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Management of epilepsy in this millennium–recent perspectives in intrtactable seizures



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  • 2. Epilepsy is A Fascinating DisorderAffecting the the Three Functions of the Brain Cognition, Conation & Affect Is Cure from this Disorder a mere Stroke of Luck? “My Opinions are founded on knowledge but modified by experience”
  • 3. Epilepsy – An Alarming issue Epilepsy affects 50 million people the world over Prevalence rates of Epilepsy are 5-10 per 1000 Over 90 % of people with epilepsy in developing countries are not on any regular,even basic treatment. A significant treatment gap. If you think you can or you can’t You are always right
  • 4. Living with epilepsy - 1992 15% no seizures, no 17% no seizures side effects + side effects 3% not taking AED 2% no answer44% recurrent seizures 19% recurrent seizures,+ side effects no side effectsn=760 The Roper Organization 1992
  • 5. Living with epilepsy - 1996 Time since last seizure 2% no answer 29% <3 weeks31% >2 years 10% 1-3 months 10% 1-2 years 18% 4-12 months n=1023 Fisher et al, Epilepsy Res 2000
  • 6. Classification of epilepsy Localized Non-Localized Idiopathic Symptomatic(No known cause) (known or CNS disease) Back pain – prize human beings pay for their upright posture Some people feel the rain; Others just get wet
  • 7. AN IDEAL ANTICONVULSANT DRUG Prevent or inhibit excessive pathological neuronal discharge Without interfering with physiological neuronal activity and Without producing untoward effect o Ideal compound not yet availableMany Ideas grow better when transplanted into another mind than in the one where they sprang UP O.W. Holmos
  • 8. Spectrum of action – Broad spectrum drugs – Narrow spectrum drugs – Intermediate spectrum drugs “Character gets you out of bed commitment moves you to actionfaith, hope and Discipline follow through to completion”
  • 9. When they tell you to grow up,they mean stop growing - P. Diccaso
  • 10. PHARMACO KINETICSAbsorptionDistributionElimination “By Nature All Men/ Women are alike but by Education widely different” - Chinese
  • 11. Pharmacokinetic properties of established AEDs Carbama Phenyt Valpro Phenob Primi zepine oin ate arbital doneBioavailability +1 +2 +2 +2 +2Parentral form -2 +2 +2 +2 0Elimination of half life +1 +2 0 +2 -1Linear kinetics +2 -2 +1 +2 +2No auto induction -2 +2 +2 +2 +2No interactions -1 -1 -1 -1 -1A score of +2 is best and –2 is least desirable . A total “pharmacokinetic score” for eachdrug should not be calculated from the table because different pharmacomineticparameters may need to be weighted differently.  The score +2 if it is suitable foronce daily dosing. +1 for twice daily dosing. 0 for 3 times daily dosing at times only,and –1 for consistent 3 times daily dosing
  • 12. Pharmacokinetic properties of newer AEDs Felbam Gabape Lamot Oxcarba Tiaga Topir ate ntin rigine zepine bine amateBioavailability +2 -1 +2 +2 +2 +2Paenteral form -2 -2 -2 -2 -2 -2Elimination half +1 -1 +1 +1 +1 -1lifeLinear kinetics +2 -1 +2 +2 +2 +2No auto induction +2 +2 +2 +2 +2 +2No interactions -2 +2 0 +1 0 0A score of +2 is best and –2 is least desirable . A total “pharmacokinetic score” for eachdrug should not be calculated from the table because different pharmacomineticparameters may need to be weighted differently.  The score +2 if it is suitable foronce daily dosing. +1 for twice daily dosing. 0 for 3 times daily dosing at timesonly, and –1 for consistent 3 times daily dosing
  • 13. Efficacy of antiepileptic drug for common seizure type Drug Partial Tonic- Absence Myoclonic Atonic/ clonic tonicPhenobarbital + + 0 ?+ ?Phenytoin + + - - 0Carbamazepine + + - - 0Sodium valproate + + + + +Ethosuximide 0 0 + 0 0Benzodiazepines + + ? + +Gabapentin + + - - 0Lamotrigine + + + + +Oxcarbazepine + + 0 0 0 The True Art of Memory is The Art of Attention - S.Johnson
  • 14. Role of NewerAntiepileptic Drugs
  • 15. “Older” AEDsPhenobarbital 1912Dilantin (phenytoin) 1938Mysoline (primidone) 1952Zarontin (ethosuximide) 1960Tegretol (carbamazepine) 1974 The True Art of Memory is The Art of Attention - S.Johnson
  • 16. Newer AEDSFelbamate 1993Gabapentin 1994Lamotrigine 1995Topiramate 1996Tiagabine 1998Levetiracetam 1999Oxcarbazepine 2000 We learn by thinking and the qualityZonisamide 2000 of the learning outcome is determined by the quality of ourPregabalin 2005 thoughts R.B. Schmeck
  • 17. Carbamazepine First line drug for  Side effects at just partial seizures for above therapeutic range years  Not effective for some Two long-acting seizure types forms now avail  Must start slowly due to (2X/day) side effects  No IV form  Lots of interactions In all of us, even in good men, there is a wild - beast nature which peers out in sleep
  • 18. Phenytoin First line for  Side effects at just above partial seizures therapeutic range for years  Not effective for some Once a day seizure types IV form  Side effects: imbalance, sedation, cogni tive, gum problems, osteoporosis  felt promise to yourself A true commitment is a heartMany interactionsfrom which you will not back down - D. Mcnally
  • 19. Valproate Works for all seizure  Side effects, esp. weight types gain & tremor Around for decades  Menstrual irregularities Rare allergic reactions  Not best for pregnancy Helps prevent  Significant drug migraines interactions New IV form New long-acting form “Character gets you out of bed commitment moves you to action faith, hope and Discipline follow through to completion”
