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

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 2030
Huying 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
Age
Hauser 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

9. • gastric acid secretion
• Slowing of gastric emptying time
• intestinal transit time
• mesentric flow
• Intestinal absorption surface
Bio-availability

10. 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-life
Leppik. Epilepsia 2006; 47 (Suppl 1): 65–70; Leppik. Geriatrics 2005; 60: 42–47; Perucca et al., Epilepsy Res 2006; 68S: S49–S63

11. • 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

12. • Decreased Renal mass, glomeruli
• GFR decline 50% by 8th decade
• AEDs primarily metabolized by kidney- Gabapentine,
Levetiracetam, Prega)balin (also Topiramate, Zonisamide)

13. • CBZ 25-40%
• PHT about 25%
• VPA about 40%
• PB about 20%
• LTG about 35%
• Gabapentine 30-50%
• Levetiracetam 20-40%

14. • 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

15. Corrected Pht level (micro g/ ml) –
measured PHT level
0.2 × Albumin( G/dl) + 0.1

16. • Cytochome p450 inhibitors-
H2 blockers, Erythromycin, Clrithromycin,
Fluconazole, Ketoconazole, INH

17. • concentration of HMG- coA reductase inhibitors-
Statins
• Low concetration of Warfarin- increased PT?INR
• Low concentration of Varapamil

18.  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 fractures
Bergey 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.

19. • CVA- 40-50%
• Metabolic disturbance- 10-15%
• Head injury- 5-10%
• Tumors- 5-10%
• Brain infections- 5-10%

20. • CVA- 30-40%
• Post traumatic- 2-3%
• Old CNS infections- 2-3%
• Alzheimer's & other Neurodegenerative- 8-10%
• Cryptogenic- 40-50%

21. • 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

22. • chlorpromazine
• Quitipine
• clozepine
• Cephalosporins
• Penicillin
• TCAs
• Venelafaxin
• Metoclopramide
• INH
• Ginko biloba
• Ginseng

23.  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 lapses
Cloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Treiman & Walker. Epilepsy Res 2006; 68 (Suppl 1): S77–S82

24. 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 seizure
Cloyd 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

25. • 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

26. 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 elderly
Cloyd et al., Epilepsy Res 2006; 68 (Suppl 1): S39–S48; Treiman & Walker. Epilepsy Res 2006; 68 (Suppl 1): S77–S82

27. • Syncope
• TIA
• Hypoglycemia
• Confusional episode due to overmedication
• Dyselectrolytemia
• Psychogenic

28. • Brief runs of temporal slow activity after 50 yrs
• small sharp spikes during sleep & drowsiness

30. • Acute symptomatic seizure due to reversible
condition- don’t treat
• Unprovoked seizure- advisable to treat even if work
up normal

31.  Selection of AED therapy should be directed by:
 tolerability
 side effect profile
 potential drug–drug interactions
 Co-morbidity
Bergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Geriatrics 2005; 60: 42–47; Leppik. Epilepsia 2006; 47 (Suppl
1): 65–70

32.  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 price
Bergey 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

33.  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 preventable
Bergey 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

34.  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 cost
Bergey et al., Adv Stud Med 2006; 6 (3C): S195–S209; Leppik. Epilepsia 2006; 47 (Suppl 1): 65–70; Perucca et al., Epilepsy Res
2006; 68 (Suppl 1): S49–S63

35. • 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)

36. • 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

37. • 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

38. • 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

39. • Sedation & depression
• Cognitive dysfunction
• Hepatic enzyme inducer-drug interactions
• Low dose- 30-60 mg
increase gradually

40. • 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

41. • 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

42. • 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

43. • 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)

44. • Structural analogue of CBZ
• Better tolerability
• Lower incidence of rash
• SE- Hyponatremia , metabolism of Estrogen
• Dose- 150 mg BD
increase gradually

45. • 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

46. 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 recommended
E

47. 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

48. 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=0.001
Rowan et al., Neurology 2005; 64: 1868–1873 *Not CBZ-CR

49. Other safety studies
Retrospective evaluation of safety and tolerability
of 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
patients
Kutluay et al., Epilepsy & Behav 2003; 4: 175–180

50. Monotherapy studies (in progress)
Comparison of LEV, LTG, and CBZ-CR as monotherapy
in 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 rate
Werhahn & Schroeder. ClinicalTrials.gov identifier: NCT00438451

51.  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 patients
Gallo. Epilepsy Res 2006; 68 (Suppl 1): S83–S86

52. 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 patients
Bergey 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., Neurology
2005; 64: 1868–1873; Stephen et al., Epilepsy & Behav 2006; 8: 434–437

53. • 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