Antiepileptic treatment in patients with epilepsy and other comorbidities☆

Article Outline

• Abstract
• 1. Introduction
• 2. Search strategy and selection criteria
• 3. Cardiovascular disease
• 4. Lung disease
• 5. Liver disease
• 6. Kidney disease
• 7. Porphyria
• 8. Organ transplantation
• 9. Thyroid disease
• 10. Metabolic disorder
  • 10.1. AEDs and bone metabolism
  • 10.2. AEDs and obesity
• 11. Infection
• 12. Mental disability
• 13. Psychiatric disorders
• 14. Cognitive impairment
• 15. Stroke
• 16. Brain tumour
• 17. Conclusions
• Conflicts of interest
• References
• Glossary
• Copyright

Abstract 

Background

A high number of patients with epilepsy have comorbidities. The type of comorbidity is an important factor in deciding on the most suitable treatment, including that for acute epileptic seizures and chronic antiepileptic treatment. Evidence-based criteria should guide the selection of the appropriate antiepileptic drugs given specific comorbidities.

Methods

We performed a comprehensive search of the scientific literature on epilepsy treatment in patients with the following comorbidities: heart disease, lung disease, liver disease, kidney disease, porphyria, organ transplantation, thyroid disease, metabolic disorder, infection, mental disability, psychiatric disorder, cognitive impairment, stroke, and brain tumour.

Results

Most of the studies were case series and retrospective analyses. No randomised controlled trials specifically designed for this type of clinical situation were identified. The level of scientific evidence to 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.

Keywords: Anticonvulsants, Comorbidity, Drug interactions, Epilepsy, Guidelines, Treatment

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1. Introduction 

Patients with epilepsy often have comorbidities. Several population surveys have found an increased prevalence of comorbid conditions in persons with epilepsy as compared with the general population. Two population studies from Canada reported a higher prevalence of stroke, diabetes, heart disease, high blood pressure, asthma, chronic bronchitis, stomach/intestinal ulcers, arthritis, thyroid conditions, migraine, Alzheimer's disease and cancer in persons with a history of epilepsy.¹ Epilepsy was also associated with an increased prevalence of mental health disorders, especially anxiety and depression, compared with the general population.² Other studies from England and California also found increased rates of somatic and psychiatric conditions in persons with epilepsy.³, ⁴

Comorbidities can be a direct cause of epilepsy, as with stroke, be in complex relationship with epilepsy, as with psychiatric disorders, or be associated with no apparent relationship as, for example, with heart disease.⁵ In any case, it has been demonstrated that people with epilepsy have a poorer health status and are more likely to report poor health-related quality of life than the general population. Although seizure freedom should continue to be a primary clinical goal, optimal care should also include identification and management of comorbidities. Likewise, the antiepileptic treatment of these patients should be taken under special consideration given potential side effects and interactions with other medications in patients with comorbidities.⁴, ⁶ In this respect we believe that bearing in mind the comorbidities of the patients with epilepsy at the time of chosing an antiepileptic drug (AED) should improve overall health and quality of life in those with epilepsy. Until recently, few options were available in the pharmacological treatment of epilepsy. In the last few years, however, more than ten AEDs have been introduced. Although overall these new AEDs have not demonstrated greater efficacy than older drugs, many of them have an improved pharmacokinetic profile and are better tolerated. These advantages make these AEDs potentially useful in patients with epilepsy and other comorbidities.⁷

Unfortunately, despite this therapeutic diversification and the high prevalence of comorbidities in patients with epilepsy, no systematic investigations have evaluated the most suitable AEDs for patients with epilepsy and with other medical problems. In this review, we searched Medline, Cochrane Library, Guidelines databases and relevant publications for research studies of epilepsy treatment in patients with other comorbidities. Our goal was to evaluate the evidence and provide recommendations based on the best available scientific evidence.

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2. Search strategy and selection criteria 

MEDLINE and the Cochrane Library databases were searched using “anticonvulsant” (Medical subject heading (MeSH) “antiepileptic drugs” (MeSH) or MeSH terms for AEDs (benzodiazepines, carbamazepine, clobazam, ethosuximide, gabapentin, levetiracetam, lamotrigine, oxcarbazepine, phenobarbital, pregabalin, phenytoin, primidone, tiagabine, topiramate, valproic acid, zonisamide, lacosamide) combined with the keywords “cardiovascular disease”, “lung disease”, “liver disease”, “kidney disease”, “porphyria”, “organ transplantation”, “thyroid disease”, “metabolic disorder”, “infection”, “mental disability”, “psychiatric disorder”, “cognitive impairment”, “stroke” and “brain tumour”.

The Canadian Medical Association (CMA) Infobase (http://www.cma.ca/cpgs/index.asp), the National Guideline Clearinghouse (http://www.guideline.gov/index.asp), the National Library for Health guidelines finder (http://www.library.nhs.uk/GUIDELINESFINDER) and other Web sites were searched for existing evidence-based practice guidelines.

