|Year : 2007 | Volume
| Issue : 1 | Page : 34-38
Anti epileptic drug usage and withdrawal in elderly persons with epilepsy
Nisha Jacob, Sanjeev V Thomas, PS Sarma
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
Sanjeev V Thomas
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Prevalence of epilepsy is highest among the elderly, but precise data on the clinical profile and response to pharmacotherapy are not readily available from the developing countries. Objective: To ascertain the clinical spectrum, pharmacotherapy, efficacy, tolerability and the outcome of treatment of epilepsy in the elderly. Materials and Methods: This study was carried out in a tertiary referral epilepsy center in Kerala State, India. We had restricted the analysis persons aged 60 years and above with two or more seizures, that we identified from the registers in the electroencephalography laboratory and medical records departments for the period 2001-2004. Data abstracted on standard forms was analyzed with SPSS package. Results: There were 116 persons (68 men) included in this study. The first seizure was after 60 years of age for 91 persons (78.4%) and the mean duration of follow up was 34.7 ± 48.3 months. Seizures were generalized tonic clonic (GTCS) for 43 and partial with or without generalization for 72 patients. One year remission was 55.8% for patients with follow-up > 12 months. Anti epileptic drug was withdrawn in 59 patients during the follow-up period, the reasons being achievement of remission 29 (49.2%), poor efficacy 14 (23.7%), adverse drug effects 9 (15.3%) and other reasons 7 (11.9%). There were 77 patients who had other concomitant illnesses (mean 2.3 drugs per person) taking other medicines (mean 2.3 drugs per persons) with potential risk of adverse drug interaction. Conclusion: Epilepsy in the elderly can be due to several underlying causes and two-third of them are likely to have other concomitant disorders requiring other drug therapy. Potential risk of drug interactions needs to be carefully evaluated while initiating pharmacotherapy for epilepsy in the elderly.
Keywords: Adverse drug effects, anti epileptic drug withdrawal, epilepsy elderly
|How to cite this article:|
Jacob N, Thomas SV, Sarma P S. Anti epileptic drug usage and withdrawal in elderly persons with epilepsy. Ann Indian Acad Neurol 2007;10:34-8
| Introduction|| |
The management of epilepsy in the elderly is of great concern due to the unique challenges in the diagnosis and the drug therapy. The proportion of elderly people is rapidly growing and the incidence of epilepsy is highest in them. According to 2001 census, there are 77 million elderly (aged above 60 years) people in India, some 75% of them are living in rural areas, 48.2% of them are women and 66% of older persons live in a vulnerable situation without adequate food, clothing and shelter. According to UN Projections, in the year 2025, a projected 1.2 billion elderly people will be living in the world; 71 percent of them are likely to be in the developing regions. Studies also confirm that the prevalence of active epilepsy increases with age in the elderly. Aging appears to be a definite risk factor for partial epilepsy and possibly for generalized-onset epilepsy. According to case-control studies, aging alone may have an epileptogenic effect on the neuron. The age-related changes in physiology and the presence of concomitant medical conditions like hepatic and renal diseases in the elderly may change the pharmacodynamics and pharmacokinetics of the drugs. They are often prescribed other medications, which increase the risk of drug interactions. The mean number of co-medications reported is 6.7 in the elderly population. This makes them prone to several adverse drug reactions, the consequences of which can be catastrophic. Hence physicians must give much importance to the tolerability and the potential of the anti epileptic drug (AED) to give rise to drug interactions while selecting an AED for the elderly. There is not much data on the AED prescription practice or concomitant treatment in the elderly persons living in developing countries that could form the basis for setting evidence based treatment plan for them. Optimal treatment of epilepsy in the elderly requires the understanding of the clinical characteristics of the different seizure types as well as the AEDs that are effective in them and knowledge of the altered pharmacokinetics and interactions of drug therapy. Our objective was to study the treatment of epilepsy in the elderly in a tertiary referral center in India in order to identify the clinical spectrum, pharmacotherapy, efficacy, tolerability and the outcome of treatment.
| Materials and Methods|| |
The study was carried out in the setting of a tertiary epilepsy care center. We identified patients with epilepsy aged 60 years or more by scrutinizing the registers (2001-2004 year period) maintained in the medical records department (in-patient and out-patient care) and the electroencephalography (EEG) laboratories. Patients who had two or more seizures only were included. All cases with non-epileptic events, cardiogenic syncope, psychogenic seizures, transient ischemic attacks and loss of consciousness were excluded. The seizures were classified according to the ILAE terminology. Seizures that occurred in relation to acute neurological insults or medical conditions were distinguished from remote symptomatic seizures.The demographic and clinical characteristics, details of pharmacotherapy and seizure frequency were abstracted from the medical records on a standard proforma. The seizure frequency was recorded according to Engel's score. The prescribed daily dosage (PDD) of individual AEDs was compared with the defined daily dosage (DDD) modified for the body weight of a standard Indian. The modified DDD for the AEDs were Phenobarbitone - PB 75 mg, Carbamazepine - CBZ 800 mg, Phenytoin - PHT 200 mg, Sodium Valproate - VPA 1000 mg, Clobazam - CLB 15 mg, Clonazepam - CLZ 6 mg, Lamotrigine LTM 200 mg, Oxcarbazepine - OXB 1200 mg. We entered the data on a standard proforma, transferred the same to Excel spreadsheet and used SPSS for windows 14 software to carry out statistical analysis.
| Results|| |
There were 116 patients (men 68, 58.6%, women 48, 41.4%) with age 60 years or more evaluated in this Institute during the study period. Their age at the time of registration ranged from 60-64 years (44), 65-69 years (44), 70-74 years (21), 75-79 years (4) and 80-84 years (2), more than 85 years (1). The age of onset of epilepsy ranged as follows: less than 50 years 12 (10.3%), 50-59 years 12 (10.3%), 60-69 years 68 (58.6%), 70-79 years 21(18.1%), 80-89 years 3 (2.6%). The mean duration of epilepsy 5.4 + 12.8 years.
There were 72 patients with partial seizures with or without generalization 43 with generalized seizures. The epilepsy syndrome was classified as Generalized Epilepsy (GE) for 38 persons (32.8%), as Localization Related Epilepsy - (LRE) for 69 persons (59.5%) and as unclassified for 9 persons (7.8%).
The neurological examination was abnormal in 66 patients (56.9%). EEG examination (n= 131 revealed epileptiform discharges in 31 records (23.7%). The CT scan findings (n=89) included normal scan 32, infarct 23, intracranial tumors 16, cerebral atrophy 7, hemorrhage, AVM and calcification three each and ring lesion 1. DSA was performed in six patients and it had confirmed bilateral carotid occlusion (one), dural arteriovenous fistula (one), venous angioma (one) and tumor-related changes (two). There were 44 persons who also had other neurological conditions (vascular disorders 21, myeloradiculopathy 9, peripheral neuropathy and central nervous system tumors 6 each, dementia and headache two each), hydrocephalus 1 (.9%).
The seizure frequency and pharmacotherapy at the time of entry to the study and at last follow-up are compared in [Table - 1].
There were 91 persons with follow-up for more than one month (mean 34.7 + 48.3 months). The total follow up duration was 3022 patient-months. Monotherapy was employed in 80% of patient. The others required polytherapy. The mean + SD, PDD/DDD ratio for different AEDs used while under follow up in this Institute was 1.18 + 0.47 (range 0.3 to 2.4). There were 163 AED exposures (either as monotherapy or polytherapy) for these patients during the follow-up period in this Institute (Phenobarbitone 19, phenytoin 89, carbamazepine 30, sodium valproate 17, others 8). AEDs were withdrawn for 59 patients, the reasons being achievement of remission (29), poor efficacy (14), adverse drug reaction (9) or other reasons (7).
