Acta Neurologica Belgica

https://doi.org/10.1007/s13760-019-01132-4

REVIEW ARTICLE

Antiepileptic drug therapy in the elderly: a clinical pharmacological

review
Upinder Kaur1 · Indal Chauhan1 · Indrajeet Singh Gambhir2 · Sankha Shubhra Chakrabarti2

Received: 13 February 2019 / Accepted: 28 March 2019

© Belgian Neurological Society 2019

Abstract
Seizure disorder is the third most common neurological disorder in the elderly after stroke and dementia. With the increas-
ing geriatric population, the situation of clinicians seeing more and more elderly epilepsy patients is very likely. Not only is
the diagnosis of epilepsy tedious in the elderly, its management raises many challenging issues for the treating physicians.
Altered physiology, age-related decline in organ function, and plasma protein binding and altered pharmacodynamics make
the elderly patients with seizure disorder a difficult group to treat. This is further complicated by the presence of comorbidi-
ties and polypharmacy which increase the chances of drug interactions. The adverse effects that might be tolerated well in
younger populations may be disastrous for the aged. Although the newer antiepileptic drugs are found to have a favorable
safety profile, there is relative scarcity of randomized-controlled trials involving older and newer antiepileptics in the geri-
atric population. This review tries to compile the available literature on management of epilepsy in the elderly population
including evidence of safety and efficacy of newer and older antiepileptics with special reference to the ‘geriatric giants’. It
also deals with the interactions between antiepileptic medications and other commonly prescribed drugs in the elderly such
as anti-hypertensives and antiischemic agents. The recommended guidelines of various international bodies are also analyzed
from the perspective of elderly with seizure disorder.

Keywords Seizures · Elderly · Antiepileptic drugs (AEDs) · Pharmacology · Safety · Geriatric giants

Introduction arrhythmias, malignancies, chronic bronchitis, osteoporo-

Seizure disorder is the third commonest neurological dis-
order in elderly after stroke and neurodegenerative diseases
[1]. Its incidence and prevalence is maximum in those above
65 years. Etiology and presentation of seizures in elderly
differ from that in adults. Mostly, stroke, neurodegenerative
disorders, infections, and metabolic insults lead to seizures
in elderly. These patients often suffer from other illnesses
like cerebrovascular disease, diabetes, hypertension, cardiac
Electronic supplementary material The online version of this
article (https​://doi.org/10.1007/s1376​0-019-01132​-4) contains
supplementary material, which is available to authorized users.
* Sankha Shubhra Chakrabarti
sankha.geriatrics@gmail.com
1
Department of Pharmacology, Institute of Medical Sciences,
Banaras Hindu University, Varanasi, India
2
Department of Geriatric Medicine, Institute of Medical
Sciences, Banaras Hindu University, Varanasi, India
sis, osteoarthritis, Alzheimer’s disease, and Parkinsonism.
Immobility, instability, altered vision and hearing, incon-
tinence, and impaired cognition are the ‘giants’ afflicting
the elderly. The presence of these comorbidities along with
issues like altered physiology and pharmacology, atypical
disease presentations, caregiver dependence, polypharmacy,
and self-medication are the reasons which make this popula-
tion unique. Older people often receive antihypertensives,
cholesterol-lowering drugs, antidiabetics, antianginals, anti-
platelets, anticoagulants, cognition enhancers, analgesics,
and antiinflammatory and anti-Parkinsonian medications.
Simultaneous use of these with antiepileptic drugs (AEDs)
may result in suboptimal or supratherapeutic concentrations
of antiepileptics, raising the importance of therapeutic drug
monitoring. Another confusing area is the choice of antie-
pileptic in elderly. Traditionally used AEDs like phenytoin,
valproate, and carbamazepine are often preferred owing to
enormous evidence of efficacy in adults, low cost, and easy
availability. These, however, carry a higher risk of adverse
effects. Newer antiepileptics like lamotrigine, levetiracetam,

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oxcarbazepine, and gabapentin have been launched, which
are believed to be non-inferior to older antiepileptics and
carry a lesser risk of drug interactions and adverse effects.
In this review, the authors briefly introduce how epilepsy
in the elderly differs from that in the young with special
emphasis on therapeutic aspects. They also try to compile
the relevant literature on the pattern of prescribing antiepi-
leptics in the elderly, safety, and efficacy of older and newer
antiepileptics in this population, the available international
guidelines on management of seizure disorder in the elderly,
and the effect of antiepileptic drugs on major health-related
geriatric domains.
Epilepsy in elderly
Focal-onset seizures are more common in the elderly as
compared to the young adult population. Whereas gener-
alized convulsions and automatisms are less often seen in
the elderly, atypical presentations as dizziness and confused
behavior as also progression to status are all more common
in this group. Similarly, the chance of recurrence of seizure
is more in the elderly with respect to the young, except for
that seen in congenital epilepsy syndromes. A particularly
dramatic difference is in the period of post-ictal confusion
which may last up to 2 days in the elderly as opposed to
minutes to a few hours in the young [1, 2].
Pattern of prescribing antiepileptics
in elderly
Despite many recommendations favoring the use of newer
antiepileptics, the shift from older antiepileptics has been
relatively recent and variations exist in prescription patterns.
A study on geriatric patients with newly diagnosed epilepsy
(2000–2004) from the Veterans Health Administration data-
base showed that, despite increasing use of newer antiepi-
leptics in older patients, phenytoin is still most preferred
[3]. Similarly, a retrospective study conducted in Brazil to
find the prescribing pattern in hospitalized elderly patients
(n = 109) found phenytoin and carbamazepine to be most
commonly prescribed and lamotrigine the least. Phenytoin
preference was attributed to its availability as intravenous
preparation, ease of switching to oral formulation, low cost,
and enormous evidence of efficacy. In contrast, lamotrig-
ine, owing to the risk of rash, requires slow titration over
weeks to achieve a maintenance dose. This and the lack of
parenteral formulations might be the reason for reluctance
among physicians to use lamotrigine, especially when rapid
seizure-control is desired [4]. Another recently conducted
Finnish study observed valproate and carbamazepine as
preferred initial antiepileptics in elderly [5]. The same two
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Acta Neurologica Belgica
antiepileptics were found to be commonly used in patients
with post-stroke seizures in a nationwide survey conducted
in Japan [6]. However, data from several other studies, albeit
from developed countries, highlight a growing preference for
newer antiepileptics such as gabapentin, levetiracetam, and
lamotrigine (Supplementary Table 1) [7–9].
Safety and efficacy of newer antiepileptics
A recently conducted meta-analysis comparing the efficacy
and tolerability of newer antiepileptics in adult patients with
refractory epilepsy found topiramate to have maximum effi-
cacy reflected by a 50% reduction in seizure frequency, fol-
lowed by levetiracetam. Lamotrigine was found to be the
least efficacious. Pregabalin had the maximum somnolence
potential. Of the 32 trials included, only one had enrolled
elderly patients, thus reducing its generalizability [10]. A
post hoc analysis of a superiority study tested continuation
rates of various AEDs among elderly. Time to treatment
withdrawal was longest with levetiracetam (LEV) [11]. A
retrospective study from New York compared the effective-
ness of ten antiepileptics in 417 elderly out-patients. The
antiepileptics studied were lamotrigine, levetiracetam, car-
bamazepine, oxcarbazepine, phenytoin, topiramate, zon-
isamide, valproate, gabapentin, and clobazam. There were
differences in retention rates which were unrelated to effi-
cacy but due to differences in adverse effects. Lamotrigine
and levetiracetam fared the best in clinical efficacy and
retention rates and oxcarbazepine the poorest. The com-
monest adverse effect, also reason for discontinuation, was
imbalance in case of lamotrigine, drowsiness, and psychi-
atric manifestations with levetiracetam, allergies in case of
phenytoin, drowsiness for carbamazepine, and tremors in
case of valproate [12]. Supplementary Table 2 details recent
studies on the safety and efficacy of antiepileptics in elderly
patients [10–15].
Pharmacokinetic features of antiepileptics
Decline in liver and renal function, reduction in plasma
protein levels and total body water, and increase in body
fat are some of the important age-related pharmacokinetic
changes which can influence the plasma AED concentra-
tions. Phenytoin is metabolized by CYP2C9- and CYP2C19-
mediated oxidation and excreted in urine. It has high plasma
protein binding and is a strong inducer of CYP3A4. Thus,
it is involved in a multitude of drug interactions. Carbamaz-
epine is metabolized by CYP3A4 and its active epoxide
moiety then undergoes glucuronidation followed by urinary
excretion. Like phenytoin, it also increases the metabolism
of other drugs metabolized by CYP3A4. Valproate is rather
Acta Neurologica Belgica
an enzyme inhibitor and increases the concentration of con-
comitant drugs. Valproate itself is subjected to metabolism
by CYP2C9 and UGT, and is also highly bound to plasma
proteins. Among newer antiepileptics, lamotrigine under-
goes glucuronide conjugation and is excreted in urine [16].
Gabapentin and pregabalin are excreted unchanged in urine
[17]. A greater fraction of topiramate is excreted unchanged
in urine and 30–50% is subjected to oxidation in the liver
[18]. Similarly, levetiracetam is largely removed by the renal
route and only around 30% is subjected to esterase [19].
The new generation antiepileptics have low plasma protein
binding and are not potent enzyme inducers. This reduces
the risk of clinically significant drug interactions. OXC is
rapidly converted into active metabolite monohydroxy deriv-
ative (MHD). It is not a strong enzyme inducer/inhibitor,
but, at a dose > 1200 mg/day, it can decrease the metabolism
of phenytoin by 40% [20]. OXC can also produce modest
decline in levels of LTG and TPM [21]. Tables 1, 2 show the
common plausible interactions of antiepileptics with drugs
used in the elderly for varied indications [18, 19, 22–32].
Guidelines on management of epilepsy
in the elderly
Other than some recommendations for focal seizures,
there have been no guidelines till date that emphasize on
drugs suitable to be given as the first-line antiepileptics in
elderly patients (Table 3) [33–35]. For newly diagnosed and
untreated focal seizures, lamotrigine and gabapentin have
been considered as efficacious monotherapy with high level
of evidence [33–35]. As opposed to the ‘wait-and-watch’
policy sometimes followed in initiating treatment for a first
unprovoked seizure in the young, AEDs should be initiated
for any seizure in the elderly. This is because of a higher risk
of recurrence and high mortality thereafter. Furthermore,
other factors such as presence of neurologic deficit, risk/
benefit ratio, cognitive status, and wish of the patient need
consideration [1, 2]. Supplementary Table 3 gives the dosing
recommendations for AEDs in elderly patients.
Antiepileptics and geriatric comorbidities—
effects and interactions
Antiepileptics and effects on cognition
Older antiepileptics including phenytoin, carbamazepine,
valproate, and phenobarbitone have been linked to cogni-
tive impairment in various age groups. Among these, phe-
nobarbitone is especially notorious. Phenytoin has been
linked to disturbances in attention, visuomotor function,
and mental speed, though overall effect is small [36]. The
cognitive profile of carbamazepine and valproate is similar
and slightly better than phenytoin [36]. Among newer antie-
pileptics, topiramate has been shown to negatively affect
cognitive domains in nearly 10% patients [37]. This may be
lessened by slow titration and monotherapy. While oxcarbaz-
epine, pregabalin, and gabapentin have been linked to mild
cognitive effects, lamotrigine and levetiracetam are thought
to be virtually free of these. Rather, unexplained positive
effects have been seen in some studies [38]. Polytherapy has
been observed to worsen cognition more. A retrospective
analysis of ten antiepileptic drugs, both older and newer ones
prescribed to elderly, showed that cognitive adverse effects
are common in patients on topiramate followed by those on
zonisamide and gabapentin [12]. Assessment of the effect
of antiepileptic drugs on cognition has been a difficult task.
Epilepsy itself is known to damage brain areas linked with
complex task performing activities. Type of seizures, loca-
tion of epileptogenic focus, dose and duration of antiepilep-
tic drug use, age of patient at drug initiation and at time of
onset of cognitive dysfunction, and use of concomitant drugs
are the issues which remain inadequately addressed in the
studies done so far [36].
Antiepileptics and cardiovascular disease/metabolic
syndrome
Antiepileptic drugs which block neuronal sodium channels
can contribute to cardiac rhythm defects by interfering with
phase 0 of action potential. Phenytoin used as monotherapy
or combined with other ­Na+-channel blockers like carba-
mazepine and lamotrigine has been linked to ECG findings
similar to Brugada syndrome [39]. Intravenous phenytoin
at high infusion rate has been linked with hypotension and
arrhythmias. As compared to young adults, a lower infusion
rate of 25–30 mg/min is recommended for the elderly and up
to 10–20 mg/min in those with cardiovascular disease [40].
Phenytoin is contraindicated in patients with heart rate less
than 60/min or with second/third degree heart block [40].
Lamotrigine and carbamazepine have been associated with
slight increase in PQ interval and decline in heart rate in
elderly, however, without significant ECG differences [41].
Carbamazepine and oxcarbazepine should also be avoided
in settings of atrioventricular block [42]. They may also
aggravate hyponatremia associated with diuretic use and can
potentiate dilutional hyponatremia in congestive heart fail-
ure. Though there have been reports of aggravation of heart
failure by pregabalin and occurrence of SUDEP with lamo-
trigine, the evidence at present is limited. There have been
a few studies assessing the impact of antiepileptic drugs on
cardiovascular risk factors in the elderly. Carbamazepine-
treated young patients have been shown to have elevations
in total cholesterol, LDL, and HDL values [43]. Similarly,
phenytoin can elevate LDL, HDL, and cholesterol levels,
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Table 1  Interactions of AEDs with other drugs commonly used in the elderly [18, 19, 22–32]
AED + other drug Effect on antiepileptic drug by the other drug Effect by antiepileptic drug on the other drug

