| Cardiovascular regulation in epilepsy with emphasis on the interictal state | ||
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Although epilepsy is now considered as a condition that for the majority of patients will remit, it may also be a chronic, progressive condition that requires early treatment to prevent complications and to improve the prognosis (Scheuer & Pedley 1990, Pellock & Willmore 1991, Dam 1997). During the last decades, the development of AEDs has been remarkable, but still about 20%-30% of patients with epilepsy suffer from drug-resistant epilepsy (Hauser & Hesdorffer 1991). For some of those patients, cessation or reduction of seizures may be achieved by resective epilepsy surgery (Dam 1997). A new method, vagal nerve stimulator (VNS), has also been introduced in the treatment of epilepsy during the last decade (Dam 1997).
Seizure-freedom with monotherapy (one drug -treatment) is the main goal of the epilepsy treatment today. Fortunately, about two thirds of the patients with epilepsy will achieve this. However, sometimes two or even three to four AEDs have to be used as polytherapy to control the seizures. For some patients, this works well enough, but the problem lies with the growing number of side effects and interactions of the AEDs that can sometimes be very difficult to cope with (Keränen et al. 1997). If polytherapy has to be used to control seizures, it should be done rationally, i.e. mechanisms of the actions of the drugs should be taken into account, as well as metabolic routes for avoiding unwanted interactions.
When a patient has been seizure free 3-5 years, the medication may be considered to taper off. This should be done slowly over several months to prevent a relapse. However, there are some epileptic syndromes, e.g. JME, which require life-time medication. In localization related symptomatic and cryptogenic epilepsies, seizure control may be difficult to achieve, and risk for relapse seizures exists if the mediacation is stopped. (Keränen 1994, Morton & Pellock 1996)
Based on various publications (Keränen et al. 1997, Kälviäinen 2001, Leppik 2001) the recommendations of antiepileptic medications are presented in Table 4. The modernized drug recommendations for various types of epilepsy is expected to be published in Finland in the near future (Isojärvi JIT, personal communication).
Table 4. The recommendations of antiepileptic medications for various types of epilepsy in their alphabethical order in each epilepsy type (modified after Keränen et al 1997, Kälviäinen 2001, Leppik 2001).
| Type of epilepsy | Medication |
|---|---|
| Localization-related epilepsies | Carbamazepine |
| Lamotrigine | |
| Oxcarbazepine | |
| Phenytoin | |
| Valproate | |
| (adjunctive therapy) | Gabapentin |
| Levetiracetan | |
| Tiagabine | |
| Topiramate | |
| Generalized epilepsies | Lamotrigine |
| Valproate | |
| Etosuximide (absence seizures) | |
| (adjunctice therapy) | Topiramate |
In general, no significant differences in the effectiveness of AEDs exists when they are adequately used in relation to the type of seizure. The newer drugs (oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentine (GBP), tiagabine (TGB), levetiracetam (LEV)) appear to be better tolerated but more expensive than standard AEDs (phenytoin (PHT), carbamazepine (CBZ) and valproate (VPA)) (Brodie & Dichter 1996, Perucca 1996). In the following, the general properties of the commonly used AEDs are discussed shortly.
PHT was the first modern antiepileptic drug. It is considered highly effective and cheap and is indicated in partial epilepsies (Browne 1997, Leppik 2001). PHT has a saturable kinetics, prolematic interaction profile and various side effects, but it is still widely used in many parts of the world (Browne 1997, Leppik 2001). PHT has previously been used as an antiarrythmic drug, and it may be considered having protective effects on the heart (Lathers & Schraeder 1982). However, it is known that some antiarrythmic drugs are associated with increased risk for sudden cardiac death, and there are also reports of triggered arrythmias during intravenous administration of PHT mainly in the predisposed elderly (Tomson et al. 1997).
CBZ is today the most commonly prescribed drug for epilepsy in Europe. It is the first-line AED in partial epilepsies but it is contraindicated in myoclonic and absence epilepsies (Loiseau & Duche 1995, Bird et al. 1996). CBZ is usually well tolerated but has a large number of drug interactions (Perucca et al. 1984, McLean & MacDonald 1986, Mattson et al. 1992). CBZ may sometimes induce atrioventricular conduction delay and brady-arrythmias in epilepsy patients with or without underlying cardiac disease (Steiner et al. 1970, Hamilton 1978, Herzberg 1978, Boesen et al. 1983). The suggested role of CBZ for increasing the risk of SUDEP is controversial (Kennebäck et al. 1997, Timmings 1998).
OXC is a 10-keto analogue of CBZ developed to avoid autoinduction and potential for drug interactions of CBZ, and it has a number of advantages over CBZ. (Faigle & Menge 1990, Larkin et al. 1991). OXC is used as a first-line AED in many countries, including Finland, and it is indicated in partial epilepsies (Dam et al. 1989, Grant & Faulds 1992). However, moderate to severe hyponatremia may be seen especially in the elderly and female patients, which may trigger epileptic seizures and cause CNS side effects (Pendelburry et al.1989, Grant & Faulds 1992, Huuskonen et al. 1998).
