Management of Refractory Epilepsy in Childhood
Keyword : Epilepsy; Surgery
The prevalence of epilepsy is 7-9 cases per 1000 population. It is estimated that 25% of epileptics have seizures which are refractory to anticonvulsant therapy1 and the prognosis for seizure control is worse for complex partial seizures.2 More than 50% of partial seizures are refractory to drug therapy.3 In childhood, seizures refractory to monotherapy are seen more commonly in the epileptic syndromes of infantile spasms, Lennox Gastaut syndrome, focal and complex partial seizures.
Assessment of Epileptics Refractory to Medical Therapy
Awareness of a patient's compliance history, environmental stressors, and seizure triggers may reduce seizure frequency without a change in medication. Therapeutic regimen should minimise side effects while maximising seizure control and compliance. Therapeutic drug monitoring improves seizure control and reduces AED side-effects in children with refractory epilepsy. Drug monitoring picks up those who defy medication control due to non-compliance. Children with refractory epilepsies are likely to be on high doses of more than one AEDs, exposing them to greater risk of toxic side-effects. Moreover, interactions with polypharmacy are varied and unpredictable. In addition, those with refractory epilepsy are likely subjects of aberrant drug pharmacokinetics.4
Prognosis in epilepsy is largely determined by the underlying etiology. When a child has epilepsy refractory to medical treatment, it is important to subject this child to more prudent assessment of the cause of the seizures and for more precise electroencephalographic (EEG) localisation of the seizure activity. Cerebral cortical dysgenesis is an important cause of medically refractory epilepsy. Neuroimaging with conventional MRI, MRI-based hippocampal volume measurements5 are useful modalities for assessment of structural cerebral abnormalities. Accurate diagnosis of the seizure type usually requires EEG monitoring. Prolonged inter-ictal EEG monitoring is mandatory in the successful management of patients with refractory epilepsy and ictal video-EEG monitoring is necessary for pre-surgical assessment of patients. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are well established functional imaging techniques in epilepsy that aids precise localisation of the seizure focus,6-7 The use of ictal and interictal SPECT provides unique information and insights into the pathophysiology of seizures.6,8
With failure of seizure control with antiepileptic monotherapy, one can resort to either polypharmacy or epilepsy surgery for suitable candidates.
Polypharmacy Therapy of Intractable Childhood Epilepsies
The abolition of seizures using a single AED can be expected in about 90% of patients.3 The remainder often receive polypharmacy in whom two or more major antiepileptic drugs (AEDs) are often used in combination. Many patients inevitably experience complicated drug interactions.9 The extent and direction of interactions with polypharmacy are varied and unpredictable. Knowledge of the interactions and side-effects of the combinations of AEDs is of vital importance. Carbamazepine, phenytoin and phenobarbitone all induce the synthesis of hepatic mono-oxygenase and conjugating enzymes. This will result in an acceleration in the metabolism of other lipid-soluble drugs with likely attenuation of their pharmacological effects. Valproate, on the other hand is an enzyme inhibitor. Discontinuation of an enzyme inducer or inhibitor will influence the concentrations of the remaining drugs. It is often in those with refractory seizures that the pharmacological phenomena of tachyphylaxis, tolerance, auto-induction characteristics of AEDs are recognised. Currently, there is no rational approach to the treatment of intractable epilepsy.
For the first time in 15 years, new AEDs, namely vigabatrin and lamotrigine, are available for the treatment of individuals with seizure disorders. Combinations of these drugs with complementary modes of action may provide a rational pharmacological approach to the management of refractory epilepsies. Adjunctive therapy with these new medications have demonstrated their efficacies in the treatment of refractory epilepsies. They have unique clinical spectrums and are reported to be safer and better tolerated than conventional therapy. Vigabatrin has been found to be effective as monotherapy or add-on therapy for cryptogenic and symptomatic partial epilepsy, West syndrome especially those secondary to tuberous sclerosis and Lennox Gastaut syndrome.10-12 Lamotrigine was found to be efficacious as add-on therapy to children with complex partial, secondary generalised tonic-clonic, myoclonic, primary generalised tonic-clonic, atonic seizures as well in those with typical or atypical absences. In 285 children with refractory seizures, significant reduction in seizures was observed in 30-50% of children.13
Adjunctive Therapy with Agents Which are not Primarily Antiepileptic Agents
For many years, the therapeutic effects of acetazolamide, clobazam, steroids corticotrophin (ACTH gel) and intravenous immunoglobulins in adjunctive therapy of difficult to control epilepsies have been recognised.
Acetazolamide has been used as an adjunctive treatment for epilepsy since 1952. The mechanism of action is through the inhibition of brain carbonic anhydrase thereby resulting in accumulation of carbon dioxide and acidosis which prevents occurrence of seizures. As monotherapy for epilepsy, its usefulness is limited because of the rapid development of tolerance to its antiepileptic effects in 3-6 months. However as adjunctive therapy with the primary AEDs such as ethosuximide, carbamazepine or phenytoin, tolerance does not develop. For refractory partial seizures, addition of acetazolamide to carbamazepine reduces seizure frequency by at least 50% in half of the patients.14 Intermittent acetazolamide has also been proven to be of value as an adjunct to treatment of catamenial epilepsy.