  • 20. Barbiturates (primidone and phenobarbital) Effective  Sedation and Once a day cognitive effects (phenobarbital)  Withdrawal Cheap IV form (phenobarbital) “By Nature All Men/ Women are alike but by Education widely different” - Chinese
  • 21. Other old medicationsAcetazolamideClonazepam & LorazepamEthosuximideKetogenic dietActh/steroids “Character gets you out of bed commitment moves you to action faith, hope and Discipline follow through to completion”
  • 22. Limitations of older AEDS Efficacy: Limited efficacy in complex partial, absence , myoclonic and atypical seizures. Adverse Events: similar neurotoxicity , idiosyncratic reactions Teratogenicity Pharmacokinetics: low aqueous solubility, hepatic metabolism Drug Interactions: enzyme induction – CBZ, PHT, PB
  • 23. Newer AEDs Equally effective as older AEDs Most better tolerated than older AEDs Most have fewer interactions with other medications than older AEDs All expensive Give us the GRACE to accept with serenity the things that cannot bechanged the COURAGE to change the things that should be changed and the WISDOM to know the difference
  • 24. Role of New epileptics Different mechanism of action- treatment of refractory seizures Rational Polytherapy Less adverse effects Less Drug Interactions A true commitment is a heart felt promise to yourself from which you will not back down - D. Mcnally
  • 25. Rational Polytherapy Combinations of different mechanism of actions for synergy of antiepileptics Avoid drug with similar effects Neurology 1995: 45; S7-11 “ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy
  • 26. Choice of AEDShould be based on: Spectrum of activity Side-effect profile Efficacy in other concomitant disease states Memory, the daughter of attention , is the teeming mother of knowledge - Martin Tupper
  • 27. Newer antiepleptics Unique features of newer antiepileptics  Gabapentin, Pregabilin and Levetiracetam: no hepatic metabolism or protein binding  No important pharmacokinetic interactions with other AEDs  Lamotrigine: associated with rash and must be titrated slowly  Topiramate, Tiagabine, Zonisamide, Oxcarbazepine: must titrate slowly to minimize cognitive side effects  Topiramate, Zonisamide:1-2% incidence of renal stones  Felbamate: aplastic anemia, hepatic failure, weight loss It is the disease of not listening, the malady of not marking, that I am troubled withal - Shakespeare
  • 28. GABAPENTIN Novel antiepileptic drug recognized as GABA agonist Recently, an inhibitory effect on the receptor subunit of the calcium channel has been shown and postulated to be responsible for its antiepileptic effect Treats ONLY partial seizures May exacerbate absence seizures Pak J Neurol Sci 2007; 2(4): 223-29Success in life is a matter not so much of talent and opportunity as of concentration and perseverance - C.W. Wendte
  • 29. Gabapentin ADVANTAGES No interactions with other drugs  DISADVANTAGES Extremely rare “allergic”  Three-times-a-day reactions dosing Can be started quickly  Does not treat all Well-tolerated types of seizures Treats pain, anxiety, restless leg syndrome Generic availability Liquid formulation Serious, sincere, systematic study surely secures supreme success
  • 30. LAMOTRIGINE Well-established AED with proven efficacy Also the most well –studied amongst the newer drugs in both adults and children Used in partial as well as generalized seizures Approved as monotherapy in partial seizures Effective in treating generalized epilepsy syndrome Pak J Neurol Sci 2007; 2(4): 223-29
  • 31. LamotrigineADVANTAGES DISADVANTAGES – Minimal effect on other – Rash if started medications quickly Must start – Works for all types of slowly (~2 months seizures to full dose) – Very well tolerated – Minimal sedation – Probably safe in pregnancy – Approved for >2 y.o. – Monotherapy Mind is the great level of all things; human thought is the process by which human ends are ultimately answered - Daniel Webster
  • 32. TOPIRAMATE Broad spectrum AED with multiple mechanism of actionsMOA:including inhibitory effects on sodium and calcium channels as well as the kainate subgroup of glutamate receptors. Additionally, it potentiates effects on GABA receptors as well as on the potassium channel. Excellent efficacy in partial seizures in adults and children Also effective in migraines Pak J Neurol Sci 2007; 2(4): 223-29 Thinking is the hardest work there is, which is probable reason why so few engage in it. - Henry Ford
  • 33. TopiramateADVANTAGES DISADVANTAGES – Minimal interactions with – Cognitive side other medications effects – Probably works for all – 1-2% renal stones seizure types – tingling/pins and – Approved for >2 y.o needles – Sprinkle form – Can decrease efficacy of oral – Approved for monotherapy contraceptives – Weight loss – Approved for migraine prevention Habit is either the best of servants or worst of masters - Nathaniel Emmons
  • 34. TIAGABINE Selective GABA reuptake blocker Adjunct in partial seizures Multiple dosing Pak J Neurol Sci 2007; 2(4): 223-29 Success is a prize to be won. Action is the road to it. Chance is what may lurk in the shadows at the road side. - O. Henry
  • 35. TiagabineADVANTAGES DISADVANTAGES – Minimal effect on – Dose is dependent on other medications concurrent AEDs – Anxiety – Occasionally makes some seizure types worsePeople of mediocre ability often achieve success because they don’t know enough to quit - Bernard Baruch
