- ing withdrawal with a benzodiazepine drug (usually clobazam 10 mg at day), given during the phase of active withdrawal. A ben- zodia zepine can also be given in clustering of seizures following withdrawal. If seizures dramat ically worsen during the period of withdrawal, the drug should usually be rapidly reinstate d. The patient should have access to immediate specialist advice during a withdrawal period . Although, as mentioned earlier, none of the currently available \201 rst- and second-line drugs have been shown conclusively signi \201 - cantly more ef \201 cacious than any oth er in population terms, indi- vidual patients who have failed to respond to one drug may we ll respond to an alternative ( 17 , 25 \200\22328 ). It follows from this that the only log ical approach to approach AED treatment, in a patient in whom improvements in seizure contr ol are desired, is to try one suitable drug after another. The treatment plan therefore sho uld comprise, at its heart, a sequence of what are in effect n = 1 treat- ment trials, each to be tried in turn if the previous trial fails to meet the targeted level of seizure cont rol. Such a sequence of drug changes can take months to complete and requires patience and tenac ity. The procedure should be oxford textbook of epilepsy and epileptic seizures 258 Duration of treatment trial This will depend on the baseline seizure rate. The trial should be long enough to have differentiated the effect of therapy from that of chance \202 uct uations in seizures. If the seizures are very frequent, it will take only a few weeks to as certain whether or not the new drug is having any effect. The ketogenic diet is the only dietary therapy shown in rand- omized studies to be effectiv e in epilepsy, but its use is restricted to children with severe epilepsy and in status epi lepticus ( 33 ) (see Chapter 12). Prognosis of chronic epilepsy \200\224 patterns of remission and relapse It has been long recognized that the majority of people with epi- lepsy who enter seizure remission do so ea rly in the course of the condition ( 2 , 3 , 5 \200\2237 , 34 , 35 ). The related propositi on that, if early treatment is unsuccessful, then the patient is likely to develop chronic epilepsy resistant to any treatment ( 7 ) is unduly pessimis- tic. It is clear that patient s enter remission after several years of continuous activity and after trials of more than two drugs ( 3 , 17 , 25 \200\22328 , 34 \200\22338 ). Serum level monitoring and drug interactions For drugs where effectiveness and/or side effe cts are closely linked to serum level \200\224 notably phenytoin, carbamazepine, and pheno barbital \200\224 measurement of the serum level can be helpful in deciding dosage. Monito ring serum level is particularly important for phenytoin which has a non-linear relationshi p between dose and serum level. Intractability and the limits of drug therapy Drug therapy will fail to control seizures co mpletely in about 10 \200\22330 % of patients with epilepsy. In this situation, the epileps y can be categorized as \200\230intractable \200\231 and therapy should provide in these p atients the best compromise between inadequate seizure control and drug induced side effect s. Individual patients will take very different view about where to strike this balance. In tractability is inevitably an arbitrary decision. At a population level, the patterns of remission and relapse during the course of their epi lepsy in people with chronic epilepsy have been investigated in a recent study, in which a model of prog- nosis was proposed (Fig. 23.1 ) ( 39 ). According to this model, about 60 % of people developing epilepsy will go into long-term (proba- bly permanent) remission withi n 5 years of diagnosis (pathway a). To what extent this good prognosis simply represents th e natural history of benign epilepsy or is a treatment effect is not known \200\224 but pr obably both play a part. The other people (40 % ) still have active epilepsy at 5 years aft er onset (i.e. are classi \201 ed as \200\230chronic \200\231 epilepsy; pathway b). About 10 % of these patients will enter subse- quent long-term remission (pathway c) and include d in this group are some of the age-speci \201 c epilepsy syndromes. About 20 % of persons