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Intractable seizure
This document discusses the classification, management, and treatment of intractable epilepsy. It begins with summaries of the 2017 ILAE classification of seizure types and reminiscences of past classifications from 1981 and 2010. It then discusses definitions of intractable epilepsy, risk factors, current treatment approaches including antiepileptic drugs, surgery, diet, and ideal drug characteristics. Newer adjunctive drugs and their effectiveness are reviewed based on clinical studies and guidelines. The impact of uncontrolled seizures on quality of life and risks are highlighted. Controlled trials showing significantly better outcomes of surgery compared to continued medical therapy are also summarized.
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Intractable seizure
- 1. Avinash ChandraAvinash Chandra AnnapurnaNeurological Institute and AlliedAnnapurna Neurological Institute and Allied Management of IntractableManagement of Intractable
- 2. Motor tonic-clonic clonic tonic myoclonic myoclonic-tonic-clonic myoclonic-atonic atonic epileptic spasms1 Non-Motor (absence) typical atypical myoclonic eyelidmyoclonia Unknown Onset Motor Onset automatisms atonic1 clonic epileptic spasms1 hyperkinetic myoclonic tonic Non-Motor Onset autonomic behavior arrest cognitive emotional sensory focal to bilateral tonic-clonic Generalized OnsetFocal Onset Aware Impaired Awareness Motor tonic-clonic epileptic spasms Non-Motor behavior arrest ILAE 2017 Classification of Seizure TypesILAE 2017 Classification of Seizure Types Unclassified2 1 These could be focal or generalized, with or without alteration of awareness 2 Due to inadequate information or inability to place in other categories From Fisher et al. Instruction manual for the ILAE operational classification of seizure types. 2017 ,Epilepsia
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- 6. IncidenceIncidence 4% of thepopulation 1% of the population 0.4% of the population 80% has epileptogenic focus WHO, 2017 Feb update Shorvon et al., 1996 Epilepsia Epilepsy First seizure ever Epilepsy (intractable)
- 7. Intractable SeizureIntractable Seizure Nogenerally accepted definition of intractability. No single step in the treatment defines medical intractability. The definition of medical intractability has to be based on the type and number of the drugs that have failed, despite the adequate trials. In our setting: - the number of AED failures to be 2 to 3, - seizure frequency to be near to none* - time factor to be 2 years.
- 8. Intractable SeizureIntractable Seizure •The ILAE proposed a definition of drug-resistant epilepsy as a failure of adequate trials of 2 tolerated and appropriately chosen and used AED schedules. • This for now, could provide an operational definition for clinical and research settings. However, with emergence of new data and novel treatments the criteria for intractability may change. • Ideally, it is lack of acceptable seizure control despite the adequate trials of appropriate drugs at adequate level with minimal side effects. Rohracher et al, 2015 Journal of Epileptology Kwan et al., 2009 Epilepsia ILAE task force, 2017
- 9. Risk of intractibilityagainst the time Berg et al., 2001 Neurology Time in months Riskin%
- 10. Intractable SeizureIntractable Seizure UnderlyingPathology is a major prognostic factor for recurrence Etiology % Controlled (>1 year) Cryptogenic Generalized 82% Partial 45% Head injury 30% Dysgenesis 40% TLE 20% HS 11% Dual Pathology 3% Sonah et al., 1998 Neurology
- 12. What Are Today’sClinical Needs?What Are Today’s Clinical Needs? Current status of epilepsy treatment When to consider intractable How many of them intractable Impact of newer drugs/ newer trials on intractable
- 13. Quantifying IntractableQuantifying Intractable SufficientNumber of Drug Trials: 2 to 4 major drugs at maximal tolerated drugs and 6 combinations. (Spectrum of opinions!) If one AED doesn’t work at maximal tolerated dosage, take that out!! Frequency change in epileptic attacks.%controlled No. of drugs
- 14. What if LeftUncontrolled…?What if Left Uncontrolled…? Quality of life (psychological, social, occupational..) Interictal dysfunction (learning, memory..) Increasing risk of SUDEP Progressive neurological dysfunction(Epileptic encephalopathy) Kindling Effect Neuropsychiatric comorbities Placing substantial burden on the individuals, carers
- 16. Management StrategyManagement Strategy AEDs polypharmacotherapies Surgical removal of epileptogenic foci disconnecting inter-transmissions Vagus nerve stimulation Diet ketogenic diet
- 17. An Ideal AntiepilepticDrugAn Ideal Antiepileptic Drug Prevent or inhibit excessive pathological neuronal discharge Does not interfere with normal physiological neuronal activity Free of adverse effect Does not exist!!!!