  • 36. LEVECTIRACETAM  Binds to synaptic vesicle protein SV2A  Effective adjunct in partial seizures  Lack of drug interaction can be used in patients with complex multiple problems Pak J Neurol Sci 2007; 2(4): 223-29We possess by nature the factors out of which personality can be made, and to organize them into effective personal life is every man’s primary responsibility - Harry Emerson Fosdick
  • 37. LevetiracetamADVANTAGES DISADVANTAGES No interactions  Behavioral/psych side Minimal liver effects metabolism  Twice per day Works for most seizure types Can start quickly Well tolerated Liquid formulation Opinion is ultimately determined by the feelings and not by the intellect
  • 38. OXCARBAMAZEPINE Similar to CBZ Adjunct and monotherapy in partial seizures Effective in patients who have failed CBZ Experience can be defined as yesterday’s answer to today’s problems
  • 39. Oxcarbazepine  As effective and better  Not for all seizure tolerated than CBZ types  Fewer interactions  Low sodium, esp. if on than CBZ diuretics also  Approved for children  Lessens effectiveness >4 of birth control pill  Approved for first-line monotherapyThree can be seen in the divisions of a human in mind, body and spirit
  • 40. ZONISAMIDE It has an inhibitory effect on both sodium and calcium channels Zonisamide is effective as adjunctive therapy in patients with partial epilepsy Also used as a second or third line alternative in refractory generalized epilepsy. Presumed effects on dopaminergic pathways, there has been some interest in treating Parkinsons disease with zonisamide as well. Discipline Weighs ounces Regret weighs Tons
  • 41. Zonisamide Used in Japan for many  1-2% kidney stones years  Occasional Works for all seizure psychiatric or types sedative side effects Approved for children  Sulfa drug Once daily Weight loss Recent addition of 25 mg capsules “Social Isolation is in itself a pathogenic Factor for disease production”
  • 42. Intranasal or Buccal Midazolam Safe and effective (studies in UK, Israel): 5- 10 mg in adults Easy to use Less social stigma Not approved in US for this usage Not easy to obtain (controlled substance) in a convenient form Shorter acting than Diastat “Knowledge can be communicated but not Wisdom” - Hermann Hesse
  • 43. New agents Brivaracetam- structural analogue of levetiracetam –more potent and efficacious in treatment of both partial and generalized epilepsy Lacosamide- Good efficacy in partial seizures. Also useful neuropathic pain Rufinamide- Efficacy seen in Lennox G Syndrome patients but only modest effects see in partial seizures Retigabine – novel AED which activates a special type of potassium Through Action You Create your Own Education - D.B. ELLIS
  • 44. Pregnancy in Women With Epilepsy 1.1 million women of childbearing age have epilepsy in the USA Issues with management of women:1 – Cosmetic consequences of some AEDs – Catamenial epilepsy – Effectiveness of hormonal contraceptives may be reduced by some AEDs – Pregnancy has a greater risk for complications – Difficulties during labor and adverse outcomes are more likely – The practitioner must choose a course that both prevents seizures and minimizes fetal exposure to AEDs With careful management the majority of women with epilepsy will have a better than 90% chance of a normal baby2 1. Yerby, 2000 2. Crawford, 1997
  • 45. Drugs that decrease efficacy of oral contraceptives Phenytoin Carbamazepine Phenobarbital Primidone Topiramate at higher doses Oxcarbazepine Whatever the Mind can conceive and Believe, the mind can Achieve - Napoleon Hill
  • 46. Weight IssuesRisk of weight gain “Risk” of weight loss Valproate – Topiramate Gabapentin – Zonisamide Pregabalin – Felbamate Weight Neutral - Levetericetam - Lamotigrine Many Ideas grow better when transplanted into another mind than in the one where they sprang UP O.W. Holmos
  • 47. Lifestyle changes to minimize seizures  Avoid sleep deprivation  Avoid alcohol  Treat fevers quickly  Occasional patients should avoid specific factors such as strobe lights, etc  Pill boxes/reminders “Men of Genius Admired: Men of Wealth envied Women of power feared But only Women of character are trusted” A- Friedman
  • 48. Summary Balance efficacy against side effects Extended-release AEDs offer improved tolerability, improved compliance and improved seizure control The benefits may be especially relevant in special populations such as children and women with epilepsy Every discovery contains an irrational element or 4 creative intuition Khrl Popper
  • 49. New AEDs: odds ratios for 50% respondersand withdrawal in randomised controlled trials Drug 50% responders Withdrawals Odds 95% CI Odds 95% CI ratio ratio GBP 2.3 1.5-3.4 1.4 0.7-2.5 LTG 2.3 1.5-3.7 1.2 0.8-1.8 OXC 3.4 2.3-4.8 2.3 1.9-2.8 TGB 3.0 2.0-4.6 1.8 1.2-2.7 TPM 4.1 2.9-5.8 2.6 1.6-4.0 VGB 3.7 2.4-5.5 2.6 1.3-5.3 ZSM 2.5 1.4-4.5 4.2 1.7-10.5
  • 50. New vs Old AEDs as monotherapy in previously untreated patientsNew Old AEDs Efficacy TolerabilityAEDs (no. studies)LTG CBZ (4) Similar LTG better PHT (1) VPA (1)OXC PHT (2) Similar OXC better CBZ (1) OXC better VPA (1) SimilarVGB CBZ (4) Similar (2) VGB better CBZ better (2)
  • 51. Odds ratio – Meta analysis – New AEDs Thought is the labour of the intellect Reverie is its pleasure
