Update Intractable Epilepsy Vijay Gupta, S.K Gupta DM, Rajinder Gupta Authors’ affiliations : Prof. Vijay Gupta, S.K Gupta, Rajinder Gupta Department of Medicine, Govt. Medical College, Jammu Accepted for publicatio November 2004 Correspondence to : Dr. Vijay Gupta Prof. & Head Post Graduate Department of Medicine, Govt. Medical College, Jammu {INDIA} JK-Practitioner2005;12(2):105-107 Intractable Epilepsy (IE) Intractable epilepsy is defined as 1 disorder in patients having at least two seizures a month for over two years despite the administration of two first line antiepileptic drugs. Epilepsy is a common chronic neurological disorder and is estimated to affect about | % of the population. Although the prognosis for majority of patients is good, up to 15-35% do not respond to adequate antiepileptic drugs and are said to suffer from ‘medically intractable epilepsy. Majority of patients with epilepsy will have remission of the disease in course of time. However, a certain percentage continue to experience seizures throughout whole life despite best available treatment. Since 1993, a host of newer antiepileptic drugs (AEDs) have been introduced in the therapeutic armamentarium for treating patients with epilepsy. A lot of advancement in surgical techniques has taken place during last ten years in the management of selected cases of epilepsy and vagal nerve stimulation has also been receiving adequate attention in sophisticated centres. Inspite ofall these achievements, even today epilepsy is considered to be a ‘major cause of public health problem with varying outcomes in relation to its prognosis. ‘A majority of patients with intractable partial epilepsy are on multiple AEDs and have symptoms of chronic AEDs toxicity. Recent trends in the management of patients with epilepsy focus on monotherapy in preference to polytherapy. Even though the combination of drugs used and their doses were proper, Intractability of seizures still persist if patient whose seizures are not controlled with completely monitored one antiepileptic drug. There is insufficient evidence to guide achoice between the standard AEDs such as phenobarbitone, phenytoin, carbamazepine and valproate and it remains to be established whether specific drug combinations are more effective than others, Many studies JK-PRACTITIONER have shown that addition of second drug in patients with intractable epilepsy, controlled seizures only in additional 10-15% of cases with increased toxicity. Thus if seizures are uncontrolled with two primary drugs, further addition of primary drugs has no clinical benefit and leads to more adverse effects. Newer AEDs such as gabapentin, vigabatrin, lamotrigine, tiagabine and topiramate have provided new choices for the medical treatment of intractable seizures. A large number of refractory cases in a developing country like India may be unable to afford newer AEDs because of high cost and its difficult to justify a 50-200 fold increase in the cost of pharmacotherapy, unless there is a substantial advantage. Because of these reasons, new AEDs will have a very limited application in Intractable epilepsy in these countries and surgery for epilepsy is a realistic approach for these cases. The goals in the assessment of a patient with presumed medically intractable epilepsy are to establish the diagnosis of a seizure disorder, to classify the type of seizures, to delineate the lesion responsible for the seizures and to explore the reasons for the intractability. Complex partial seizures with secondary generalization are the most common seizures to undergo intractability among the seizures that were classified according to International League against Epilepsy Classifications. The generalized seizures which undergo intractability are generally those which arein combination with other seizures Burden Of Disease In India In India epilepsy has a prevalence of 2.5-5.6 per thousand. The burden and magnitude of the problem of intractable epilepsy is not exactly known due to non-availability of uniform epidemiological data. It is estimated that, approximately 2,40,000-3,20,000 patients would be suffering from intractable epilepsy in India and incidence of intractable epilepsy (IE) is around 6-711,00,000. Vol.12. No. 2, April-June 2005 105True Versus Pseudointractability It is pertinent to find out pseudointractability before designating a given case as Intractable Epilepsy. The important conditions which cause problem in the diagnosis, are noncompliance, incorrect diagnosis(e.g., syncope, pseudoseizure, cataplexy, migraine, sleep disorders ete.) inappropriate