Advances in medical and surgical treatments of epilepsy

A C F Hui 許志輝，J M K Lam 藍明權，S H Li 李兆雄

HK Pract 2003;25:419-425

Summary

Epilepsy is a common and disabling condition. During the Decade of the Brain our understanding of the aetiology, pathophysiology and prognosis of epilepsy has grown dramatically. In this article we focus on three areas of advances in treatment: new anti-epileptic drugs, vagus nerve stimulation and epilepsy surgery.

摘要

癲癇是常見可以致殘的疾病。在這個腦力革命的時代，對癲癇的病因、病生理和預後的認識都有突飛猛進的發展。 本文集中闡述新癲癇藥物，迷走神經刺激和癲癇手術三方面的新進展。

Introduction

Epilepsy is the most common of the serious chronic neurological illnesses. Many different disorders may cause recurrent seizures and some clinicians refer to these seizures as the Epilepsies.¹ More people have active epilepsy than there are patients with multiple sclerosis, Parkinson's disease, Guillain-Barr syndrome, myasthenia gravis or muscular dystrophy combined.² Recurrent seizures have a number of important consequences: risk of falls and injuries, increased mortality rates, status epilepticus, risk of developing sudden unexpected death and psychological morbidities.^3,4 Seizures may lead to anxiety, poor self-esteem, restrictions in lifestyle, loss of driving privileges, independence, education and employment. The ultimate goal of treatment is that the patient should have as normal a life as possible. Seizure control refers to the impact of treatment on seizure frequency, type and severity. Examples of "outcome scales" to gauge the effectiveness of control include the Liverpool and the National Hospital Seizure Severity Scales. Some patients may underestimate the frequency of attacks as they are amnesic for the event. Seizure diaries may also be unreliable. Total freedom from seizures is the most important objective because seizure reduction alone as an outcome measure has limited clinical value.⁵ Another aim of treatment is epilepsy control which takes into account problems beyond controlling the seizures alone. Issues such as drug side-effects, sensible dosing, tolerability should be considered; in some cases, seizure attacks may be controlled but only at the expense of intolerable side-effects.

New antiepileptic drugs

Patients are commonly treated according to the seizure type as defined by the International League Against Epilepsy Seizure Classification based on clinical and electroencephalogram data.⁶ This is the classification that is used in new antiepileptic drug (AED) trials and is also commonly referred to in most textbooks. However this classification does not take into consideration important information such as aetiology, pathophysiology or prognosis.⁷ In other areas of clinical practice, physicians do not just manage signs and symptoms such as "jaundice" but they look at and treat the underlying condition such as hepatitis, haemolytic anaemia or cholangiocarcinoma. Experience with the new AEDs showed that less than 2% of patients achieved freedom from attacks and that there is no effect on the mortality rate in patients with refractory epilepsy.⁸ In clinical trials (often supported in whole or in part by pharmaceutical companies), most of the new AEDs appear to have better pharmacokinetic profiles than established drugs but each has its own side-effect profile (Table 1). A number of severe reactions have come to light at post-marketing surveillance after the drug had been licensed e.g. aplastic anaemia with felbamate and visual field defects with vigabatrin. As a result, both of these drugs are now rarely prescribed de novo.^9,10

Currently monotherapy is preferable to using multiple drugs. The use of a single drug, at an adequate dosage, has many advantages such as improved compliance, lower costs, less chance of drug interactions and less potential for teratogenicity.¹¹ There are fewer side-effects and, as a result, there is better quality of life with improved alertness, mood and concentration.¹² Switching patients from multiple AEDs to monotherapy has actually shown to produce better seizure control.¹³ The incidence of adverse effects increases with the number of drugs prescribed and combinations of a number of drugs are more likely to result in idiosyncratic reactions, e.g. increased chance of having allergic reactions when lamotrigine is added to patients already taking valproate. Although the development of new agents with their different mechanisms of actions have raised the possibility of favourable pharmacodynamic and pharmacokinetic interactions, there is still limited evidence for any particular combination.¹⁴ In studies which have compared the new AEDs with established drugs, the new agents are as efficacious as but not superior to the older agents.^15,16 A meta-analysis of 20 randomised placebo-controlled clinical trials of the new AEDs (gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and zonisamide) on patients with refractory partial epilepsy showed the efficacy of the new drugs, in terms of 50% seizure reduction and tolerability, are similar.¹⁷ (Topiramate appeared to offer a higher response rate but the confidential confidences overlapped with other agents). Direct comparative studies of new AEDs are limited. In the largest study to date, gabapentin and lamotrigine were found to be equally effective in the treatment of patients with newly diagnosed epilepsy.¹⁸

