This document summarizes information about refractory epilepsy. It begins by defining refractory epilepsy as persistent seizures under antiepileptic drug treatment. It then discusses predictive factors of refractory epilepsy like epileptic syndrome, response to previous drugs, age at onset, and structural brain abnormalities. The document outlines evaluation and management approaches including optimizing medical treatment, surgical options like resection or palliation procedures, and other therapies like the ketogenic diet.

1. Refractory EpilepsyChair Person: Prof Y S N Raju MD, DCH, PGDGMSpecialty Expert: Dr RukminiDNB(Med),DM(Neuro)Presenter: Dr Bhavanadhar, Jr. Resident (MD)Dept. of Medicine, NIMS, Hyd, AP, India19th July 2011

2. “Refractory epilepsy is a distressing problem for patient and doctor.”

3. IntroductionEpilepsy is a disorder of the brain that is characterised by an enduring predisposition to generate epileptic seizures.Approximately 3% of individuals developing this disorder during a lifetime and about 0.5 - 0.9% of the population of various countries having epilepsy at any given time.It affects approximately 50 million people in the world and 5/1000 in India**Refractory Epilepsy Ravat And Jain J Indian Med Assoc, Vol 108, No 7, July 2010

4. In epilepsy, 3 prognostic groups are generally considered(1) Spontaneous remission (20- 30%) as seen in benign epilepsy with centrotemporal spikes or childhood absences.(2) Remission on anti-epileptic drugs (AEDs) (20 -30%) as occurs in most focal epilepsy and myoclonic juvenile epilepsy syndromes.(3) Persistent seizures under AEDs (30-40%) among which refractory epilepsy (RE) is included.*Refractory Epilepsy:A Clinically Oriented Review Beleza. EurNeurol 2009;62:65–71

5. Why is RE important?Chronic uncontrolled epilepsy  an ↑ risk for mood disorders, physical injuries and sudden unexpected death(SUDEP). Other consequences are the social and cultural stigmas associated with the recurrence of seizures. They may suffer more  ignorance, prejudice and discrimination than actual manifestations of the disease.Finally, RE is a major economic burden to society

6. Clinical and EEG predictive factors of refractoriness are red flags in the context of epilepsy managementPrompt diagnosis of refractoriness is of paramount importance for consideration of other therapies Early surgical intervention, when successful, might also prevent or reverse the disabling psychosocial consequences

7. DefinitionAccording to Task Force of the ILAE Commission on Therapeutic Strategies (2009), it is defined as “Failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”An ‘appropriate’ intervention should have previously been shown to be safe and effective, with appropriately documented evidence preferably in RCTs.To be adequate, this requires application of the intervention at adequate strength/dosage for a sufficient length of time.

8. Predictive Factors of RefractorinessThere are many factors reported to influence the probability of achieving seizure freedom or predicting future refractoriness. Some potential prognostic factors identified in some studies includeEpileptic syndromeResponse to previous AEDsAgeSeizure type and frequencyStructural cerebral abnormalitiesElectroencephalography

9. Epileptic syndromeIn a remarkable study of a cohort of children with epilepsy followed up for over 30 years into adulthood, Sillanpaa et al. it has been shown that 78% of patients with symptomatic generalised epilepsy, 49% of patients with symptomatic partial epilepsy and13% of all patients with idiopathic generalised epilepsy were refractoryCatastrophic epilepsies of childhood and some localisation related epileptic syndromes are especially found to be treatment resistant

10. Response to previous AEDsWithin a given syndrome, the probability of having a good response to Rx is inversely proportional to the no. of drugs to which a pt has previously not responded.Absence of seizure freedom when two past AEDs proved inefficient is a crucial predictor of refractoriness.A recent study* showed 61% seizure freedom with the first AED, which decreased to 41% when first AED was not effective and second AED added and to 16% or less when previous 2 AEDs proved inefficient*Ko TS, Holmes GL EEG and clinical predictors of medically intractable childhood epilepsy. ClinNeurophysiol 1999;

11. AgeA younger age at onset of epilepsy predicts refractoriness. Seizures in the immature brain of a child may result in non-pruning of neurons and contribute to high numbers of gap junctions.This leads to abnormal connectivity, the hyperconnected cortex leading to more epileptogenicity

12. Seizure type and frequencyDifferent types of seizures respond differently to the available AEDs. There are certain types of seizure which when present may predict future refractoriness. Besides this, high seizure frequency (> 1 seizure/month) occurring soon after the Dx of epilepsy either before or after Rx onset also correlates with refractoriness

13. Structural cerebral abnormalitiesLocalisation of the epileptogenic zone and the type of structural cerebral abnormalities also play an important role in refractoriness. The temporal lobe is probably the most epileptogenic area as it is the most common of the focal epilepsy syndromes. The motor (hand and face area) and sensorimotor cortices are other areas with low seizure thresholds.

