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Treatment of Epilepsy in Eldery Population

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Lecture delivered at Indian academy of Geriatrics and Association of Physician of India, Kota, Rajasthan

Lecture delivered at Indian academy of Geriatrics and Association of Physician of India, Kota, Rajasthan

Published in: Health & Medicine

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  • 1. Vijay Sardana MD; DM(Neurology) Professor & Head Deptt. Of Neurology,Govt Medical college, Kota
  • 2. • Highest occurrence• Atypical presentations• Rec falls from GTCS- Head injury, fractures• Medical non compliance• Increased adverse drug effects• Co- morbidity & drug interaction• Few AED drug trials in adults
  • 3. • >65 yrs- elderly population- 13% Drug consumption- 32%• Average elderly- 3 medicines in addition to AEDs
  • 4. Increase in the proportion of the elderly in Germany (>65 years), 1910–2030 (projected) 50 Proportion of population (%) 40 30 27% 20 17% 15% 10 5% 0 1910 1950 1990 2030Huying et al., Seizure 2006; 15: 194–197 Year
  • 5. • Annual incidence (30-50/1,00,000- all ages) 65-69 yrs- 87/1,00,000 >70 yrs- 147/1,00,000 >80 yrs- 159/1,00,000• Prevalence- 1.5% above 65 yrs• 0.7% elderly people treated for Epilepsy• Epilepsy 3rd most common Neurological condition after Stroke & Dementia
  • 6. Age-specific incidence of epilepsy in Rochester, Minnesota, 1935–1984 200 150 Incidence (per 100,000) 100 50 0 0 20 40 60 80 AgeHauser et al., Epilepsia 1993; 34 (3): 453–468
  • 7. • Decline in functional independence• Fear of falls & loss of self confidence• Stigma• Reactions of family & friends• Exclusion from activities, marginalization• Assumption of impending death• Loss of driving privileges• Disempowerment & perception of shrinkage of life space
  • 8. • gastric acid secretion• Slowing of gastric emptying time• intestinal transit time• mesentric flow• Intestinal absorption surface Bio-availability
  • 9. Plasma concentration and clearance  Ageing: effect on PK parameters by decreasing:  plasma protein content  liver metabolic capability  renal clearance  and increasing:  the volume of distribution (for lipophilic drugs)  elimination half-lifeLeppik. Epilepsia 2006; 47 (Suppl 1): 65–70; Leppik. Geriatrics 2005; 60: 42–47; Perucca et al., Epilepsy Res 2006; 68S: S49–S63
  • 10. • liver blood flow & mass- 25% lower above 65• Cytochrome p450 system- decline with age AEDs metabolized-PHT, PB, CBZ, OX- CBZ, Ethosuximide, VPA ,Topiramate• Hepatic glucoronidation conjucation- less affected AEDs metabolized- LTG, VPA, Zonisamide
  • 11. • Decreased Renal mass, glomeruli• GFR decline 50% by 8th decade• AEDs primarily metabolized by kidney- Gabapentine, Levetiracetam, Prega)balin (also Topiramate, Zonisamide)
  • 12. • CBZ 25-40%• PHT about 25%• VPA about 40%• PB about 20%• LTG about 35%• Gabapentine 30-50%• Levetiracetam 20-40%
  • 13. • S Albumin slightly with age aggravation – ac systemic & Neurological illnesses free/unbound drug remains unchanged in spite of total low s. conc.• Highly protein bound- PHT, VPA ,, Clonazepam, Clobazam, Diazepam (also CBZ) – free fraction can rise to toxic levels
  • 14. Corrected Pht level (micro g/ ml) – measured PHT level 0.2 × Albumin( G/dl) + 0.1
  • 15. • Cytochome p450 inhibitors- H2 blockers, Erythromycin, Clrithromycin, Fluconazole, Ketoconazole, INH
  • 16. • concentration of HMG- coA reductase inhibitors- Statins• Low concetration of Warfarin- increased PT?INR• Low concentration of Varapamil
  • 17.  Osteoporosis is a common problem in elderly  Changes in bone density in elderly could result from:  reduced exercise  poor calcium intake  impaired vitamin D metabolism  AED use increases risk of osteoporosis  decrease in bone mineral density  induction of CYP450 – alterations in sex steroid or vitamin D metabolism  enzyme-inducing AEDs (e.g., PHT, PB) and VPA have greatest effect  Polytherapy has higher risk  Newer AEDs safe  potential 2-fold increase in hip fracturesBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Cloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Mintzer et al., Epilepsia 2006;47: 510–515; Sato et al., Neurology 2001; 57: 445–449; Martindale. In: Sweetman, 2002.
