Abstracts
Epilepsy is very prevalent among elderly inpatients and treatment is far from ideal.
Objective
To analyze prescribing patterns of antiepileptic drugs (AEDs) for hospitalized elderly with epilepsy, their relations with comorbidities and comedications.
Method
We assessed prescription regimen of elderly patients that were under AED use for treatment of epileptic seizures, during hospitalization. One hundred and nine patients were enrolled. AED regimen was categorized into two groups: Group 1 defined as appropriate (carbamazepine, oxcarbazepine, valproic acid, gabapentin, clobazan and lamotrigine) and Group 2 as inappropriate (phenytoin and phenobarbital).
Results
We found 73.4% of patients used inappropriate AEDs (p<0.001). Monotherapy was prescribed for 71.6% of patients. The most common comorbidity was hypertension. Potentially proconvulsant drugs as comedications were used for nearly half of patients.
Conclusion
Inappropriate AED therapy was commonly prescribed regimen for elderly inpatients. Some recommendations are discussed for a better care of elderly inpatients with epilepsy.
antiepileptic drugs; elderly; epilepsy; epileptic seizures
Epilepsia é frequente entre idosos hospitalizados e o tratamento costuma ser aquém do ideal.
Objetivo
Analisar os padrões de prescrição de drogas antiepilépticas para idosos hospitalizados com epilepsia, bem como sua relação com comorbidades e comedicações.
Método
Revisamos os prontuários de pacientes idosos internados com diagnóstico de epilepsia e que estavam em uso de droga antiepiléptica (DAE) durante o período de hospitalização. Cento e nove pacientes foram incluídos no estudo. O regime de DAE foi categorizado em dois grupos: Grupo 1, definido como apropriado (carbamazepina, oxcarbazepina, ácido valpróico, gabapentina, clobazam e lamotrigina) e Grupo 2, como inapropriado (fenitoína e fenobarbital).
Resultados
73,4% dos pacientes usaram DAE inapropriadas (p<0,001). Regime de monoterapia foi usado por 71,6% dos pacientes. Hipertensão arterial foi a comorbidade mais frequente. Medicações concomitantes potencialmente proconvulsivantes foram usadas por quase metade desta população.
Conclusão
Regime de droga antiepiléptica inapropriada foi o mais utilizado em pacientes idosos internados. São discutidas algumas recomendações para melhor cuidado ao paciente idoso hospitalizado com epilepsia.
drogas antiepilépticas; idosos; epilepsia; crises epilépticas
Epilepsy is a common serious chronic neurological condition of the central nervous system
(CNS) leading to poor quality of life and substantial morbidity and mortality11 . Banerjee PN, Filippi D, Allen Hauser W. The descriptive
epidemiology of epilepsy-a review. Epilepsy Res. 2009;85(1):31-45.
http://dx.doi.org/10.1016/j.eplepsyres.2009.03.003.
https://doi.org/10.1016/j.eplepsyres.200...
. It is the third most frequent
neurological disorder in the elderly following stroke and dementia and even more
relevant because, in this growing age group, it is often neglected22 . Johnston A, Smith PE. Epilepsy in the elderly. Expert Review of
Neurotherapeutics 2010;10:1899-910..
In Brazil and in developed and some developing countries the demography profile is
changing with increasing life expectation, thus the elderly comprise the fastest growing
group of the population33 . Assis TM, Costa G, Bacellar A, Orsini M, Nascimento OJ. Status
epilepticus in the elderly: epidemiology, clinical aspects and treatment. Neurol
Int. 2012;4(3):e17. http://dx.doi.org/10.4081/ni.2012.e17.
https://doi.org/10.4081/ni.2012.e17...
. Currently 25
to 30% of new onset epilepsy is diagnosed in elders44 . Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet.
2000;355(9213):1441-6.
http://dx.doi.org/10.1016/S0140-6736(00)02149-8.
https://doi.org/10.1016/S0140-6736(00)02...
,55 . Trinka E, Bauer G, Oberaigner W, Ndayisaba JP, Seppi K,
Granbichler CA. Cause-specific mortality among patients with epilepsy: results
from a 30-year cohort study. Epilepsia. 2013;54(3):495-501.
http://dx.doi.org/10.1111/epi.12014.
https://doi.org/10.1111/epi.12014...
