CHAPTER 11
Medical Treatment

Fergus J. Rugg‐Gunn

TREATING EPILEPSY

Epilepsy treatment has mainly focused on pharmacological options, with almost 30 antiseizure medications (ASM) now available worldwide. For about two‐thirds of people with epilepsy, ASM are the most effective way to achieve seizure remission. While several non‐pharmacological treatment options are available, such as surgery, modulators, and specialised diets, these are only feasible in a select number of cases. For instance, resective surgery is a highly successful treatment for many people with focal drug‐resistant epilepsy (DRE). However, fewer than five per cent of new cases will ultimately be candidates for this treatment. See Chapter 15, Epilepsy Surgery.

Historically, pharmacological treatment of epilepsy began in the 1850s with bromide, followed by phenobarbital in 1912, marking the beginning of modern pharmacotherapy. The mid‐20th century saw the introduction of phenytoin, carbamazepine, ethosuximide, and valproate. These, along with phenobarbital, are now collectively known as older ASM. They remain in use today, primarily in low‐ and middle‐income countries (LMIC) due to cost, and in high‐income countries (HIC) as ‘legacy drugs’ or as later‐stage treatment options. People often hesitate to discontinue these older ASM, even when advised, due to concerns about seizure recurrence or a perceived ongoing need, which contributes to their continued use as ‘legacy drugs’.

Significant advances in ASM development occurred from the 1970s onward, driven by dedicated drug development programmes. This led to the approval of 18 new ASM since the 1990s, including lamotrigine, levetiracetam, oxcarbazepine, zonisamide, lacosamide, and cenobamate. These newer ASM often have improved tolerability profiles compared to older drugs, though a clear distinction in efficacy is not always apparent.

Despite this wide array of ASM options, challenges persist. While ASM are chosen based on seizure type and individual clinical profiles, tolerability and drug resistance can still be issues. For up to one‐third of people with DRE, other interventions such as surgery or neurostimulation need consideration.

INITIAL EVALUATION

Establishing a firm diagnosis before starting treatment is essential. This process is not always easy, particularly in the early stages of epilepsy or with infrequent, unwitnessed episodes. ‘Trials of treatment’ to clarify the diagnosis are seldom justified. They often lead to further uncertainty, which can escalate polypharmacy and diagnostic disengagement. Ideally, there is a detailed first‐hand witness account with a home video recording to review, as diagnostic tests are often non‐confirmatory. See Chapter 10, First Seizure Clinic. In practice, the misdiagnosis rate is high, ranging from five to 30%.¹

Risk of seizure recurrence

Estimating the risk of seizure recurrence is critical in deciding whether to initiate therapy. Approximately half of the people who have a first unprovoked non‐febrile seizure will have further events.

Recurrence risk is initially high and gradually decreases over time. In a UK study, the recurrence risk was 44% within the initial six months, 32% in the subsequent six months, and 17% in the second year following the first seizure.² It follows that the greater the elapsed time since the first attack, the less likely is subsequent recurrence (Figure 11.1). Often, seizures will have already recurred by the time of clinic attendance. In a hospital‐based study, the median number of convulsions before diagnosis was four (range: 1–36), and the median number of focal seizures was six (range: 1–180). If more than one seizure has occurred, the future risk of further episodes without treatment is, in most circumstances, over 70%, and the more that have occurred, the greater the risk of further attacks. Several factors influence the risk of recurrence:

Aetiology Higher risk in those with structural cerebral lesions, and lowest in people with acute symptomatic seizures provoked by a reversible factor such as metabolic derangement or drug and toxin exposure. For seizures of unknown cause, the risk is approximately 40%.

FIGURE 11.1 Actuarial percentage risk of recurrence after a first seizure (from the National General Practice Study of Epilepsy). The lines represent the risk of recurrence in all participants (n = 564) at the time of the first seizure. The subsequent risks are for those who remained seizure‐free at 6, 12, and 18 months after the first seizure.

