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Epilepsy: Prognosis and Treatment

Epilepsy: Prognosis and Treatment. William H Theodore MD Chief, Clinical Epilepsy Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland, USA. Prevalence and Incidence. Third most common neurologic disorder

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Epilepsy: Prognosis and Treatment

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  1. Epilepsy: Prognosis and Treatment William H Theodore MD Chief, Clinical Epilepsy Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland, USA

  2. Prevalence and Incidence • Third most common neurologic disorder • First seizure incidence: 20-70 / 100,000 • Epilepsy incidence: 30-50 / 100, 000 • Prevalence: 5-10 / 1000 • Reported higher in some developing countries • Cumulative adjusted lifetime risk: 1.3%–3.3% Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences. New York, NY: Demos; 1991:1.

  3. Etiology of Symptomatic EpilepsyUSA Annegers 1993

  4. Epidemiology by Seizure Types Generalized TC (23%) Complex Partial (36%) Simple Partial (14%) Unclassified (3%) Myoclonic (3%) Other Generalized (8%) Absence (6%) Partial Unknown (7%) Reproduced with permission from Hauser WA. Epilepsia. 1992;33(suppl 4):S10.

  5. Prognosis After a Single Seizure • Reported 30-70% recurrence over 3 years • sampling, etiology, seizure types • Increased if underlying lesion • Decreased if avoidable acute precipitant • CBZ reduced recurrence in children (Camfield 1989) • 1/3 stopped drug due to side effects • 18% Rx vs 38% no RX in 2 years • PHT, CBZ, VPA, PB (First Seizure Trial Group 1989)

  6. Table 2: AED Mechanisms and Clinical Efficacy

  7. Epilepsy Therapy in 525 Patients Kwan and Brodie 2000

  8. s l l s s l l s l l l s s l l l s l l s l s s l s s s s s s s s s s s s s s s s s l l Veterans Administration Cooperative Study 100 l l 80 l l l l l l l l l l 60 l Percent Continuing 40 phenobarbital s s phenytoin 20 primidone s s carbamazepine l l 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Reproduced with permission from Mattson RH, et al. NEngl J Med. 1985;313:145-151.

  9. SANAD Study Time to 12 month remission % remaining on drug Marsan et al 2007

  10. Reasons for AED FailureVA Cooperative Study Mattson et al 1985

  11. Prognosis of ‘Drug-Refractory’ EpilepsyRe-evaluation of 246 patients • Drug failure before index date: • maximum tolerated dose in 54% • idiosyncratic reaction in 6.5% • intolerable side effect in 19% • unknown reasons in 21%. • 6-month terminal seizure remission: • 14% of AED-treated patients (about 5% per year of study) • 52% of surgery patients • persistent intractability: • Duration > 10 years, mental retardation, status, > 6 AEDs No drug seemed superior Callhagan et al 2008

  12. Some Emerging AEDs

  13. Why do AEDs Fail? • About 30% of patients do not respond at all • About 10% of patients with good initial AED response cease to respond • Pharmacokinetic • Drug interactions • Enzyme induction • Tolerance to non-BZP AEDs ? • Receptor, channel response changes • Drug efflux transporters •  PgP, MRPs,

  14. AED Tolerance • Long-term BZPs: ↓ allosteric GABA-BZP site interactions • VGB tolerance in MES model: ↓ GAD due to GABA feedback inhibition Loscher & Schmidt 2006

  15. Altered NA+ Channel Responses? No MTS MTS Remy et al 2003

  16. Multiple Drug Transporters (p-glycoproteins) • Pump lipophilic drugs and other xenobiotics out of cells • Role in cancer chemotherapy resistance • May be overexpressed in human epileptic tissue, especially TLE • Unreplicated link between MDR gene polymorphisms and human AEDresistance Loscher 2007

  17. PgP Affects Brain Phenytoin Levels Loscher 2007

  18. Possible Therapeutic Maneuvers • Manage with drug holidays, dose adjustments? • Alternate AEDs? • Lower starting doses? • Cross-tolerance ? • Choose drugs with different mechanisms? • PgP inhibition • verapamil • tariquidar

  19. Natural History of Epilepsy • Natural history of untreated epilepsy unknown • Bromides since 1857 • PB available since 1912 Charles Locock Alfred Hauptman

  20. Natural History of Epilepsy • Natural history of untreated epilepsy unknown. • Course may ‘fluctuate.’ • No difference in seizure-free rate if treatment begun after 1st or 2d seizure • In ‘resource poor’ countries, spontaneous remission rate ~ 30% • prognosis not related to pretreatment GTCS # Hauser et al 1998

  21. Early onset LRE may not become clearly intractable for many years • 7 centers: 333 patients evaluated for resective surgery for localization-related epilepsy prospectively identified at initial evaluation • Latency from epilepsy onset to 2 AED failure 9.1 years • 26% reported at least 1 yr remission • 8.5% 5 year remission Berg et al 2003

  22. Intractable Epilepsy:Comparison of Diagnostic Criteria Berg et al Epilepsia 2006

  23. ILAE Epilepsy Outcome Categories *at least 12 months AND three times the longest interseizure interval in 12 months prior to new intervention Kwan et al Epilepsia 2009

  24. Drug Resistant EpilepsyILAE 2009 Failure of informative trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Kwan et al Epilepsia 2009

  25. Data Needed to Determine if a Therapeutic Intervention is “Informative” Mode of application (e.g., formulation, dose, dosing interval) Compliance Duration of exposure Was there was effort to optimize dose? Reason(s) for discontinuation Unsatisfactory seizure control   Adverse effects   Psychosocial reasons, for example, planning for pregnancy   Administrative reasons, for example, lost to follow up   Financial issues, for example, cannot afford drug Other reasons Kwan et al Epilepsia 2009