- 18. AEDs Blockade of voltage-gatedNa+ Phenytoin, CBZ, Valp. Lamotrigine Inhibition of glutamatergic neurotransmission Phenobarb., Topiramate Enhancement of GABAergic neurotransmission Barbiturates, BDZ, Valp. Vigabatrin, Gabap. Ca+ gated channels Ethosux Other Targets NMDA/AMPA/ K+..
- 19. Chronological development ofAEDs Golyala et al, Seizure 2017
- 20. AED ConsiderationsAED Considerations Dosingon serum at ‘therapeutic level.’ Interaction (e.g. CYP450 or ) Spectrum of AEDs Genetic consideration (HLA-B* 1502, P-glycoproteins, ABCB1)
- 21. Adjunctive AEDs –Focal OnsetAdjunctive AEDs – Focal Onset AAN guideline (refractory partial )Update 2017 Adult Children Levetiracetam √ Oxcarbazepine/CBZ √ √ Lamotrigine √ √ Topiramate √ √ Zonisamide √ Tiagabine √ Gabapentin √ √ LevelALevelA
- 22. Adjunctive AEDs –Genralized OnsetAdjunctive AEDs – Genralized Onset AAN guideline (refractory partial )Update 2017 Adult Children Levetiracetam Oxcarbazepine/CBZ Lamotrigine Topiramate √ √ Zonisamide Tiagabine Gabapentin LevelALevelA
- 23. Impact of AEDson IntractabilityImpact of AEDs on Intractability AED Seizure Syndrome Observation period Seizure Free Our Experience Levetiracetam Focal onset 16 weeks 5.7% 14 weeks 8.2% 4 out of 6 12 weeks 8.2% Generalized onset 16 weeks 15.6% 12 weeks 3 out of 3 Vigabatrin Focal onset 12 weeks 6% Not categorized N/A 50% Clobazam Not categorized 48 weeks 8% Focal/impaired awareness 12 weeks 74% 3 out of 3 Generalized onset 48 weeks 15% 12 weeks 3 out of 8 Acetazolamide Focal onset 12 weeks 44% CBZ+Valproat e Focal to Genaralized tonic clonic 48 months 38% 12 weeks 6 out of 7
- 24. Controlled Randomized ClinicalTrial of EpilepsyControlled Randomized Clinical Trial of Epilepsy SurgerySurgery Surgical treatment for epilepsy has offered the chance of cure or greater cure for this disorder. • Single center trial, 116 children refractory (medical therapy group 59, surgery group 57). Outcome, seizure free 12 months- 7 % vs 77% • Single center trial, for TLE, 80 Adults (medical 40, TLE surgery 40). Outcome, seizure free 12 months 58% vs 8% Dwivedi et al., 2017 NEJM Weibe et al., 2001 NEJM
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Editor's Notes
- #8 One could define intractability as the probability of seizure control by further steps of 5% or less, like the p-value. The certainty that a patient will remain refractory to medications can only be approached in an asymptotic manner and
- #9 Multiple factors including number of antiepileptic drug (AED) failures, seizure frequency and duration of unresponsiveness, etiology, and epilepsy syndromes are considered in formulating the definition of pharmaco-resistant epilepsy.
- #14 A patient who has one seizure every 2 months or a patient who has one seizure every day will not require the same amount of time for you to decide that the drug has failed.
- #15 Studies suggest that each year there are about 1.16 cases of SUDEP for every 1,000 people with epilepsy, although estimates vary.
- #18 Even ingle seizure can be treated !!! Since anoxic damage created by seizure
- #21 does not necessarily control the epilepsy. It simply provides the rough guide of response
- #24 https://www.ncbi.nlm.nih.gov/pubmed/2492225 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401646/ https://www.ncbi.nlm.nih.gov/pubmed/20117743 https://www.ncbi.nlm.nih.gov/pubmed/7642889 http://journals.sagepub.com/doi/abs/10.1177/088307389501000306?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed