Seizure 19 (2010) 375–382

Contents lists available at ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Review

Antiepileptic treatment in patients with epilepsy and other comorbidities§

J. Ruiz-Giménez a,*, J.C. Sánchez-Álvarez b, F. Cañadillas-Hidalgo c, P.J. Serrano-Castro d
on behalf of the Andalusian Epilepsy Society
a
Unidad de Epilepsia, Servicio de Neurologia, Hospital Universitario Virgen de las Nieves, Granada, España
b
Servicio de Neurologia, Hospital Clinico Universitario San Cecilio, Granada, España
c
Servicio de Neurologı´a, Hospital Universitario Reina Sofia, Cordoba, España
d
Unidad de Neurologia y Neurofisiologı´a, Hospital Torrecardenas, Almeria, España

A R T I C L E I N F O A B S T R A C T

Article history: Background: A high number of patients with epilepsy have comorbidities. The type of comorbidity is an
Received 9 November 2009 important factor in deciding on the most suitable treatment, including that for acute epileptic seizures
Received in revised form 18 April 2010 and chronic antiepileptic treatment. Evidence-based criteria should guide the selection of the
Accepted 20 May 2010
appropriate antiepileptic drugs given specific comorbidities.
Methods: We performed a comprehensive search of the scientific literature on epilepsy treatment in
Keywords: patients with the following comorbidities: heart disease, lung disease, liver disease, kidney disease,
Anticonvulsants
porphyria, organ transplantation, thyroid disease, metabolic disorder, infection, mental disability,
Comorbidity
psychiatric disorder, cognitive impairment, stroke, and brain tumour.
Drug interactions
Epilepsy Results: Most of the studies were case series and retrospective analyses. No randomised controlled trials
Guidelines specifically designed for this type of clinical situation were identified. The level of scientific evidence to
Treatment guide clinical decisions is therefore low.
Conclusions: In this review we make recommendations based on the best scientific evidence available for
treating epilepsy in patients with other comorbidities, including the treatment of epileptic seizures in
acute situations as well as chronic antiepileptic treatment. When no scientific evidence is available, our
recommendations are based on pharmacokinetic criteria and tolerability of antiepileptic drugs, using
accumulated experience and the consensus of the members of the Andalusian Epilepsy Society.
ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
2. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
3. Cardiovascular disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
4. Lung disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
5. Liver disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
6. Kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
7. Porphyria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
8. Organ transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
9. Thyroid disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
10. Metabolic disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
10.1. AEDs and bone metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
10.2. AEDs and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

§
This review has been extracted, modified and adapted from the Andalusian Guideline on Epilepsy 2009 (http://www.guiasade.com), written by: O. Alonso-Luengo, E.
Bauzano-Poley, H. Busquier-Hernández, R. Camino-León, F. Cañadillas-Hidalgo, J. Galán-Barranco, F.J. Gascón-Jiménez, A. Galdón-Castillo, D. Garcı́a-Solı́s, J. Gutiérrez-Garcı́a,
M. Ley-Martos, E. López-Laso, J. Martı́nez-Antón, C. Martı́nez-Parra, C. Martı́nez-Quesada, J. Mercadé-Cerdá, M.D. Morales-Martı́nez, V. Moreno-Alegre, M. Nieto-Barrera, E.
Pita-Calandre, M.M. Quesada-Lucas, P.A. Quiroga-Subirana, J. Ramos-Lizana, C. Robles-Vizcaı́no, J.J. Rodrı́guez-Uranga, S. Roldán-Aparicio, M. Rufo-Campos, J. Ruiz-Giménez,
J.C. Sánchez-Álvarez, P.J. Serrano-Castro, F. Villalobos-Chaves.
* Corresponding author at: Hospital de Rehabilitación y Traumatologia, Servicio de Neurologia, Carretera de Jaen, s/n 18013, Granada, Spain. Tel.: +34 659091751;
fax: +34 958021564.
E-mail address: jesusruizgimenez@hotmail.com (J. Ruiz-Giménez).

