New Onset of Epilepsy in the Elderly Dec 6, 2013

Transcription

1 New Onset of Epilepsy in the Elderly Dec 6, 2013 Ilo E. Leppik, MD Professor of Neurology and Pharmacy University of Minnesota American Epilepsy Society Annual Meeting

2 Disclosure During my almost 40 years in this field, I have received honoraria, consulting fees and or research grants from almost all companies developing or manufacturing drugs and devices related to epilepsy. The majority of my research funding has come from the NIH or other federal sources. My current commitments are: chairing the data and safety committee for the Medtronic deep brain stimulator and consulting with Eisai. Upsher Smith, UCB and Lundbeck.

3 Learning Objectives Appreciate complexities of choosing the optimal AED Learn about proper use of therapeutic drug monitoring in the elderly Understand the importance of life situations on the quality of life American Epilepsy Society 2013 Annual Meeting

4 Impact on Clinical Care and Practice Deciding if to treat after a single seizure Choosing the best AED for elderly Best use of AED monitoring

5 The Elderly with Epilepsy Community dwelling Nursing home Hospital intensive care unit

6 I m supposed to respect my elders But it s getting harder and harder for me to find one now

7 Health status is more important than age Young healthy Middle healthy Old healthy Young Medical problems Middle Medical Problems Old Medical problems Young frail Middle frail Old frail

8 Defining Epilepsy Classical = Two or more unprovoked seizures Could a single seizure in the context of a CNS disorder be diagnosed as epilepsy? Debate at AES 2007* A diagnostic must be assigned to prescriptions 345.xx (epilepsy) or (convulsion) Who makes the diagnosis in elderly? Very few neurologists involved A seizure may not be epilepsy Cardiac, Metabolic, Respiratory, Drugs/ alcohol, Infections *Fisher RS, Leppik IE. Debate:When does a seizure imply epilepsy? Epilepsia (Suppl 9); 7-12.

9 Etiology of Epilepsy, Age % 2% 5% 2% 51% Cryptogenic 51% Stroke 38% Degenerative 12% 38% Tumor 5% Trauma 2% Infection 2% Hauser WA, et al. Epilepsia. 1993;34:

10 Seizures in Alzheimer s Clinically apparent (mostly convulsive) seizures in Alzheimer s 7% to 21% of persons with sporadic AD have at least one unprovoked seizure. Seizure incidence increases in earlier onset AD* Risk ratio = 87 if onset Risk ratio = 3 if onset years of age *Amatniek et al. Epilepsia 2006; 47:

11 Incidence per 100,000 Community dwelling incidence (new cases/yr) 200 Age-Specific Incidence of Epilepsy By gender, in Rochester, MN Up-slope starts at age 50 ( ) (overall ~ 169/100 K PY) 150 Males Females Total Age (years) Hauser WA, et al. Epilepsies 1993; 34:

12 Incidence of Epilepsy in US Nursing Homes* US Medicare data base of 8 million plus subjects. Entry = No epilepsy on admission; 1-3 year of follow-up. 3,613,926 NH residents followed forward Overall = 1,642 / 100KPY (10 fold higher than outpatients) stroke = 2,762/ 100K PY. head injury= 4,566 /100K PY. Parkinson's Disease = 1,766/100K PY. dementia (any type) =1,644/100K PY. No predisposing diagnoses, 1,245/100K PY. Eberly LE, Leppik IE, Svendsen KH, Li S, Harms SL, Garrard, JM, Virning,B. Incident Epilepsy/Seizure Disorder in US Nursing Homes by Predisposing Conditions, Neurology 74 ; 2010 (Suppl 2): A42.

13 Prevalence (cases at a point in time) In Community higher as older * 1.8% identified as having epilepsy by having an ICD-9-CM code representative of this condition.* In nursing homes, lower as older** Overall 6% to 10% by ICD-9 codes 345.xx or % in 65-74; 8.3% in 75-84; 3.7% in 85+ In intensive care units*** 30% of patients following cardiorespiratory arrest., 1% to 21% with intracerebral hemorrhage, *Pugh MJV, et al. Potentially inappropriate antiepileptic drugs for elderly patients with epilepsy. J Am. Geriatric Soc. 2003; 52., **Leppik. I. Epilepsy. In: Hazzard's Geriatric Medicine & Gerontology, Sixth Edition Eds: Jeffrey B. Halter et al New York, NY, McGraw-Hill Inc, 2009: Chapter 69; ***Sutter R, Stevens RD, Kaplan PW. Continuous electroencephalographic monitoring in critically ill patients: indications, limitations, and strategies. Crit Care Med. 2013; 41: Leppik 2007