. The prevalence of active epilepsy in the elderly is up to
1.5%, almost three times higher than in younger adults, but among nursing home residents
may exceed 5%22 . Johnston A, Smith PE. Epilepsy in the elderly. Expert Review of
Neurotherapeutics 2010;10:1899-910.,66 . Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci
2010;1184(1):208-24.
http://dx.doi.org/10.1111/j.1749-6632.2009.05113.x.
https://doi.org/10.1111/j.1749-6632.2009...
.
Epilepsy in the elderly presents several peculiarities that are unlike from epilepsy in
younger individuals. Elders are at greater risk of cerebrovascular diseases,
neurodegenerative and metabolic disorders that are associated with seizures occurrence.
Special features of the treatment with antiepileptic drugs (AEDs) in the elderly arise
from their physiologic changes as from the pharmacokinetics and pharmacodynamics of
these drugs. The pharmacokinetics of AEDs are complex in elderly patients owing to lower
protein binding, impaired hepatic metabolism, altered volume of distribution, decreased
renal clearance, and decreased enzyme inducibility77 . Waterhouse E, Towne A. Seizures in the elderly: nuances in
presentation and treatment. Clev Clin J Med. 2005;72(Suppl3):S26-37.
http://dx.doi.org/10.3949/ccjm.72.Suppl_3.S26.
https://doi.org/10.3949/ccjm.72.Suppl_3....
. As a consequence of these age-related physiological
changes, equivalent dosages would be expected to produce higher serum concentrations in
elders than in younger patients. Adverse effects of AEDs are the most important issue in
epilepsy management, especially among the elderly. Furthermore, some AEDs may exacerbate
problems that are common in elders such as tremor, ataxia and cognitive difficult88 . Faught E. Monotherapy in adults and elderly persons. Neurology
2007;69(24 Suppl 3):S3-9.
http://dx.doi.org/10.1212/01.wnl.0000302370.01359.8f
https://doi.org/10.1212/01.wnl.000030237...
. Elders often require medication for
their comorbidities in addition to AED, so drug interactions should be a reason for
concern. Thus, many epilepsy experts consider some old AEDs (phenobarbital, primidone
and phenytoin) as inappropriate (suboptimal) drugs for elders and emphasize the need for
careful choice of an appropriate AED for this population77 . Waterhouse E, Towne A. Seizures in the elderly: nuances in
presentation and treatment. Clev Clin J Med. 2005;72(Suppl3):S26-37.
http://dx.doi.org/10.3949/ccjm.72.Suppl_3.S26.
https://doi.org/10.3949/ccjm.72.Suppl_3....
,99 . Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Amuan ME, Tabares J
et al. Trends in antiepileptic drug prescribing for older patients with
new-onset epilepsy: 2000-2004. Neurology 2008;70(22 Pt 2):2171-8.
http://dx.doi.org/10.1212/01.wnl.0000313157.15089.e6.
https://doi.org/10.1212/01.wnl.000031315...
,1010 . Pugh MJ, Cramer J, Knoefel J, Charbonneau A, Mandell A, Kazis L et
al. Potentially inappropriate antiepileptic drugs for elderly patients with
epilepsy. J Am Geriatr Soc 2004;52(3):417-22.
http://dx.doi.org/10.1111/j.1532-5415.2004.52115.x.
https://doi.org/10.1111/j.1532-5415.2004...
.
Prescription of AED is increasing as the prevalence of epilepsy rises and remains the
mainstay of seizure prevention1111 . Nicholas JM, Ridsdale L, Richardson MP, Ashworth M, Gulliford MC.
Trends in antiepileptic drug utilisation in UK primary care 1993-2008: cohort
study using the General Practice Research Database. Seizure. 2012;21(6):466-70.
http://dx.doi.org/10.1016/j.seizure.2012.04.014.
https://doi.org/10.1016/j.seizure.2012.0...
.
Despite the high incidence of epilepsy in the elderly and the increase in treatment
options, there are few studies specifically focusing on the clinical use of AEDs in this
population. Moreover, some studies of AED metabolism have been done in elderly,
especially those who are frail.
The purpose of this study was to observe and characterize the prescribing patterns of AEDs regimen for hospitalized elderly with epilepsy as well their comorbidities and comedications. We also evaluated if AED treatment was according to the current clinical recommendations, practice guidelines and expert consensus opinion.
Method
Retrospective, cross-sectional study was performed on hospitalized elderly patients, with epilepsy and epileptic seizures in a tertiary center in Salvador (Bahia, Brazil). We defined elderly persons as individuals aged 60 years and above. All patients were under assistance of the neurology team. Data acquisition was carried out from January 1st, 2009 through December 31nd, 2010. We analyzed charts of 782 elderly inpatients to ascertain prescribing patterns during length of hospitalization. They were admitted to the hospital for several neurological disorders. Of the total, 120 patients had previously diagnosed epilepsy (unprovoked seizures) or had new-onset epileptic seizures. Patients with acute symptomatic seizures (provoked seizures) were excluded from the study (11 patients). Overall, 109 patients who were under regular use of AED were selected to the study. In this sample, 39.4% (43) of patients had been using AED previously to their admission and, the remaining had their onset of prescription during hospitalization. All patients were older than 60 years at the time of their first seizure. Epilepsy was the reason for AED prescription for all enrolled patients. The collected data were: age, gender, AEDs, types of seizures, comorbidities and potentially proconvulsant comedications. We categorized AED regimen based on clinical recommendation, mostly taking into account the adverse-effects profile of AEDs for this population of elderly inpatients, into two subgroups: group 1 defined as appropriate AEDs (carbamazepine, oxcarbazepine, valproic acid, gabapentin, clobazan and lamotrigine) and group 2 as inappropriate AEDs (phenytoin and phenobarbital). AED regimens included monotherapy and polytherapy (combination therapy with two or more AEDs).
This study was approved by the Ethics Committee of the Sao Rafael Hospital of Salvador, Brazil.
The statistical analysis was carried out with SPSS version 21.0. Percentages and the mean with standard deviations were used to express baseline data. Chi-square was used for comparative analysis among categorical variables in the group of appropriate and inappropriate AEDs, as well as monotherapy and polytheraphy. Statistical significance was defined as a p-value <0.05.
Results
One hundred and nine patients (90.8% / 120) were enrolled in the study (Figure 1). The mean age of the patients with new-onset epilepsy was 75±9 years, 55% females.
Inappropriate AEDs, such as phenytoin and/or phenobarbital in combination with any AED, were the most prescribed AED regimen for more than two-thirds of patients (n=80) (73.4%; 95%CI=64% to 81%; p<0.001) (Figure 2).
The most commonly used AED was phenytoin, in 53 patients (48.6%; 95%CI=39% to 58%). Carbamazepine was the second most prescribed AED in monotherapy in 10 patients (9.2%; 95%CI=5% to 16%) and when combined with other AED reaches 13.8% / 15 of patients. Lamotrigine was unless prescribed AED (n=6) in mono and polytherapy (5.4%; 95%CI=2% to 12%) (Table 1). Most patients (n=78) were in monotherapy (71.6%; 95%CI=62% to 80; p<0.001). Polytherapy with two and three AEDs were prescribed for 25.7% / 28 and 2.7% / 3 of patients, respectively (Figure 3).
The type of epileptic seizure was ascertained in 60.5% / 66 of patients. Generalized seizures were described in 33% / 36 of patients and focal seizures in 27.5% / 30 of them. Among the patients included in this study, 8.2% / 9 presented status epilepticus.
The most common comorbidities identified were systemic arterial hypertension (90%) and systemic infections (40%) followed by ischemic stroke, (38.5%). Other comorbidities are displayed in Table 2.
Comedications with potential proconvulsant effects were used by approximately half of these patients (n=54) (49.5%; 95%CI=40% to 59%) and some of them had more than one of these prescribed drugs. Opioids pain killers, antiarrhythmics, B-blockers and antibiotics (quinolone and carbapenem) were the most prescribed potentially proconvulsant drugs (Table 3).
Discussion
To our knowledge, this is the first study performed in Brazil, regarding prescribing patterns of AEDs for hospitalized elderly with new-onset epilepsy.
Although AEDs may be prescribed for many other conditions, such as neuropathic pain
and psychiatric disorders, we limited our study to prescriptions issued to patients
who had been diagnosed with epilepsy. The most prescribed AED regimen in this study
was the group of inappropriate AEDs for 73.4% (80/109) of patients. We found that
phenytoin, in monotherapy, was the drug of choice for these hospitalized elderly
with epilepsy in 48.6% (53/109). When combined with other AEDs, phenytoin
prescription reaches 70.5% (77/109). These findings were particularly unexpected
because we found only a small number of patients (9/109) who presented status
epilepticus, a condition for which intravenous medications are required, and could
be one of the reasons for phenytoin administration during hospitalization. Our
results are similar to other published studies in which phenytoin was the most
frequently prescribed AED for elderly people with epilepsy (EPWE), despite its
saturation kinetics and high potential interaction profile44 . Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet.
2000;355(9213):1441-6.
http://dx.doi.org/10.1016/S0140-6736(00)02149-8.
https://doi.org/10.1016/S0140-6736(00)02...