1059-1311/$ – see front matter ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.seizure.2010.05.008
376 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382

11. Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

12. Mental disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
13. Psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
14. Cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
15. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
16. Brain tumour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
17. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

1. Introduction nytoin, primidone, tiagabine, topiramate, valproic acid,

zonisamide, lacosamide) combined with the keywords ‘‘cardio-
Patients with epilepsy often have comorbidities. Several vascular disease’’, ‘‘lung disease’’, ‘‘liver disease’’, ‘‘kidney disease’’,
population surveys have found an increased prevalence of ‘‘porphyria’’, ‘‘organ transplantation’’, ‘‘thyroid disease’’, ‘‘meta-
comorbid conditions in persons with epilepsy as compared with bolic disorder’’, ‘‘infection’’, ‘‘mental disability’’, ‘‘psychiatric
the general population. Two population studies from Canada disorder’’, ‘‘cognitive impairment’’, ‘‘stroke’’ and ‘‘brain tumour’’.
reported a higher prevalence of stroke, diabetes, heart disease, high The Canadian Medical Association (CMA) Infobase (http://
blood pressure, asthma, chronic bronchitis, stomach/intestinal www.cma.ca/cpgs/index.asp), the National Guideline Clearing-
ulcers, arthritis, thyroid conditions, migraine, Alzheimer’s disease house (http://www.guideline.gov/index.asp), the National Library
and cancer in persons with a history of epilepsy.1 Epilepsy was also for Health guidelines finder (http://www.library.nhs.uk/GUIDE-
associated with an increased prevalence of mental health LINESFINDER) and other Web sites were searched for existing
disorders, especially anxiety and depression, compared with the evidence-based practice guidelines.
general population.2 Other studies from England and California Relevant articles and abstracts were selected and reviewed by
also found increased rates of somatic and psychiatric conditions in the authors, and the reference lists from these sources were
persons with epilepsy.3,4 searched for additional trials, as were the reference lists from
Comorbidities can be a direct cause of epilepsy, as with stroke, relevant review articles. Our search covered all relevant data to
be in complex relationship with epilepsy, as with psychiatric October 1, 2009. Most of the studies identified were case series and
disorders, or be associated with no apparent relationship as, for retrospective analyses. No randomised, controlled trials specifical-
example, with heart disease.5 In any case, it has been demonstrated ly designed for this type of clinical situation were identified. The
that people with epilepsy have a poorer health status and are more guidelines on epilepsy treatment identified and reviewed8–10 do
likely to report poor health-related quality of life than the general not provide information about epilepsy treatment in relation to
population. Although seizure freedom should continue to be a comorbidities. The level of scientific evidence to guide clinical
primary clinical goal, optimal care should also include identifica- decisions is therefore low. One exception is the guideline for the
tion and management of comorbidities. Likewise, the antiepileptic management of epilepsy in adults with an intellectual disability
treatment of these patients should be taken under special published by the International Association of the Scientific Study of
consideration given potential side effects and interactions with Intellectual Disability.11
other medications in patients with comorbidities.4,6 In this respect In the absence of human evidence, we used AED pharmacoki-
we believe that bearing in mind the comorbidities of the patients netic criteria and tolerability, as well as the accumulated
with epilepsy at the time of chosing an antiepileptic drug (AED) experience and consensus of the members of the Andalusian
should improve overall health and quality of life in those with Epilepsy Society. The results of the review and recommendations
epilepsy. Until recently, few options were available in the are presented below organized by type of comorbidity.
pharmacological treatment of epilepsy. In the last few years,
however, more than ten AEDs have been introduced. Although 3. Cardiovascular disease
overall these new AEDs have not demonstrated greater efficacy
than older drugs, many of them have an improved pharmacoki- In the acute management of an epileptic seizure, intravenous
netic profile and are better tolerated. These advantages make these phenytoin (PHT) can cause arrhythmias and hypotension. The risk
AEDs potentially useful in patients with epilepsy and other is higher if there is a history of heart disease or if PHT is given at a
comorbidities.7 rapid infusion rate. If intravenous use is necessary in a patient with
Unfortunately, despite this therapeutic diversification and the heart disease, the infusion rate must not exceed 10 mg/min, and
high prevalence of comorbidities in patients with epilepsy, no electrocardiographic and blood pressure monitoring must be
systematic investigations have evaluated the most suitable AEDs performed.12 The use of intravenous PHT or fosphenytoin is
for patients with epilepsy and with other medical problems. In this contraindicated in patients with severe heart disease and second or
review, we searched Medline, Cochrane Library, Guidelines third degree atrioventricular block.13 Valproic acid (VPA) is a good
databases and relevant publications for research studies of alternative to PHT in these patients because no abnormalities have
epilepsy treatment in patients with other comorbidities. Our goal been observed in heart rate or in blood pressure, even when a fast
was to evaluate the evidence and provide recommendations based intravenous infusion rate is used.14 Levetiracetam (LEV) also
on the best available scientific evidence. appears safe, although few studies on its use in emergency
situations are available. Benzodiazepines (BZD) can be used with
2. Search strategy and selection criteria careful monitoring of respiratory function.15–17
In chronic antiepileptic treatment, carbamazepine (CBZ),
MEDLINE and the Cochrane Library databases were searched oxcarbazepine (OXC) and PHT should be used with caution in
using ‘‘anticonvulsant’’ (Medical subject heading (MeSH) ‘‘antiep- patients with heart disease, and they should be avoided in the
ileptic drugs’’ (MeSH) or MeSH terms for AEDs (benzodiazepines, event of atrioventricular conduction dysfunction.18 Pregabalin
carbamazepine, clobazam, ethosuximide, gabapentin, levetirace- (PGB) should be used with care in cases of heart failure due to left
tam, lamotrigine, oxcarbazepine, phenobarbital, pregabalin, phe- ventricular systolic dysfunction.19 In general, enzyme-inducing
 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382 377