  • 52. Long-term use ofgabapentin, lamotrigine, and vigabatrinVariable GBP LTG VGB (n=361) (n=1050) (n=713)Mean daily dose (mg) 1575 303 2444Seizure free (%) 1 3 3Reason forwithdrawal (%) Lack of efficacy 42 25 36 Adverse event 10 13 12 Both 12 6 15Standardisedmortality ratio 7.7 10.4 6.8
  • 53. Economic aspects of antiepileptic treatment Cost of AEDs for 1 year of treatment in ItalyDrug Dose (mg/day) Cost (Euro)PB 150 47PRM 750 55ESM 750 82PHT 350 83CBZ 1200 202VPA 3000 472VGB 3000 1420GBP 1800 1705LTG 400 1875TPM 400 2716FBM 3600 5987
  • 54. Common long-term AED side effects  energy level   emotional and  school performance mental wellbeing  overall QoL   coordination and balance  memory   sex life  concentration   job performance  thinking clearly Fisher et al, Epilepsy Res 2000 Science is below the mind; Spirituality is beyond the mind
  • 55. Serious adverse effects of AEDs Serious adverse effects of AEDs include  Dose-related  Chronic  Idiosyncratic  Teratogenic  Drug interaction disorders Parent : Carbamazepine Active metabolite : 10,11 carbamazepine epoxide . Polymechanistic with metabolites with no antiepileptic activity but with side effects Parent : felbamate Active metabolite : various . Polymechanistic but metabolites with antiseizure activity“ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy
  • 56. Summary Seizure freedom in >50% of newly diagnosed patients Safe administration in all patients, especially children and elderly Birth defects in <3% of cases Lower healthcare costs compared with cost of treatment Positive impact on QoL (if and when objective measures are available) When they tell you to grow up, they mean stop growing
  • 57. Combinations based on drug interactionsLeast Useful RationaleCarbamazepine with phenytoin Phenytoin induces carbamazepine metabolism, leading to need for much higher carbamazepine doses.Phenobarbital with Phenobarbital is a powerful inducer ofcarbamazepinePhenytoin, valproate CYP 450 systemValproate with phenobarbital Valproate decreases phenobarbital metabolismValproate with phenytoin Both compete for protein binding sites, reducing the value of total drug level measurement Discipline Weighs ounces Regret weighs Tons
  • 58. Combinations based on drug interaction. contdLeast Useful RationaleFelbamate with Many drug – drug interactionsphenytoin, carbamazepine andvalproateUsefulGabapentine with any drug No drug interactionValproate with lamotrigine Valproate inhibits metabolism of Iamotrigine, reducing dose and cost of treatment with Iamotrigine “Social Isolation is in itself a pathogenic Factor for disease production”
  • 59. Combination based on mechanism of actionMost Useful RationaleCarbamazepine or phenytoin Widely different mechanisms ofwith actionsgabapentine, tiagabine, topiramate, felbamateLeast UsefulCarbamazepine and phenytoin Similar mechanisms of actionTiagabine, gabapentine, and Similar mechanisms of actionvigabatrin The art of medicine is caring for the heart of the patient
  • 60. Combinations based on side effectsPossibly Useful RationaleValproate with felbamate or Felbamate and topiramate have beentopiramate associated with weight loss, valproate with weight gain.Least UsefulCarbamazepine and valproate Valproate and carbamazepine bothin women of child bearing may increase risk for spina bifida;potential valproate inhibits metabolism of 10,11 carbamazepine epoxide, which may be teratogenicGive us the GRACE to accept with serenity the things that cannot bechanged the COURAGE to change the things that should be changed and the WISDOM to know the difference
  • 61. Medical outcome The risk of recurrence after a first unprovoked seizure Remission from seizures Relapse after drug withdrawal Maintaining the right attitude is easier than regaining the right mental attitude
  • 62. Prognosis of a first unprovoked seizure Overall risk of recurrence after 1 year varied between 16 & 36% among different studies Risk is greatest in the first year of index seizures Risk of another seizure following a second seizure is 79% (Camfield et al 1985) Higher rate of recurrence in symptomatic than idiopathic 10%, 24%, 29% at 1, 3, 5 years respectively in idiopathic seizure 26%, 41%, 48% at 1, 3, 5 years respectively in symptomatic seizure (Hauzer et al 1992) NATURE, TIME AND PATIENCE are the 3 great physicians
  • 63. Prognosis of a first unprovoked seizure Risk of recurrence is more if the index seizure is 1. Status epilepticus (Hauzer et al 1990) 2 Complex partial seizure (Camfield et al) (CPS 78.9% Vs. GTCS 44%) Risk of recurrence is more if there is previous history of febrile seizures Risk of recurrence is more if the EEG shows epileptiform discharges Normal EEG does not rule out seizure recurrence. Recurrence risk is 12% after a first unprovoked seizure with a normal EEG (Van Donselaar et al 1992) Opinion is ultimately determined by the feelings and not by the intellect
  • 64. Remission of Epilepsy Various studies show remission ranges of 50-70%, depending upon 1 year - 5 year seizure-free intervals The group for the study of prognosis of epilepsy in Japan showed 3 year remission rate of 58.3% (1981) Annegers et al used stringent criteria of 5 year seizure-free interval – showed remission rate of 65% in 10 years and 76% in 20 years With respect to specific seizure types, absence seizure, GTCS, simple partial seizures, secondary GTCS and CPS, all had remission rates of 68%, 69%, 50%, 60% and 61% respectively Truth comes out of error sooner than that of confusion