,1212 . Huber DP, Griener R, Trinka E. Antiepileptic drug use in Austrian
nursing home residents. Seizure. 2013;22(1):24-7.
http://dx.doi.org/10.1016/j.seizure.2012.09.012.
https://doi.org/10.1016/j.seizure.2012.0...
,1313 . Collins NS, Shapiro RA, Ramsay RE. Elders with epilepsy. Med Clin
North Am. 2006;90(5):945-66.
ttp://dx.doi.org/10.1016/j.mcna.2006.06.002
https://doi.org/10.1016/j.mcna.2006.06.0...
. These studies were performed previously or very soon
after the earliest published guidelines advising the use of the second generation
AEDs for the treatment of elders with epilepsy. In the USA, a study conducted using
National data from the Veterans Health Administration (VA) and Medicare to identify
trends in AED prescribing for older patients with epilepsy found that phenytoin was
the most commonly used AED (66.1%) in spite of the growing number of clinical
recommendations for other drugs99 . Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Amuan ME, Tabares J
et al. Trends in antiepileptic drug prescribing for older patients with
new-onset epilepsy: 2000-2004. Neurology 2008;70(22 Pt 2):2171-8.
http://dx.doi.org/10.1212/01.wnl.0000313157.15089.e6.
https://doi.org/10.1212/01.wnl.000031315...
. A
recent study conducted to evaluate clinical characteristics of patients with
hospital-onset seizure, from 20 to 99 years old, has demonstrated that phenytoin was
the most common AED prescribed de novo for 61% of patients both at seizure
presentation and at discharge1414 . Fields MC, Labovitz DL, French JA. Hospital-onset seizures: an
inpatient study. JAMA Neurol. 2013;70(3):360-4.
http://dx.doi.org/10.1001/2013.jamaneurol.337.
https://doi.org/10.1001/2013.jamaneurol....
.
In our study carbamazepine, in monotherapy, was the second most prescribed AED for
9.2% (10/109) of patients and lamotrigine was prescribed for small proportion of
patients, 5.4% (6/109).
A variety of factors may have contributed to scarce use of the newly AEDs in this population. First of all, the availability of few AEDs with suitable formulation for intravenous administration makes phenytoin the drug of choice when rapid seizure cessation is required; following this acute phase, usually it is maintained in its oral form until patient discharge. The lower frequency for carbamazepine prescription in this study is not clear even though this drug is marketed for over 30 years, has similar efficacy and cost to phenytoin and is well known by neurologists. Although lamotrigine has better tolerability, it requires slow titration which may hampers its prescription for hospitalized patients, especially for those requiring quick seizure control. Thus, this could be the reason lamotrigine had few number of prescriptions in our study. Indeed, the paucity of studies comparing phenytoin with newer AEDs in the elderly, may have contributed to the suboptimal prescription for this population.
Most patients had seizure remission with their first drug and become seizure-free on
one AED (71.6%); the remaining patients required polytherapy with either two or
three AEDs. Monotherapy is the most appropriate regimen for epileptic patient,
regardless of age and it is particularly interesting for older people88 . Faught E. Monotherapy in adults and elderly persons. Neurology
2007;69(24 Suppl 3):S3-9.
http://dx.doi.org/10.1212/01.wnl.0000302370.01359.8f
https://doi.org/10.1212/01.wnl.000030237...
.
In total, 87% (95) patients of this study had multiple comorbidities. The most common
were systemic arterial hypertension (90%), systemic infections (40%) followed by
ischemic stroke (38.5%) and diabetes mellitus (33%). One study conducted for
Austrian nursing home residents found that all of them had at least two
comorbidities and these findings were confirmed by another Germany cross-sectional
study1212 . Huber DP, Griener R, Trinka E. Antiepileptic drug use in Austrian
nursing home residents. Seizure. 2013;22(1):24-7.
http://dx.doi.org/10.1016/j.seizure.2012.09.012.
https://doi.org/10.1016/j.seizure.2012.0...
,1515 . Huying F, Klimpe S, Werhahn KJ. Antiepileptic drug use in nursing
home residents: a cross-sectional, regional study. Seizure. 2006;15(3):194-7.
http://dx.doi.org/10.1016/j.seizure.2006.02.002.
https://doi.org/10.1016/j.seizure.2006.0...