Table 1
Precautions in the management of AEDs together with other commonly used drugs in heart disease.
Antiplatelets Salicylates increase the free fraction of VPA.
Ticlopidine increases the levels of PHT and CBZ.
Antiarrhythmics Enzyme-inducing AEDs increase the metabolism of antiarrhythmics and so it may be necessary to increase the doses of the latter.
Dilthiazem and verapamil increase the levels of CBZ.
Amiodarone increases the levels of PHT.
Antihypertensives Enzyme-inducing AEDs increase the metabolism of beta-blockers and dihydropyridine calcium antagonists
PHT reduces the active metabolite of losartan by up to 63%.
VPA increases levels of nimodipine by 50%.
Oral anticoagulants (OAC) Enzyme-inducing AEDs reduce the anticoagulant effect of OACs
Complex interaction with PHT: PHT increases the initial effect of the OAC and then reduces it. OACs can increase
the levels of PHT. The dose of both drugs must be adjusted if used together.
Diuretics PHT reduces the diuretic response to furosemide.
Use with precaution when associated with CBZ or OXC because of the risk of hyponatraemia.
Digoxin PHT significantly reduces digoxin levels.
Anti-lipidemics In general, enzyme-inducing AEDs stimulate the metabolism of these drugs.

AEDs should be avoided because of their many interactions with
drugs that are commonly used in heart disease20 (Table 1). The
most recommended AEDs are LEV, lamotrigine (LTG), topiramate
(TPM), VPA and zonisamide (ZNS). Gabapentin (GBP) can also be
useful as an add-on therapy.
4. Lung disease
Parenteral use of barbiturates, BZD and PHT can cause
respiratory depression. When used in patients with respiratory
impairment, the heart rate, respiratory rate and oximetry should
be monitored. Access to cardiopulmonary resuscitation equipment
should also be considered. Parenteral VPA offers a safe and
effective alternative.14,21 LEV can also be effective in these
situations.15,17,22
In the chronic treatment of patients with respiratory im-
pairment, AEDs with a potential for inducing respiratory depres-
sion, such as barbiturates and BZDs, should be avoided. BZDs,
moreover, increase bronchial secretions, particularly in children.21
Enzyme-inducing AEDs reduce theophyline concentration and
theophyline can lower the levels of CBZ and PHT.20
5. Liver disease
In the case of hepatic dysfunction, the hepatic metabolism of
some AEDs is impaired, and there may be associated hypoalbu-
minaemia. For this reason it is important to consider the
pharmacokinetics of AEDs in the presence of hepatic dysfunction
(Table 2). If the hepatic impairment is mild, however, it is generally
not necessary to adjust the AED dose.23
PB should be avoided in the acute management of epileptic
seizures in patients with liver disease because it can trigger or
aggravate hepatic encephalopathy. BZDs are metabolised in the
liver and can also cause hepatic encephalopathy. They should only
be used if absolutely needed and at lower doses than normal.24 VPA
is contraindicated because of its hepatotoxic capacity in patients
with underlying liver disease.25 PHT should be used with caution
because, due to its high protein binding, the free fraction is

Table 2
Pharmacokinetic properties of AEDs of particular interest in the case of hepatic impairment, renal impairment and/or haemodialysis.