  • 18. • CVA- 40-50%• Metabolic disturbance- 10-15%• Head injury- 5-10%• Tumors- 5-10%• Brain infections- 5-10%
  • 19. • CVA- 30-40%• Post traumatic- 2-3%• Old CNS infections- 2-3%• Alzheimers & other Neurodegenerative- 8-10%• Cryptogenic- 40-50%
  • 20. • Stroke – cause in 30-50%. Ac stage-6% 5 years-15%• Occult/obvious• 15% elderly ‘idiopathic looking seizures show imaging evidence of CVA• Seizure a risk factor for subsequent stroke, even greater than cholesterol & HT• Stroke patients 20 times more likely to develop Epilepsy as compared to gen population
  • 21. • chlorpromazine• Quitipine• clozepine• Cephalosporins• Penicillin• TCAs• Venelafaxin• Metoclopramide• INH• Ginko biloba• Ginseng
  • 22.  Epilepsy is often incorrectly diagnosed in the elderly  Causes of misdiagnosis include:  difficulty obtaining patient histories  absence of classic symptoms  attribution of symptoms to comorbid diseases  Elderly patients are often referred with a diagnosis of altered mental status, confusion, and memory lapsesCloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Treiman & Walker. Epilepsy Res 2006; 68 (Suppl 1): S77–S82
  • 23. Types of seizure  Majority of newly-diagnosed cases = partial onset epilepsy  incidence of partial onset seizures is 98% in epilepsy patients aged >75 years  Complex partial seizures most common seizure type –accounting for nearly 40% of seizures  After a stroke, initial seizure is often a secondary generalised partial seizureCloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Leppik. Geriatrics 2005; 60: 42–47; Ramsay et al., Neurology 2004; 62(Suppl 2): S24–S29
  • 24. • Classical aura less common• Post ictal phase can be prolonged• Todd’s paresis more common, often mistaken for Stroke• Atypical presentations of partial seizures- Dizziness, vague feeling related to head, memory loss & confusion
  • 25. Status Epilepticus (SE)  Incidence of SE ~5–10-fold higher in older individuals (most often partial SE)  Symptoms of non-convulsive SE are common with other elderly disorders – may lead to diagnostic difficulties  Mortality significantly greater in the elderly (36-50%) versus in younger adults (26%)  No specific treatment protocol for elderlyCloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Treiman & Walker. Epilepsy Res 2006; 68 (Suppl 1): S77–S82
  • 26. • Syncope• TIA• Hypoglycemia• Confusional episode due to overmedication• Dyselectrolytemia• Psychogenic
  • 27. • Brief runs of temporal slow activity after 50 yrs• small sharp spikes during sleep & drowsiness
  • 28. • Acute symptomatic seizure due to reversible condition- don’t treat• Unprovoked seizure- advisable to treat even if work up normal
  • 29.  Selection of AED therapy should be directed by:  tolerability  side effect profile  potential drug–drug interactions  Co-morbidityBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Geriatrics 2005; 60: 42–47; Leppik. Epilepsia 2006; 47 (Suppl1): 65–70
  • 30.  The ideal AED for the elderly should have the following properties:  Complete absorption  Linear pharmacokinetics  No active metabolites  Clearance unaffected by renal impairment  No induction/inhibition of hepatic enzymes  Broad-spectrum efficacy  No adverse cognitive effects  No effects on bone loss  Rapid titration  Range of formulations  Reasonable priceBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Geriatrics 2005; 60: 42–47; Leppik. Epilepsy Res 2006;68 (Suppl 1): S71–S76