Source: Adapted from Hart et al.²
EEG Recurrence risk is high if the first EEG shows spike and wave discharges; the predictive value of a normal EEG or other abnormalities after a single seizure is uncertain.
Imaging Recurrence is more likely if there is a structural cerebral abnormality.
Age Recurrence risk is greater in those under the age of 16 or over 60 years, most likely reflecting the underlying aetiology.
Seizure type and syndrome Focal seizures are more likely to recur than generalised seizures because of a probable underlying aetiology. Children with self‐limited epilepsy syndromes, for instance, epilepsy with centrotemporal spikes, only have a few seizures. Conversely, in more severe childhood epilepsy syndromes, recurrent episodes are almost inevitable.

Type, timing, and frequency of seizures

Some types of epileptic seizures, such as focal aware seizures, absences or seizures during sleep, will have a lesser impact on quality of life. The benefits of treating such seizures, even if frequent, can be outweighed by the disadvantages. If the baseline seizure frequency is low and events are minor, treatment drawbacks may be unacceptably high for some individuals.

PRINCIPLES OF ANTISEIZURE MEDICATION TREATMENT

The decision to initiate ASM treatment has important implications for a person with newly diagnosed epilepsy. In addition to its biological effects, treatment confers illness status, confirms the state of ‘being epileptic’, and can affect self‐esteem, social relationships, education, and employment. Treatment depends on balancing the benefits and risks and must be tailored to the individual’s specific needs. Benefits of treatment include a lower risk of seizure recurrence, injury and death, and the psychological and social benefits of no further seizures. Drawbacks include potential adverse effects of the medication, psychological and social effects, and the cost and inconvenience. Chronic, long‐term, or subtle adverse effects can be significant and should be considered in any decision to initiate treatment, as well as in the choice of agent.

INITIATING TREATMENT: SINGLE SEIZURES AND EARLY EPILEPSY

The MRC Multicentre trial of Early Epilepsy and Single Seizures (MESS) and the First Seizure Trial (FIRST) compared immediate versus deferred ASM treatment for reducing seizure recurrence and assessed long‐term outcomes. Immediate ASM treatment reduced the risk of further seizures in the first 2–3 years compared to deferred treatment. There was, however, no significant difference in long‐term remission rates between the immediate and deferred groups. Both studies noted that recurrence risk was higher in people with focal seizures, an abnormal EEG, or neurological deficits.^{It is on this basis that ASM treatment is not typically recommended following a single seizure with a low recurrence risk. For individuals with a higher recurrence risk, the principles and protocol for the initial treatment of epilepsy for adults are shown in Practice Point boxes.}

PRACTICE POINTS

Protocol for Initial Treatment for Adults

Establish diagnosis. Investigations will usually involve EEG and MRI scanning in all, particularly those with focal epilepsy.
Identify and advise about precipitating factors. Avoidance of these factors may obviate the need for drug therapy.
Decide upon the need for an ASM. If therapy is needed, baseline biochemical and haematological parameters should be measured.
Advise about treatment goals, likely outcome, risks, and logistics of therapy. Individuals should be given clear instructions to seek immediate medical attention if signs of hypersensitivity or idiosyncratic drug reactions develop.
Start with monotherapy with the chosen first‐choice ASM, initially at low doses, and titrate slowly to a low‐maintenance dose. Emergency drug loading is seldom necessary unless status epilepticus threatens.
If seizures continue, titrate the dose upwards to higher‐maintenance dose levels according to clinical need and tolerability, guided, if appropriate, by serum level monitoring. In about half, initial therapy will result in seizure remission.
If seizures continue, alternative monotherapy should be tried with another appropriate first‐choice ASM. The second ASM should be introduced and titrated to a low‐maintenance dose, and the first ASM can then be withdrawn in slow decremental steps. If seizures continue, the dose of the newly introduced ASM should be increased to the maximal dose.
If these steps fail, a third alternative monotherapy should be tried similarly. If seizures continue or recur after initial therapy with one to three ASM tried in monotherapy as above.
- The diagnosis should be reassessed in people with continuing events to exclude dissociative seizures or explore the possibility of a progressive lesion or disorder/syndrome. Suboptimal adherence should also be considered.
- Alternative monotherapies or polytherapy should be considered.
- The person should be referred for specialist epilepsy advice regarding other pharmacological and non‐pharmacological therapies, such as resective surgery.

CHOICE OF INITIAL MONOTHERAPY

The choice of medication for use in newly diagnosed and DRE is based mainly on seizure type and syndrome (Tables 11.1 and 11.2). Details of ASM in current usage are shown in Tables 11.3–11.7.