14. ElectroencephalographyEEG is useful for predicting refractoriness.The quantity of interictal spikes is predictive of severity in temporal lobe epilepsy. Oligospikers, patients with temporal lobe epilepsy with less than 1 spike per hour, correlate with less severe epilepsy. In addition, some studies describe the association between multifocal spikes and intractability

15. Evaluation and Management of REPatients with RE should be referred to an epilepsy specialist for further diagnostic evaluation, to confirm refractoriness,optimisation of pharmacotherapy, and consideration of other therapies such as epilepsy surgery. Over the past decades, more specialised epilepsy centres have opened providing comprehensive care with team including epileptologist, neurosurgeon, neuroradiologist, neuropsychologist, psychiatrist and pharmacist, offering not only the option of a presurgical assessment but also comprehensive diagnostic and treatment strategies services

16. The evaluation should be done to:Establish the diagnosis of epilepsy . Rule out pseudorefractory epilepsyDefine electroclinical syndromeEstablish the aetiology of epilepsyEvaluate the medical treatment - Therapeutic drug monitoring (TDM), proper choice of AED and side-effect profile.Select ideal surgical candidate – Optimal electroclinicoradiological and neuropsychologic correlation.

17. Establish the diagnosis of epilepsyRE can only be diagnosed on an individual basis ie, after a patient’s epilepsy has failed to respond to an appropriate treatment.Pseudorefractoriness indicates a condition in which seizures persist because the condition has not been adequately treated.The most common causes of pseudorefractory include:Inappropriate diagnosisPoor compliance Incorrect drug choiceInadequate dosage or administration regimenInappropriate lifestyle

18. Inappropriate diagnosisSometimes, patients are labelled as having RE because of the symptoms that are incorrectly diagnosed as epileptic seizures. Epilepsy mimics behavioural spells, autonomic disorders, cardiac arrhythmias, migraine, orthostatic hypotension, panic attacks, TIA, tremor, vasovagal syncope.E.g., some patients with epilepsy present with non-epileptic attack disorder (NEAD) in addition to epileptic seizures and other have only NEAD, drug therapy may not be effective in treating NEAD

19. Poor complianceFailure to take a medication as prescribed is one of the most common causes of therapeutic failure in epilepsy. Poor compliance is often due to unsatisfactory patient doctor relationship, and may be minimised by counsellingTDM is the optimal drug concentration range at which most patients achieve the desired therapeutic effect with no undesirable side-effects.TDM can be used along with clinical criteria to guide the therapy

20. Incorrect drug choiceIncorrect drug choice is most commonly a consequence of diagnostic errors. It derives from the misclassification of the type of epilepsy. E.g., carbamazepine and phenytoin will not be effective in patients with absence seizures or myoclonic seizures.

21. Inadequate dosage or administration regimenTailoring dosage to individual needs is at least as important as choosing the right drug for the successful treatment of epilepsy.Although monitoring serum drug concentrations may be useful in adjusting dosage, some pts achieve optimal responses at above or below the therapeutic ranges.Some AEDs have a short elimination half-life and multiple daily doses may be required to avoid fluctuations in serum concentrations.

22. Inappropriate lifestyleInadequate control can be related to a failure to avoid situations known to precipitate or aggravate their seizures. Such factors may include excessive alcohol intake, excessive sleep deprivation or an irregular sleep-wake cycle, drug abuse and exposure to undue stress. Evaluation of psychosocial problems should be part of the comprehensive assessment of patients, as this may influence significantly the efficacy of drug treatment

23. Define electroclinical syndromeElectroencephalography (EEG)Routine EEG is very useful for the clinical diagnosis of epilepsy and the underlying syndrome. Sampling during a regular 20-30 minutes study might be insufficient, particularly if sleep is not obtained.A repeat study or prolonged recording might be needed to detect interictalepileptiform abnormalities.Results of EEG are very specific and only 1.2% of the non-epileptic population, children more than adults, have false-positive epileptiform activity**Zivin L, Marsan CA Incidence and prognostic significance of epileptiform activity in the EEG of non-epileptic subjects. Brain 1968; 91:751-78.