During the follow-up period, 89 patients were hospitalized (range 1-4). Indications for hospitalization were management of seizures (34), evaluation of other neurological disorders (27) and other reasons (12). Some ten patients had more than one reason for admission. There were seven patients who had status epilepticus.
There were 52 patients (GE 20, LRE 29) who had follow-up for more than 12 months, 29 of them (GE 12 patients - 60%, LRE 15 patients - 51.7%) had remained seizure-free (remission) for 12 or more months. The percentage of remission was higher among those who had normal CT scan (80%) or MRI (66.6%) when compared to those with abnormal scans but the difference was not statistically significant (0.07). With regard to the seizure type and remission, 63.6% of those who had GTCS, as against 44.8% of those with partial seizures + secondary generalization had achieved one year remission. One-year remission was observed more frequently with GE (60%) when compared to LRE (48.3%). The remission rate for those on monotherapy was 52.8% while that for those on polytherapy was only 25%.
At the time of the last follow-up, 65 patients were continuing AEDs - 55 patients (84.6%) as monotherapy [Table - 1]. During the follow-up, AED was withdrawn in 59 patients, the reasons being remission (29 patients, 49.2%), poor efficacy (14 patients, 23.7%), intolerance (nine patients, 15.3%) and other reasons (seven patients, 11.9%).
There were 77 patients who had other concomitant illnesses including hypertension (49), diabetes (31), dyslipidaemia (nine), cardiovascular disorders (25), respiratory diseases (seven), psychiatric illnesses (five), endocrine disorders (three), tumors involving other parts of the body (three) and other disorders (five). Some 26 patients were not taking any other medicines. The average number of medicines per person was 2.3 drugs. Medications used by others included anti-hypertensives (46), anti-platelet agents (43) oral hypoglycaemic agents (17), anti-lipidemic agents (15), cardiovascular drugs (12), insulin (11), psychotropic agents (seven), beta agonists (three), thyroxin (five), drugs acting on intestinal motility (four) oral anticoagulants (three), theophylline (two), diuretics (three), steroids (two), donepezil (two), anti-tuberculosis treatment (two) and miscellaneous drugs in five patients.
| Discussion|| |
We have analyzed the demographic and clinical characteristics of 116 persons aged 60 years or more attending to one tertiary referral center. In this series the etiology of epilepsy was idiopathic in 25 patients (38.5%). In the Rochester community-based study, idiopathic epilepsy was lowest (49%) in those aged 65 years or more and highest (84%) in the age group of 15-34 years. Prevalence of idiopathic generalized epilepsy in this series was lower (11.8%) than that reported from an institution in Japan (15.3%). In the Japanese study, 76.3% patients had symptomatic partial epilepsy while there were only 67.62% with LRE in this series . The commonest disorders causally associated with epilepsy in the elderly are vascular disorders (32.4%), degenerative disorders (11.5%), trauma (3.3%) and neoplasms (2.7%).3 In this series there were more neoplasms (10.4%) while degenerative diseases were less (6%). Several community studies have confirmed that stroke is an important cause of seizures and epilepsy in the elderly.,,,
Majority of patients in this series had frequent seizures and were on polytherapy at the time of referral to this Institute. Nevertheless good seizure control could be achieved with monotherapy in 80% of them. The one-year remission rate for those with follow-up more than 12 months was lower (50%) than that (75%) for the community based data from United States. This could be a referral bias due to preferential referral of difficult to treat cases being referred to this tertiary referral center. The proportion of patients who achieved one-year remission was higher in those with generalized seizures, generalized epilepsy, normal imaging and monotherapy. The numbers were too small to make any statistical assessment.