Clobazam is a benzodiazepine drug which is used for its psychotropic, hypnotic and muscle relaxant effects. It has been shown to have anticonvulsant effects useful in the control of generalised tonic-clonic, myoclonic and absence seizures as well as against partial and reflex epilepsy. Clobazam acts through the benzodiazepine receptors which are linked to the inhibitory action of GABA.
Add-on clobazam therapy in an average daily dose of 0.8 mg/kg resulted in seizure control or in seizure reduction of 90% or more in 41-47% of children. Significant seizure reduction of 50-90% was experienced by another 24%.15,16 However side effects and tolerance necessitated withdrawal of therapy in 35%.15 It was found that after 6 months of add-on therapy, good and excellent control was achieved in 70-80% of patients with drug resistant generalised tonic-clonic seizures and in 50% of those with partial seizures.17 Although deterioration of seizure control will occur in some patients, long-term benefit without development of tolerance can be expected in 28%.18
Steroids and ACTH
Steroids and corticotrophin (ACTH) were initially reported to be efficacious in a variety of seizure disorders.19,20 The mechanism of their action is unknown. Although prednisone and ACTH were found to be of most benefit to children with infantile spasms, other types of refractory myoclonic, generalised and partial seizures have also been reported to respond to steroids.21
Walker in 1969 was first to propose the possible immunological mechanism involved in the pathogenesis of some epileptic events. This hypothesis has been substantiated by experimental findings that injection of gamma globulin containing antibodies against brain tissues into various species of animals has resulted in epileptiform activity. Trauma to brain has also resulted in development of brain-specific antibodies and epilepsy. In man, there is association of epilepsy and the epileptic syndromes to disorders of immunoglobulins.22,23 It has been suggested that some of the chronic resistant epilepsy and epileptic syndromes are reflective of a chronic viral encephalopathy or meningoencephalitis in those in occult immunodeficient states. Intravenous immunoglobulin (IVIG) may then act as treatment of the immunodeficient state. Infection and inflammation will also release brain tissue antigens and elicit production of brain-specific antibodies. Autoantibodies against brain tissue have been postulated to have a pathogenetic role in epilepsy. Fc receptor blockade by exogenous gamma globulin blocks the binding of autoantibodies and reverses the autoimmune process responsible for initiation of the epileptic seizures.
IVIG has been given to children with resistant post-encephalitic seizures. those with intractable myoclonic and partial epilepsies related to Rasmussen's syndrome, infantile spasms and Lennox Gastaut syndrome.24-28 Ariizumi et al found that response to IVIG treatment is most efficacious in the first two years of the seizures than later and works significantly better in children with a low serum IgA level.25 Various protocols using varying dosages and intervals in between infusions were used.22,24-31 In a double blind dose finding clinical study, it was found that there was a positive trend in favour of intravenous immunoglobulin treatment but there was no relationship between doses (100 mg, 250 mg or 400 mg/kg per infusion) and efficacy.30
Epilepsy refractory to antiepileptic medication is an incapacitating disease with high costs for the person and the society. Surgery has given hope to these desperate cases and has become a viable therapeutic option for many children with refractory epilepsy. When a focal epilepsy proves refractory to medical therapy, surgical treatment is available and increasingly used. Most interventions consist of focal cortical resections and by far the most common operation is a temporal lobectomy. When surgical candidates are selected appropriately, results are excellent, especially for temporal lobe epilepsy.
Surgical approach to the treatment of drug resistant epilepsy is based on two broad principles. The first is to treat focal brain pathology and the second is to restrict the propagation of epileptic discharge by transection of anatomical pathways. Four principal surgical procedures are practised in the treatment of childhood epilepsy: temporal lobectomy, limited extratemporal cortical excision, hemispherectomy and corpus callosotomy. Careful selection and presurgical evaluation of patients is crucial. The presurgical evaluation includes clinical evaluation, EEG-video monitoring, neuropsychological testing and structural as well as functional imaging.
A review of the literature on the effectiveness of epilepsy surgery revealed that a third of patients had no improvement in the control of their seizures after surgery. Another third improved but still required AEDs for control of seizures. The final third is seizure free but some still require antiepileptic medication.32 Epilepsy surgery thus benefits two thirds of patients with intractable seizures and makes the condition more amenable to medical therapy.
Resistant epilepsy is still a challenging problem in neurological practice. The modalities discussed have given some encouraging results with more to desire. As more new drugs with single mechanisms of action become available, there is potential for more rationalised polytherapy for resistant seizures when these agents are used in combination for synergistic effect. When surgical candidates are selected appropriately, results are promising especially for temporal lobe epilepsy.
1. Reynolds EH, Elwes RDS, Shorvon SD. Why does epilepsy become intractable? Prevention of chronic epilepsy. Lancet 1983;2:952-4.
2. Annegers JP, Hauser WA, Eweback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20:729-37.
3. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondary generalised tonic-clonic seizures. N Engl J Med 1985;313:145-51.
