refractory epilepsy

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  • 1. Dr Parag MoonSenior ResidentDept of NeurologyGMC Kota

2. DefinitionIn investigational studies, criteria of refractorinessinclude:(1) absence of response to 2 AEDs tolerated atreasonable doses;(2) minimum frequency of seizures (e.g. 1 seizure permonth) to be considered refractory or the duration ofminimum remission (e.g. 6 12 months) to be qualifiedas nonrefractory,(3) duration of 1 year to 1 decade of noncontrolledepilepsy 3. Flexible scale of refractorinesspotential (no seizure freedom with AEDs taken lessthan 1 year and predictive factors for refractoriness)probable (no seizure freedom more than 1 year with atleast 2 AEDs)definitely refractory(catastrophic epilepsy or nofreedom of seizure for more than 1 year after 5 years oftreatment with at least 3 AEDs) 4. Predictive Factors of Refractoriness1. Epileptic syndromeOnly 13% with idiopathic generalized epilepsy, and nocase with idiopathic partial epilepsy, were refractory.Typical refractory generalized epilepsy of pediatricages are the Ohtahara syndrome, early myoclonicencephalopathy (neonatal period), West syndrome,Dravet syndrome (infancy) and Lennox-Gastautsyndrome (early childhood) .In focal epilepsy, hippocampal sclerosis, corticaldysplasia and hemorrhage are associated withrefractoriness . 5. 2. Localization of the epileptogenic zoneThe temporal lobe ,striate cortex, namely the fourthlayer .3.Response to AEDs-Absence of seizure freedom when2 past AEDs proved inefficient4.Younger Age of onset5.Seizure frequency at epilepsy onset 6. 6. Electroencephalography -Quantity of interictalspikes is predictive of severity in temporal lobeepilepsyOligospikers-less than 1 spike per hour less severeepilepsyAssociation between multifocal spikes andintractability 7. Frequency of refractory epilepsy varies from 10 to37.5% 8. Diagnosis of Refractory EpilepsyExclude false refractoriness related to nonepilepticseizures, inadequate AEDs, noncompliance andseizure-precipitating factorsDefined as inadequate control of seizures despite atleast 2 potentially effective AEDs (mono- orpolytherapy) taken in tolerable doses 9. Treatment of Refractory EpilepsyNon pharmacologicClassic ketogenic diet -high fat content and lowcarbohydrate ContentThe medium chain triglyceride (MCT) dietModified Atkins diet (MAD)Low glycemic index treatment (LGIT). 10. Classic ketogenic diet is a high fat and lowcarbohydrate diet that uses long chain fatty acids(LCFAs) as its main source of fat.Patient must consume 34 grams of fat for every 1 gramof carbohydrate plus proteinIn MCT more carbohydrates and proteins can beconsumed for every gram of fat and is more ketogenicNo limit on the amount of protein consumed or thetotal number of calories per day in MAD 11. Typical MAD uses a ratio of 1 gram of fat for everygram of carbohydrate plus protein, is less restrictivethan the other two high fat diets.LGIT restricts carbohydrate intake to food items with aglycemic index of less than 50 at 4060 grams per day,in order to prevent large fluctuations in blood glucoseconcentrations, which are thought to exacerbateseizures. 12. 15.6%15.8% of patients on the diet can achieve seizurefreedom whilst 33.0%55.8% of the patients can have a>50% reduction in number of seizuresWest syndrome (infantile spasms)-ketogenic diet isused as a first line agent.Also recommended for patients suffering from glucosetransporter defects and pyruvate dehydrogenasedeficiency, 13. Effects of a ketogenic diet can be seen within a fewdays and is cost effectiveSide effects of dietary treatments are constipation,acidosis, temporary hypercholesterolemia, kidneystones and hunger, Growth restrictionContraindicated in pyruvate decarboxylasedeficiency, primary carnitine deficiency, fatty acidoxidation abnormalities, the porphyrias and somemitochondrial