  • 65. Remission of Epilepsy Generalized idiopathic seizure is one of the most important prognosticators of remission Early age of seizure onset is a consistent predictor of intractability (Berg et al – 1996) Factors having no prognostic values in remission include gender, race, family history, time between diagnosis and initiation of therapy When they tell you to grow up, they mean stop growing P. Diccaso
  • 66. Relapse after drug withdrawal Overall relapse rate varies from 20 – 36.5% (Emerson et al) Children have lower relapse rates 12 – 36.3% (Emerson et al) 50 – 80% relapses occur during medication withdrawal Mental retardation and abnormal neurological examination are associated with poor outcome Every discovery contains an irrational element or 4 creative intuition - Karl Popper
  • 67. Relapse after drug withdrawal The quality standards of American Academy of Neurology published their recommendation for discontinuing AEDs in seizure-free patients Their recommendations were based on a review of medical literature from 1967 to 1996 The 9 factors related to the probability of successful antiepileptic withdrawal are: sex, age of seizure onset, seizure type, aetiology, neurological examination and IQ, duration of seizure freedom on antiepileptic drugs, treatment regimen, age at relapse and normalization of the EEG The secret of walking on water is Knowing where the stones are
  • 68. Relapse after drug withdrawal Seizure-free for 2-5 years on AEDs Single type of partial or generalized seizure Normal neurological examination Normal IQ EEG normalizing with treatment With all the above profiles, 69% chance in children and 61% in adults, of a successful withdrawal. Thought is the labour of the intellect Reverie is its pleasure
  • 69. INTRACTABLE EPILEPSY Definition - one or more sz/mo over one y - adequate trial: 2 first line AEDs and 1 or more. Burden of refractory epilepsy . - Physical injury. - Psycho social costs. - SUDEP Take time to think; it is the source of power Take time to read; it is the foundation of wisdom Take time to work; it is the price of success
  • 71. Outline Definition Epidemiology Taxonomy Pathophysiology of intractable seizures Pre-operative diagnosis and work-up Management options
  • 72. DefinitionsA seizure is the clinical manifestation ofexcessive, synchronous, abnormal firing oflarge populations of neurons
  • 73. Intractable epilepsy A persistent seizure activity that prevents the individual from normal function or development. Characterized by two antiepileptic drug (AED) failures, at least one seizure per month for 18 months, and no seizure-free periods longer than three months during that time. *no consensus
  • 74. EpidemiologyPrevalence of epilepsy is 5 to 10 per 1000 in the North American populationSecond most common cause of mental health disabilityApproximately 20% of individuals with a diagnosis of epilepsy have seizures that are not adequately controlled by AEDs
  • 75. Why do patients fail to respond? Paroxysmal events that are not epileptic Psychogenic seizures Misdiagnosis of seizure type Non-compliance with medication Epileptic disorder with different pathophysiologic mechanism than that targeted by the AED Unreliable reporting of seizures
  • 76. When should we intervene surgically?Failed medical management with >2 AEDs i.e. At least one seizure every 1-2 monthsANDSeizures are associated with any of:- Impaired LOC- Injury (e.g. from falls)- Accompanied by stigmatizing behaviour (e.g. disrobing, uttering obscenities)- Accompanied by unpleasant or noxious auras (e.g. vomiting, intense fear)- Unpredictable occurrence
  • 77. Factors to consider when making the surgical decision Patient’s social environment Expectations Level of function Quality of life Severity and frequency of seizures Medical consequences of the epilepsy
  • 78. Taxonomy of surgically remediable epilepsy syndromes
  • 79. Pathophysiology of epilepsy Alteration in neuronal excitability by changes in voltage-gated and transmitter- gated ion channels Focal reduction in inhibitory neurotransmission Alterations in gene expression Changes in cellular plasticity of neurons with age or in response to injury Developmental alterations in cerebral cortex
  • 80. Goal of resective epilepsy surgeryComplete resection of the epileptogenic zone (the area of cortex that is required to generate clinical seizures)Its location and boundaries are defined by: seizure semiology electrophysiologic recordings functional testing neuroimaging techniques
  • 81. Seizure Semiology Clinical features of a seizure may suggest a location for the symptomatogenic zone and have lateralizing value
  • 82. Seizure SemiologyIctal speech Non-dominant temporal lobeDystonic limb posturing Contralateral to side of temporal lobe seizure onsetPost-ictal nose wiping Ipsilateral to temporal lobe of onsetPost-ictal dysnomia > 2 min Onset in the dominant temporal lobeForceful head version Contralateral hemisphereimmediately prior to asecondarily generalized tonic-clonic seizurenonforced head turning at ictal Ipsilateral hemisphereonset without a toniccomponent or hemifacialclonic twitchingAsymmetric tonic limb The extended limb is usuallyposturing, the "figure four contralateral to the hemispheresign," of onset
  • 83. Seizure SemilogyLocalized contralateral clonic Broca’s areaactivity and aphasia withspeech arrestAssymetrical bilateral Supplementary motor areaproximal limb movement,version of head, facialgrimacing with speech arrestor vocalization, and preservedconsciousnessOlfactory, psychic, and Orbitofrontal and cingulateemotional auras followed by seizurescomplex automatismsNo warning, Bilateral tonic Prefrontalclonic activity with version,forced thinking, falls,autonomic signs