Gabapentin

The exact mode of action of gabapentin is uncertain but studies suggest that it may promote the synthesis of an inhibitory neurotransmitter, [gamma]-aminobutyric acid (GABA). Up to one-third of patients with partial seizures improved significantly during controlled trials, but none seemed to have become totally seizure-free.^19-22 It is used as an adjunctive treatment or as a single agent for partial seizures but not for other seizure types such as myoclonus or absence. Gabapentin is not metabolised, exhibits no protein binding and does not induce hepatic enzymes. Its potential for drug interaction is small and no clinical significant interaction has been reported so far. It is usually well tolerated and its side-effects are mainly related to the central nervous system viz: drowsiness, dizziness, diplopia, ataxia and headache.^19-22

Lamotrigine

The mode of action of lamotrigine is related to its potential to modulate sodium channels and block the release of glutamate. Up to one-third of patients achieved 50% seizure reduction in controlled trials in patients with partial seizures.^23-26 It is effective in patients receiving monotherapy, patients with generalised seizures and in the elderly.^{15,16,18,25,26} Hepatic enzyme inducers decrease the half-life of lamotrigine while valproate blocks its metabolism. Skin hypersensitivity reaction is the most common serious idiosyncratic side-effect.

Topiramate

Four mechanisms of action have been proposed for topiramate. First, topiramate blocks voltage-activated sodium channels: secondly it interacts with GABA receptors. Thirdly, it blocks kainate/AMPA receptors and lastly it weakly inhibits carbonic anhydrase. It is a broad-spectrum AED that is effective in treating generalised as well as partial seizures.^27-30 Topiramate has minimal interaction with other AEDs. Apart from CNS side-effects such as dizziness, drowsiness, headaches and impaired cognition, unusual complications include paraesthesias, nephrolithiasis and weight loss.

Vagus nerve stimulation

The vagus nerve stimulator consists of an implantable lithium-powered generator (NeuroCybernetic Prosthesis system, Cyberonics Inc.) with a bipolar lead which is attached to the left vagus nerve. It was first approved in 1997 for use in the United States as an adjunctive treatment for patients with refractory partial-onset seizures. Eighty-percent of the nerve fibres which consist of afferent fibres, terminate in the nucleus solitarius (NTS) located in the dorsal medullary complex of the vagus. The NTS has extensive projections to a number of potential epileptogenic structures such as the insula, amygdala and hippocampus.³¹ These anatomical connections help explain how electrostimulation of the vagus nerve could have an anticonvulsant action. Vagus nerve stimulation (VNS) may exert an anti-seizure effect via neurotransmission, as increase in GABA and decrease in glutamate transmissions have been demonstrated in animal models; microinjection of the NTS with glutamate antagonists or GABA suppresses experimentally induced seizures in animals. Two multicentre trials of this device have shown a reduction in seizure frequency in patients with refractory epilepsy. Patients randomised to high frequency stimulation had a mean seizure reduction of 24.5-28% while the figures for those on low frequency stimulation were only 6.1-15%.^32,33 At implantation, the system is set at an initial output current of 0.5mA, a pulse-width of 500 seconds, and frequency of 20-50Hz. Two weeks following implantation, the system is activated: output current is then titrated upwards in steps of 0.50mA until the anti-epileptic effect is maximal or when the current reaches 3.00mA. The other parameters namely: pulse duration, duty cycles and frequency can also be adjusted. At follow up visits the patient is monitored for shortness of breath, throat tightness/discomfort, excessive hoarseness, and dysphagia. VNS is well tolerated and, in contrast with the AEDs, has no cognitive side-effects.

At the Prince of Wales Hospital, among 13 patients (mean age 25 years, range 13-40 years) with a long history of disabling refractory seizures, 46% of patients experienced a 50% or more reduction in seizure frequency, of whom one became seizure free. The device was removed in five patients due to lack of efficacy. Seven patients reported minor short-term adverse events, such as cough and neck discomfort.

Efficacy with long-term use were similar to the new generation of anticonvulsants; but again few patients with refractory epilepsy became totally free from further attacks.^34,35

Epilepsy surgery

Surgical treatment of epilepsy has gained momentum over the past two decades with surgical centres becoming established worldwide. This has been made possible by the recognition of syndromes that are amenable to resection, the increased use of video-EEG monitoring and the availability of magnetic resonance imaging (MRI) to identify intracranial pathology accurately and preoperatively.³⁶ The need therefore for intracranial EEG and "awake" surgery has been reduced for patients with a clearly defined syndrome such as mesial temporal lobe epilepsy; but in complex cases, these invasive techniques remain essential. Patients are evaluated for surgery if they have an epilepsy syndrome that causes intractable seizures despite adequate trials of one to two AEDs. The origin of the seizures may be deduced from analysis of clinical, electrophysiological, structural imaging (magnetic resonance scanning) and neuro-psychological information. If all four strands of evidence point to a single epileptogenic zone, resection of this focus can proceed; but if the data are discrepant, further investigations become necessary. Integration of magnetic resonance (MR) and functional images such as MR spectroscopy, ictal single photon emission computerised tomography (ictal-SPECT) and positron emission tomography may be required for complex cases.