4. Pan SQ, Hu ZX, Cai HS. A study on phenytoin pharmacokinetics in 15 patients with refractory epilepsy. Chung Hua Nei Ko Tsa Chih 1992;31:290-2,318.
5. Raymond AA, Fish DR, Sisodiya SM, Alsanjari N, Stevens JM, Shorvon SD. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain 1995;118:629-60.
6. Mullan BP, O'Connor MK, Hung JC. Single photon emission computed tomography. Neuroimaging Clin N Am 1995;5:647-73.
7. DeCarli C, Mclntosh AR, Blaxton TA. Use of positron emission tomography for the evaluation of epilepsy. Neuroimaging Clin N Am 1995;5:623-45.
8. Newton MR, Austin MC, Chan JG, McKay WJ, Rowe CC, Berkovic SF. Ictal SPECT using technetium-99m-HMPAO: methods for rapid preparation and optimal deployment of tracer during spontaneous seizures. J Nucl Med 1993;34:666-70.
9. Brodie MJ. Established anticonvulsants and treatment of refractory epilepsy. Lancet 1990:ii:350-4.
10. Murri L, ludice A. Vigabatrin as first add-on treatment in carbamazepine resistant epilepsy patients. Acta Neurol Scand 1995; 162(Suppl):40-2.
11. Goldsmith P, de-Bittencourt PR. Rationalized polytherapy for epilepsy. Acta Neurol Scand 1995;162(Suppl):35-9.
12. Raucci U, Spalice A, Basile LA, et al. New drugs in the treatment of childhood epilepsy: vigabatrin (study of 61 subjects). Pediatr Med Chir 1994;16:575-8.
13.Wallace SJ. Lamotrigine - a clinical overview. Seizure 1994;3(Suppl A):47-51.
14. Oles KS, Penry JK, Cole DLW, Howard G. Use of acetazolamide as an adjunct to carbamazepine in refractory partial seizures. Epilepsia 1989;30:74-8.
15. Sheth RD, Ronen GM, Goulden KJ, Penney S, Bodensteiner JB. Clobazam for intractable pediatric epilepsy. J Child Neurol 1995;10:205-8.
16.Munn R, Farrell K. Open study of clobazam in refractory epilepsy. Pediatr Neurol 1993;9:465-9.
17. Callaghan N, Goggin T. Clobazam as adjunctive treatment in drug resistant epilepsy - report on an open prospective study. Ir Med J 1984;77:240-4.
18. Remy C. Clobazam in the treatment of epilepsy: a review of the literature. Epilepsia 1994;35(suppl 5):S88-91.
19. McQuarie I, Andersson JA, Ziegler MR. Observations on antagonistic effects of posterior pituitary and corticoadrenal hormones in the epileptic subject. J Clin Endocrinol Metab 1942;2:406-10.
20. Klein R, Livingston S. The effect of adrenocorticotrophic hormone in epilepsy. J Pediatr 1950;37:733-42.
21. Snead III OC, Benton JW, Myers GJ. ACTH and prednisone in childhood seizure disorders. Neurology 1983;33:966-70.
22. Benson M, Blennow G, Rosen I. Intrathecal immunoglobulin production and minor motor seizures. Acta Paediatr Scand 1987;76:147-50.
23. Duse M, Tibert S, Plebani A, et al. IgG2 deficiency and intractable epilepsy of childhood. Monogr Allergy 1986;20:128-34.
24. Sandstedt P, Kostulas V, Larsson LE. Intravenous gamma globulin for post-encephalitic epilepsy. Lancet 1984;2:1154-5.
25. Schwartz SA, Gordon KE, Johnston MV, Goldstein GW. Use of intravenous immune globulin in the treatment of seizure disorders. J Allergy Clin Immunol 1989;84:603-7.
26. Ariizumi M, Baba K, Shiihara H, et al. High dose gamma globulin for intractable childhood epilepsy. Lancet 1983;2:162-3.
27. Ariizumi M, Baba K, Ogawa K, et al. Early treatment of intractable childhood epilepsy with intravenous immunoglobulin. Nihon Univ J Med 1984;26:229-42.
28. Ariizumi M, Baba K, Okubo O. Immunoglobulin therapy in the West syndrome. Brain Dev 1987;9:422-5.
29. Bedini R, de Feo MR, Orano A, L Rocchi. Effects of gamma globulin therapy in severely epileptic children. Epilepsia 1985;26:98-102.
30. van-Rijckevorsel-Harmant K, Delire M, Schmitz-Moorman W, Wieser HG. Treatment of refractory epilepsy with intravenous immunoglobulins. Results of the first double-blind/dose finding clinical study. Int J Clin Lab Res 1994;24:162-6.
31. Etzioni A, Jaffe M, Pollack S, Zelnik N, Benderly A, Tal Y. High dose intravenous gamma-globulin in intractable epilepsy of childhood. Eur J Pediatr 1991;150:681-3.
32. Dasheiff RM. Epilepsy surgery: Is it an effective treatment? Ann Neurol 1989;25:506-10.
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