disorders 14. Herbal medicineCannabinoids have the largest body of evidencesupporting their use as anticonvulsant.Approved in canada and licensed in 14 states ofAmericaOther -kava (Piper methysticum) and mistletoe(Viscum sp) 15. Surgical managementCandidates for Epilepsy SurgeryIdeally have a single epileptogenic focus in a non-eloquentcortical regionIntractable epilepsyPresent for a substantial duration (usually years)Refractory to medical therapySubstantially impairing quality of lifeBenefit of surgery should outweigh the risks 16. Evaluation of Candidates forEpilepsy SurgeryLocalization of seizures by interictal EEGLocalization by brain imaging-MRI; PET scanningLocalization by video-EEG monitoring of seizures (may combine with ictal SPECT)Localization by neuropsychological testingOther methods-Depth electrodes,Cortical grids orstrips,Nuclear magnetic resonancescans,Magnetoencephalography 17. Types of Resective Epilepsy SurgeryTemporal lobectomyExtratemporal resections (lobar: frontal, occipital)Corpus CallosotomyHemispherectomyMultiple subpial transections 18. 68% of the patient who received temporal lobectomiesexperienced seizure remission for 2 years.Side effects period of disability, infection, transientendocrine abnormalities, transient dysphoria,depression,occasionally maniaPermanent neurological and neuropsychologicalcomplicationsPossibility to create new lesions which may becomeepileptogenic 19. Vagus Nerve Stimulation (VNS)Approved by FDA in July 1997Patients with intractable epilepsy 12 yo Intermittent electrical stimulation isdelivered to the left vagus nerve, whichhas ascending fibers with widespreadconnections to the limbic, autonomicand reticular brain regions 20. Proposed Mechanisms of Actionfor VNSDesynchronization of EEGSuppression of spikesBlock ictal rhythmic build-up in a seizureRelease of GABA and GlycineEffects on limbic and brainstem systemsIncreased thalamic blood flow 21. Benefits of Vagus NerveStimulationMedian seizure reduction of 24.5%28.0% in the groupreceiving high level VNS compared to just 6.1%15.0%in patients receiving low level VNSEffect increases over timeSeizure severity decreasedImproved level of alertness (medication may bedecreased)Few adverse effects-Hoarseness, sleepapnoea,infection (rare)Batteries require replacement every ~ 10 yrs 22. Deep brain stimulationDBS involves electrical stimulation of specificsubcortical nuclei, which have widespread neuralconnections.Anterior nucleus of the thalamus is often the target ofDBS.Centromedian nucleus is also a potential location forDBS 23. Complications -Infection, hemorrhage andstimulation-induced seizuresImpaired memory and higher levels of depression 24. Responsive neurostimulation (RNS)Does not deliver electrical stimulation throughout theday.RNS device is composed of a combined recorder andstimulator deviceDetects clinically relevant epileptiform discharges anddelivers an appropriate electrical stimuli in responseReduction in seizure frequency of 37.9% in thetreatment arm compared to 17.3% in the control group 25. Other modalities available-repetitive transcranialmagnetic stimulation (rTMS).Based on principles of electromagnetic induction,where small intracranial electric currents aregenerated by a strong fluctuating extracranialmagnetic field.Risk of precipitating seizures 26. Thanks 27. ReferencesPharmacotherapeutic and Non-Pharmacological Optionsfor Refractory and Difficult-to-Treat Seizures ;James W.Mitchell et al ; Journal of Central Nervous System Disease2012:4 ;105115Refractory Epilepsy: A Clinically Oriented Review;PedroBeleza; Eur Neurol 2009;62:6571Schuele SU, Luders HO: Intractable epilepsy: managementand therapeutic alternatives. Lancet Neurol 2008; 7: 514524Treatment of refractory epilepsy: Barbara Oslon: Adv StudMed 2005:5:470-473


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