Table 11.1 Antiseizure medications by seizure type.

Seizure type	First‐line drugs	Second‐line drugs	Other drugs that may be considered	To be avoided, as they may aggravate seizures
Generalised tonic–clonic	Carbamazepine Lamotrigine Levetiracetam Oxcarbazepine Sodium valproate	Clobazam Lacosamide Perampanel Topiramate Zonisamide	Acetazolamide Brivaracetam Cenobamate Clonazepam Eslicarbazepine Phenobarbital Phenytoin	Tiagabine Vigabatrin
Absence	Ethosuximide Lamotrigine Levetiracetam Sodium valproate	Clobazam Clonazepam Topiramate Zonisamide	Brivaracetam Lacosamide Perampanel Phenobarbital	Carbamazepine Gabapentin Oxcarbazepine Pregabalin Tiagabine Vigabatrin
Myoclonic	Levetiracetam Sodium valproate Topiramate	Clobazam Clonazepam Piracetam Zonisamide	Brivaracetam Lamotrigine Perampanel	Carbamazepine Gabapentin Oxcarbazepine Pregabalin Tiagabine Vigabatrin
Tonic	Lamotrigine Levetiracetam Sodium valproate	Clobazam Clonazepam Lacosamide Topiramate Zonisamide	Acetazolamide Brivaracetam Perampanel Phenobarbital Phenytoin	Carbamazepine Oxcarbazepine
Atonic	Lamotrigine Levetiracetam Sodium valproate	Clobazam Clonazepam Lacosamide Rufinamide Topiramate	Acetazolamide Brivaracetam Perampanel Phenobarbital	Carbamazepine Oxcarbazepine Phenytoin
Focal with/without bilateral tonic–clonic	Carbamazepine Lamotrigine Levetiracetam Oxcarbazepine	Clobazam Lacosamide Perampanel Sodium valproate Topiramate Zonisamide	Acetazolamide Brivaracetam Cenobamate Clonazepam Eslicarbazepine Gabapentin Phenobarbital Phenytoin Pregabalin Tiagabine

Table 11.2 Antiseizure medications by epilepsy syndrome seen in adult practice.

Epilepsy syndrome	First‐line drugs	Second‐line drugs	Other drugs	To be avoided, as may aggravate seizures
Juvenile absence epilepsy	Ethosuximide Lamotrigine Levetiracetam Sodium valproate	Topiramate Zonisamide	Brivaracetam Clonazepam Clobazam Lacosamide Perampanel	Carbamazepine Gabapentin Oxcarbazepine Phenytoin Pregabalin Tiagabine Vigabatrin
Juvenile myoclonic epilepsy	Lamotrigine Levetiracetam Sodium valproate Topiramate	Clobazam Clonazepam Piracetam Zonisamide	Acetazolamide Brivaracetam	Carbamazepine Gabapentin Oxcarbazepine Phenytoin Pregabalin Tiagabine Vigabatrin
Generalised tonic–clonic seizures	Lamotrigine Levetiracetam Sodium valproate	Carbamazepine Clobazam Lacosamide Oxcarbazepine Perampanel Topiramate Zonisamide	Acetazolamide Brivaracetam Cenobamate Clonazepam Eslicarbazepine Phenobarbital Phenytoin	Tiagabine Vigabatrin
Focal epilepsies: cryptogenic, symptomatic	Lamotrigine Levetiracetam Oxcarbazepine	Carbamazepine Clobazam Lacosamide Perampanel Sodium valproate Topiramate Zonisamide	Acetazolamide Brivaracetam Cenobamate Clonazepam Eslicarbazepine Gabapentin Phenobarbital Phenytoin Pregabalin Primidone Vigabatrin
Self‐limited epilepsy with centrotemporal spikes	Lamotrigine Levetiracetam Oxcarbazepine	Carbamazepine Sodium valproate Topiramate Zonisamide
Self‐limited epilepsy with occipital paroxysms	Lamotrigine Levetiracetam Oxcarbazepine	Carbamazepine Sodium valproate Topiramate Zonisamide
Lennox–Gastaut syndrome	Carbamazepine Lamotrigine Oxcarbazepine Sodium valproate	Clobazam Lacosamide Levetiracetam Rufinamide Topiramate Zonisamide	Brivaracetam Cannabidiol Cenobamate Clonazepam Phenytoin Phenobarbital Vigabatrin
West syndrome	ACTH or corticosteroid Vigabatrin	Lamotrigine Sodium valproate Topiramate Zonisamide	Felbamate

ACTH, adrenocorticotropic hormone.