. There are many reasons for
concern when treating EPWE, in which the presence of multiples comorbidities (Table 2), such as arterial hypertension,
systemic infections, stroke, diabetes mellitus, dementias, neoplasias,
cardiopathies, etc., requires the need of comedications in addition to AED. EPWE,
when hospitalized, are frailer than their counterparts and may be more at risk from
adverse reactions of the AED even at standard doses on account of impaired drug
elimination, physiological reduction in rate of drug metabolism and reduced seizure
threshold. Malnutrition, rheumatoid arthritis, renal insufficiency are common
conditions that may lower albumin levels and contribute to impair concentrations of
protein-bound AEDs such as valproate and phenytoin. In this set, the use of
polypharmacy is especially a problem because it increases risk of drug interactions,
and even drug related deaths1616 . Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.
Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia.
2013;54(1):11-27.
http://dx.doi.org/10.1111/j.1528-1167.2012.03671.x.
https://doi.org/10.1111/j.1528-1167.2012...
,1717 . Levy RH, Collins C. Risk and predictability of drug interactions
in the elderly. Int Rev Neurobiol. 2007;81:235-51.
httpl://dx.doi.org/10.1016/S0074-7742(06)81015-9.
https://doi.org/10.1016/S0074-7742(06)81...
. Moreover, the clearance of most first and second
generation AEDs is reduced by about 20-40% in elderly patients compared with young
adults1818 . Perucca E. Age-related changes in pharmacokinetics: predictability
and assessment methods. Int Rev Neurol. 2007;81:183-99.
http://dx.doi.org/10.1016/S0074-7742(06)81011-1.
https://doi.org/10.1016/S0074-7742(06)81...
. Drugs that are
renally cleared, such as gabapentin, pregabalin and levetiracetam are desirable
because this results in fewer drug-drug interactions1313 . Collins NS, Shapiro RA, Ramsay RE. Elders with epilepsy. Med Clin
North Am. 2006;90(5):945-66.
ttp://dx.doi.org/10.1016/j.mcna.2006.06.002
https://doi.org/10.1016/j.mcna.2006.06.0...
.
In our study the patients were monitored clinically and merely 1.8% / 2 of them had
measurement of serum AED concentrations. Serum AED concentrations may be important
for dosage adjustment in elderly patient, however in the case of drugs that are
highly proteins bound the level of pharmacologically active drug (fraction unbound)
may be underestimated1818 . Perucca E. Age-related changes in pharmacokinetics: predictability
and assessment methods. Int Rev Neurol. 2007;81:183-99.
http://dx.doi.org/10.1016/S0074-7742(06)81011-1.
https://doi.org/10.1016/S0074-7742(06)81...
. For
elderly patients treated with phenytoin, a highly protein binding AED, who have
decreased serum albumin concentration, it is suggested that measuring free phenytoin
levels may be a better indicator of efficacy and toxicity than total
concentrations66 . Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci
2010;1184(1):208-24.
http://dx.doi.org/10.1111/j.1749-6632.2009.05113.x.
https://doi.org/10.1111/j.1749-6632.2009...
. Moreover,
phenytoin nonlinear pharmacokinetics and the capacity to induce or inhibit its
metabolism can produce concentrations which may vary from sub therapeutic to toxic
for some patients1313 . Collins NS, Shapiro RA, Ramsay RE. Elders with epilepsy. Med Clin
North Am. 2006;90(5):945-66.
ttp://dx.doi.org/10.1016/j.mcna.2006.06.002
https://doi.org/10.1016/j.mcna.2006.06.0...
.
Seizures induced by drugs are associated with use of comedications, high doses,
parenteral administration and comorbidities44 . Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet.
2000;355(9213):1441-6.
http://dx.doi.org/10.1016/S0140-6736(00)02149-8.
https://doi.org/10.1016/S0140-6736(00)02...
. In our study 41% (45/109) of patients had potentially
proconvulsant comedications prescribed: 33% (36/109) received one drug and 8.25%
(9/109) got two drugs (Table 3). Compared to
the Austrian study, where 91% of the residents were treated with at least one
proconvulsant drug, our elderly inpatients perhaps received better level of care
probably because they were assisted by neurologist during their hospitalization1212 . Huber DP, Griener R, Trinka E. Antiepileptic drug use in Austrian
nursing home residents. Seizure. 2013;22(1):24-7.
http://dx.doi.org/10.1016/j.seizure.2012.09.012.
https://doi.org/10.1016/j.seizure.2012.0...
.
Drug treatment for epilepsy changed in the last two decades mainly because of the
progress in epilepsy clinical research and the development of several new drugs.