Phenytoin
Warfarin Complex; subtherapeutic effect/supratherapeu-
tic effect/biphasic
Steroids (prednisone, dexamethasone) ↑ Metabolism; subtherapeutic effect
Amitriptyline, bupropion, paroxetine, halop- ↓ Metabolism; supratherapeutic effect ↑ Metabolism; subtherapeutic effect
eridol, risperidone, olanzapine, clozapine
Amiodarone ↓ Metabolism; supratherapeutic effect
Antacids ↓ Absorption
Phenytoin and carbamazepine both
Opioids Possible ↓ absorption because of antimotility ↑ Metabolism; subtherapeutic effect. May pre-
property of opioids cipitate opioid withdrawal features
Isoniazid/erythromycin/allopurinol/metroni- ↓ Metabolism; supratherapeutic effect
dazole/amiodarone
Antimicrobials (itraconazole/doxycycline/ Supratherapeutic effect ↑ Metabolism; subtherapeutic effect
metronidazole/albendazole)
Dabigatran/rivaroxaban ↑ Metabolism; subtherapeutic effect
Theophylline ↑ Metabolism; subtherapeutic effect
Nimodipine ↑ Metabolism; subtherapeutic effect
Diazepam, clonazepam, alprazolam ↑ Metabolism; subtherapeutic effect
Amiodarone, digoxin, statin, beta blockers, ↑ Metabolism; subtherapeutic effect
nifedipine, nimodipine
Carbamazepine
Warfarin Subtherapeutic effect
Diuretics ↑ Risk of hyponatremia (also with OXC)
Ivabradine ↓ Concentration; subtherapeutic effect
Valproate
Amitriptyline/nortriptyline/paroxetine ↓ Metabolism; possible supratherapeutic effect
Statins Liver toxicity
Antiplatelets/anticoagulants ↑ Risk of bleeding
Imipenem, meropenem ↓ Metabolism; supratherapeutic effect
Warfarin ↓ Plasma protein binding, probably ↓ metabo-
lism; supratherapeutic effect
Rivaroxaban/dabigatran May ↓ effect by inducing P-glycoprotein/may ↑
effect by inhibiting CYP-3A4
Opioids ↓ Absorption due to antimotility effect of May ↓ tolerance to opioids
opioids/↑ sedation
Phenytoin and valproate both
NSAIDs ↓ Plasma protein binding; ↑ plasma concentra-
tion
Newer AED + other drug Effect on antiepileptic drug Effect on other drug

