Epilepsy
Figure 2: Outcome in 525 Patients with Epilepsy who Received Antiepileptic Drug Therapy
n=525 patients recruited into study Overall 63% (n=331) seizure-free
polytherapy into two categories: empiric and validated. It is generally recommended that the validated type of polytherapy be attempted before other strategies and, if possible, if monotherapy AEDs in appropriate dosages for an adequate length of time of trial have failed.17
Patients previously not treated with AEDs, n=470
Overall 64% (n=301) seizure-free
Patients previously not treated with AEDs, n=55
Overall 56% (n=31) seizure-free
47% (n=222) controlled by first AED
53% (n=248) not controlled by first AED
Although monotherapy is considered to be the gold standard for drug treatment of epilepsy, there is renewed interest in polytherapy. This is due to the advent of new AEDs with novel mechanisms of action with fewer drug–drug interactions, and the recognition that most patients with refractory epilepsy are eventually treated with combinations of drugs. It is important to give careful consideration to drug additions and conversions: add-on therapy may be less risky than substitution in patients with frequent or severe seizures.19
A prospective study for substitution with lamotrigine was conducted in 54 centers across Europe.11
The study recruited 347 patients with
44% (n=207) seizure-free during continued therapy with first AED
3% (n=15) remained seizure-free after
discontinuation of AED
Response to second AED 13% (n=61)
9% (n=41) seizure-free during
monotherapy with second AED
4% (n=20) remained seizure-free after
discontinuation of second AED
Response to third or
multiple AEDs 4% (n=18)
epilepsy in whom seizures were not fully controlled with monotherapies of sodium valproate (n=117), carbamazepine (n=129), phenytoin (n=92), or Phenobarbital (n=9). If upon addition of lamotrigine a ≥50% reduction in seizures occurred, an attempt was made to withdraw the original AED and, if successful, a 12-week period of lamotrigine monotherapy followed. A total of 73% patients completed the add-on phase, of whom 47% responded to treatment (64% valproic acid, 41% carbamazepine, 38% phenytoin). The response rate was higher in patients with idiopathic tonic–clonic seizures compared with patients with partial seizures (61 versus 43%; p
1% (n=6) seizure-free during
monotherapy with third AED
AED = antiepileptic drug. Adapted from Kwan and Brodie, 2000.10
Inadequate knowledge of receptor pharmacology (or a lack of attention to it) may also result in irrational polytherapy. Therefore, knowledge of AED mechanisms, as well as both experimental and clinical approaches to understanding drug effects, would seem important if clinicians are to design ‘rational’ therapeutic regimens.
Rational Polytherapy—How Do We Get There? Defined conceptually, rational polytherapy is an understanding that AED combinations with differing mechanisms of action are more efficacious than polytherapy with AEDs that function similarly. It is a logical concept since the pathophysiology of epilepsy is believed to be a consequence of two opposing types of neural imbalance.5
It is possible to divide rational 72
3% (n=12) seizure-free during therapy with two AEDs
Rational choice of drug combinations is currently based more on avoidance of pharmacodynamic or pharmacokinetic side effects than evidence for supra-additive efficacy. Although indications suggest that combinations of AEDs with differing mechanisms of action are most effective, further investigation is necessary, with attention to the effects of the various combinations on both toxicity and seizure control.19
Animal Models and Isobolograms
AED therapy is primarily aimed at reducing excitability through blockage of voltage-gated Na+ or Ca+ channels, or by increasing inhibition through the enhancement of γ-aminobutyric acid (GABA) currents.20
In
the past AEDs were discovered by serendipity, but the most recent AEDs have been specifically designed to target one of the many receptors or neurotransmitters involved in the generation of seizures. Once identified, putative AEDs are first studied in animal models of seizures (usually in rodents) to determine whether they will be effective in generalized or partial seizures, prior to clinical studies.20,21
Antiseizure
drug screening has not only enabled a large number of relatively safe and effective AEDs onto the market, but it has also allowed further insight into the pathophysiology of seizures. However, it should be understood that this screening of AEDs is carried out in models of seizure and not models of epilepsy. This demonstrates that the
US NEUROLOGY
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