Hepatic metabolism Plasma protein Dose adjustment in renal Dose adjustment in haemodialysis (HD)
binding (%) impairment (RI)

BZD ++ = =
CBZ ++ 75 = =
ESM ++ 0 # 25% of dose if Crt < 10% 50% can be eliminated in 6 h of HD.
Best given after HD
GBP – 0 Crt>80: = 200–300 mg after HD in a single
dose or 100–150 mg/day + SD of 125–250 after HD
Crt 50–79: 200–600 mg/8 h
Crt 30–49: 100–300 mg/8 h
Crt 15–29: 300/48 h to 600/24 h
Crt < 15: 300/48 h to 300/24 h
LEV + <10 Crt 50–79: 0.5–1 g/12 h 250–500 mg after HD
Crt 30–49: 250/750 mg/12 h
Crt < 30: 250–500 mg/12 h
LTG ++ 55 # dose in moderate and severe RI 20% is eliminated in 4 h of HD. Best given after HD
OXC ++ 40 # 50% of dose if Crt < 30% ? Avoid in HD due to insufficient data
PB/PRM ++ 45 # Normal dose SD
PHT ++ 90 = =
PGB  0 Crt > 60: = Single SD of 25–100 mg after HD
Crt 30–59: 25–100/8 h
Crt 15–30: 25–50/8 h
Crt < 15: 25–75/day (3 intakes)
TGB ++ 96 = =
TPM + 15 # 50% in moderate and severe RI. 50–100 mg/12 h
50–100 mg after HD
VPA ++ 90 = SD may be needed
ZNS + 40 ? Slower dose adjustment 200–400 mg/day after HD
SD of 100–200 mg the morning before HD