Single‐drug therapy will control seizures in about 70% of people with epilepsy. Advantages of monotherapy are:

Better tolerability and fewer adverse effects
Simpler and less intrusive regimens
Better adherence
No potential for ASM pharmacokinetic or pharmacodynamic interactions.

Early comparative studies suggested that carbamazepine and phenytoin should be the first choice in focal epilepsy or with convulsive seizures, compared to phenobarbitone and primidone, which were less effective or poorly tolerated.⁶ Over the last 30 years, multiple ASM have been licensed with improved tolerability and fewer drug–drug interactions, but generally no greater efficacy. SANAD I was a large, pragmatic trial comparing standard ASM, carbamazepine for focal epilepsy, sodium valproate for generalised/unclassified epilepsy, with the newer ASM, lamotrigine, gabapentin, topiramate, and oxcarbazepine. It assessed long‐term clinical effectiveness, tolerability, quality of life, and cost‐effectiveness for people with newly diagnosed epilepsy. This suggested that, for focal epilepsy, lamotrigine was superior to carbamazepine, gabapentin, and topiramate for time to treatment failure, and non‐inferior to carbamazepine for 12‐month remission. While carbamazepine was effective, it was less well‐tolerated than lamotrigine, and it was established that lamotrigine was the initial monotherapy of choice for focal epilepsy.⁷ For the generalised/unclassified arm of the trial, sodium valproate was significantly better than topiramate for time to treatment failure and was superior to lamotrigine for 12‐month remission. Valproate was confirmed as the most effective treatment for generalised or unclassified epilepsy.⁸ Quality of life and health economic outcomes were assessed, showing lamotrigine and valproate to be cost‐effective options.

The subsequent SANAD II trial compared the newer ASM, levetiracetam and zonisamide, with lamotrigine for focal epilepsy and sodium valproate for generalised/unclassified epilepsy. For focal epilepsy, levetiracetam or zonisamide were inferior to lamotrigine for time to 12‐month remission, and lamotrigine was superior in terms of time to treatment failure (Figure 11.2). Lamotrigine was also superior in the cost–utility analysis. Lamotrigine remains the first‐line treatment for focal epilepsy,⁹ and this is consistent with other studies.¹⁰ For generalised/unclassified epilepsy, levetiracetam was inferior to valproate for time to 12‐month remission (Figure 11.3). Valproate was superior to levetiracetam in achieving 12‐month remission, with a similar rate of adverse reactions. At 2 years, a 15% difference in treatment failure rates was observed between levetiracetam and valproate. In summary, for generalised/unclassified epilepsy, levetiracetam was more costly and less effective than valproate, and valproate remains the preferred first‐line treatment.¹¹ However, the significant risk of teratogenicity with sodium valproate limits its use in women of childbearing potential. Newer ASM, such as lacosamide, perampanel and cenobamate, have appeared since SANAD II. This makes it crucial for new pragmatic head‐to‐head trials comparing ASM. Such trials would determine the most appropriate first‐line monotherapies for focal and generalised epilepsies.

A line graph compares survival probability over time, depicting decreasing trends for 3 epilepsy treatments, lamotrigine, levetiracetam, and zonisamide. — **FIGURE 11.2** Kaplan–Meier plot of time to treatment failure for focal epilepsy: lamotrigine versus levetiracetam and lamotrigine versus zonisamide.

*Source:* Marson et al.⁹ / with permission of Elsevier.

HR = hazard ratio.

A line graph compares survival probability over time, depicting decreasing trends for levetiracetam and valproate. — **FIGURE 11.3** Kaplan–Meier plot of time to treatment failure of generalised/unclassified epilepsy: levetiracetam versus valproate.

*Source:* Marson et al.¹¹ / with permission of Elsevier.

