CW Chan

Epilepsy is a chronic neurological disease which affects about 0.5% of the population and has the highest incidence in childhood. Patients with epilepsy present with loss of consciousness, convulsions and paroxysmal neurological symptoms of funny spells. The diagnosis of epileptic seizures is primarily clinical, but investigations including EEG and neuro-imaging studies (CT Scan, MRI, SPECT, PET and others) are helpful in classifying the types of epilepsy and elucidating underlying etiology. About 30% of children with epilepsy has identifiable neurologic or systemic disorders. Anti-epileptic drugs (AED) are the mainstay of treatment and about 70% of patients are well controlled with AED monotherapy.

Epileptic Syndromes

The development of an international classification for epilepsies and epileptic syndromes has led to substantial progress in the understanding and treatment of patients with epilepsy. Epilepsies and epileptic syndromes are identified first by seizure types (partial, generalized, undetermined types and special syndromes) and then by etiology (idiopathic, symptomatic and cryptogenic). There have been significant advances in the understanding of six major epileptic syndromes. The first three syndromes: benign childhood epilepsy with centrotemporal spikes (BECTS), juvenile myoclonic epilepsy (JME) and childhood absence epilepsy (CAE) are the three commonest epileptic syndromes and each has been the focus of significant research. Patients with centrotemporal spikes (benign rolandic epilepsy) may not require anticonvulsant therapy and their seizures always remit by mid-adolescence. Juvenile myoclonic epilepsy was the first major epilepsy syndrome for which a gene focus, Epilepsy-Juvenile-Myoclonic I (EMJ-I), was found. The underlying neuronal pathways and cellular mechanisms of the generalized absence seizures of childhood absence epilepsy are well delineated.

The other three syndromes (West syndrome, Lennox-Gastaut syndrome and Acquired Epileptic Aphasia) are devastating catastrophic epileptic syndromes. The focus of research in West syndrome (with the classic triad of infantile spasm, hypsarrhythmia in EEG and arrested psychomotor development) has been to develop more effective therapeutic interventions (both medical and surgical) and to improve better understanding of its pathogenesis. New effective medications are available for patients with Lennox-Gastaut syndrome (childhood epileptic encephalopathy), but one of them (felbramate) has been associated with previously unrecognized serious side effects (aplastic anaemia and hepatic failure). Acquired Epileptic Aphasia is an example of poorly understood epileptic syndrome. A multicentre-collaborative group has been organized under Washington University, St Louis, Missouri U.S.A. (the centre where the first case was reported) to re-examine this clinical entity and produce a better understanding of its pathogenesis and treatment.

Currently used Anti-epileptic Drugs (AED)

The last two first-line anticonvulsants to be introduced were carbamazepine in 1967 and sodium valproate in 1974. These are still the best drugs for controlling most types of seizures. There remains, however, a great deal of scope for improving our treatment of epilepsy. About 70% of patients are adequately controlled with antiepileptic monotherapy. The addition of a second or third line drug will provide substantial improvement in only around 10% of the remainder. The more antiepileptic drugs the patient takes, the greater the incidence of adverse effects, particularly cognitive impairment and teratogenesis.

The modes of action of established antiepileptic drugs are multiple, complex and overlapping. Their effects on the central nervous systems are widespread and rather indiscriminate: a neuropharmacological blunderbuss rather than a Laser! The introduction of three new anticonvulsants with novel mechanisms of action over the past five years has revolutionized clinical approach to refractory epilepsy. Vigabatrin, Lamotrigine and Gabapentin have led the way for a plethora of newer agents that are being extensively tested in scientifically-based studies world-wide.

Intractable Seizures

This is defined as resistant epilepsy which does not respond to treatment with combination of more than three anticonvulsants for more than two years (number of drugs and dosage used more important than duration of history of seizure attacks).

Currently patients with Intractable Seizures are recommended to be admitted into Epilepsy Centres where New Anticonvulsants, Epilepsy Surgery, Vagus Nerve Stimulation and other means of treatment are provided with the aid of modern high-tech investigation tools under strict supervision by experienced personnel.

Epilepsy Centre

Patients who continue to have seizures that cannot be ascribed to poor compliance with therapy should be referred to an Epilepsy Centre for several reasons. First of all, the more seizures a patient has, the more difficult it is to control the epilepsy; that seizures may beget seizures has been hypothesized for more than a century (the Kindling Phenomenon). Secondly, it may be hard to classify the seizures on the basis of accounts by untrained eyewitnesses. Video-EEG monitor can result in a definitive diagnosis and classification. In some patients, apparently uncontrolled seizures are really pseudoseizures, which are better treated with psychotherapy. Thirdly, patients with uncontrolled seizures often receive multiple drugs, which may have substantially toxic effects that can be reduced by simplification of the regime. Fourthly, in patients who have not had adequate responses to the standard drugs, there may be an opportunity to try an experimental drug. Finally, appropriate decisions about surgical treatment are best made at specialized centres.

New Anti-Epileptic Drugs

Vigabatrin is a GABA analogue which acts as 'suicide' inhibitor of GABA-transaminase which is the enzyme responsible for degradation of GABA. It binds irrevocably to its target enzyme and so facilitates GABA-ergic inhibition by interfering with its catabolism. Other possible modes of actions have also been suggested.

Lamotrigine is a folate-antagonist. Folic acid was shown to have proconvulsant properties in the mid-1960s. Accordingly antiepileptic drug development at research laboratory concentrated on folate antagonism as a method of identifying potential new antiepileptic drugs. Lamotrigine is the fruit of such research though it is now known that much of its therapeutic properties are not linked to the original intention. It is chemically and functionally unrelated to other antiepileptic drugs. Its anticonvulsant effect arises from a blockade of sodium channels, limiting the pre-synaptic release of glutamate and aspartate and, thus, stabilizing neuronal membranes. This, however, is unlikely to be the whole story.