  • 31.  In elderly, AEDs are the fifth highest cause of AEs among all drug categories  Dose-dependent and drug-specific AEs can occur at lower drug blood levels than in younger patients  AEs such as somnolence, dizziness and gait disturbances increase the risk of falls  Many AEs associated with AED use in elderly may be preventableBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Epilepsia 2006; 47 (Suppl 1): 65–70; Leppik. Geriatrics 2005;60: 42–47; Perucca et al., Epilepsy Res 2006; 68S: S49–S63; Ramsay et al., Neurology 2004; 62 (Suppl 2): S24–S29
  • 32.  In general, newer AEDs – fewer drug interactions  Older AEDs, particularly CBZ, PHT and PB, significant drug interactions  Side effect profile needs considering  VPA – not best choice in patients with tremor  CBZ – caution in patients with sodium balance issues  Newer AEDs – much more expensive  However, avoiding complications may balance extra costBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Epilepsia 2006; 47 (Suppl 1): 65–70; Perucca et al., Epilepsy Res2006; 68 (Suppl 1): S49–S63
  • 33. • Membrane stabilizing drugs(DPH,CBZ, LTG)- risk of promoting arrythmias• DPH, CBZ- used with caution in Autonomic dysfunction• CBZ- can precipitate urinary retention (anticholinergic effect)
  • 34. • Initiate with lower dosage than adults• slow titration with modest maintenance dose• renal, hepatic & plasma protein assessment before starting• Monotherapy better than polytherapy• Substitute first drug if not controlled• Drug combinations should be avoided/sparingly used• Blood levels whenever indicated
  • 35. • Most prescribed AED• Non linear kinetics• Age related decrease in metabolism• SE-ataxia, imbalance,• More common in elderly• Dose- 200mg/day 50 mg step increment• Relative contraindication in cardiac conduction defects
  • 36. • Dose & frequency adjustment needed• Use slow release preparations• Hyponatremia• Small risk of osteoporosis• Ataxia, dizziness more common• Dose- 100mg/day– increase 100 mg/ 2 weeks— 400mg/day maintenance
  • 37. • Sedation & depression• Cognitive dysfunction• Hepatic enzyme inducer-drug interactions• Low dose- 30-60 mg increase gradually
  • 38. • Age related decrease in clearance- prolonged half life• No hepatic induction- best PK profile among older AEDs for elderly• Don’t use if Hepatic disease• Dose- start 200mg/day 200 mg increment 600mg/day initial maintenance dose
  • 39. • Equally effective, often at lowes dosages than younger adults• Better tolerability• Lower risk of drug interaction• Reduced need for therapeutic drug monitoring Newer drugs approved for monotherapy- Oxcarbazepine,Lamotrigine,Levetiracetam
  • 40. • Safe in elderly if renal function is normal• Not metabolized, minimal protein binding so age doesn’t alter its metabolism/ distribution• Dosage- 900-1800 mg/day• SE- dizziness, somnolence, weight gain & pedal oedeme
  • 41. • Ca & Na channel blocker• Modest protein binding• Also has mood stabilizing & mood enhancing properties• Effective in both partial & gen seizures• Dose- 25 mg 100 mg maintenance 50-100 (VPA & LTG) 200 (Other C p450 inducer)
  • 42. • Structural analogue of CBZ• Better tolerability• Lower incidence of rash• SE- Hyponatremia , metabolism of Estrogen• Dose- 150 mg BD increase gradually
  • 43. • Rapid absorption, high bio-availability• No known drug interaction• Effective in low dosage• IV & syrup available• SE- somnolence, asthenia, in coordination, irritability, personality change• Dose- 125 mg increase 125-250 mg maintenance 750-1000 mg
