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Antiepileptic Drugs in Patients With Stroke 

Antiepileptic Drugs in Patients With Stroke
Chapter:
Antiepileptic Drugs in Patients With Stroke
Author(s):

Ali A. Asadi-Pooya

and Michael R. Sperling

DOI:
10.1093/med/9780190214968.003.0021
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Stroke and cerebrovascular lesions are the main cause of epilepsy in the elderly. The risk for development of epilepsy is 17-fold higher after stroke than in the age-matched general population; it is estimated that 10%–15% of stroke patients develop epilepsy (Ferro & Pinto, 2004). Seizures can be a presenting feature of acute stroke or may be a late complication.

Many similarities exist between cerebral ischemia and epilepsy regarding brain damage and autoprotective mechanisms that are activated following the injurious insult. Therefore, drugs that are effective in minimizing seizure-induced brain damage may also be useful in minimizing ischemic injury. On the other hand, some AEDs may have detrimental effects in stoke patients, and there is evidence that recovery is worse in patients treated with particular AEDs after stroke (Goldstein, 2000; Stepien et al., 2005).

There is no clinical evidence that prophylactic anticonvulsant treatment after stroke protects against the development of epilepsy. Transient AED therapy may be needed after a seizure occurring in the setting of an acute stroke (seizure occurring within the first week after a stroke), but prolonged, usually lifelong therapy is required after delayed seizures (seizure occurring more than 1 week after a stroke) due to high probability of seizure recurrence. When selecting an AED for a patient with stroke, one should consider the impact of an AED on comorbidity and comedications, the adverse effects, and cost among other factors (Stepien et al., 2005; Ryvlin & Montavont, 2006; Gilad 2012).

On the other hand, concern has been raised recently that some AEDs might increase the levels of serologic markers associated with an increased risk of vascular diseases (see Chapter 15 and Chapter 17). The duration of exposure to some AEDs may also predict acceleration of atherosclerosis. Based on these mechanisms, patients exposed to some AEDs could have an increased risk of vascular diseases such as stroke. In a recent study, the authors found that exposure to phenytoin was associated with a higher stroke risk as compared to carbamazepine. In addition, a longer duration and higher dosage of phenytoin demonstrated a dose–response relationship to increased stroke risk. Besides, studies have found that patients with epilepsy have higher stroke-related morbidity and mortality, which is probably related to AEDs, at least in part (Hsieh et al., 2013).

Benzodiazepines

Benzodiazepines may have potential detrimental effects in stroke patients (Schallert et al., 1986; Goldstein, 2000). In addition, adverse effects are significant in the elderly (Levy et al., 2002; Drug Facts and Comparisons, 2007). These are not recommended.

Carbamazepine

Carbamazepine has had some degree of neuroprotective activity in an ischemic/hypoxic model of neuronal injury (Willmore, 2005). However, due to enzyme induction and drug interactions, other AEDs may be a better choice (Levy et al., 2002; Parrish et al., 2006; Drug Facts and Comparisons, 2007). Because it induces cytochrome P-450 enzymes, doses of warfarin and other drugs (e.g., statins) will need to be increased.

Eslicarbazepine

Occurrence of hyponatremia is a potential problem. Besides, in vivo studies suggest that eslicarbazepine acetate can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., simvastatin). Although the pharmacokinetics of eslicarbazepine are not affected by age independently, dose selection should take in consideration the greater frequency of renal impairment and medical comorbidities and drug therapies in the elderly patient.

Gabapentin

This drug does not demonstrate significant interaction with anticoagulants, antiplatelet agents, or other medications commonly prescribed in stroke patients, and its safety profile is relatively favorable (Stepien et al., 2005). Low target dosages (900–1200 mg/day) and slow titration over several weeks are appropriate in stroke patients (Stepien et al., 2005).

Lacosamide

This drug does not demonstrate significant interaction with anticoagulants, antiplatelet agents, or other medications commonly prescribed in stroke patients, and its safety profile is relatively favorable, but cardiovascular adverse effects and possibility of syncope should be kept in mind. The intravenous formulation can be used in patients with swallowing difficulty. Lacosamide treatment following status epilepticus attenuated neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model (Licko et al., 2013).