Relevant articles and abstracts were selected and reviewed by the authors, and the reference lists from these sources were searched for additional trials, as were the reference lists from relevant review articles. Our search covered all relevant data to October 1, 2009. Most of the studies identified were case series and retrospective analyses. No randomised, controlled trials specifically designed for this type of clinical situation were identified. The guidelines on epilepsy treatment identified and reviewed⁸, ⁹, ¹⁰ do not provide information about epilepsy treatment in relation to comorbidities. The level of scientific evidence to guide clinical decisions is therefore low. One exception is the guideline for the management of epilepsy in adults with an intellectual disability published by the International Association of the Scientific Study of Intellectual Disability.¹¹

In the absence of human evidence, we used AED pharmacokinetic criteria and tolerability, as well as the accumulated experience and consensus of the members of the Andalusian Epilepsy Society. The results of the review and recommendations are presented below organized by type of comorbidity.

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3. Cardiovascular disease 

In the acute management of an epileptic seizure, intravenous phenytoin (PHT) can cause arrhythmias and hypotension. The risk is higher if there is a history of heart disease or if PHT is given at a rapid infusion rate. If intravenous use is necessary in a patient with heart disease, the infusion rate must not exceed 10mg/min, and electrocardiographic and blood pressure monitoring must be performed.¹² The use of intravenous PHT or fosphenytoin is contraindicated in patients with severe heart disease and second or third degree atrioventricular block.¹³ Valproic acid (VPA) is a good alternative to PHT in these patients because no abnormalities have been observed in heart rate or in blood pressure, even when a fast intravenous infusion rate is used.¹⁴ Levetiracetam (LEV) also appears safe, although few studies on its use in emergency situations are available. Benzodiazepines (BZD) can be used with careful monitoring of respiratory function.¹⁵, ¹⁶, ¹⁷

In chronic antiepileptic treatment, carbamazepine (CBZ), oxcarbazepine (OXC) and PHT should be used with caution in patients with heart disease, and they should be avoided in the event of atrioventricular conduction dysfunction.¹⁸ Pregabalin (PGB) should be used with care in cases of heart failure due to left ventricular systolic dysfunction.¹⁹ In general, enzyme-inducing 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.

Table 1. Precautions in the management of AEDs together with other commonly used drugs in heart disease.

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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 impairment, AEDs with a potential for inducing respiratory depression, 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

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5. Liver disease 

In the case of hepatic dysfunction, the hepatic metabolism of some AEDs is impaired, and there may be associated hypoalbuminaemia. 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

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

	Hepatic metabolism	Plasma protein binding (%)	Dose adjustment in renal impairment (RI)	Dose adjustment in haemodialysis (HD)
BZD	++		=	=
CBZ	++	75	=	=
ESM	++	0	↓ 25% of dose if Crt<10%	50% can be eliminated in 6h of HD.
				Best given after HD
GBP	–	0	Crt>80: =	200–300mg after HD in a single dose or 100–150 mg/day + SD of 125–250 after HD
			Crt 50–79: 200–600mg/8h
			Crt 30–49: 100–300mg/8h
			Crt 15–29: 300/48h to 600/24h
			Crt<15: 300/48h to 300/24h
LEV	+	<10	Crt 50–79: 0.5–1 g/12h	250–500mg after HD
			Crt 30–49: 250/750mg/12h
			Crt<30: 250–500mg/12h
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 25–100mg after HD
			Crt 30–59: 25–100/8h
			Crt 15–30: 25–50/8h
			Crt<15: 25–75/day (3 intakes)
TGB	++	96	=	=
TPM	+	15	↓ 50% in moderate and severe RI.	50–100mg/12h
				50–100mg after HD
VPA	++	90	=	SD may be needed
ZNS	+	40	? Slower dose adjustment	200–400 mg/day after HD
				SD of 100–200mg 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.

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 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

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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

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7. Porphyria 

The induction of hepatic haemosynthesis on the part of enzyme-inducing AEDs can exacerbate the symptoms of porphyria. 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 necessary, 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

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8. Organ transplantation 

To optimise AED treatment in transplant recipients, we must consider three fundamental factors:

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.

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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

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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 withdrawal of VPA.⁴⁷

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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 treatment) 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. 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, ⁵⁰, 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 recommended. 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

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

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.

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

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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

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13. Psychiatric disorders 

To optimise antiepileptic treatment in patients with concomitant psychiatric disorders, the following should be considered:

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14. Cognitive impairment 

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

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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 anticoagulants²⁰ (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, ⁶⁵, 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

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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 chemotherapy, patients treated with enzyme-inducing AEDs had lower survival rates than patients treated with non-enzyme-inducing AEDs.⁶⁹

Table 5. Pharmacological interactions between AEDs and cytotoxic and corticosteroid drugs.

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. (↓) Decreased plasma level. (=) No significant effect.

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 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

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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.

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

(*) Useful as add-on therapy. (The medications are ordered alphabetically and not necessarily by order of recommendation.)

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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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