Mainly hepatic metabolism: ++; partly hepatic metabolism: +; extrahepatic metabolism: ; Crt: creatinine clearance in ml/min; (?) no data available, use with caution; = no
dose adjustment required; SD: supplementary dose.
378 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382
increased in the presence of hypoalbuminaemia with the
possibility of intoxication.27 LEV is the most recommended
therapeutic alternative in the acute phase of epileptic seizures
in patients with liver disease.15,22,26
In chronic treatment, the most suitable AEDs are those with a
low level of protein binding and limited hepatic metabolism: GBP,
LEV, OXC, PGB and TPM.27 However, in the event of severe liver
disease, it may also be necessary to adjust the dose of these AEDs
because of the renal dysfunction that is often concomitant. For this
reason, in the presence of severe liver disease it is advisable to
reduce the normal dose of LEV by 50% and the normal dose of TPM
by 30%.28 OXC has low protein binding and a lower potential for
enzyme induction compared to CBZ. BZD, CBZ, ethosuximide
(ESM), phenobarbital (PB), PHT, primidone (PRM), tiagabine (TGB)
and ZNS can be used under close surveillance. The use of LTG and
VPA is not recommended.27
6. Kidney disease
In patients with renal impairment, AEDs which are mainly
eliminated by the kidneys will have a longer half life and tend to
accumulate in the blood because of the reduced glomerular
filtration rate and tubular secretion.29 For this reason, LEV is not
recommended in acute management.15,30 Care should be taken
with the chronic use of GBP, LEV, LTG, OXC, PB, PGB, PRM, TPM and
ZNS because these AEDs are eliminated to a greater or lesser extent
by the kidneys. They are not strictly contraindicated, but major
dose adjustments will be needed, along with close surveillance
because of the risk of toxicity. Moreover, after haemodialysis,
plasma levels of these AEDs change and supplementary doses will
be required. The AEDs most affected by haemodialysis are the most
hydrosoluble ones, the ones with a low level of protein binding and
those with a lower distribution volume31 (Table 2). Furthermore,
TPM and ZNS should be avoided in the event of nephrolithiasis or
when there is a possibility of developing it.32,33 The most
recommended AEDs in renal impairment and haemodialysis are
those that are mainly eliminated by the liver, such as BZD, CBZ,
ESM, PHT, TGB and VPA.31
7. Porphyria
The induction of hepatic haemosynthesis on the part of
enzyme-inducing AEDs can exacerbate the symptoms of porphyr-
ia. Treatment with CBZ, PB, PHT, PRM, TPM, VPA and ZNS should be
avoided. A porphyrinogenic capacity has also been shown in in
vitro studies on LTG and TGB.34
The use of non-enzyme-inducing AEDs such as GBP, LEV and
PGB is recommended. OXC has been used successfully in an
isolated case of porphyria cutanea tarda and also in another case of
intermittent acute porphyria.35 If parenteral treatment is neces-
sary, the use of LEV should be considered. Intravenous magnesium
sulphate and BZDs have also been used in isolated cases of status
epilepticus, although in theory BZDs can worsen porphyria
symptoms.36
8. Organ transplantation
To optimise AED treatment in transplant recipients, we must
consider three fundamental factors:
1. The possible presence and degree of hepatic or renal dysfunction
in patients who are liver or kidney recipients.
2. Pharmacological interactions between AEDs and immunosup-
pressive drugs. Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) can
reduce plasma levels of cyclosporine, tacrolimus, sirolimus and
corticosteroids and so it may be necessary to increase the dose of
these drugs. VPA only causes a minimal reduction of cyclospor-
ine and tacrolimus levels. Cyclosporine binds largely to plasma
proteins, and this can significantly increase the free fraction of
AEDs that have a high percentage of protein binding. Azathio-
prine, mycophenolate and muromonab-CD3 (OKT3) are not
significantly affected by AEDs.20 In this respect, the good
pharmacokinetic properties of second-generation AEDs make
them very useful in transplant recipients.37
3. AED side effects may have a negative impact on the transplanted
tissue. VPA should be avoided in liver transplantation and in the
engraftment phase of bone marrow transplantation (the first 2–
6 weeks).38 CBZ, OXC, PB and PRM should be avoided in bone
marrow transplant cases.39
Given these factors, we conclude that GBP, LEV, PGB and TPM
are the most appropriate AEDs to treat epilepsy in patients with
liver transplantation. BZD, LTG and VPA are the most appropriate in
patients with kidney transplantation. GBP, LEV, LTG and TPM are
the most appropriate in bone marrow transplantation.
9. Thyroid disease
Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) influence thyroid
hormone metabolism, causing a decrease in total and free thyroxin
levels. This modification is usually subclinical and reverses when
AEDs are withdrawn, particularly in healthy patients. However, it
may be clinically significant in patients with hypothyroidism who
are on replacement therapy.40,41 Likewise, VPA can cause a
subclinical, reversible increase in TSH.42 Although data on the
effect of second-generation AEDs are currently insufficient, it is
likely that the AEDs with a moderate enzyme-inducing effect (OXC,
TPM) will also affect thyroid hormones, while the non-enzyme-
inducing AEDs will not affect them.43
10. Metabolic disorder
10.1. AEDs and bone metabolism
Enzyme-inducing AEDs and PHT in particular accelerate
vitamin D catabolism and increase bone turnover.44 VPA interferes
with osteoblast function. Although LEV and LTG do not appear to
have a significant effect in this respect, a case–control study
revealed that enzyme-inducing and non-enzyme-inducing AEDs
alike are an independent risk factor for osteoporosis.45
10.2. AEDs and obesity
Some AEDs are associated with weight gain (CBZ, CLB, GBP, PGB
and VPA) and others with weight loss (TPM and ZNS). The majority
have a neutral effect in this respect.46 Some studies with small
sample size found that patients on VPA treatment who gained
weight showed insulin resistance that was reversible on with-
drawal of VPA.47
11. Infection
There are important interactions between AEDs and anti-
infective agents that should be considered in the management of
infectious diseases (particularly those requiring prolonged treat-
ment) and of symptomatic seizures from infectious processes.48
In the treatment of neurocysticercosis, enzyme-inducing AEDs
reduce the concentration of praziquantel and albendazole by over
50%. In the treatment of tuberculosis, isoniazid inhibits the
metabolism of CBZ, PHT and VPA, and can cause toxicity.
 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382 379

Table 3
Principal pharmacological interactions between AEDs and commonly used antibiotics.