Lamotrigine

This drug has fared well in randomized comparison trials in the elderly population (see Chapter 11) and is a good choice for stroke patients (Stepien et al., 2005). Lamotrigine also has had some degree of neuroprotective activity in an ischemic/hypoxic model of neuronal injury (Willmore, 2005). In addition, lamotrigine may help treat central poststroke pain (Vestergaard et al., 2001; Frese et al., 2006).

Levetiracetam

Due to its favorable pharmacokinetic profile and lack of drug interaction, this drug is a good choice for acute or chronic use. The intravenous formulation can be used in patients with swallowing difficulty. Levetiracetam may have some neuroprotective activity.

Oxcarbazepine

This drug is a reasonable choice, although the relatively common occurrence of hyponatremia is a potential problem. In dosages <900 mg daily, this drug does not demonstrate significant interaction with anticoagulants, antiplatelet agents, or other medications commonly prescribed in stroke patients, and its safety profile is relatively favorable (Stepien et al., 2005).

Perampanel

This drug does not demonstrate significant interaction with anticoagulants, antiplatelet agents, or other medications commonly prescribed in stroke patients, and its safety profile is relatively favorable. Elderly patients had an increased risk of falls compared to younger adults.

Phenobarbital

This is a suboptimal drug for chronic use and is mainly needed if status epilepticus occurs. Phenobarbital has had some degree of neuroprotective activity in an ischemic/hypoxic model of neuronal injury (Willmore, 2005). However, there are reports of delay in functional recovery in animal models of stroke or brain damage (Stepien et al., 2005). Phenobarbital may have potential detrimental effects in stoke patients (Goldstein, 2000). Importantly, due to adverse effects and drug interactions, use with precaution in elderly patients (Levy et al., 2002; Drug Facts and Comparisons, 2007).

Phenytoin

This drug is suboptimal for acute and long-term use, although the intravenous formulation offers acute treatment advantages. Hepatic enzyme induction, drug interactions, and its zero-order kinetics all pose difficulties (Levy et al., 2002; Drug Facts and Comparisons, 2007). Because it induces cytochrome P-450 enzymes, doses of warfarin and other drugs (e.g., statins) will need to be increased. Moreover, there are reports of alteration or delay in functional recovery in animal models of stroke or brain damage (Brailowsky et al., 1986; Stepien et al., 2005). Phenytoin may have detrimental effects in stroke patients as well (Goldstein, 2000). Likewise, prophylactic phenytoin may contribute to poor functional and cognitive outcomes in a dose-dependent manner after subarachnoid hemorrhage (Naidech et al., 2005). Phenytoin may also cause fever, which is associated with poor outcome and increased length of stay in direct proportion to the length of time the patient is febrile. However, phenytoin has demonstrated efficacy in treating central poststroke pain (Frese et al., 2006). Phenytoin has also shown neuroprotective activity in an ischemic/hypoxic model of neuronal injury (Willmore, 2005).

Pregabalin

There are little data regarding the use of this agent after stroke, but it has a good pharmacological profile.

Tiagabine

This drug is rarely used after stroke.

Topiramate

This drug is a reasonable choice, although drug interactions and cognitive side effects must be carefully monitored. Topiramate has neuroprotective properties and also reduces hemorrhagic incidence in focal cerebral ischemia in animal models; the human benefit has not been shown (Ferro & Pinto, 2004; Willmore, 2005).

Valproate

This agent has significant drug interactions, inhibits cytochrome P-450 enzymes, and binds extensively to plasma proteins. For these reasons, it is not an especially good choice for poststroke seizures. Acutely, it can be given intravenously if swallowing is not possible, which is an advantage. It may stabilize mood as well, which is an added benefit.

Zonisamide

This drug has a favorable pharmacological profile and is a reasonable choice. Zonisamide is an anticonvulsant compound that reduced infarct volume in ischemia-induced neuronal damage. Neuroprotective efficacy of zonisamide pretreatment was also shown in hypoxic/ischemic damage in neonatal rats (Ferro & Pinto, 2004; Willmore, 2005). Adverse effects are sometimes important, and the potential for renal stones should be remembered.

Recommended Antiepileptic Drugs in Epilepsy Patients With Stroke

Lacosamide, lamotrigine, levetiracetam, gabapentin

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