selection of AEDs (e.g, carbamazepine and phenytoin may increase seizure frequency in complex partial seizures (CPS) in many childhood epileptic syndromes with multiple seizures types, gabapentin may inctease complex. partial seizures in some patients); concomitant use of certain epileptogenic drugs (viz, penicillin, INH, theophyline, insulin, lithium, prednisolone, oral contraceptive pills, chloroquine etc.) Predictive Factors In Intractable Epilepsy Presently accepted various predictive factors in IE are Seizure Typ |. Partial seizures Multiple seizure types High seizure ftequency Seizure onset in infancy Febrile seizures. Non idiopathic(non-inherited) Specific Epilepsy Syndromes (e.g, West Syndrome, LennoxGaustat Syndrome) Clinical 1, Focal neurological deficit Family history of epilepsy Cerebral palsy Mental retardation Behavioural disorders EEG abnormality Etiological 1.” Organic brain lesions (¢.g, mesial temporal lobe sclerosis, tuberous sclerosis, congenital cerebral anamoliesete.) Head trauma CNS infections Hypoxic ischaemic encephalopathies Metabolic disturbances (viz. phenylketonuria, maple syrup urine disease, mitochondrial encephalopathy), Multiple Drug Resistance Gene And IE Recently a multiple drug resistance gene (MDR-1) has been demonstrated in some patients with Intractable epilepsy. This gene expresses a p-glycoprotein pump that is capable of exporting hydrophobic drugs out of cells and ultimately back across the blood brain barrier. Overexpression of MDR-I would be a reasonable explanation for repeated failure of drug resistance in certain patients, yet itis unlikely that all AEDs are substrates for the pumps. Other possible explanation for drug resistance might be genetic polymorphisms in drug targets, Management of Intractable Epilepsy Inpatients in whom treatment appears to be ineffective, the diagnosis of epilepsy and adherence to therapy should be reviewed. Consideration should also be given to the presence of a progressive cerebral disorder, such as a tumour or metabolic effect, and the patient investigated accordingly. Precise classification of the types of seizure and of the JK-PRACTITIONER epilepsy, from the clinical and EEG data, and careful recording of seizures and side effects are an essential if rational management decision are to be made. ‘The general principles of managing uncontrollable seizures are as follows: + Review diagnosis and history of the epilepsy. The types of seizures and the epilepsy syndrome should be classified on the basis of clinical features and the EEG. Inaddition, imaging of the brain with high quality MRI scanning is appropriate at this time, looking for an underlying structural lesion. Check serum concentrations of AEDs. + Review pastand present AED treatment 4 Select the AED that is most likely to be efficacious and with the least side effects. * Adjust the dose of the selected drug to the optimum with increments made if seizure continue and side effects donotoccur, + Attempt to reduce and discontinue the other AEDs, particularly those that have not aided seizure control and they are suspected of giving rise to adverse effects + Ifseizure continue despite a maximal tolerated dose of a first line AED, another first line drug should then be ‘commenced, and increased to an optimal dose. * Ifacombination of two first ine AEDS is unhelpful, the drug which appears to have the most effect and fewest side effects should be continued, and the other AED replaced with a second-line drug. The chances of the addition of a second-line drug resulting in a 50% reduction of seizures is 20-50%, the chances of the patient becoming seizure free is less than 10%. + Ifthe second line drug is ineffective, withdrawal of the initial agent should be considered. * Considered using anovel AED. Because of the limited clinical experience with the newer AEDs it appears appropriate to recommend these drugs for the patients with partial seizure disorders in whom other drugs are not effective or cause intolerable side effects. Several new antiepileptic drugs have been introduced in Indian market including gabapentin, lomotrigine, topiramate and oxcarbazepine. Thed efficacy of thesedrugs in intractable epilepsy is uncertain, and it is not yet known whether they cause less cognitive impairment and have fewer other adverse or teratogenic effects in Indian patients than conventional AEDs. # The above scheme will generally take a number of months or even years to work through. If satisfactory control cannot be obtained with drugs, consider the possibility of surgical treatment of theepilepsy. SURGICAL OPTIONS : Of those