Valproate effects on generalized spike-wave discharges and photoparoxysmal response


To the Editors:

We commend Muhle et al. on their 30-year review of the use of valproate (VPA) in idiopathic generalized epilepsy (IGE). We note some comments and concerns, most importantly, the title and conclusion: “valproate does not reduce photoparoxysmal responses in IGEs” is not supported by their data, which indicates that treatment with VPA eliminated the photoparoxysmal response (PPR) in 7 (29%) of 24 patients.

The authors did not cite landmark literature of VPA effectiveness in IGE patients in general and its effect on the PPR in particular. VPA reduces frequency and duration of (poly) spike-wave activity in IGE patients and reduces PPR in a dose-related way (Rowan et al., 1979; Stephan et al., 1981; Rimmer et al., 1987; Braathen et al., 1988). Muhle counted and quantified spike-wave discharges (SWDs), and their result with respect to spontaneous and hyperventilation (HV)-induced SWDs mirrors well-established literature. However, their method may have been less than optimal, as “up to four” 20-min EEGs appears to be a rather slender sample, and SWD quantification would be better assessed by a series of 24-h EEGs (Stephan et al., 1981).

Concerning the effect of VPA on the PPR: Harding & Jeavons’ investigations demonstrated that VPA significantly reduces or fully suppresses the PPR in 78%, including abolition of the response in 54% (Harding & Jeavons, 1994). Comparable results have been obtained by other groups (Villarreal et al., 1978; Kasteleijn-Nolst Trenite, 1989).

In addition, there are methodologic problems with the Muhle study:

  • 1 How were Muhle’s patients selected? Were they consecutive? How were the referrals obtained? We note the high percentage of patients with photosensitivity (50%) and possible confounding with an excess of female patients (79%). There is a study that shows that female patients might respond to VPA less well than male patients (Kasteleijn-Nolst Trenite & Reed, 2007), so perhaps a higher dose is needed in that group to abolish the PPR, but we are not informed whether treatment was titrated.
  • 2 Change in PPR range is an important measure of VPA effect. Muhle has not determined the PPR range, and because of their method, confusion with spontaneous discharges was also possible. VPA initially narrows the PPR range, and then if fully effective, it abolishes the PPR in a dose-dependent way (Stephan et al., 1981; Binnie et al., 1986; Kasteleijn-Nolst Trenite, 1989; Trenite, 2006). Reduction in the PPR range is reported as a more consistent marker of decreased tendency to seizures than normalization of the EEG (Binnie et al., 1986; Binnie, 2001), and it is a more reproducible physiologic measure, similar in concept to an exercise electrocardiography (ECG) test compared to a resting ECG.
  • 3 Muhle’s PPR terminology is inconsistent, and we have difficulty defining exactly how many patients had a PPR. Localized PPRs are usually not reported, as it is well established that type I and type II (localized) responses correlate poorly with epilepsy or photosensitive seizures, and are a poor marker of antiepileptic drug efficacy (Bickford et al., 1952; Binnie et al., 1986; Kasteleijn-Nolst Trenite, 1989; Waltz et al., 1992; Binnie, 2001; Trenite, 2006).
  • 4 There is inconsistency in numbers of patients: Several patients seem to disappear from the sample as the report proceeds and computation of the various subsets of patients is difficult.

The Muhle article illustrates a number of important issues. It reports an EEG intermittent photic stimulation (IPS) test strategy, which although forward thinking in 1975 is not generally accepted. Recent iterations of EEG IPS protocols have led to the point of consensus and a standardized IPS protocol that results in quantifiable data with robust interobserver and trans-Atlantic reproducibility (Binnie, 2001; Kasteleijn-Nolst Trenite et al., 2007; Trenite et al., 2007). It leaves the reader puzzled when terminology is inconsistently used and data presented that does not match the conclusion.


None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.