Gabapentin
Antacids ↓ Absorption
Eslicarbazepine
Statins ↓ Concentration
Lamotrigine
Opioids Additive/synergistic analgesic effect in
neuropathic pain
Sertraline Serum concentration may ↑
Acetaminophen/carbamazepine Serum concentration may ↓
Levetiracetam
Dabigatran/rivaroxaban May ↓ effect by inducing P-glycoprotein

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Table 1  (continued)
Newer AED + other drug Effect on antiepileptic drug Effect on other drug

Opioids Adjuvant analgesic effect; may ↓ require-

ment of opioids
Topiramate
Risperidone/pioglitazone/digoxin Clearance ↑; plasma concentration ↓
Amitriptyline, metformin, lithium, hydrochlo- Clearance ↓; plasma concentration ↑
rothiazide
Propranolol/sumatriptan/hydrochlorothiazide/ Clearance ↓; plasma concentration ↑
amitriptyline/metformin/lithium

Table 2  Effect of AEDs on plasma concentration of other AEDs [18, 19, 22–32]
Precipitant AED Object AED Effect on plasma concentration of object AED

PHT/CBZ CLB/LTG/ESL/TPM/VPA Decreases

PGB/GBP/LEV No effect
OXC (active metabolite, MHD) Decreases
OXC LTG Decreases/no effect
PHT May increase by 40%
ESL PHT Increases by 30%
LTG/CBZ No effect
TPM Decreases by 18%
VPA PHT Increases/no effect
TPM Slight decrease in concentration (not significant)
LTG Increases significantly; dose reduction of LTG is required
TPM VPA Slight decrease in concentration
Increased risk of hyperammonemia
PHT May increase
LTG No effect
CBZ No effect
LEV PHT/CBZ/VPA/LCM/CLB/PGB/GBP/LTG No effect
LTG LCM/CLB/PGB/GBP No effect
PHT/CBZ/VPA No effect
PGB/GBP LEV/LTG/PHT/CBZ/VPA/TPM/LCM/OXC/CLB No effect

CBZ carbamazepine, CLB clobazam, GBP gabapentin, LEV levetiracetam, LTG lamotrigine, ESL eslicarbazepine, OXC oxcarbazepine, PHT
phenytoin, TPM topiramate, VPA valproate, PGB pregabalin, GBP gabapentin, LCM lacosamide, MHD monohydroxy derivative, AED antiepi-
leptic drug

whereas the data concerning valproate are variable. Oxcar-
bazepine, levetiracetam and topiramate can also increase
LDL [44]. In another study, significant decline in total cho-
lesterol, triglyceride, and non-HDL cholesterol was seen
after patients on phenytoin or carbamazepine were shifted to
levetiracetam or lamotrigine [45]. Eslicarbazepine has been
found to not produce unfavorable effects on lipid metabolism
in a recent retrospective study [46].
Long-term use of phenytoin, valproate, and carbamaz-
epine has been linked with increased common carotid intima
media thickness, an independent risk factor for cerebrovas-
cular and cardiovascular disease. Valproate has been associ-
ated with metabolic syndrome and insulin resistance. Non-
alcoholic fatty liver disease (NAFLD) has been observed
with valproate and carbamazepine use. Valproate, carbamaz-
epine, pregabalin, and gabapentin are linked with weight
gain. Lamotrigine, oxcarbazepine, and levetiracetam are
weight neutral, while topiramate and zonisamide are known
to cause weight reduction [47].
Antiepileptics and bone health
Epilepsy can lead to falls and fractures, particularly in
elderly. This is compounded by the tendency of AEDs to
decrease bone strength and bone mineral density. Cerebel-
lar disturbances produced by AEDs may result in falls and
trivial trauma may produce fractures. Phenytoin and carba-
mazepine, by acting as enzyme inducers, can decrease the

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Table 3  Recommendations by expert bodies in treatment options for seizure disorder in the elderly [33–35]
ILAE guidelines (2013) NICE guidelines AES/AAN guidelines
(2018) (2018)
Type of seizures Antiepileptic drugs Status Level of evidence

Newly diagnosed/ Lamotrigine, gabap- Efficacious/effective as A No recommendation Lamotrigine should

untreated focal-onset entin monotherapy (level B) and gabap-
seizures in elderly Carbamazepine Possibly efficacious/ C entin may (level C)
effective as mono- be considered
therapy
Topiramate, valproate Potentially efficacious/ D
effective
Oxcarbazepine, leveti- No data/inadequate E
racetam, phenytoin, efficacy
pregabalin, clonaz-
epam, clobazam
Generalized tonic– No data No data No data No recommendation No recommendation
clonic seizures
Myoclonic seizures No data No data No data No recommendation No recommendation
Absence seizures No data No data No data No recommendation No recommendation

ILAE International League against Epilepsy, NICE National Institute for Health and Care Excellence, AES/AAN American Epilepsy Society/
American Academy of Neurology