Among the different AEDs used, PHT was the most frequently used drug (61.84%) followed by CBZ, PB and valproate. Newer AEDs were under utilized probably because of prohibitive cost and less clinical experience with them [Table - 2]. In a study of nursing home residents elsewhere, PHT was found to be the most commonly used AED. In a community based study, phenytoin was prescribed as an initial medication in slightly more than half (52%) of the patients with seizures and carbamazepine and valproate (VPA) were the next most commonly prescribed. The availability of intravenous formulation and absence of sedative effect make PHT a favorable drug for initiation in the elderly especially when they are admitted with acute seizures. However, elderly persons are more prone to the adverse effects of PHT such as cardiac arrhythmia, hypotension, ataxia and peripheral neuropathy and osteoporosis. PHT is approximately 90% bound to plasma proteins and its free fraction is likely to be higher in the elderly who have reduced serum albumin levels.
It is important to note that AEDs were withdrawn for reasons other than remission in 30 patients (55.5% of all AED withdrawals). In this study 15.3% of patients had adverse effects resulting in discontinuation of the drug. In the community-based study in USA, 27% patients experienced adverse events resulting in discontinuation of the initial AED.
In this study, 77 patients had other concomitant illnesses and 63.63% patients were detected to have hypertension, 40.25% patients had diabetes and 3.89% patients had cancer. In a large cohort from USA, 64% of patients presented clinically with hypertension less than one-third of patients were diabetic and less than one-fourth had a history of cancer. The possibility of developing seizures increases five-fold in hypertensive patients.
Nearly four fifth of patients in this series were taking one or more other medications besides AEDs. The mean number of co medications in this study was much less (2.3) than that used elsewhere (5-7).,, There were 56 instances where the other medications could potentially interact with AEDs. Verapamil can potentially increase the blood level of CBZ by inhibiting its metabolism. Enzyme inducing AEDs such as PB, PHT and CBZ could reduce the effect of warfarin and other oral anticoagulants by enhancing its hepatic metabolism. AEDs have a similar effect on tricyclic antidepressants (TCA) while TCAs in turn increase the blood level of AEDs.,, AEDs with least potential for drug interactions would be preferable in such instances. Newer AEDs have several pharmacokinetic and pharmacodynamic advantages over conventional drugs when prescription in elderly is considered. Gabapentin may be recommended as initial monotherapy or add-on therapy for treating seizure disorders in elderly who take several medications. A recent study has shown that oxcarbazepine is safe to use in elderly patients and that its tolerability in this age group is similar to that of younger adult patients. Lamotrigine is weakly bound to plasma proteins and being extensively metabolized by the liver, is beneficial for patients with severe renal disease. In another study including 150 elderly patients with newly diagnosed epilepsy, lamotrigine was found to be superior to carbamazepine in having fewer side-effects, better patient completion and outcome and the ability to reduce seizures. Since one in four patients runs the risk of potential drug interaction, care should be taken while prescribing AEDs in the elderly.
There are several limitations for this retrospective study that included only those patients who had attended this referral center. There were few patients above the age of 80 years making it difficult to demonstrate the clinical characteristics of epilepsy and the drug therapy in the very old. Nevertheless, our results agree with observations from other studies in that, epilepsy is a common neurological problem in the elderly. The prognosis of epilepsy in the elderly is comparable to that in the other age groups and depends on the type of epilepsy and associated brain damage. Over three fourth of them have one or more co morbidities and would be taking co medications that may have a bearing on the selection and use of AEDs. Physicians need to carefully assess the potential risk of altered metabolism of AEDs and possible interactions with other commonly used medicines in the elderly.
