It is difficult to give definitive guidance on combining medications for refractory seizures. Several general principles are worth noting. First, it may seem sensible to avoid drug combinations with similar putative mechanisms because their side effects may be additive, for example, the addition of lamotrigine to carbamazepine or of phenytoin to carbamazepine may not be ideal but at the same time, it should be mentioned that the mechanism of action has little influence on clinical effectiveness and drugs of a similar class are often combined. Second, the clinician should be aware of known interactions through metabolic pathways such as valproate combined with either lamotrigine or phenobarbital as they share the cytochrome P450 degradation pathway. Third, although it is appropriate to use drugs that are known to be effective for the class of seizures under treatment, it is often necessary to extend the choices beyond these restrictions.
The therapeutic dose for any given patient must be determined, to some extent by clinical effect, guided by measurement of serum levels, as described below. Inquiry regarding seizure control and drug side effects is more valuable than adjustment of medication based solely on drug concentrations. Blood for serum levels is ideally drawn in the morning before the first dose of antiepileptic medication (“trough levels”), a practice that introduces consistency in measurement. A drug should not be discarded as being ineffective, even at the upper limits of therapeutic blood levels, when a slight increase in dosage would have led to suppression of attacks. On the other hand, drug levels can be helpful in detecting noncompliance or poor absorption in instances of inadequate seizure control. The management of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Furthermore, in some instances, asking the patients about seizure frequency may be unreliable. Some patients find it helpful to use a dispenser that is filled with medications with sufficient pills to last the week. This indicates to the patient whether a dose had been missed and whether the supply of medications is running low.
In general, higher serum concentrations of drugs are necessary for the control of focal seizures than for generalized ones. The usual blood level assay is of the total concentration of the drug (see Table 15-5); this is not a precise reflection of the amount of drug entering the brain, because—in the case of the most widely used antiepileptics—the large proportion of drug is bound to albumin and does not penetrate nervous tissue. Also, in patients who are malnourished or chronically ill or who have a constitutional reduction in proteins, there may be intoxication at low total serum levels. Certain antiepileptic drugs also have active metabolites that are not measured by methods ordinarily used to determine serum concentrations but nonetheless produce toxicity. This is particularly true for the epoxide of carbamazepine. The situation may be further complicated by interactions between one drug and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by valproic acid, leading to toxicity through the buildup of carbamazepine epoxide. In circumstances of unexplained toxicity in the face of conventionally obtained serum levels that are normal, measurement may be undertaken of the levels of free drug and the concentration of active metabolites.
The use of saliva for measurement of free drug levels has merit but has not been adopted frequently in practice. The measurements correlate with free drug levels. It has the advantage of allowing the patient to collect a sample before breakfast and avoid venipuncture.