levels of vitamins D and K. These drugs also interfere with
intestinal calcium absorption, inhibit IGF, and can disturb
the bone milieu via hormonal imbalance. In contrast, val-
proate damages bones by directly suppressing osteoblasts
[48]. Among newer antiepileptics, gabapentin was found to
increase bone loss in community-dwelling older men. How
gabapentin causes bone loss is unclear, but activation of cen-
tral sympathetic nervous system and inhibitory action of nor-
epinephrine on osteoblasts has been hypothesized. Increased
risk of fractures was found with gabapentin and clonazepam
in another retrospective study on older epilepsy patients.
Interestingly, the study found valproate to be safe [49]. The
data considering levetiracetam and topiramate are conflict-
ing. Considering the impact of antiepileptics, particularly the
older ones on bone homeostasis, serum vitamin D, calcium,
phosphate, and alkaline phosphatase should be measured
at least annually in patients taking antiepileptics and daily
oral supplements with 1–1.5 g calcium and 1000–2000 IU of
Vitamin D3 should be ensured. Dose of vitamin D3 can be
increased up to 4000 IU/day if phenytoin or carbamazepine
is being used [50]. There are no universal guidelines on
prophylactic use of bisphosphonates, calcitonin, or hormo-
nal replacement therapy for the prevention of osteoporotic
fractures in elderly on AEDs. These can be tried, however,
considering the risk of fractures.
Antiepileptics and urinary problems
There have been several reports of carbamazepine-induced
urinary retention both in males and females. Carbamazepine
structurally resembles TCAs and can produce anticholinergic
symptoms within days to months. Carbamazepine and,
to a variable extent, oxcarbazepine have ADH like action
which contributes to water retention [51]. They should,
therefore, be avoided in elderly patients suffering from pro-
static or other causes of urinary tract obstruction. Because
of the anticholinergic profile of carbamazepine, it should
be avoided in elderly patients with glaucoma and chronic
constipation. Prophylactic lubricant eye drops and stool sof-
teners can be advised in susceptible populations. Gabapen-
tin has been shown to be associated with urinary and fecal
incontinence in elderly patients. Incontinence was seen to
occur within 1–4 weeks of therapy initiation and was found
to be reversible with drug discontinuation [52]. Probable
mechanisms suggested include modulation of GABAergic
neuronal supply to the external urethral sphincter, causing
its relaxation; and modulation of α2δ subunit of N-type C­ a2+
channels present on A-δ and C-fibers, resulting in decreased
calcium entry and poor detrusor contraction. As a corol-
lary, the resulting increase in bladder capacity might be use-
ful in neurogenic overactive bladder. The central action of
gabapentin on the micturition center in pons via modulation
of GABA and glutamate is another tentative mechanism.
Topiramate can cause nephrolithiasis and metabolic acido-
sis by inhibition of carbonic anhydrase in the kidney. This
may predispose the vulnerable elderly to urinary retention
and infections. Lamotrigine-induced burning sensation over
vulvar area and painful micturition has been described in
an adult female with bipolar depression [53]. Reversible
day time enuresis has been shown to be associated with val-
proate (at 900 mg/day) [54]. Till date, there have been no