have continuous epilepsy, with no periods of remission (pathway d), and about 10 % epileps y with an intermittent pattern of relapse and remission (pathway e). Lifestyle measures Although this chapter is focused primarily on drug treatment, it must be emphasized that this is only part of an approach to ther- apy. Many seizures are provoked by factors such as stress, tired- ness, emotional disturbance, circadian rhythms, the menst rual cycle, alcohol, and lack of sleep. Avoiding provoking factors can be extremely importa nt. Such \200\230lifestyle \200\231 manipulation can assist drug therapy and render a prev iously refractory epilepsy completely con- trolled. These factors should not be overlooked. Their importance varies according to the type of epilepsy. In IGE, especially in ado- lesc ence, the avoidance of sleep deprivation or excessive alcohol intake can be very bene \201 cial. Many patients learn to recognize dangerous times, and take individual avoidance meas ures. Photosensitive patients should be counseled to avoid relevant stimuli. Occasionally, patients with established mild epilepsy can avoid drug treatment altogether with these simp le measures. Alternative or complementary medicine can be a useful adjunct to therapy ( 22 ). Of course, it needs to be emphasized that seizure freedom is not the only good outcome, and therapy will often reduce the severity, timing, or frequency of seizures in bene \201 cia l ways which are not represented in this model. Acknowledgements This chapter is partly derived from Shorvon S. Handbook of Epilepsy Treatm ent (3rd edn). Oxford: Wiley Blackwell, 2009. This work Surgical and dietary therapy Resective surgical therapy for epilepsy should be considered i n all patients with chronic epilepsy, both adults and children ( 28 ) although it will be p ossible or appropriate in only a small minority (perhaps 5 % ). In adults, surgery is most effective in lesional and in mesial temporal lobe epilepsy, where surgical therapy can resu lt in seizure freedom in about 50 % of cases and signi \201 cant improve- ment in a furthe r 30 % ( 29 , 30 , 31 ). In other clinical situations, the outcome of surgery is less good. The assessment of a patient for suitability for epilepsy surgery should be carried out in experienced centers, where the necessary experience and resources are available. Surgical t herapy is considered further in Chapters 27 \200\22329. New onset of seizures Pathway a Pathway b Continuous pattern, or relapse within 5 years of onset ( 40%) Long-term remission developing within 5 years of onset ( 60%) Pathway c Pathway d Pathway e Intermittent pattern \200\223 active epilepsy with periods or remission ( 10%) Long-term remission developing >5 years after onset ( 10%) Continuous patern \200\223 no period of remission ( 20%) Vagal nerve stimulation is another option for intractable epi- lepsy, but must be considere d palliative only, and very few patients become seizure-free using this technique and few b ene \201 t in the longer term. Fig. 23.1 Patterns of epilepsy over time. Neligan A, Bell G, Sander S, Shorvon S. How refra ctory is refractory epilepsy? Patterns of relapse and remission in refractory epilepsy. Epi lepsy Res 2011; 96 (3):225 \200\22330. CHAPTER 23 the medical treatment of chronic active epilepsy 259 was undertaken at UCLH/UCL who received a proportion of fund- ing from the Department of He alth \200\231s NIHR Biomedical Research Centers funding scheme. Myoclonic Epilepsy: The Janz Syndrome , pp. 11 \200\223 32 . Stroud : Wrightson Biomedical Publishing Ltd , 2000 . 19. Zaccara G , Franciotta D , Perucca E . Idiosyncratic adverse reactions to antiepileptic drugs . Epilepsia 2007 ; 48 : 1223 \200\223 44 . 20. Patsalos PN , Perucca E . Clinically important drug interactions in References epilepsy: interactions between antiepileptic drugs and other drugs . Lancet Neurol 2003 ; 2 : 473 \200\223 81 . 1. Shorvon S . The treatment of chronic epilepsy: a review of recent 21. Patsalos PN , Perucca E . Clinically important drug interactions in studies of clinical ef \201 cacy and side effects . Curr Opin Neurol 2007 ; 20 : 159 \200 \223 63 . epilepsy: general features and interactions between antiepileptic drugs . 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