Some of the standard AEDs, phenobarbital, primidone and phenytoin, identified as
suboptimal AEDs for the elderly with newly diagnosed epilepsy, generally have a less
favorable safety profile due to their side effects and potential drug
interactions99 . Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Amuan ME, Tabares J
et al. Trends in antiepileptic drug prescribing for older patients with
new-onset epilepsy: 2000-2004. Neurology 2008;70(22 Pt 2):2171-8.
http://dx.doi.org/10.1212/01.wnl.0000313157.15089.e6.
https://doi.org/10.1212/01.wnl.000031315...
,1010 . Pugh MJ, Cramer J, Knoefel J, Charbonneau A, Mandell A, Kazis L et
al. Potentially inappropriate antiepileptic drugs for elderly patients with
epilepsy. J Am Geriatr Soc 2004;52(3):417-22.
http://dx.doi.org/10.1111/j.1532-5415.2004.52115.x.
https://doi.org/10.1111/j.1532-5415.2004...
. The other two standard AEDs,
carbamazepine and valproate, have not been included in the suboptimal group for use
in older patients in existing clinical recommendations99 . Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Amuan ME, Tabares J
et al. Trends in antiepileptic drug prescribing for older patients with
new-onset epilepsy: 2000-2004. Neurology 2008;70(22 Pt 2):2171-8.
http://dx.doi.org/10.1212/01.wnl.0000313157.15089.e6.
https://doi.org/10.1212/01.wnl.000031315...
. Carbamazepine has simpler pharmacokinetics which makes
it easier to adjust dosing, although incurs drug interactions, resulting in less
severe adverse effects than phenytoin. In EPWE carbamazepine use should be a reason
of concern because its propensity to induce the metabolism of other lipid-soluble
drugs44 . Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet.
2000;355(9213):1441-6.
http://dx.doi.org/10.1016/S0140-6736(00)02149-8.
https://doi.org/10.1016/S0140-6736(00)02...
,99 . Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Amuan ME, Tabares J
et al. Trends in antiepileptic drug prescribing for older patients with
new-onset epilepsy: 2000-2004. Neurology 2008;70(22 Pt 2):2171-8.
http://dx.doi.org/10.1212/01.wnl.0000313157.15089.e6.
https://doi.org/10.1212/01.wnl.000031315...
,1919 . Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV,
Browne TR et al. Comparison of carbamazepine, phenobarbital, phenytoin, and
primidone in partial and secondarily generalized tonic-clonic seizures. New Engl
J Med. 1985;313(3):145-51.
http://dx.doi.org/10.1056/NEJM198507183130303.
https://doi.org/10.1056/NEJM198507183130...
. The AEDs with enzyme-inducing properties, such
as carbamazepine, phenytoin and phenobarbital may promote drug-drug interactions
which are particularly relevant for EPWE because usually they are under use of
multiple medications to treat their comorbidities such as stroke, cardiovascular
disease and neurodegenerative disorders. These enzyme-inducing AEDs may reduce the
levels of drugs such as warfarin, donepezil, galantamine which is a further reason
for care1717 . Levy RH, Collins C. Risk and predictability of drug interactions
in the elderly. Int Rev Neurobiol. 2007;81:235-51.
httpl://dx.doi.org/10.1016/S0074-7742(06)81015-9.
https://doi.org/10.1016/S0074-7742(06)81...
. Many other drugs
commonly used by EPWE are affected by enzyme inducers, such as calcium channel
blockers and HMG-CoA reductase inhibitors (atorvastatin, lovastatin and
simvastatin). Carbamazepine may have its level significant elevated when
co-administrated with ticlopidine, verapamil and diltiazem. In addition, there is
risk of phenytoin toxicity when administered with diltiazem1717 . Levy RH, Collins C. Risk and predictability of drug interactions
in the elderly. Int Rev Neurobiol. 2007;81:235-51.
httpl://dx.doi.org/10.1016/S0074-7742(06)81015-9.
https://doi.org/10.1016/S0074-7742(06)81...
. Valproate should remain the drug of first choice
for patients with generalized and unclassified epilepsies and has a low adverse
effect profile in olders2020 . Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwic
DW et al. The SANAD study of effectiveness of valproate, lamotrigine, or
topiramate for generalised and unclassifiable epilepsy: an unblinded randomised
controlled trial. Lancet 2007;369(9566):1016-26.
http://dx.doi.org/10.1016/S0140-6736(07)60461-9
https://doi.org/10.1016/S0140-6736(07)60...
.