LTG is one of the first AEDs of the new generation, it is well tolerated and indicated as adjunctive or monotherapy in partial and generalized epilepsies, as well as in Lennox-Gastaut syndrome. LTG has a wide spectrum of antiepileptic activity, the mechanism of which is not completely understood. LTG does not induce or inhibit hepatic P450 enzymes. However, the concomitant administration of other AEDs may affect the metabolism of LTG. (Binnie 1997, Leppik 2001)
GBP is indicated as adjunctive therapy in partial and generalized epilepsies. The interactions and side effects are few. Potentially severe side effects have not been reported. (Chadwick & Browne 1997, Leppik 2001) The lack of hepatic metabolism is a major advantage, and GBP does not have any drug interactions. (Chadwick & Browne 1997, Leppik 2001)
TGB may be used as an adjunctive therapy in partial epilepsies. It is not a hepatic enzyme inducer or inhibitor and it does not affect the kinetics of other drugs. However, concomitant enzyme-inducing AEDs markedly increase the clearance of TGB. Some clinical observations suggest that TGB could trigger status epilepticus. (Sommerville 1997, Leppik 2001)
Vigabatrin has high efficacy and low interaction profile. However, its propensity to cause asymptomatic peripheral visual field failure severely limits the use (Ben-Menachem & French 1997).
The mechanism of action of VPA is still uncertain, but it is known to block voltage dependent sodium channels, affect calcium (T) conductance and modifie GABA receptors (Loscher 1981, Franceschetti et al. 1986). It has a number of complex interactions with antiepileptic and other drugs (Levy & Koch 1982, Perucca et al. 1984). VPA is the drug of choice in generalized epilepsies and it is also efficient in partial epilepsies (Davis et al. 1994, Morton & Pellock 1996). In general, VPA is well tolerated (Leppik 2001). The most problematic side effects may be the reproductive endocrine disorders, i.e. weight gain, menstrual disorders, polycystic ovaries, and hyperandrogenism in female patients (Isojärvi et al. 1993, Isojärvi et al 1998). Hyperinsulinemia has also been reported (Pylvänen et al. 2003).
TPM has multiple modes of action. It does not have any significant interactions with concomitant AEDs, but other AEDs may change TPM concentrations. TPM is indicated in partial and generalized epilepsies as adjunctive therapy and as monotherapy if epilepsy is refractory to commonly used AEDs. Hypersensitivity or idiosyncratic effects have not been reported. (Kramer & Reife 1997, Leppik 2001)
LEV is a novel AED recently licensed. It expresses significant anticonvulsant activity against partial seizures. LEV has been regarded as a new AED with ideal pharmacokinetics (Isoherranen et al. 2001). The mechanisms of action are still unsettled, but the existing experimental data show that LEV might be a selective blocker of N-type calcium channels (Lukayanetz et al 2002), which is a unique mode of antiepileptic function in AEDs. LEV is usually well tolerated and the incidence of hypersensitive reactions is similar to that of placebo (French et al. 2001).
Certain benzodiazepines are mainly used to suppress acute seizures, and as additional therapy to control seizures, for example during certain phases of menstrual cycle in female patients and in severe chilhood epilepsies (Ko et al. 1997).
Ethosuximide is only indicated in generalized absence seizures and it is widely used in the world. It has an effect on calcium T-channel conductance, and side effects are common. (Leppik 2001)
Piracetam is used in cortical myoclonus of various etiologies. It is closely related to LEV, but piracetam may be useful particularly in patients with refractory myoclonus.
In partial epilepsies such as TLE, resection of the epileptic focus can sometimes be performed to control the epileptic seizures refractory to pharmacotherapy. If the patients are carefully selected for the surgery, the outcome is good, as majority of patients become seizure-free, improve in their cognitive capacity and have remarkable improvement in the quality of life as a whole. The risks of modern epileptic surgery are acceptably low, with ovarall mortality being less than 0.5% and morbidity less than 5%. Increased mortality rates are associated with intractable epilepsy and there are indications that this risk might be reduced by epileptic surgery. (Engel JJr 1996, Duchowny et al. 1997)
In patients with refractory idiopathic generalized epilepsy, only palliative epilepsy surgery may be performed. (Larsen & Iivanainen 1994). International recommended standards of neurosurgery have recently been published (Binnie & Polkey 2000).
A new approach to the treatment of epilepsy is vagal nerve stimulator (VNS). It is a device that has been designed to electrically stimulate the left branch of the 10th cranial nerve, the vagus nerve, in constant frequency. The basic mechanisms of VNS are not completely understood. The experimental data suggest that the antiepileptic actions of vagal stimulation are largely mediated by projections from the nucleus of the solitary tract (NTS) to the reticular formation and the amygdalohippocampal complex and by diffuse projections to the cortex. It also seems to modify the concentrations of various amino acids of the brain, e.g. GABA. It can be used as a treatment to those refractory patients who are not candidates for surgery and the results are comparable to those of the new AEDs as add-on treatment. Side effects seem to be few. (Wilder 1997)