  • 84. Cortical zonesSymptomatogenic zone: The area of cortex that, when activated by an epileptiform discharge, reproduces the initial ictal symptoms. The zone is defined by careful analysis of the ictal symptoms that can be done with a thorough seizure history and analysis of ictal video recordingsIrritative zone: The area of cortical tissue that generates interictal electrographic spikesSeizure onset zone: The area of cortex from which clinical seizures are generated. This may be larger or smaller than the epileptogenic zone. When the epileptogenic zone is smaller than the seizure onset zone, partial resection of the seizure onset zone may lead to seizure freedom because the remaining seizure onset zone has been weakened sufficiently, rendering it incapable of generating further seizuresArea of functional deficit: Area of cortex that is functionally abnormal in the interictal period
  • 85. EEG Recordings Interictal and ictal Scalp EEG is used to localize the seizure discharges. Detects radially oriented electrical activity that is attenuated in strength and spatially distorted by tissue between brain and scalp Limitation: capable of detecting a seizure discharge only after it has extended considerably and has activated a relatively large area of cortex
  • 86. EEG RecordingsPatients with temporal lobe epilepsy (TLE)have epileptiform activity consisting ofspikes and/or sharp waves that are usuallymaximal at the anterior temporal (F7 and F8electrodes) and the mid temporal regions(T3 and T4 electrodes).
  • 87. Indications for Invasive EEG monitoring  Bilaterally independent temporal lobe seizures  Extratemporal lobe-onset seizures with rapid propagation to the medial temporal lobe  Temporal lobe seizures of localized onset, but with normal MRI and FDG-PET findings  Discordant EEG localization and imaging findings  To distinguish neocortical from medial TLE  Lateralization of seizures to a particular lobe though no abnormalities are seen on structural or functional imaging  Epileptogenic zone located in or near eloquent cortexIntracranial electrode placement is associated with a 2-3% complication rate
  • 88. NeuroimagingThe goal is to locate and define anatomic epileptogenic lesions.MRI: shown to have better chance of detecting positive pathology than CT scan. Limitation: cortical dysplasia may be subtle or not visualized on MR imagingFDG-PET: interictal cortical hypometabolism correlates with the epileptogenic zone in temporal and extratemporal epilepsy
  • 89. Hippocampal Sclerosis80-95% ofpatients withsurgicallyprovenhippocampalsclerosis havehippocampalatrophy andhyperintensityon T2-weighted MR
  • 90. FDG PET in a patient with mesial temporal epilepsyshowing hypometabolism in are aof left mesial temporal lobe
  • 91. Neuroimaging Ictal SPECT and functional MRI measurelocal changes in cerebral blood flow (arelative increase of ictal blood flow withrespect to the interictal state). This increaseof blood flow is a direct autoregulatoryresponse to the hyperactivity of neuronsduring epileptogenic activation.
  • 92. Functional Testing Wada test is used mainly to lateralize eloquent cortex with regard to language and memory and is used only secondarily as a supplementary method to determine the localization of the epileptogenic zone
  • 93. What is a Wada Test?Injection of sodium amobarbital into one carotid artery totemporarily inactivate the ipsilateral cerebralhemisphere, allowing independent testing of memory andlanguage function of the contralateral hemisphere.IAP is believed to anesthetize ipsilateral carotid arterydistribution, which includes the amygdala and the anteriorhippocampus.Injection ipsilateral to the epileptogenic zone assesses thefunctional adequacy of the contralateral hippocampus to sustainmemoryContralateral hemiparesis and ipsilateral EEG slowing confirmthe adequacy of injection
  • 94. Epilepsy syndromesamenable to surgery
  • 95. Mesial Temporal Lobe Epilepsy History of early insult in infancy or childhood Hippocampal sclerosis and atrophy on MRI Abnormal Creatine/NAA on MRS Temporal hypometabolism on interictal PET Characteristic pattern of hypoperfusion and hyperperfusion on SPECT Anteromedial epileptogenic zone on EEG Memory deficits on Wada testing Histology: loss of principal hippocampal neurons, synaptic re-organization, sprouting of mossy fibers, enhanced expression of glutamate receptors
  • 96. Figure 149-7 Diagram of a coronal slice through the medial temporal lobe. The hippocampus is composed of 2 <ss>U</ss>-shaped lamina of gray matter, the cornu ammonis (C) and dentate gyrus (D). Between them is thewhite matter of the molecular layer (*). The hippocampus is bordered by the alveus (arrowheads), choroid fissure(ChF), and temporal horn (TH) superiorly. The alveus converges medially to form the fimbria (F), which in turn is a component of the fornix. The ambient cistern (AC) and brainstem (BS) are situated medially. Inferior to the hippocampus is the parahippocampal white matter and gyrus (PHG). The temporal horn (TH) borders the hippocampus on its lateral aspect. CS, collateral sulcus; FG, fusiform gyrus or lateral occipital-temporal gyrus;ITG, inferior temporal gyrus. (From Bronen RA: Epilepsy: The role of MR imaging. AJR Am J Roentgenol 159:1165- 1174, 1992.)