CBZ LTG PB PHT VPA

Albendazole # = # = # =
Carbapenems #
Ciprofloxacin #"
Clarithromycin "
Doxycycline # # #
Erythromycin "
Fluconazole " " "
NRTI = = = = = = = = =
NNRTI # " = " # " # " = "
PI # " = " # " # " = "
Isoniazid " " "
Ketoconazole "
Metronidazole # " # #
Praziquantel # = # = # =
Rifampicin # # # # #
Sulphonamides "

The arrows on the left hand side of the boxes indicate the effect of interaction on the plasma levels of the antibiotics and the ones on the right hand side indicate the effect on
plasma levels of AEDs. (") Increased plasma level. (#) Decreased plasma level. (=) No significant effect. NRTI: nucleoside reverse transcriptase inhibitors. NNRTI: non-
nucleoside reverse transcriptase inhibitors. PI: protease inhibitors.

Table 4
Optimisation of treatment in patients with epilepsy with psychiatric comorbidity.

Antiepileptic treatment Psychiatric treatment

Recommended To be avoided Recommended To be avoided

Depression CBZ, GBP, LTG, OXC, PGB, VPA PB, PHT, PRM, TGB, TPM Citalopram Escitalopram Sertraline Amoxapine Maprotiline Bupropion
Trazodone Venlafaxine
Anxiety BZD, GBP, PGB, VPA LEV BZD SSRIs –
Psychosis LTG, OXC, VPA ESM, LEV, TPM Olanzapine Quetiapine Risperidone Chlorpromazine Clozapine

Conversely, rifampicin reduces the plasma concentration of CBZ,
LTG, PB, PHT and VPA.20
AED treatment in HIV infection depends on whether or not the
patient is on antiretroviral therapy. If the patient is not on
antiretrovirals, any AED can be prescribed. Some studies suggest
that VPA might stimulate the viral replication of latent HIV in vitro,
but more recent results are negative and there is thus no evidence
against it.49–51 If the patient is on antiretroviral treatment, then the
reciprocal interactions between AEDs and antiretrovirals must be
taken into consideration (Table 3). In these cases, non-enzyme-
inducing AEDs that are not metabolised in the liver are recom-
mended. The most suitable AEDs for HIV patients are LEV, PGB and
TPM. GBP can be useful too, but usually as a secondary therapy line.48
Any AEDs can be used in general and neuromeningeal
infections, although it is advisable to select ones that have few
interactions. Table 3 summarises the most significant interactions
between AEDs and antimicrobial agents.20,52
12. Mental disability
There is a much higher incidence of epilepsy amongst patients
with mental disabilities than in the general population. AED
efficacy is similar in patients with and without mental disabilities
although patients with mental disability are generally more
susceptible to AED side effects and often require continued
treatment over longer periods.53 Therefore, monotherapy should
be used whenever possible.54
AEDs with sedative effect or potential cognitive reduction, such
as BZD, CBZ, PB, PHT, PRM and TPM should be avoided for long term
treatment. However, the use of Diazepam (oral or rectal route) or
Midazolam (buccal or intranasal route) is recommended for acute
treatment of prolonged and cluster seizures.11 Whenever possible,
AEDs that have a lower rate of cognitive adverse effects such as
GBP, LEV, LTG, OXC and VPA should be used.11,55,56 One should also
consider that other side effects in AEDs are often potentiated in
these patients, and therefore patients with impaired coordination
or gait should avoid the use of CBZ, LTG, OXC, PB, PHT and PRM and
patients with severe behavioural problems should avoid the use of
LEV, TPM and ZNS.54
13. Psychiatric disorders
To optimise antiepileptic treatment in patients with concomi-
tant psychiatric disorders, the following should be considered:
1. Possible influence of AEDs on psychiatric symptoms. Depending
on the type of psychiatric comorbidity, some AEDs are more
appropriate than others57–59 (Table 4).
2. Pharmacological interactions. Enzyme-inducing AEDs can lower
the plasma levels of other psychotropic drugs (neuroleptics,
tricyclic and selective serotonin reuptake inhibitor antidepres-
sants), hindering the control of psychiatric symptoms. The
interaction between VPA and amitriptyline or nortriptyline can
cause an increase of up to 60% in the plasma levels of these
drugs, causing intoxication. There are no significant interactions
between AEDs and lithium.20
Tricyclic antidepressants (TCAs) can inhibit AED metabolism,
causing toxicity symptoms. The same occurs with some
selective serotonin reuptake inhibitor antidepressants (SSRIs)
such as fluoxetine, paroxetine and fluvoxamine, although these
drugs have a better pharmacokinetic profile than TCAs. Other
antidepressants such as citalopram, escitalopram, sertraline,
trazodone and venlafaxine do not have a significant effect on
AED metabolism.20,58,59
Most antipsychotic drugs interfere with the hepatic metab-
olism of AEDs to a variable degree. Clozapine should be avoided
in patients with epilepsy, while olanzapine, quetiapine and
risperidone do not usually require dose adjustment, even when
used in combination with enzyme-inducing AEDs.58
380 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382