Valproate is associated with reduced protein binding and unbound clearance in the
elderly, so clinical response may be achieved with a lower dose66 . Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci
2010;1184(1):208-24.
http://dx.doi.org/10.1111/j.1749-6632.2009.05113.x.
https://doi.org/10.1111/j.1749-6632.2009...
. Furthermore, valproate has a beneficial mood
stabilizing effect which may be appropriate for elderly with both disorders66 . Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci
2010;1184(1):208-24.
http://dx.doi.org/10.1111/j.1749-6632.2009.05113.x.
https://doi.org/10.1111/j.1749-6632.2009...
,2020 . Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwic
DW et al. The SANAD study of effectiveness of valproate, lamotrigine, or
topiramate for generalised and unclassifiable epilepsy: an unblinded randomised
controlled trial. Lancet 2007;369(9566):1016-26.
http://dx.doi.org/10.1016/S0140-6736(07)60461-9
https://doi.org/10.1016/S0140-6736(07)60...
.
The development of several new AEDs (gabapentin, lamotrigine, levetiracetam,
oxcarbazepine, tiagabine, topiramate, zonisamide), that combine efficacy and low
incidence of side effects has been improving the quality of care for epileptic
patient1010 . Pugh MJ, Cramer J, Knoefel J, Charbonneau A, Mandell A, Kazis L et
al. Potentially inappropriate antiepileptic drugs for elderly patients with
epilepsy. J Am Geriatr Soc 2004;52(3):417-22.
http://dx.doi.org/10.1111/j.1532-5415.2004.52115.x.
https://doi.org/10.1111/j.1532-5415.2004...
,1111 . Nicholas JM, Ridsdale L, Richardson MP, Ashworth M, Gulliford MC.
Trends in antiepileptic drug utilisation in UK primary care 1993-2008: cohort
study using the General Practice Research Database. Seizure. 2012;21(6):466-70.
http://dx.doi.org/10.1016/j.seizure.2012.04.014.
https://doi.org/10.1016/j.seizure.2012.0...
. These new second-generation
drugs have more favorable pharmacokinetics such as low protein binding and no
hepatic metabolization which minimize adverse effects and drug interactions2121 . Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic
drug effects: toward a clinically and neurobiologically relevant taxonomy.
Neurology 2009;72(14):1223-9.
http://dx.doi.org/10.1212/01.wnl.0000345667.45642.61.
https://doi.org/10.1212/01.wnl.000034566...
,2222 . Tatum WO. Antiepileptic drugs: adverse effects and drug
interactions. Continuum (Minneap Minn) 2010;16 3 Epilepsy:136-58.
http://dx.doi.org/10.1212/01.CON.0000368236.41986.24.
https://doi.org/10.1212/01.CON.000036823...
.
In the VA Cooperative #428 Study, a randomized, double-blind study of gabapentin,
lamotrigine and carbamazepine in elderly community-dwelling epilepsy patients with
newly diagnosed seizures, the authors concluded that lamotrigine and gabapentin
should be considered as initial therapy for older patients with newly diagnosed
seizures because their better tolerability and effective seizure control. In this
study, hypersensitivity occurred more frequently with carbamazepine than with
lamotrigine and hyponatremia occurred more frequently in carbamazepine than in
gabapentin patients2323 . Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM
et al. New onset geriatric epilepsy: a randomized study of gabapentin,
lamotrigine, and carbamazepine. Neurology 2005;64(11):1868-73.
http://dx.doi.org/10.1212/01.WNL.0000167384.68207.3E.
https://doi.org/10.1212/01.WNL.000016738...
.
The SANAD study, Arm A, identified that lamotrigine was clinically better than
carbamazepine because of its tolerability advantage and it was recommended as the
AED choice for patients (children and people older 65 years) diagnosed with partial
onset seizures2424 . Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA,
Chadwick DW et al. The SANAD study of effectiveness of carbamazepine,
gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial
epilepsy: an unblinded randomised controlled trial. Lancet.
2007;369(9566):1000-15.
http://dx.doi.org/10.1016/S0140-6736(07)60460-7
https://doi.org/10.1016/S0140-6736(07)60...
. An international
multicenter randomized double-blind controlled trial of lamotrigine and
sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the
elderly showed comparable effectiveness, with trend for higher seizure-free rates
for carbamazepine and better tolerability for lamotrigine2525 . Saetre E, Perucca E, Isojärvi J, Gjerstad L. An international
multicenter randomized double-blind controlled trial of lamotrigine and
sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in
the elderly. Epilepsia. 2007;48(7):1292-302.
http://dx.doi.org/10.1111/j.1528-1167.2007.01128.x
https://doi.org/10.1111/j.1528-1167.2007...