Surgery can be divided into "disconnection" and "resection" procedures. Examples of disconnection techniques are corpus callosotomy and multiple subpial transections. In the former, the anterior two-thirds to three quarters of the corpus callosum is divided in order to prevent seizures from spreading to the opposite cerebral hemisphere. Multiple subpial transection is a technique in which a number of vertical 5mm deep incisions are made in an area thought to be responsible for producing seizures but which is adjacent to or partially within functioning cortex.^37,38 The rationale is that this would abolish epileptogenic activity without impairing vital functioning areas of the brain. By disrupting interneuronal connections that predominantly project parallel to the cortex, epileptogenic tissue can be isolated into anatomically restricted blocks. Cortical function is preserved as the connections to subcortical structures that run perpendicular to the surface of the cortex are relatively spared.

The most commonly performed resection is selective amygdalohippocampectomy with or without anterior temporal lobectomy.^39,40 Seizures originating from the mesial temporal lobe structures typically give rise to complex partial seizures (behavioural arrest, a blank stare and automatisms) which may then go on to generalised tonic-clonic seizures. The causes of temporal lobe epilepsy include hippocampal sclerosis, tumours, vascular malformations, neuronal migration disorders and acquired brain damage. Other types of surgery consist of neocortical resections in which the epileptogenic lesion is removed from the lateral temporal, frontal, parietal and occipital lobes.

Predictors for successful seizure remission include a history of febrile seizures, a known cause for the epilepsy, and absence of secondarily generalised seizures. Patients with anterior temporal abnormalities on EEG alone, with restricted temporal lobe hypometabolism and the presence of hippocampal sclerosis in resected tissue are more likely to become seizure free.^41-45 From observational studies, the percentage of patients who become totally seizure free after this procedure is in the 80-90% range. In the only randomised controlled trial comparing best medical with surgical treatments to date, approximately 65% of patients who underwent surgery became seizure free compared to less than 10% of medically treated cases.⁴⁶ Psychological and social outcomes depend on a variety of factors such as pre-operative health-related quality of life status, presurgical neurocognitive status and the extent and type of surgery. For example after temporal lobectomy of the dominant lobe, patients may be at higher risk of impaired verbal skills; on formal and detailed neuropsychological testing, confrontation naming is impaired in the immediate post-operative period but not long term, while verbal fluency is unaffected with some studies actually showing improvement after surgery.⁴⁷ In general, there is improvement in self-reported emotional and psychosocial functioning in those who became seizure free.⁴⁷ At our centre, 21 patients (5 men and 16 women with a mean age of 28 years, range 15-44 years) with intractable seizures were operated on from 1997 to 2002. Fourteen out of the 21 patients (67%) became seizure free and another 4 (19%) achieved substantial reduction in the number of seizures. The mean duration of follow-up period was 21 months and there was no mortality or serious morbidity. All patients who were working are able to continue with their normal employment.

Discussion

Despite the introduction of new drugs and VNS, around a quarter of patients continue to have intractable seizures.^48,49 Future studies on new drugs should ideally be carried out with a syndrome-orientated approach, in well-defined populations and using meaningful outcomes. Aetiology by itself does not seem to be the only determinant of outcome and response to treatment. Genes encoding proteins, such as multidrug-resistance associated proteins and which may limit drug penetration into the brain, are overexpressed in epileptogenic brain tissues of patients with pharmacoresistant epilepsy.⁵⁰ Treatments which inhibit these factors are being evaluated.

Non-surgical treatments do not influence the underlying pathological process. In this sense, the term "anti-epileptic drug" is misleading as existing medical therapies only suppress the symptoms of epilepsy, acting therefore as anti-ictal agents.⁵¹ Ictogenesis is a rapid electrical and chemical event whereby seizures are initiated and elaborated.⁵² At a molecular level these drugs work by targeting calcium, potassium and voltage-gated sodium channels that mediate the release of neurotransmitters. There is increasing recognition that the ideal AED should be one which act against epileptogenesis, the gradual biochemical and histological process of transformation, during which the brain becomes susceptible to developing recurrent seizures.⁵² This process involves cellular changes such as reorganisation of axonal projections and changes in neurotransmission. At present there is no protective drug which can prevent the development of epilepsy in conditions which are associated with seizures such as brain injury or stroke. Only surgery can offer a cure and eliminate the need for drugs. But not all sufferers are suitable candidates for epilepsy surgery because some patients may have seizures which are multi-focal in onset or have normal MRI, usually associated with a lower success rate. There continues to be a need for development of anti-epileptogenic, neuroprotective agents and for identification of new targets for drug treatment.

Key messages

1. The ideal goal of treatment is to abolish all seizures and not just to reduce the number of attacks.
2. New anti-epileptic drugs are in general better tolerated than established agents.
3. Vagus nerve stimulation is a new form of treatment for patients with refractory epilepsy.
4. Epilepsy surgery is an effective cure for suitable patients with intractable seizures.