  • 44. Levetiracetam dosage recommendations – patients with renal impairment  Dose adjustment recommended in elderly with compromised renal function Creatinine Group clearance Dosage and frequency (ml/min) Normal >80 500–1500 mg twice daily Mild 50–79 500–1000 mg twice daily Moderate 30–49 250–750 mg twice daily Severe <30 250–500 mg twice daily End-stage renal disease – 500–1000 mg once daily2 patients/undergoing dialysis1 1750 mg loading dose is recommended on first day of treatment with LEV 2Following dialysis, a 250 to 500 mg supplemental dose is recommendedE
  • 45. Other safety studies Comparison of LTG and CBZ in elderly patients with newly-diagnosed seizures Randomised, double-blind monotherapy study Conclusions  LTG – more completers (LTG 71%, CBZ* 42%; p<0.001)  LTG – lower drop-outs due to AEs (LTG 18%, CBZ* 42%)  Rash – AE most frequently associated with withdrawal (LTG 3%, CBZ* 19%)  LTG – higher SF in last 16 weeks of treatment (LTG 39%, CBZ* 21%; p=0.027)Brodie et al., Epilepsy Res 1999; 37: 81–87 *Not CBZ-CR
  • 46. Monotherapy studies LTG, GBP and CBZ in elderly patients with newly-diagnosed, partial-onset seizures Conclusions  Primary outcome measure: higher 12-month retention rates for GBP and LTG compared with CBZ*  Seizure freedom rates at 12 months: LTG 51.4%, GBP 47.4%, CBZ* 64.3%; p=ns  Terminations due to AEs: LTG 12.1%, GBP 21.6%, CBZ* 31%; p=0.001Rowan et al., Neurology 2005; 64: 1868–1873 *Not CBZ-CR
  • 47. Other safety studiesRetrospective evaluation of safety and tolerabilityof OXC therapy in elderly patients Retrospective evaluation Conclusions  No significant differences in premature discontinuations due to AEs (>65 vs. 18–64 years)  No significant changes in hepatic, renal, or haematological profiles  OXC tolerability in the elderly – similar to younger patientsKutluay et al., Epilepsy & Behav 2003; 4: 175–180
  • 48. Monotherapy studies (in progress)Comparison of LEV, LTG, and CBZ-CR as monotherapyin elderly patients with epilepsy Randomised, double-blind, Phase IV monotherapy trial (in progress) Objective  To compare safety, tolerability and efficacy of LEV versus LTG and CBZ-CR as monotherapy in newly- diagnosed patients, ≥60 years, with focal epilepsy Study design  360 patients expected to be enrolled  58-week treatment period Primary outcome  58-week retention rateWerhahn & Schroeder. ClinicalTrials.gov identifier: NCT00438451
  • 49.  Surgical intervention (lesionectomy or lobectomy) is an alternative to AED therapies, and may be suitable for:  those with comorbid conditions  medically intractable candidates  Palliative procedures (DBS, VNS) may also be options for elderly patientsGallo. Epilepsy Res 2006; 68 (Suppl 1): S83–S86
  • 50. Overall conclusion  Incidence of epilepsy – higher in elderly  AED use in elderly complicated by:  age-related changes in pharmacokinetics and pharmacodynamics  adverse drug reactions – increased risk due to comorbid conditions  Only two available randomised, double-blind trials  superior tolerability of newer AEDs (LTG, GBP)  further studies needed  Publications so far suggest LTG, LEV and GBP are preferred AEDs for elderly patientsBergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Karceski et al., Epilepsy & Behav 2005; 7 (Suppl 1): S1–S64; Leppik.Epilepsia 2006; 47 (Suppl 1): 65–70; Perucca et al., Epilepsy Res 2006; 68 (Suppl 1): S49–S63; Rowan et al., Neurology2005; 64: 1868–1873; Stephen et al., Epilepsy & Behav 2006; 8: 434–437
  • 51. • Have a higher degree of suspicion for diagnosis• use newer AEDs. Consider co-morbidity in selecting• Start with low dose & titrate slowly to a target dose of one half to two third of younger population• Boost the morale