  • 97. Frontal Lobe Epilepsy Second most common epilepsy syndrome referred for surgery Wide variety of seizure types depending on origin and spread Often prominent motor manifestations Interictal EEG spikes in one or both frontal lobes, temporal spikes may be seen Neuroimaging is usually negative
  • 98. Lesional partial epilepsy 30% of patients undergoing epilepsy surgery have a structural lesion as underlying pathologye.g. Focal encephalomalacia, tumor, vascular malformation, congenital developmental anomaly Anatomical location is primary determinant of seizure presentation
  • 99. Neocortical cryptogenic epilepsyClinical history and electrical data suggest seizure of cortical origin but no structural lesion is identifiedSurgical treatment based on EEG delineation of the epileptogenic zone.
  • 100. Surgical Approaches for EpilepsyResective Surgery Temporal lobe resections (anteromedial selective amygdalohippocampectomy); Extratemporal resections; Lesional resections; Anatomic or functional hemispherectomyDisconnection surgery Corpus callasotomy; Multiple subpial transections; Keyhole hemispherotomiesRadiosurgery Mesial temporal lobe epilepsy; hypothalamic hamartomasNeuroaugmentative surgery Vagal nerve stimulators; Deep brain stimulationDiagnostic surgery Depth electrodes; subdural strip electrodes; subdural grids
  • 101. Summary of Surgical Procedures for Epilepsy Anteromedial temporal resection (AMTL): The superior temporal gyrus is spared, and the middle and inferior temporal gyrus is resected 4-5 cm from the tip of the nondominant side and 3-4 cm of the dominant side. The amygdala is resected totally; the hippocampus and the parahippocampal gyrus are resected to the level of the colliculus. Standard en bloc anterior temporal lobectomy: This resection is similar to the AMTL except that the superior temporal gyrus, 2 cm from the temporal tip, also is resected. Amygdalo-hippocampectomy: In this procedure, the amygdala, hippocampus, and parahippocampal gyrus are resected, with sparing of the lateral and basal temporal neocortex. Lesionectomy: The lesion as delineated by MRI is resected, with a margin. In some cases, electrocorticography may be recommended to guide the margins of the resection.
  • 102. Summary of Surgical Procedures for Epilepsy Tailored neocortical resection: This resection is based on imaging and EEG data and is tailored on the basis of functional mapping data such that eloquent cortical regions are spared. In some cases multiple subpial transections (MST) are recommended when the epileptogenic zone involves eloquent cortex. With MST, the horizontal fibers that are important for seizure propagation are interrupted at 5-mm intervals. The vertically oriented fibers that are important for function remain intact. Functional hemispherectomy: It consists of removal of sensorimotor cortex and the temporal lobe. The frontal lobe and the parieto-occipital lobes are left intact but are disconnected from cortical and subcortical structures. Corpus callosotomy: The anterior two thirds of the corpus callosum is resected. Sometimes, a complete callosotomy is performed; however, the risk of developing disconnection syndrome is greater with this procedure. May be employed in the setting of non-localized tonic, clonic, or atonic seizures that cause falls and injury. Multilobar resection: This usually involves the frontoparietal, parieto-occipito- temporal, or parieto-occipital lobes. The technique includes corticectomy (resection of grey matter), lobe excision (resection of grey and white matter), lobe disconnection, or a combination of these.
  • 103. Is surgery for epilepsy effective?At 1 year 58% of patients who underwent surgery were free of seizures impairingawareness versus 8% of patients who received medical treatment. Patientswho underwent surgery also had significantly better HRQOL.