Table 5
Common side effects that can be potentiated must also be
Pharmacological interactions between AEDs and cytotoxic and corticosteroid drugs.
taken into consideration. SSRIs can cause hyponatraemia and so
they must be used with caution when combined with CBZ or CBZ PB PHT VPA
OXC.57 Anthracyclines # # # # # # #
3. Potential epileptogenic effect of antidepressants and antipsy- Cyclophosphamide # # #
chotics. As a general rule the epileptogenic risk is low for TCAs, Cisplatin # # # #"
Corticosteroids # # # #"
SSRIs and antipsychotics alike. The risk is especially minimised
Etoposides # # #
when these drugs are used within the therapeutic range, with a Fluorpyrimidines # "
slow dose titration and avoiding complex combinations Irinotecan topotecan # # #
between them. There are, however, exceptions, and certain Methotrexate # # # #
antidepressants such as amoxapine, maprotiline and bupropion Nitrosureas # # # " "
Taxoides # # #
and certain neuroleptics such as clozapine and chlorpromazine Vincristine # # #
have a higher epileptogenic risk.59
The arrows on the left hand side of the boxes indicate the effect of interaction on the
plasma levels of the cytotoxic and corticosteroid drugs and the ones on the right
hand side indicate the effect on plasma levels of AEDs. (") Increased plasma level. (#)
14. Cognitive impairment Decreased plasma level. (=) No significant effect.

Cognitive impairment as a consequence of reduced brain

functional reserve or degenerative disease can be aggravated by
AEDs. Before starting treatment with an AED, especially in the
elderly, the patient’s cognitive condition should be assessed to
avoid using AEDs that can aggravate incipient mental impairment.
Among the AEDs with the most severe impact on cognitive
function are BZD, PB and PRM, and to a lesser degree PHT and TPM.
The AEDs with the least impact on cognitive function are GBP, LEV,
LTG and PGB. In general, high doses and combination AED therapy
aggravate the harmful potential of the drugs from a cognitive
standpoint.60,61
15. Stroke
For different reasons conventional AEDs such as BZD, CBZ, PHT,
PB and VPA are in general less recommended in patients with
stroke. Firstly, a delay in functional recovery has been reported as a
result of their use in patients with stroke.62,63 Furthermore, they
can have significant interactions with salicylates and oral antic-
oagulants20 (Table 1). In spite of these disadvantages, the
availability of PHT and VPA in IV form makes them still a good
choice for use in acute situations in these patients.
Some recent AEDs such as GBP, LEV, LTG, OXC and TPM do not
seem to have interactions with antiplatelets or anticoagulants or to
affect functional prognosis following a stroke.20 Both GBP and LEV
have been evaluated specifically in stroke patients and they have
been shown to be safe and effective in these patients.64–66
There is evidence from clinical trials that LTG and GBP are more
effective than CBZ in elderly patients with epilepsy, many of whom
have suffered a stroke.67 In a prospective, randomised study with
64 stroke patients who had suffered a first seizure, it was
demonstrated that LTG was better tolerated than CBZ, and no
significant differences were observed in efficacy.68
16. Brain tumour
In patients with brain tumours, pharmacological interactions
between AEDs and cytotoxic agents and corticosteroids should be
considered (Table 5). In a retrospective study of patients with
glioblastoma multiforme treated with conventional chemothera-
py, patients treated with enzyme-inducing AEDs had lower
survival rates than patients treated with non-enzyme-inducing
AEDs.69
AED tolerability must be considered in patients with brain
tumours because they appear to suffer more side effects than the
general population, including more frequent skin rashes. Severe
cutaneous reactions have been reported in patients treated with
CBZ, PHT or PB who were being given brain radiotherapy.70 As is
the case with stroke, the availability of an IV form of PHT makes it
still a good choice for use in acute situations in these patients.
Response to conventional AEDs seems to be variable, with 70%
of patients with brain tumours treated with CBZ, 51% of those
treated with PHT, and 44% of those treated with VPA having
persistent seizures. This suggests that VPA could be the
conventional AED of choice in patients with brain tumours.71
LEV has shown good efficacy and tolerability in monotherapy in
prospective studies in patients with brain tumours.72 In a recent

Table 6
Recommendations for the use of AEDs in patients with epilepsy and other comorbidities.