Gabapentin, a chemical analogue of GABA, was intended to act as a GABA agonist. It was thought too that, being hydrophilic, blood-brain-barrier penetration would be facilitated. Interestingly, the anticonvulsant properties of gabapentin are not dependent on any direct action on the GABA-ergic systems. This drug appears to bind to a membrane site near the glutamate-receptor, which may represent a transport system for L-amino acids. A recent study suggests that gabapentin may also limit the rate of firing of sodium-dependent action potentials.

All three new drugs are well absorbed by oral route and excreted through the kidney. There is very little evidence of drug interaction and the side effects reported so far are minimal. They are effective against most types of refractory epilepsies. As Gabapentin has so far been extensively studies in adults only, it is not recommended for children below twelve years of age up to this moment.

Other newer anticonvulsive drugs currently being studied at clinical and research levels with promising results include Oxcarbazepine, Felbamate, Tiagabine, Remacemide, Stiripentol and Topiramate; these and many others may prove valuable as second-line therapy in refractory epilepsy and may represent tip of a growing iceberg for more new drugs to be launched in the near future.

It is always impressive to witness any antiepileptic drug which demonstrates efficacy in refractory epilepsy. Their use as adjunctive therapy, however, is likely to exaggerate their side-effect profiles also. The use of double-blind, controlled trials in previously untreated patients will demonstrate the true worth of these new drugs in comparison with the much less expensive and more established compounds. Monotherapy may well prove the new crops of anticonvulsants more benign.

The ultimate goal for everyone involved in the development of antiepileptic drugs is the discovery of effective and safe agents with well-defined mechanisms of action. One may find it a useful strategy to combine drugs that independently influence either excitatory or inhibitory processes. As time passes, the best combinations are likely to be discovered serendipitously. The use of two agents acting on the "same of side of the fence", such as vigabatrin and tiagabine, may be a logical approach in refractory single seizure type. A narrow range of biochemical effects may lead to enhanced tolerability during such dual therapy, and "selective" co-prescribing could be the key to improving seizure control with fewer side effects. This approach should supersede the current empiricism and lead to the rational evolution of combination therapy for the treatment of refractory epilepsy.

Epilepsy Surgery

Surgical treatment of epilepsy is becoming a well-established therapy for infants and young children with severe, medically intractable seizures. As in older children and adults, the presurgical evaluations of potential surgical candidates should consist of a detailed history, neurologic and neuropsychologic examination together with anatomic and functional neuro-imaging (MRI, SPECT and PET). The "gold standard" test, however is the recording of ictal events by using simultaneous EEG and Videomonitoring. Although resective operations like temporal lobectomy for temporal lobe epilepsy, lesionectomy for dysembryonic neuroepithelial tumours (DNT) and hemispherectomy (for seizure onset on side with hemiplegia) are commonly performed in children, palliative operation (where no tissues are removed) such as corpus callosotomy (for drop attacks) and subpial resection (for Landau-Kleffner syndrome) are also practised with increasing frequency amongst paediatric patients. Efficacy of surgery in children compares favourably with results from adult patients. In addition, because the immature brain is more plastic than the mature brain, recovery of function is often greater after surgery in children than in adults. Early surgery in children with intractable surgery is thus strongly recommended. Overall success rate for epilepsy surgery is over 80%. It is encouraging to report that such operations are ready to be launched in Hong Kong soon.

Vagus Nerve Stimulation

This is indicated for patients with intractable seizures where no definite focus is detectable and where medical treatment is ineffective. The procedure consists of implanting a device called Vagus Nerve Stimulator (VNS), which contains a small generator with three electrodes wrapped around the vagus nerve in the neck. A current is released to stimulate the vagus nerve every 5 minutes. It is believed that the antiepileptic effect of this treatment regime is mediated via the inhibitory effect of the monoaminergic systems at brainstem level. This inhibitory effect slowly builds up in the brain over a period of several months.

The efficacy and safety of VNS for treatment of seizures have been documented in clinical studies in several centres in North America, Europe and Hong Kong (the Chinese University of Hong Kong). The only complication is transient discomfort of the throat which usually last for a few days after the implantation. Therefore, with careful patient selection criteria, VNS provides an effective therapeutic option to those patients who suffer from intractable seizures.

Conclusion

Paediatric Epileptology is a rapidly expanding subspecialty within Child Neurology. The present update attempts to browse through some important aspects and endeavours to highlight recent advances in the classification and understanding of common epileptic syndromes as well as management of intractable seizures using new antiepileptic drugs, surgery and vagus nerve stimulation.

For management with antiepileptic drugs, the diagnosis of epilepsy must be sound and there should be no correctable underlying condition. The patient and his parents must be counseled about the implication of diagnosis, the need for long term therapy and the importance of compliance. The choice of drug should be based on proper classification of the type of seizure and epileptic syndrome. Initial dose should be low and increased incrementally to a maintenance dose that controls the seizures without toxic effects; dose should be titrated to the limit of tolerability without obsession about the plasma concentration. Monotherapy is the preferred approach for most patients and a second drug, or even a third, should be substituted for the first before a combination of drugs is contemplated. Patients should be referred to an Epilepsy Centre for expert management when seizure persists despite treatment with first-line antiepileptic drugs. Surgery should be considered for patients with drug-resistant partial seizures or generalized seizures with multiple falls. For selected patients, vagus nerve stimulation may be considered as treatment options.

Good communication with the patient and his family combined with simple, clear, and sympathetic explanation of the plan of action and potential pitfalls, are essential prerequisites for success in the management of children with epilepsy. In most cases, treatment is effective and children with epilepsy can usually lead healthy and productive lives.