.
Updated review of ILAE, concluded that gabapentin and lamotrigine are established
efficacious and effective as initial monotheraphy for elders with newly diagnosed or
untreated partial-onset seizures2626 . Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C,
Kälviäinen R et al. Updated ILAE evidence review of antiepileptic drug efficacy
and effectiveness as initial monotherapy for epileptic seizures and syndromes.
Epilepsia. 2013;54(3):551-63.
http://dx.doi.org/10.1111/epi.12074
https://doi.org/10.1111/epi.12074...
.
Guidelines from American Academy of Neurology, American Epilepsy Society and expert
consensus opinions have been recommending the use of second-generation AEDs for the
treatment of new-onset epilepsy in the elderly2727 . French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden
CL et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment
of refractory epilepsy: report of the Therapeutics and Technology Assessment
Subcommittee and Quality Standards Subcommittee of the American Academy of
Neurology and the American Epilepsy Society. Neurology. 2004;62(8):1261-73.
http://dx.doi.org/10.1212/01.WNL.0000123695.22623.32
https://doi.org/10.1212/01.WNL.000012369...
. These recommendations are based on available evidence
regarding the potential deleterious effects of long-term enzyme induction with
AEDs1616 . Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.
Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia.
2013;54(1):11-27.
http://dx.doi.org/10.1111/j.1528-1167.2012.03671.x.
https://doi.org/10.1111/j.1528-1167.2012...
. However, despite the
relative tolerability and efficacy of the newer AEDs, they have similar efficacy
when compared to first generations AEDs, are generally more costly and some of them
are not available in poor-resources countries2222 . Tatum WO. Antiepileptic drugs: adverse effects and drug
interactions. Continuum (Minneap Minn) 2010;16 3 Epilepsy:136-58.
http://dx.doi.org/10.1212/01.CON.0000368236.41986.24.
https://doi.org/10.1212/01.CON.000036823...
. On the other hand, frequently the management of
epilepsy in elderly people is inconsistent because initial drug selection is often
made by primary care physicians with less experience in selection and adjusting the
dosages of newer drugs. Indeed, inappropriate prescription for EPWE, is associated
with negative health outcomes and economic consequences1616 . Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.
Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia.
2013;54(1):11-27.
http://dx.doi.org/10.1111/j.1528-1167.2012.03671.x.
https://doi.org/10.1111/j.1528-1167.2012...
. The treatment gap, meaning those people with
active epilepsy not on treatment or on inadequate treatment is highly variable and
is mainly attributed to lack of access to or knowledge of AEDs, poverty, cultural
beliefs, delivery infrastructure and few trained physicians. The choice of drug in
the majority of developing countries depends on availability and cost, so
phenobarbital and phenytoin, despite their side effects, are still the most
prescribed drugs in these countries.
Our study has several limitations due to its retrospective design implicating a restraint data acquisition. It is possible that some patients with epileptic seizures may not be included. On the other hand, because this population consists exclusively of hospitalized elderly patients, these patterns of care may not reflect the care for the general geriatric population in this institution. Besides, AEDs such as phenytoin, phenobarbital and valproic acid rather than lamotrigine, carbamazepine, oxcarbazepine, gabapentin, pregabalin and topiramate are available for use by parenteral route, which should have contributed to their choice in the hospital setting. Despite these limitations, this study contributes to provide knowledge on patterns of antiepileptic drug therapy for elderly inpatients with new-onset epilepsy in the light of current clinical recommendations for prescribing in this age-group.
Efforts should be done in order to raise the adherence to clinical practice guidelines for treating elderly patients with new-onset epilepsy. Therefore, this study argues for the need for more double-blind trials of AED treatment, in geriatric epilepsy patients.
We conclude that elderly inpatients in our tertiary center were mainly treated with inappropriate antiepileptic drugs, mainly phenytoin. The new generation AEDs was prescribed for a small number of patients. Furthermore, nearly half of the patients had potentially proconvulsant drugs prescribed as comedications.
As the population in most countries lives longer, the challenge is the appropriateness of prescribing older people with multiple chronic conditions and under use of multiple comedications.
Acknowledgment
We acknowledge Dr. Genoile Oliveira Santana Silva for her contributing in the statistical analysis.
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Publication Dates
-
Publication in this collection
Nov 2014
History
-
Received
01 Mar 2014 -
Reviewed
25 July 2014 -
Accepted
15 Aug 2014