Most recommended AEDs Less recommended AEDs AEDs to be avoided

Heart disease LEV, LTG, TPM, VPA, ZNS. GBP* CBZ, OXC, PGB, PHT _
Lung disease LEV, LTG, OXC, PGB, TPM, VPA, ZNS. GBP* CBZ, PHT BZD, PB, PRM
Hepatic impairment LEV, OXC, PGB, TPM. GBP* BZD, CBZ, ESM, PB, PHT, PRM, TGB, ZNS LTG, VPA
Renal impairment BZD, CBZ, ESM, PHT, TGB, VPA GBP, LEV, LTG, OXC, PB, PGB, PRM, TPM, ZNS _
Porphyria LEV, OXC, PGB. GBP* BZD CBZ, LTG, PB, PHT, PRM,
TGB, TPM, VPA, ZNS
Liver transplantation LEV, PGB, TPM. GBP* CBZ, PB, PHT, PRM VPA
Kidney transplantation BZD, LTG, VPA AEDs with renal excretion _
Bone marrow transplantation LEV, LTG, TPM. GBP* _ CBZ, OXC, PB, PRM, VPA
Hypothyroidism BZD, LEV, LTG, PGB, ZNS. GBP* OXC, TPM, VPA CBZ, PB, PHT, PRM
Osteoporosis BZD, LEV, LTG, PGB, ZNS. GBP* VPA CBZ, PB, PHT, PRM
Obesity TPM, ZNS CBZ, CLB GBP, PGB, VPA
HIV LEV, PGB, TPM. GBP* BZD, LTG, OXC, VPA, ZNS CBZ, PB, PHT, PRM
Mental disability LEV, LTG, OXC, VPA. GBP* PGB, ZNS BZD, CBZ, PB, PHT, PRM, TPM
Cognitive impairment LEV, LTG, PGB. GBP* CBZ, OXC, VPA, ZNS BZD, PB, PHT, PRM, TPM
Stroke LEV, LTG. GBP* CBZ, OXC, PHT, TPM, VPA BZD, PB, PRM
Brain tumour LEV, VPA. GBP*, PGB*, ZNS* CBZ, LTG, OXC, PHT, TPM PB, PRM

(*) Useful as add-on therapy. (The medications are ordered alphabetically and not necessarily by order of recommendation.)
 J. Ruiz-Giménez et al. / Seizure 19 (2010) 375–382
observational study on patients with glioma, the higuest responder
percentage was obtained with a combination of VPA and LEV.73
OXC monotherapy has showed similar efficacy and a lower
incidence of side effects than traditional AEDs in a comparative
study.74 LTG is a well-established treatment in focal epilepsy
related to brain tumours, although it takes time to attain a
therapeutic dose and there is an increased risk of exanthema. GBP
has shown good efficacy and tolerability in add-on therapy in
patients with brain tumours.70 Preliminary data from recent and
small clinical series indicate that PGB and ZNS may represent valid
alternatives as add-ons in brain tumour-related epilepsy, although
larger studies are needed.75,76
17. Conclusions
A high percentage of patients with epilepsy have some
comorbidity, and this is an important factor when selecting the
most suitable AED. Although the level of scientific evidence
concerning epilepsy treatment in patients with other associated
diseases is low and rarely supported by clinical trials, there is a
need for evaluating available data that support the use of certain
AEDs in the presence of specific diseases. Table 6 summarises
which AEDs are most recommended in each situation and which
should be avoided or are less recommended, based on the best
evidence available and the experience and consensus of the
members of the Andalusian Epilepsy Society.
Conflicts of interest
The authors have received research grants and speaker fees
from Eisai, Esteve, GSK, Iquinosa, Janssen-Cilag, Juste, Novartis,
Parke-Davis, Pfizer, Sanofi and UCB-Pharma.
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