MEDICAL MANAGEMENT OF DRUG‐REFRACTORY EPILEPSY

Whilst informative studies of first‐line monotherapies have been conducted and guidelines published,¹² there is a paucity of data regarding the choice of subsequent medications, particularly when used in combination for DRE. This requires a tailored, bespoke individual approach to ensure the most appropriate treatment strategy is employed. A two‐stage procedure should be adopted. First, the diagnosis is reassessed, and the previous treatment history is reviewed. Second, a treatment plan needs to be devised.

ASSESSMENT

The steps in assessment are summarised in Practice points. DRE is defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom.¹³ Confirming the diagnosis, reviewing the syndrome and seizure types, and checking medication adherence are mandatory steps in understanding the nature of apparent drug resistance. Reviewing previous treatment history is also essential, as the response to a drug is typically relatively consistent over time. Review which drugs have been previously tried, the response in terms of effectiveness, tolerability, maximum dose, and why the drug was withdrawn.

PRACTICE POINTS

Assessment and Treatment Plan in People With DRE

Assessment

Review diagnosis and aetiology
Classify seizures and syndrome
Review adherence to prescription
Establish the presence and nature of adverse effects
Review drug history in terms of dosage, length of therapy, efficacy, reasons for discontinuation:
- Which drugs were useful in the past?
- Which drugs were not helpful or caused side effects in the past?
- Which drugs have not been used in the past?
Review precipitants and non‐pharmacological factors

Treatment plan

Document proposed sequence of medications to try
Decide what background medication to continue
Decide upon the sequence of drug additions and withdrawals
Decide the duration of drug ‘trials’ by taking into account baseline seizure frequency
Decide when to do plasma level monitoring
Consider surgical therapy
Consider non‐pharmacological measures such as lifestyle, dietary manipulation, neuromodulation
Recognise the limitations of therapy
Provide information on the above

TREATMENT PLAN

A treatment plan is a stepwise series of treatment trials, each being tried if the previous attempt does not control seizures without acceptable side effects. The treatment plan is ideally devised to trial each ASM in a reasonable dosage, singly or as a two‐drug therapy (or, more rarely, a three‐drug combination).

Combination therapy is needed in about one‐third of those developing epilepsy, and the prognosis for seizure remission, even on combination therapy, is less good. Seizure‐free rates decreased from approximately 50% for the first ASM, but response after this first drug progressively reduced, with only a smaller number of people benefiting from the subsequent ASM.¹⁴

Accordingly, there is often inertia in the treatment of DRE, which should be resisted, as an active and logical approach to therapy can prove successful.¹⁵

The choice of ASM combinations has not been satisfactorily assessed, but several therapeutic strategies, known as rational prescribing, may improve the chances of a successful outcome.¹⁶ For example, there is some evidence that combining ASM with differing modes of action may yield a synergistic effect.^17,18 Conversely, combining ASM with the same mechanism of action is more likely to result in adverse effects than improved efficacy.¹⁹ Successive ASM trials with similar modes of action are unlikely to result in improved seizure control, and introducing a medication with a novel mode of action may be more successful. Switching ASM to once‐daily dosing regimens is an effective therapeutic strategy in people with poor seizure control related to medication non‐adherence.²⁰

People must be advised about the implications of polytherapy regarding drug interactions, teratogenesis, and potential pharmacodynamic effects. This will involve deciding which ASM to introduce, which to withdraw, and which to retain. Decisions will need to be made about the duration of each treatment trial.

Choice of a drug to introduce or retain: Rational decisions depend on a well‐documented history of ASM therapy. Generally, these should be drugs that are appropriate for the seizure type and that have either not been previously used in optimal doses or have been used and proven unhelpful. Treatment should be tailored to individual requirements, considering comorbidities, comedication, obesity, gender, lifestyle, age, and presence of renal or hepatic disease.
Choice of a drug to withdraw: These are ASM that have been given at optimal doses and that were either ineffective or caused unacceptable adverse effects. ASM should not be continued if they have had little benefit, particularly if this impacts the choice of an untried drug due to potential pharmacokinetic or pharmacodynamic interactions.
Duration of a treatment trial: This will depend on the baseline seizure rate. The trial should be long enough to differentiate the effect of therapy from that of spontaneous fluctuations in seizures. ILAE proposed that an individual should be considered ‘seizure free’ in response to a new ASM once they have gone without a seizure for at least three times the duration of their most extended pre‐intervention inter‐seizure interval in the preceding 12 months.¹³
Trial of therapy: It is usual to aim for treatment with one or two suitable ASM. If drugs are being withdrawn, it is wise to maintain one drug as a foundation in the withdrawal period.
Drug withdrawal: Withdrawal, or a sudden reduction in the dose of an ASM, can result in worsening seizures or status epilepticus if the withdrawn drug has a positive contribution. Only one medication should be withdrawn at a time. If seizures flare up when an ASM is withdrawn, it should be reinstated, and the possibility of using a higher dose should be considered.
Drug addition: New drugs added to a regimen should be introduced slowly to minimise adverse effects. Aiming initially for a low‐maintenance dose is usual, but higher doses are often required.