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significant reports of urinary problems in elderly patients on
lamotrigine, levetiracetam, or phenytoin.
Antiepileptics and hyponatremia
Hyponatremia is the commonest electrolyte abnormality
seen in elderly and an independent risk factor for mortality.
Stroke which is the commonest cause of seizures in elderly
is known to cause hyponatremia. This emphasizes the need
to use the antiepileptic with least potential to cause hypona-
tremia in elderly. Oxcarbazepine and carbamazepine have
been particularly associated with a risk of hyponatremia
[55]. In a recently published cohort study, risk of hypona-
tremia with OXC was more in those who had already expe-
rienced hyponatremia with CBZ [56]. Eslicarbazepine too
is not safe in this regard. Levetiracetam use in elderly has
also been linked with SIADH in a few case reports [57].
Risk exists with phenytoin, valproate, and topiramate, as
well [55]. The explanation for association of phenytoin and
hyponatremia is obscure, since the drug is known to induce
a diabetes insipidus like state.
Antiepileptics and psychiatric disorders
Depression is encountered as a common comorbidity in
patients suffering from epilepsy. The inevitable concomitant
use of antiepileptics and antidepressants in epilepsy patients
with depression is accompanied by many pharmacokinetic
and pharmacodynamic drug interactions (Table 1).
Valproate, carbamazepine, oxcarbazepine, and lamotrig-
ine are used as mood stabilizers in bipolar disorder (BPD).
They are also useful in the management of depression as
an adjunct to standard antidepressants. On the other hand,
levetiracetam has been shown to cause depressive features
like anhedonia, change in sleep patterns, and fatigability in
elderly patients [58]. In the adverse event analysis part of
a comparative study done in the elderly population, neuro-
psychiatric adverse effects were commonly seen with leveti-
racetam and clobazam followed by topiramate, gabapentin,
and oxcarbazepine [12]. In contrast, there are studies in adult
epilepsy patients where levetiracetam has been linked with
improvement in depression and anxiety scores [59]. In light
of limited studies assessing the neuropsychological effects
of antiepileptics in elderly and variable findings in adults, it
might not be wrong to suggest that use of any antiepileptic
in general should be stopped or withheld if there is clini-
cally significant worsening of mental status after its initia-
tion. Compared to the general population, suicide risk is five
times higher in epilepsy patients and this is influenced by the
nature of AED being used. In a retrospective database study,
suicide-related behavior was found to be strongly associ-
ated with the use of antiepileptic drugs (gabapentin, lamo-
trigine, topiramate, levetiracetam, phenytoin, and valproate)
in elderly patients (hazard ratio = 4.5) [60]. This is contrary
to the findings of a well-cited study where lamotrigine and
valproate were almost given antisuicidal status [61]. Many
of these observational studies have been criticized owing to
inconsistencies in the methods and presence of confounding
factors. The mortality risk of not prescribing antiepileptics is
high and decisions should always be individualized. Lamo-
trigine and valproate have been quoted to be safe in patients
with concomitant psychosis, but the use of antiepileptics pri-
marily for psychosis management should be avoided owing
to limited compelling evidence [27].
Among antiepileptics, only carbamazepine has been
found to be useful in the management of behavioral and
psychological symptoms of dementia (BPSD) in various
controlled studies. At the same time, the drug does not
have the most desirable safety profile [62]. A randomized,
placebo-controlled trial, failed to show any positive effect
of oxcarbazepine on BPSD with 8 week oxcarbazepine
treatment [63]. Valproate, lamotrigine, and gabapentin
have been shown to produce favorable results on BPSD
but not in controlled studies [62].
Antiepileptic drugs and stroke
Cerebrovascular accident is the most common cause of
seizures in late age. Compared to ischemic CVA, hem-
orrhagic CVA is complicated by seizures more often.
Post-stroke seizures can be early (< 2 weeks) or late
(after 2 weeks). While late-onset seizures often require
treatment, antiepileptic drugs can also be given in early
post-stroke seizures in case of recurrence. Plausibility of
drug interactions with older antiepileptics needs special
attention (Table 1) [64]. That phenytoin, valproate, and
carbamazepine can delay functional recovery after stroke
has also been pointed out by some studies [65]. Newer
antiepileptics like levetiracetam, lamotrigine, topiramate,
and gabapentin can be preferred in such situations.
Antiepileptics and vision changes
Elderly individuals often suffer from age-related ocular
pathologies like cataract, glaucoma, presbyopia, and dry
eyes [66]. Carbamazepine can cause diplopia, nystagmus,
change in color perception, and contrast sensitivity. These
effects can come at therapeutic or toxic drug levels [67].
Because of its antimuscarinic action, it can cause dry
eyes and precipitate an attack of angle closure glaucoma
[68]. Topiramate use has also been linked with precipita-
tion of attacks of angle closure glaucoma in susceptible
users [66]. Phenytoin toxicity can manifest as diplopia,
nystagmus, and alteration in color perception. Impaired
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 Acta Neurologica Belgica

Table 4  Common AEDs and their secondary effects relevant to geriatric practice
Secondary effect Older AEDs Newer AEDs

Cognition impairment More with PHB > PHT
Less with VPA and CBZ
Mood abnormalities CBZ/VPA used as mood stabilizers
Hyponatremia More with CBZ
Some risk with PHT and VPA
Cardiac conduction abnormalities More with PHT/CBZ
Less with VPA
Decline in bone density and risk of fractures More with PHT > CBZ
Some risk with VPA
Urinary retention More with CBZ
Less with VPA, PHT
Vision abnormalities More with CBZ, PHT
Less with VPA
Weight gain More with CBZ, VPA
Relatively safe: PHT
Respiratory suppression More with IV fast PHT
Less with VPA, CBZ
More with TPM
Some risk with GBP and ZNS
Less with PGB
Relatively safe: LTG and LEV
Depression and psychosis risk with LEV
LTG to be used cautiously in anxious patients and TPM
in depressed patients
More with OXC, also with ESL
Some risk with LEV and TPM
Relatively safe: PGB, GBP, LTG
Some risk with OXC
Caution advised with LCS
Relatively safe: PGB/GBP/LTG&LEV
Some risk with TPM and GBP
Relatively safe: LTG/LEV/PGB
Nephrolithiasis risk with TPM
Relatively safe: LTG, LEV, PGB, GBP
Angle closure glaucoma risk with TPM
Some risk of diplopia with OXC
Relatively safe: LTG, LEV, PGB, GBP
More with PGB, GBP
TPM causes weight loss
Relatively safe: LTG, LEV, OXC
Some risk with GBP in patients with comorbidities
Relatively safe: LTG, LEV, PGB, GBP, TPM, OXC, ESL