14 Seizure Types GTC 27.1% CPS 38.3 % Mixed Partial 7.5% SPS 14.3 % GTC & Partial 12.8% Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-9 VA Coop Study #428*

15 Geriatric Epilepsy Management Aging Process Underlying Pathology Seizure Frequency Management Comorbidities Pharmacokinetics Medication Side Effects

16 Co-morbidities-medical Incidence and severity of these are unknown Depression Anxiety Visual impairment Osteoporosis Memory loss Other medical disorders Leppik 2011

17 Social Issues Loss of driving privileges Lack of spousal support Emotional shock of developing epilepsy Cost of medication Fear of seizures, falling, embarrassment Adult children of parents (role reversal from pediatric practice) Leppik 2011

18 First Seizure in Elderly: To treat or not to treat, that is the question Reasons to treat Prevent another seizure What is the risk of 2 nd seizure After a stroke,in Alzheimer s, etc? Unknown etiology? Reason not to treat Cognitive side-effects Increasing falls and fractures

19 First seizure in Elderly Prospective observational study of adults seen by a hospital-based first seizure service between 2000 and 2011 #. The likelihood of a second seizure at one year was 53% (95% CI 45-62) in older patients and 48% (95% CI 44-51) in younger patients. Independent predictors of seizure recurrence were: remote symptomatic etiology. first seizure arising from sleep. epileptiform abnormality on EEG. partial seizures. not age. # Lawn N, Kelly A, Dunne J, Lee J, Wesseldine A. First seizure in the older patient: Clinical features and prognosis. Epilepsy Res Sep 2. pii: S (13) doi: /j.eplepsyres [Epub ahead of print].

20 2 nd seizure after 1 st seizure: stroke 159 patients Early-onset seizures occurred in 57 patients late-onset (>14 days post-stroke) in 102 patiens 68 (43%) with 1 st seizure had recurrence Risk factors for more seizures Late onset 1 st seizure (p>0. 01) Hemorrhagic component Occipital involvement Low Rankin score after 1 st seizure Berges S, Moulin T, Berger E, Tatu L, Sablot D, Challier B, Rumbach L. Seizures and epilepsy following strokes: recurrence factors. Eur Neurol. 2000;43(1):3-8.

21 WHICH AED? Ideal Properties of an AED for Elderly Efficacy Safety No drug interactions Good bioavailability Linear elimination kinetics Wide therapeutic index Weight neutral Renal elimination Broad spectrum No protein binding Parenteral formulations Lack of idiosyncratic effects Ideal AED for patient : The one that works

22 Summary of Properties ZNS TPM LEV LTG GBP VPA PHT () CBZ IV Renal Excretion No relevant interactions Efficacy AED Safety Broad Spectrum ()

23 GBP,LTG,CBZ in Elderly* 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day CBZ 600 mg/day Early terminations: LTG 44.2%, GBP 51% CBZ 64.5% (p = ) Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures. *Rowan AJ, Ramsay RE, Collins JF et alva Study 428 group. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology Jun 14;64(11):

24 Studies of Other AEDs in Elderly LEV vs CBZ, 128 patients, prospective, 1 year* no significant difference in number of seizure-free patients between LEV and CBZ (p = 0.08); LEV caused significantly fewer (p = 0.02) side effects than CBZ; attention deficit, frontal executive functions and functional scales) were significantly worse in the CBZ group. Lamotrigine vs CBZ, double-blind, newly diagnosed 125 eligible subjects** A borderline difference in the SEALS Dysphoria subscores favored lamotrigine. Neither LTG nor CBZ seems likely to cause significant changes in health-related quality of life measure at therapeutic doses. Zonisamide pooled analysis of data from clinicall studies (N=95)*** Incidence was lower in elderly versus adult patients for treatment-related TEAEs (55.8% vs. 72.7%), severe TEAEs (11.6% vs. 20.4%), serious TEAEs (12.6% vs. 16.6%), and TEAEs leading to withdrawal (17.9% vs. 22.1%) *Consoli D, et al. Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective randomized open-label study (EpIC Project). Cerebrovasc Dis. 2012;34(4): **Saetre E, et al. Antiepileptic drugs and quality of life in the elderly: results from a randomized double-blind trial of carbamazepine and lamotrigine in patients with onset of epilepsy in old age. Epilepsy Behav Mar;17(3): ***Trinka E, Segieth J, Giorgi L. TOLERABILITY AND SAFETY OF ZONISAMIDE IN ELDERLY PATIENTS WITH PARTIAL EPILEPSY: RESULTS OF A POOLED ANALYSIS. J Neurol Neurosurg Psychiatry Nov;84(11):e2. doi: /jnnp

