Treatment of Epilepsy in Elderly population

Vijay SardanaMD; DM(Neurology)

Professor & HeadDeptt. Of Neurology,

Govt Medical college, Kota

Overview of problems in Elderly with Epilepsy

• 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

Epilepsy in Elderly: multiple drugs

• >65 yrs- elderly population- 13% Drug consumption- 32%

• Average elderly- 3 medicines in addition to AEDs

Proportion of elderly people in a developed country (Germany)

Increase in the proportion of the elderly in Germany (>65 years), 1910–2030 (projected)

1910 1950 1990 2030Year

20

40

0Prop

ortio

n of

pop

ulat

ion

(%)

Huying et al., Seizure 2006; 15: 194–197

10

30

50

5%

15%17%

27%

Epilepsy in Elderly

• 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

Incidence of epilepsy by age groupAge-specific incidence of epilepsy in Rochester, Minnesota, 1935–1984

Hauser et al., Epilepsia 1993; 34 (3): 453–468

Inci

denc

e (p

er 1

00,0

00)

50

150

100

00 20 40 60

Age

200

80

Implications of seizures in elderly

• 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

Changes in old age

Drug absorption in Elderly

• gastric acid secretion• Slowing of gastric emptying time• intestinal transit time• mesentric flow• Intestinal absorption surface

Bio-availability

Age-related pharmacokinetic alterations – II

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

Hepatic clearance in Elderly

• 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

Renal clearance in Elderly

• Decreased Renal mass, glomeruli

• GFR decline 50% by 8th decade

• AEDs primarily metabolized by kidney- Gabapentine, Levetiracetam, Prega)balin (also Topiramate, Zonisamide)

AED oral clearance in ElderlyDecrement

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

Protein binding

• 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

PHTlevels in hypoalbumenic states

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

Concomitant other drugs

• Cytochome p450 inhibitors-

H2 blockers, Erythromycin, Clrithromycin, Fluconazole, Ketoconazole, INH

Induction of cytochrome p450 by AEDs

• concentration of HMG- coA reductase inhibitors- Statins

• Low concetration of Warfarin- increased PT?INR

• Low concentration of Varapamil

AEDs and osteoporosis 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.

Elderly-: Acute symptomatic seizureEtiology

• CVA- 40-50%

• Metabolic disturbance- 10-15%

• Head injury- 5-10%

• Tumors- 5-10%

• Brain infections- 5-10%

Elderly: unprovoked seizuresEtiology

• CVA- 30-40%

• Post traumatic- 2-3%

• Old CNS infections- 2-3%

• Alzheimer's & other Neurodegenerative- 8-10%

• Cryptogenic- 40-50%

Stroke & Epilepsy in Elderly

• 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

Elderly & Drug induced seizures

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

Diagnosis/misdiagnosis

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

Clinical manifestations

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

Seizure in Elderly: characteristics

• 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

Clinical manifestations

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

Paroxysmal phenomenon mimicking seizures in Elderly

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

Confusing EEG changes

• Brief runs of temporal slow activity after 50 yrs

• small sharp spikes during sleep & drowsiness

Treatment

Single seizure in Elderly: to treat or not

• Acute symptomatic seizure due to reversible condition- don’t treat

• Unprovoked seizure- advisable to treat even if work up normal

AED selection

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

Ideal AED for elderly patients

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

AEDs and adverse events

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

Older versus newer AEDs

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 Res2006; 68 (Suppl 1): S49–S63

AEDs in elderly: systemic side effects

• 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)

General rules of treatment

• 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

Phenytoin

• 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

Carbamazepine

• 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

Phenobarbital

• Sedation & depression

• Cognitive dysfunction

• Hepatic enzyme inducer-drug interactions

• Low dose- 30-60 mg increase gradually

Sodium Valproate

• 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

Newer AEDs: advantages

• 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

Gabapentine

• 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

Lamotrigine• 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)

Oxcarbazepine• Structural analogue of CBZ

• Better tolerability

• Lower incidence of rash

• SE- Hyponatremia , metabolism of Estrogen

• Dose- 150 mg BD increase gradually

Levetiracetam• 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

Dose adjustment recommended in elderly with compromised renal function

Levetiracetam dosage recommendations – patients with renal impairment

E

GroupCreatinineclearance (ml/min)

Dosage and frequency

Normal >80 500–1500 mg twice dailyMild 50–79 500–1000 mg twice dailyModerate 30–49 250–750 mg twice dailySevere <30 250–500 mg twice daily

End-stage renal disease patients/undergoing dialysis1 – 500–1000 mg once daily2

1750 mg loading dose is recommended on first day of treatment with LEV2Following dialysis, a 250 to 500 mg supplemental dose is recommended

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)

Other safety studiesComparison of LTG and CBZ in elderly patients with newly-diagnosed seizures

Brodie et al., Epilepsy Res 1999; 37: 81–87

Randomised, double-blind monotherapy study

*Not CBZ-CR

Monotherapy studiesLTG, GBP and CBZ in elderly patients with newly-diagnosed, partial-onset seizures

Rowan et al., Neurology 2005; 64: 1868–1873

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

*Not CBZ-CR

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

Other safety studies Retrospective evaluation of safety and tolerability of OXC therapy in elderly patients

Kutluay et al., Epilepsy & Behav 2003; 4: 175–180

Retrospective evaluation

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

Monotherapy studies (in progress)Comparison of LEV, LTG, and CBZ-CR as monotherapy in elderly patients with epilepsy

Werhahn & Schroeder. ClinicalTrials.gov identifier: NCT00438451

Randomised, double-blind, Phase IV monotherapy trial (in progress)

Surgery

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

Conclusion

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

Take home

• 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

Thanks