determined to be the potential candidates for surgical interventions, an extensive evaluation including video/EEG telemetry, anatomical (MRI) and functional (Positron emission tomography PET or single emission computerized tomography SPECT), imaging and extensive neurophysiological testing, with or without angiography or Amytal testing is performed. Surgical interventions consists of either a resective and/ordisconnected procedure, A’ RESECTIVE PROCEDURES : This include the differenttypes of lobectomy, e.g, temporal, frontal etc., 106 Vol.12, No. 2, Apr -June 2005topectomy (excision of a small area tailored to the seizure focus itself) or hemispherectomy (the “ultimate” focal resection with the removal of one-half the brain). Resective procedures are more likely to result in a cure since they excise the seizure focus itself. B._DISCONNECTIVE PROCEDURES : This include corpus callostomy and multiple pial transactions and tend to be more palliative rather than curative since they do not eliminate the seizure but interrupt the propagation of the seizures, limiting their ‘generalization. Despite that, these procedures can improve the patients quality of life by decreasing the frequency and intensity oftheseizures. C._VAGAL NERVE STIMULATION (VNS). Another type surgical procedure available for treatment of intractable epilepsy now a days are the implantation of neural stimulators, more specifically, the vagal nerve stimulator (VNS). The VNS was FDA approved in 1997 and has been found to be significantly lessen the intensity and frequency of seizures greater than 50% in over half the patients who are medically intractable and are not the candidate for other types of surgical interventions, INDICATIONS OF EPILEPSY SURGERY : 1. Medically intractable epilepsy 2. Seizures significantly affect the quality of ife 3. Localized seizure focus. 4. Presence of signs predictable of seizure persistence. CONTRAINDICATIONS OF EPILEPSY SURGERY: 1. Benign, self limited epilepsy syndrome. 2. Neurodegenerativeand metabolic disorders. 3. Non-compliance with drugs. Further Reading EPILEPSY SURGERY (2nd JK-PRACTITIONER 4, Severe family dysfunctions. 5. _ Associated psychosis. ROLE OF KETOGENIC DIET IN INTRACTABLE EPILEPSY: Ketogenic diet is one of the oldest method of treating childhood epilepsy. In children with intractable seizures who have failed drug therapy and are not candidate for epilepsy surgery, this therapy is as or more effective than, the addition of new antiepileptic drugs. The ketogenic diet consists of a high proportion of fats and small amounts of carbohydrates and proteins, The basis of therapeutic effectiveness of the ketogenic diet is because of the ketosis, that develops when the brain is relatively deprived of glucose as an energy source and it must shift to utilization of ketone bodies as the primary fuel. One-third to one half of the children of intractable epilepsy appear to have an excellent response to the ketogenic diet in terms of a matked or complete cessation of seizures or reduction in seizure activity FUTURE TREATMENT PROSPECTS OF INTRACTABLE EPILEPSY : GAMMA KNIFE RADIOSURGERY (GKR): This, is one of the very promising technology in the treatment of intractable epilepsy. Clinical trials of GKR for temporal lobe epilepsy are presently ongoing in the United States. This therapy has been trialed in Europe and elsewhere and, preliminarily, has been found to have similar seizure free outcomes as surgical resection of the temporal lobe focus in patients with temporal lobe epilepsy. In the future, there is, the potential that GKR could actually replace the open surgery through this minimally invasive approach. ‘On the horizon and presently intense areas of research are on the use of deep brain stimulation (DBS), gene transferand cellular transplantation, evaluations. Apicon2003 intractable epilepsy. Epilkepsia 1986: 2702): 124 2. DEVINSKY ©. Patients with refractory seizures. N Engl 1 Med 7. LE ‘Management JIMA 2002. 1K TE. Issues inthe treatment cof epilepsy. Epilepsia 2001: 42: S1- 86. et al. Diagnostic and therapeutic evaluation of patients with intractable epilepsy. Neurology 1977-27; 1006-1011 1999. 340: 1585-70. 8, MATTSON RH, Cramer JA, Collins 11, RAO MB. Radhakrishnan K, Is 3. ENGEL JIR, Surgery for seizures N Engl led 1996: 334:647-52, JE. Delgado Esoueta AV. et al ‘Comparison of carbamazepine, epilepsy surgery possible in countries with limited. resources? Tntractable epilepsy and surgery HONS ©, LUDERS and et al 9. MURTHY JMK. Medically Refractory. Epilepsy-Presurgical Neweol Clin2001: 19:371-107, Vol.12, No. 2, April-June 2005 107