25 Evidence for choosing among AEDs in elderly There is some evidence for superiority of newer AEDs over CBZ No comparisons for phenytoin vs newer AEDs My opinion: Avoid AEDs with significant drug interactions Elderly healthy are like women of childbearing potentialmay have new medical conditions next visit. Avoid AEDs that are highly protein bound Favor AEDs with long half-lives Favor AEDs with suspension, sprinkle or IV formulations

26 Polypharmacy in the Elderly All elderly are treated with polypharmacy, but only one of them is an AED. Many studies have been done about AED-AED interactions, - But very few about AED- other drugs

27 Effect of Enzyme-Inducing AEDs Non-AEDs Anticoagulants Warfarin Clopidogrel Plasma Level Reduction 50%??? 3A4/5 metabolism Ca-channel blockers 30% 93% Statins 50% 80% Antidepressants 27% 31% Levy RH, et al, eds. Antiepileptic Drugs. 5th ed., 2002.

28 Simvastatin acid ( g/ml) Simvastatin ( g/ml) Effect of CBZ on Serum Simvastastin 2 subjects a Placebo CBZ Time (Hours) b Placebo CBZ Ucar M, et al. Eur J Clin Pharmacol. 2004;51: Time (Hours)

29 Age-related changes affecting PK and TDM Pharmacokinetics (PK) Absorption Gastric Ph GI transit time Elimination Hepatic Renal Therapeutic Drug Monitoring (TDM) Protein binding Of AED Of other drugs

30 Indications for Therapeutic Drug Monitoring* When therapeutic goal has been reached At least 4 half-lives beyond dose change Side-effects Breakthrough seizure Co-medications added or removed Change in health status Monitor compliance Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia Jul;49(7):

31 Case report: The woman who inspired me 76 year old woman from northern Minnesota Developed complex partial seizures, poorly controlled Local MD prescribed phenytoin and valproate Developed Alzheimer's and Parkinson s Total AED levels normal range Sent to MINCEP last stop before NH. Unbound levels high Lived for 18 more years after adjustment of AEDs enjoying independent life, Into NH because of lack of care givers and arthritis We traded copies of our books; she wrote it in NH because she did not want to partake in activities with the old people! Lived to 94 years of age

32 The woman who inspired me 2 decades ago

33 AED Concentration Effect of Age on AED Dosing Ranges Risk of Toxicity Dosing Ranges Risk of Seizures Adults Elderly adapted from: Bergey GK. Neurology. 2004;63:S Cloyd J. In: Seizures and epilepsy in the elderly

34 TDM Caveats Usual laboratory values are inappropriate Abnormal protein binding Elderly may need lower concentrations for efficacy May have side-effects more readily Unbound (free) levels needed for AEDs that have binding greater than 70% Monitoring of drugs other than AEDs should be done (but is rarely performed) Usual fluctuations in compliant outpatients is less than 20%, but levels in some NH patients bounce more than 200%.

35 Total PHT Concentrations (ug/ml) 35 Individual Total Phenytoin Serum Concentrations in Elderly Nursing Home Residents 30 Aged (n=18) Aged (n=21) Aged 85+ (n=17) Individual elderly residents categorized into age group at enrollment Birnbaum A, Leppik IE et al. Neurology. 2003;60:555-9.

36 Conclusions Epilepsy is common in elderly Elderly have many co-morbidities Although there is little evidence for it, the first seizure in elderly often leads to treatment Because of drug interactions of AEDs with other drugs, those AEDs with few interactions are preferred TDM is important but laboratory ranges may not be appropriate. Much more research needs to be done in elderly.

37 Choosing the right dose is important. Use TDM to guide.