| References|| |
|1.||Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993;34:453-68. [PUBMED] |
|2.||de la Court A, Breteler MM, Meinardi H, Hauser WA, Hofman A. Prevalence of epilepsy in the elderly: The Rotterdam Study. Epilepsia 1996;37:141-7. [PUBMED] |
|3.||Hauser WA. Seizure disorders: The changes with age. Epilepsia 1992;33:S6-14. [PUBMED] |
|4.||Ng SK, Hauser WA, Brust JC, Healton EB, Susser MW. Risk factors for adult - onset first seizures. Ann Neurol 1985;18:153. |
|5.||Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989;9:297-301. [PUBMED] |
|6.||Schachter SC. Antiepileptic drug therapy: General treatment principles and application for special patient populations. Epilepsia 1999;40:S20 - 5. [PUBMED] |
|7.||Ramsay RE, Rowan AJ, Pryor FM. Special considerations in treating the elderly patient with epilepsy. Neurology 2004;62:S24-9. [PUBMED] [FULLTEXT]|
|8.||Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489-501. [PUBMED] |
|9.||Thomas SV, Koshy S, Sudhakaran Nair CR, Sarma SP. Frequent seizures and polytherapy can impair quality of life in persons with epilepsy. Neurol India 2005;53:46-50. |
|10.||Hiyoshi T, Yagi K. Epilepsy in the elderly. Epilepsia 2000;41:31-5. [PUBMED] |
|11.||Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Epileptic seizures after a first stroke: The Oxfordshire community stroke project. BMJ 1997;315:1582-7. [PUBMED] [FULLTEXT]|
|12.||Loiseau J, Loiseau P, Duche B, Guyot M, Dartigues JF, Aublet B. A survey of epileptic disorders in southwest France: Seizures in elderly patients. Ann neurol 1990;27:232-7. [PUBMED] |
|13.||Ruggles KH, Haessly SM, Berg RL. Prospective study of seizures in the elderly in the Marshfield Epidemiologic Study Area (MESA). Epilepsia 2001;42:1594-9. [PUBMED] [FULLTEXT]|
|14.||Luhdorf K, Jensen LK, Plesner AM. Etiology of seizures in the elderly. Epilepsia 1986;27:458-63. [PUBMED] |
|15.||Garrard J, Cloyd JC, Gross C, Hardie N, Thomas LW, Lackner TE, et al . Factors associated with antiepileptic drug use among elderly nursing home residents. J Geriontol A Biol Sci Med Sci 2000;55:M384-92. |
|16.||Greenblatt DJ. Reduced serum albumin concentration in the elderly: A report from the Boston Collaborative Drug Surveillance Program. J Am Geriatr Soc 1979;27:20-2. [PUBMED] |
|17.||Ng SK, Hauser WA, Brust JC, Susser M. Hypertension and the risk of new-onset unprovoked seizures. Neurology 1993;43:425-8. [PUBMED] |
|18.||Lackner TE, Cloyd JC, Thomas LW, Leppik IE. Antiepileptic drug use in nursing home residents: Effect of age, gender and comedication on patterns of use. Epilepsia 1998;39:1083-7. [PUBMED] |
|19.||Cloyd JC, Lackner TE, Leppik IE. Antiepileptic drugs in the elderly: Pharmacoepidemiology and pharmacokinetics. Arch Family Med 1994;3:589-98. [PUBMED] |
|20.||Wurden CJ, Levy RH. Carbamazepine: Interactions with other drugs. In : Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. Lippincott Williams and Wilkins: Philadelphia; 2002. p. 247-61. |
|21.||Freedman MD, Olatidoye AG. Clinically significant drug interactions with the oral anticoagulants. Drug Saf 1994;10:381-94. [PUBMED] |
|22.||Monaco F, Cicolin A. Interactions between anticonvulsant and psychoactive drugs. Epilepsia 1999;40:S71-6. [PUBMED] |
|23.||Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 1984;25:S118-31. [PUBMED] |
|24.||Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia 2002;43:365-85. [PUBMED] [FULLTEXT]|
|25.||Martin R, Meador K, Turrentine L, Faught E, Sinclair K, Kuzniecky R, et al . Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia 2001;42:764-71. [PUBMED] [FULLTEXT]|
|26.||Kutluay E, McCague K, D'Souza J, Beydoun A. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy Behav 2003;4:175-80. [PUBMED] [FULLTEXT]|
|27.||Rowan AJ. Reflections on the treatment of seizures in the elderly population. Neurology 1998;51:S28-33. [PUBMED] |
|28.||Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res 1999;37:81-7. |
[Table - 1], [Table - 2]