ROLE OF ANTISEIZURE MEDICATION LEVEL MEASUREMENTS

ASM levels should not guide dosing strategy. However, measuring the serum, plasma, or salivary levels of some ASM helps assess toxicity and adverse effects, changes in concentrations during pregnancy, evaluate interactions, and determine adherence.²¹ Additionally, phenytoin’s kinetics are nonlinear, so levels should be regularly measured.

INFORMATION

Consent to treatment must be informed, and individuals should be given sufficient time to discuss and explore their treatment options. Treatment is a balance between the benefits and the risks. It is essential to inform people about the risks associated with therapy so that they can make an informed decision. It is recommended to follow any discussion with written information.

TREATMENT OF PEOPLE WITH EPILEPSY IN REMISSION

Epilepsy is considered to be in remission if seizures have not occurred over a long period (conventionally, two, three, or five years). Approximately two‐thirds of people will be in remission after starting treatment, but some may oscillate between periods of remission and relapse. Some people with untreated epilepsy also remit; in the long term, at least half are in remission and off medication. Drug doses should be minimised for people in remission to avoid significant adverse effects. Consideration of long‐term effects, such as bone disease or adverse cardiovascular consequences, should be noted, and advice about such topics as pregnancy and contraception should be given when appropriate. At the annual review, seizure type, syndrome, aetiology, investigations, and previous treatment should be reviewed and recorded. Additionally, routine haematological and biochemical checks should be performed.

DISCONTINUATION OF DRUG THERAPY

The decision to withdraw ASM depends mainly on the risk level the person is prepared to accept, as withdrawal is never risk‐free. Recurrence risk should be estimated, considering factors listed in Practice points.

Useful risk information on the probability of remaining seizure‐free after withdrawal can be derived from the MRC ASM withdrawal study, which included over a thousand people who had been seizure‐free for two years or more (Figure 11.4). Within two years of starting withdrawal, 59% remained seizure‐free, compared with 79% of those who opted to stay on therapy.²² Other studies have had essentially similar findings.²³

Seizure‐free period The longer an individual is seizure‐free, the lower the chance of relapse. The overall risk of relapse after drug withdrawal, for instance, after a five‐year seizure‐free period, is under 10%.
Duration of active epilepsy Precise data are lacking, but the shorter the history of active seizures, the lower the relapse risk.
Epilepsy type and severity Two or more seizure types increase the relapse risk, should remission occur. Symptomatic epilepsy, focal to bilateral tonic–clonic or myoclonic seizures, neurological deficit, or learning disability increases the relapse risk.
Electroencephalography In generalised epilepsies, the persistence of spike–wave complexes is the most useful prognostic EEG feature, indicating a higher relapse risk. This is especially the case in childhood and juvenile absence epilepsy. The presence of focal spikes or background changes in adults is of little help in estimating relapse risk after ASM withdrawal. Other EEG abnormalities have no predictive utility.

FIGURE 11.4 MRC drug withdrawal study. The actuarial percentage of people seizure‐free among those randomised to continue or slowly withdraw ASM. Two years after randomisation, 79% of those who continued treatment and 59% who withdrew were seizure‐free.

Source: Chadwick et al.²⁴ / Reproduced with permission from John Wiley & Sons.
Age There is no clear relationship between age and relapse risk, although age‐specific syndromes have specific prognostic patterns. There is a low relapse risk in self‐limited childhood epilepsies or absence epilepsy.

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11: Medical Treatment