  • 104. ReferencesEngle J (2001) Intractable epilepsy: definition and neurobiology. Epilepsia 42(suppl 6):3Wiebe S et al. (2001) A randomized controlled trial of surgery for temporal lobe epilepsy. NEJM 345: 311-318.Youman’s Neurological Surgery, 5th EditionZimmerman R and J Sirven (2003) An overview of surgery for chronic seizures. Mayo Clin Proc. 78: 109-117
  • 105. Factors that characterize refractory epilepsy Intractable seizures Excessive drug burden Neurobiochemical plasticity changes Cognitive deterioration Psychosocial dysfunction Dependent behavior Restricted life style Unsatisfactory quality of life Increased mortality Imagination is more Important than Knowledge
  • 106. ADVERSE PROGNOSTIC FACTORS Multiple seizure types. High frequency of seizures. Partial seizures. Seizure onset in infancy. Severe EEG abnormality. Organic brain lesion. Every thing should be made as simple as possible; but not simpler
  • 107. Interation of AE/Epilepsy: Risk of aggravation Carbamazepine: infantile spasms, epilepsies with myoclonic (JME) or absence seizures. EECSWS, Lennox-Gestaut syndrome. Phenobarbital : infantile spasms, Dravet syndrome. Vigabatrin : epilepsy with myoclonus and absences. Lamotrigine : Dravet syndrome. Benzodiazepines : Tonic spasms in LGS. Tiagabine and Gabapentin : Absence and myoclonus. You are what you think and not what you think you are
  • 108. INTENSIVE EEG MONITORING Extracranial Scalp electrodes,sphenoidal. Semi invasive Foramen ovale electrodes Epidural pegs, pins,silver wires. Invasive Subdural strip, grid electrodes Intracerebral electrodes. “Healthy Mind and Healthy expression of Emotion go hand in Hand”
  • 109. NEURO IMAGING  CT Scan : For gross structural lesions – Cerebral tumours,Calcified lesions  MRI : Superior to CT- scan  Optimal MRI : High resolution Special sequencesA great many people think they are thinking when they are merely re arranging their prejudices W. James
  • 110. MR IMAGING Hippocampal sclerosis Developmental malformations Disorders of neuronal migration Cavernous haemangiomas Dysembryoblastic neuro-epitheliomas Indolent gliomas Post-operative assesmentA open foe may prove a curse ; but a pretended friend is worse
  • 111. SURGERY FOR EPILEPSY  Pre-surgical evaluation : Clincial  EEG, Video EEG, MR- imaging  SPECT, neuro-psychological evaluation, WADA- test ( Occasional need for intracranial electrodes, corticography,depth recording, stimulation for localisation of indispensable areas).It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  • 112. RESULTS OF EPILEPSY SURGERYSURGERY CURED IMPROVEDTemporal lobe 53 – 55 % 23 – 28 %Extra temporal 43 % 27%Hemispherectomy 63 % 25%Corpus callosotomy 4–8% 80% Truth comes out of error sooner than that of confusion
  • 113. EFFICACY OF AEDS Monotherapy Monotherapy Monotherapy 1st AED 2nd AED 3rd AED Seizure free 47 %Newly Seizure freediagnosed 13 %epilepsyN= 10 Uncontrolled Seizure free Seizure free Seizure 10 % 3% 53% Uncontrolled Uncontrolled Uncontrolled Sz Sz Sz 40% 30 % 36% Discipline Weighs ounces; Regret weighs Tons
  • 114. CONCLUSIONTEN STEP APPROACH FOR SUCCESSFUL DIAGNOSIS AND MANAGEMENT OF EPILEPSY1. Epilepsy is a disorder of the Brain and not of the Mind.2. Epilepsy is broadly classified as Generalised or Partial.3. This is a fascinating disorder affecting all the three functions of the brain.(Cognition,Conation and affect).  Cognition- in simple definition means perception plus thinking.  Conation – movement in general.  Affect- motor expression of an emotion. We do not know one millionth of one percent about anything – Thomas Edison
  • 115. CONCLUSION4. It represents four types of partial seizures coming from four lobes of the brain. I ) Frontal Lobe – supplementary motor area i) Adversive seizures ii) Epilepsia partialis continua (motor movement of the lip, thumb or toe). II ) Parietal Lobe – Sensory seizure ( sudden benumbed feeling of the limb/ face.) III ) Temporal Lobe – (Auditory, smell / aura , vertigo ) – clinically of three types stare – automatisms- resolution. Automatisms – resolution Loss of consciousness with automatism IV ) Occipital Lobe – visual aura seizures arising from all four lobes can result in secondary generalization.5. There are five types of generalized seizures – Tonic, clonic, Tonic clonic , Absence and Myoclonic . The Truth is Fear & Immorality are two of the greatest inhibitors of Performance to progress
  • 116. CONCLUSION6. Differential Diagnosis for epilepsyi) Migraine. ii) Transient Ischemic Attacks (TIA).iii ) Syncope. iv ) Narcolepsy.v) Hypoglycemia ,Hyperglycemia. vi ) Psychogenic.7. Seven investigations are mandatory : (rest are optional ) i ) Hemogram. ii ) Blood sugar iii ) Renal function tests ( Urea and Creatinine ) iv ) Liver functions (SGOT,SGPT, SERUM NH3 and GGT ). v) EEG, (Telemetric recording ). vi) CT / MRI ( If partial seizures are present ). vii) Screening for malignancy. ( Epilepsy in elderly ). Optional ; SPECT,PET,fMRI. “The True Art of Memory is The Art of Attention” - S.Johnson
  • 117. CONCLUSION8. Treatment – Commonly effective in epilepsyi) Commonly used : CPS Carbamazepine / Phenytion / Sodium Valproate.ii) Latest drugs : TGL Topiramate – use it as add on or as monotherapy. Gabapentin – primary drug in partial seizures Lamotrigiine.iii) Sparingly used : PV Old – Phenobarbitone New – Vigabatrine. Thought is the labour of the intellect Reverie is its pleasure
  • 118. CONCLUSION9. Etiology – Etiology of epilepsy in the finger tips.T (thumb) – Trauma, Toxic,Tumour.I (Index finger) – Infection ( bacterial / viral )M ( Middle finger ) – Metabolic, endocrineD (Diamond Ring finger ) – Degeneration, - Demyelination.L ( Little finger ) - Little flow or absent flow of blood Vascular.H ( Hand ) – Hereditary and Nutritional disorders. Through Action You Create your Own Education - D.B. ELLIS
  • 119. CONCLUSION10. Epilepsy education3 S – support group – tele film and video self help group – information service social skill – patient professional personal educationP – Patient – Physician give and talk.D – Drugs do`s and don`tsR – Role playC – Compliance calendar . Whatever the Mind can conceive and Believe, the mind can Achieve Napoleon Hill
  • 121. Dedicated to my family formaking everything worthwhile
  • 122. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDER THANK YOU East west Pharma