24. Video - EEGFor the majority of patients with epilepsy, routine EEG is sufficient to classify seizure type and to initiate treatment. However, for RE and an unconfirmed seizure, video-EEG monitoring is the best diagnostic tool available. Continuous video and EEG monitoring over time in a controlled environment helps localize seizure focus, determinetype, and quantify the no. of seizures. Equally important, video-EEG monitoring can differentiate seizures from NEAD and from physiologic events that may be confused with epilepsy.

26. AetiologyMagnetic resonance imaging (MRI)High-resolution MRI has revolutionised the ability to determine the cause of focal epilepsies and to predict long-term outcome & spontaneous remission in pts.Specific epilepsy sequences interpreted by experienced radiologists can detect subtle abnormalities up to 90% of chronic focal epilepsies that would be missed in > 50% of pts. Hippocampalvolumetry, 3T MRI, Diffusion tensor imaging, etc, have revolutionalised the management of epilepsy.

28. Functional neuro-imagingThis includes ictal and interictal SPECT, PET, fMRI and MRS. All of these readings are aimed at identifying the seizure-onset zone.Interictal SPECT is most useful in temporal lobe epilepsy, and hypoperfusion indicates the region of seizure onset.Ictal SPECT is logistically difficult. It involves injection of the tracer during a seizure and is strongly dependent on the injection time. Hyperperfusion indicates seizure onset.

29. An ictal FDG-PET was obtained in a patient who presented several epigastric auras during the 10 minutes following FDG injection, showing a clear-cut left mesial temporal glucose hypermetabolism. The latter was replaced by a left mesial temporal hypometabolism on a second FDG-PET performed interictally.

30. FDG-PET can identify MRI-negative medial temporal lobe epilepsy but less helpful in neocortical epilepsy. fMRI is being used for localising the primary motor cortex and lateralising language function.MRS may be useful in patients who have otherwise normal MRI.

31. FDG-PET and FMZ-PET in a patient with a right TLE and mesial temporal sclerosis on MRI. FDG-PET demonstrates right mesial temporal and temporo-polar hypometabolism, whereas FMZ-PET abnormality is restricted to the mesial temporal structure

32. Neuropsychological evaluationNeuropsychological testing gives an overall estimate of intellectual functioning and helps localising areas of the brain that are abnormal. Memory testing can help lateralise dysfunction to the left or right hemisphere. E.g., Low scores on verbal memory tests are s/o dominant temporal lobe and non-verbal memory impairment suggests nondominant temporal lobe involvement. Risk of epilepsy surgery is its effects on memory & cognition hence baseline neuropsychological testingPatients are also counselled regarding realistic expectations of surgical outcome.

33. Psychiatric evaluationMood disorders, esp. major depression and anxiety, are common in epilepsy with an lifetime prevalence of > 60%.Detailed psychiatric evaluation is needed for early detection of depression and to differentiate from symptoms related to drugs, sleep problems, or cognitive disturbances. If any illness like anxiety disorder or depression found they should be treated appropriately.Surgery deferred till patient treated optimally. Postop assessment by psychiatrist is helpful for maximum benefit and better adjustment to the new circumstances.

34. TreatmentMedical and surgical treatment options for patients with epilepsy have significantly improved in the past decade. Risks and benefits of a curative or palliative surgical procedure or experimental therapy have to be weighed against the chance of improvement & side-effects of additional medical therapy.Medical refractoriness is no longer a prerequisite for surgery, if surgically remediable lesional epilepsy syndrome is found, surgical intervention should be planned, In other conditions optimisation of pharmacotherapy should be considered.

35. Courtesy : JT Butler Management of refractory epilepsy CME Vol 24, No 9 (2006)

36. Optimisation of pharmacotherapyA systematic protocol for treatment of RE using a new AED might improve seizure control in a substantial proportion of cases. The nihilistic view that intractability is inevitable if seizure control is not obtained within a few years of the onset of therapy is incorrect. In RE, it is convenient to perform a systematised management be AED i.e, increase until the maximum tolerable dose;If no response, replace the AED; if there is a partial response, add another AED which should be chosen based on the action of the first AED, its efficacy and adverse effects.

37. AAN Guideline Treatments For Refractory Epilepsy

39. SurgeryThe surgical treatment of drug resistant epilepsy has become increasingly more valuable and life saving due to major advances in structural and functional neuro-imaging, EEG monitoring and surgical techniques. Surgery can be either, curative (definitive), aiming at a resection of the epileptogenic focus through a resective or a disconnective surgical procedure or palliative, with the purpose of reducing the intensity and/ or the frequency of a certain seizure type.

40. Curative (definitive) surgeryCurative surgery is based on removal of the entire epileptogenic area without causing a permanent neurological deficit.

41. They include focal resective surgeries and hemispherectomy.Focal resective surgeryThe localisation of the epileptogenic zone in focal epilepsy is typically based on seizure semiology, interictal and ictal EEG, as well as neuroimaging findings.

42. Contd.Mesial temporal sclerosis is the most common cause of RE and has best prognosis if surgically treated with anterior temporal lobectomy (ATL) Complications of ATL are rare and include quadratic visual field defect, and transient hemiparesis.The outcome of surgery greatly depends on the underlying cause of epilepsy. Pts with vascular malformations, low-grade tumours, dysembryoplasticneuro-epithelial tumours, and cystic lesions have outcomes are as good as those with hippocampal sclerosis

43. Cerebral hemispherectomy or hemispherotomyIt should be considered in patients where seizure focus is limited to one hemisphere and patient already has disabling hemiparesis with useless hand. It has been reported to decrease seizure frequency and improve developmental quotient in children with catastrophic hemispheric epilepsy of diverse aetiologies such as malformations of cortical development, Rasmussen’s encephalitis, Sturge-Weber syndrome, and remote vascular insults.

45. Palliative interventionsComplete seizure control is not possible in some pts, but useful palliation can be achieved with techniques such as Corpus callosotomy, and Multiple subpialtransectionsVagal nerve stimulation,

46. Corpus callosotomyIt is the interruption of pathways of spread of seizure between the two hemispheres. The initial surgery may cut the anterior two-thirds of the corpus callosum, leaving the rest intact. If this does not provide sufficient seizure control, the remaining portion may be cut later on. This procedure mostly used to prevent the falls due to atonic seizures in Lennox-Gastaut syndrome

48. Multiple subpialtransections (MST)MST may be an option for patients with RE whose seizures begin in areas of the brain that cannot be safely removed. In addition, there must be a reasonable chance that the person will benefit from surgery. MST stops the seizure impulses by cutting nerve fibers in the grey matter of the brain sparing the vital functions concentrated in white matter. It is reported to achieve a significant seizure reduction

50. Vagal nerve stimulation (VNS)This is indicated in adults with RE in whom definitive surgery is not possible or who had undergone surgery without success. VNS uses an implanted stimulator that sends electric impulses to the left vagal nerve in the neck via a lead wire implanted under the skin. A 50% reduction in seizure frequency has been reported in about one-third of patients. However, seizure freedom is rare

52. Ketogenic dietThe ketogenic diet is a high-fat, adequate- protein, low-carbohydrate diet primarily used to treat RE in paediatrics patients. If there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies.The ketone bodies pass into the brain and replace glucose as an energy source. An elevated level of ketone bodies in the blood, a state known as ketosis, leads to a reduction in the frequency of epileptic seizures.A recent RCT* showed a reduction in seizure frequency in more than 50% in 38% of children with drug resistant epilepsy*Neal EG .et al The ketogenic diet for the treatment Lancet Neurol 2008; 7: 500-6.

53. Ketogenic diet

54. Treatments under InvestigationPolymers, electrical brain stimulation and prediction of seizures may be available in the future for treating patients with refractory epilepsy.Cell transplantation and gene therapy, although holding great promise, are still far from routine clinical usePolymers containing AEDs consist of 2-3mm microspheres that might be placed in epileptogenic zone.Advantages include: (1) new AEDs could be used including those which do not cross the BBB or show systemic toxicity; (2) they may be useful when the epileptogenic zone is near eloquent cortex; (3) they prevent noncompliance

55. Electrical brain stimulation is still not accepted as a routine Rx for epilepsy, because there is no consensus regd. the better region to stimulate and in type of seizure. Finally, a seizure detector coupled with a trigger AED infusion pump has been developed with success in the mouse . Research has also been done in predicting seizuresHopefully, in the future a device may predict seizures and automatically administer AEDs to prevent them from occurring.

56. ReferencesRefractory Epilepsy Ravat and Jain. J Indian Med Assoc, Vol 108, No 7, July 2010Refractory Epilepsy : A Clinically Oriented Review Beleza. EurNeurol 2009;62:65–71JT Butler Management of refractory epilepsy CME Vol 24, No 9 (2006)AAN Guideline Summary for CLINICIANS TREATMENTS FOR REFRACTORY EPILEPSYCurrent concepts. Patients with Refractory Seizures NEJM Volume 340;20 May 20, 1999