PHB phenobarbitone, CBZ carbamazepine, CLB clobazam, GBP gabapentin, LEV levetiracetam, LTG lamotrigine, OXC oxcarbazepine, ESL
eslicarbazepine, PHT phenytoin, TPM topiramate, VPA valproate, ZNS zonisamide, GBP gabapentin, PGB pregabalin, IV intravenous, AED
antiepileptic drug

color vision has also been observed with valproate. Both
these drugs have been implicated in cataract formation
[69]. Blurring of vision and diplopia have been observed
with lamotrigine, respectively, at therapeutic and toxic
dose [66]. However, there is no evidence of serious or
troublesome visual insults with lamotrigine, gabapentin,
levetiracetam, and oxcarbazepine.
Antiepileptic drugs and lung disease
Phenytoin and phenobarbitone can cause respiratory sup-
pression particularly on fast intravenous administration [27].
Arterial blood gas analysis with frequent monitoring of ­PO2,
­PCO2, ­SO2, serum bicarbonate, and arterial pH should be
done if such drugs are to be used in patients with asthma,
COPD, pulmonary edema, or left-ventricular failure. Though
rare, but gabapentin has been associated very recently with
severe respiratory depression. The risk is particularly high
in people with concomitant respiratory insufficiency, neu-
rologic disease, renal dysfunction, elderly, and when used
in conjunction with other CNS depressants. Despite these
reports, gabapentin along with levetiracetam, lamotrigine,
and valproate remains safer options in seizure disorder
patients with concomitant lung disorders [27].
Status of other new AEDs (perampanel,
lacosamide, and brivaracetam)
There are no head-to-head comparison trials of perampanel,
brivaracetam, and lacosamide in elderly population. Few
retrospective observational studies have evaluated the effi-
cacy and safety of lacosamide use in the elderly, the largest
being of 128 patients (≥ 65 years) which observed that 68%
patients with focal seizures were seizure-free at 12 months
when the drug was used as monotherapy. Compared to the
general population, lethargy, dizziness, and somnolence
were more common in the elderly subset but without any
differences in drug retention rates [70]. Perampanel use as
adjunct AED has been evaluated recently in a pooled analy-
sis of European population. 135 patients of age ≥ 65 years,
mostly with focal seizures, were included in the total data
set of 2396 patients. Only 28% elderly were seizure-free at
12 months [71]. In a subgroup analysis of three phase III
studies assessing the efficacy of add-on perampanel therapy
versus placebo, the drug was projected to have similar effi-
cacy in elderly as that in adult patients. Adverse effects were
more in the elderly, but, since the sample size of elderly
patients was very small (28 patients), the results cannot be

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Acta Neurologica Belgica
generalized [72]. As far as clinical data on brivaracetam are
concerned, the authors could find only one study pertain-
ing to elderly patients which was a pooled analysis of three
phase III studies involving only 32 patients of age ≥ 65 years.
Brivaracetam was used as an adjunct in focal seizures. Over-
all, safety and efficacy of drug were shown to be similar
in elderly and adult patients. Headache, paresthesias, and
somnolence were the common adverse effects [73]. Since
data concerning these new AEDs are scarce in elderly, larger
studies with a focus on geriatric specific complaints are
needed to draw major conclusions.
Conclusion
In this review, we have tried to analyze the pharmacologi-
cal issues with antiepileptic drug therapy in the elderly, the
impact these drugs can have on the major health problems
of elderly and the available literature on the safety and effi-
cacy of AEDs in elderly. Clearly, the data on antiepileptic
drugs in the elderly are scarce. With enough clinical experi-
ence of use of older antiepileptics in the general population,
phenytoin, carbamazepine, and valproate are still the choice
drugs in elderly, though the trend is shifting towards leveti-
racetam, gabapentin, and lamotrigine. These newer AEDs
have been shown to provide equivalent seizure protection
with relatively fewer interactions and adverse effects. Spe-
cific AEDs may be preferable while considering their effects
on cognition, cardiac function, body weight, fracture risk,
hyponatremia, urinary symptoms, ocular diseases, and the
risk of respiratory depression (Table 4). The authors have
provided information on therapeutically relevant drug inter-
actions involving antiepileptics and other drugs. ‘Start low
and go slow’ technique should be followed for the manage-
ment of epilepsy in the elderly. Large simple trials with
head-to-head comparison of older and newer antiepileptics
in elderly patients can generate evidence base and provide
new insights in the field of management of epilepsy in the
elderly.
Compliance with ethical standards
Conflict of interest Dr. Chakrabarti received honoraria from Novartis
and Intas Pharmaceuticals. None of the other authors report any con-
flict of interest.
Informed consent/ethical approval Not applicable.
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