  26. Early onset LRE may not become clearly intractable for many years 7 centers: 333 patients evaluated for resective surgery for localization-related epilepsy prospectively identified at initial evaluation Latency from epilepsy onset to 2 AED failure 9.1 years 26% reported at least 1 yr remission 8.5% 5 year remission Berg et al 2003

  27. Epilepsy ‘Pattern:’ Remittent KCNQ2 or KCNQ3 benign familial convulsions Some absence Non-remittent ‘drug responsive’ JME Non drug-responsive but treatable Localization-related Poorly responsive LGS Clinical Features at Onset: Early age of onset presentation in status epilepticus ? abnormal neurological exam partial seizures at diagnosis mixed seizure types ~ developmental delay multiple seizures prior to treatment seizure clustering, ‘density’ Structural lesion Predicting Intractable Epilepsy

  28. New onset TLE in Children: MRI and Prognosis Spooner et al 2006

  29. Prospective Study of Finnish Children1964-1992 Sillanpaa et al 1999

  30. Drug Therapy: Prognosis by Seizure Type (n=1102) Mattson et al 1996

  31. What is Intractable Epilepsy?(modified after DC Taylor) • The Lesion or Disease: • mesial temporal sclerosis, malformation • The Illness: • intermittent seizures • The Predicament: • social • psychological • economic • AEDs treat the illness, not the disease • Is that important?

  32. Progression of Epilepsy • “The interparoxysmal mental state of epileptics often presents grave deterioration.” • “Each fit apparently leaves a change in the nerve centers, facilitating the occurrence of other fits.” • Gowers 1890 • “Mental deterioration follows relentlessly.’’ • Cecil’s Textbook of Medicine 1929Edwin G ZabriskieAssociate Professor of Neurology, Columbia UniversityPhysician to the Neurological Institute

  33. Neuropsychological and functional Prognosis in TLE • Surgery accelerates decline if unsuccessful • Stops or reverses it if successful • In Finnish pediatric study, adverse socio-economic effects even in patients who entered adult life in remission off AEDs Silanpaa et al 1998; Jokeit et al 2000; Helmstaedter et al 2003

  34. Depression and Epilepsy • Depression in Population > 18 survey data • 36.5% epilepsy • 27.8% asthma • 11.8% control • Adults ever told of epilepsy: RR 2.5 • Adults with active epilepsy: RR 3.0 • Reduced quality of life • Increased medical resource use Cramer et al 2003, Ettinger et al 2004, 2005, Kobau et al 2006

  35. Quality of Life Seizure control usually considered most important measure Complete seizure-freedom usually has a much greater effect on HRQOL measures than simply reduced frequency Depression has greater adverse impact than seizure frequency itself in some studies Drug side effects and unemployment Issue of when to withdraw drugs after successful surgery

  36. Seizure Control, Depression, and Anxiety • Several studies suggest seizure frequency predicts anxiety and depression symptoms • Multicenter surgery study • ↓ depression ~ seizure control • 6.1% new depression in non-seizure free patients Devinsky et al Neurology 2005; Baker Neurology 2006

  37. Death • Standardized mortality ratio is increased in epilepsy, even if no underlying illness • Marked increase in sudden unexplained death • SUDEP related to: • GTCS • > 2 AEDs • Death after TLE • SMR for patients with recurrent seizures 4.69 • seizure free patients: no difference vs age- and sex-matched population of the United States • Persistent seizures ~ death in Finnish pediatric study • Death is due to uncontrolled epilepsy Silanpaa et al 1998; Sperling et al 1999

  38. Approaches to Intractable Epilepsy • Surgery • Focal resection • hemispherectomy • Callosotomy (palliative) • Ketogenic Diet • Experimental Drugs • Brain Stimulation

  39. ‘Intractable’ TLE: Comparison of Medical and Surgical Outcome Helmstaedter et al 2003 Wiebe et al 2001 Non-randomized Clinical Series Controlled Temporal Lobectomy Trial One year 2-10 years

  40. The Ketogenic Diet 20% Protein 5% Carbs 10% Protein 30% Fat 85% Fat 50% Carbs

  41. Potential Mechanisms of Action • Ketosis • Acetone • Aspartate, GABA • Polyunsaturated fatty acids • Mitochondrial uncoupling • Glucose modulation • Enhanced glutamate transport • Opening KATP channels • Acidosis • Caloric restriction • Decreased IL-1ß • Neurosteroids

  42. Ketogenic Diet • Traditionally started gradually in the hospital after a 24-48 hour fast • Families educated daily • Ratio (fat: carbs and protein) • 4:1 more strict • 3:1 for infants, adolescents • Calories 60-100% • Fluids 85-100% • Solid foods and/or formula • Requires dietician support • Strong family committment

  43. Side Effects • Constipation • Slowed weight gain • Acidosis when ill • Vitamin deficiency (if unsupplemented) • Renal stones • Impaired height and weight • Dyslipidemia • Gastrointestinal upset

  44. Ketogenic Diet Randomized Controlled Study 10/65 who stopped diet not included in analysis Neal et al Lancet Neurology 2008

  45. Brain Stimulation for Epilepsy • Vagal Nerve Stimulation • Transcranial Magnetic stimulation • Intracranial stimulation • Surface electrodes (‘responsive’) • Deep Brain Stimulation • Hippocampus • Thalamus • Cerebellum Torpedo fuscomaculata

  46. VNS • Requires surgery, but extracranial • Effects broadly comparable to new AED trials • 30-40% ≥ 50% seizure frequency reduction • In open label extension effect sustained ≥ 12 months • Very rare patients seizure-free • Only consider when no chance for resective surgery Refractory Generalized Epilepsy Nei et al Epilepsia 2006

  47. Transcranial Magnetic Stimulation

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