Abstract:
I investigated change in Photoparoxysmal Response (PPR) as a marker of Anti-Epileptic-Drug (AED) efficacy using Juvenile Myoclonic Epilepsy (JME) and EEG photosensitivity as epilepsy models, with sodium valproate (VPA) and lamotrigine (LTG) as test agents. I reviewed the need for improved methods of evaluating AED efficacy and EEG photosensitivity. Then single doses of LTG, VPA and placebo were tested in a blinded 3 way cross-over design that correlated AED pharmacokinetics with changes in EEG PPR and standardised photoparoxysmal response (SPR), along with subjective and objective adverse effect evaluations. I confirmed a prompt but short lasting effect of LTG on the SPR (< 36 hrs) and a limited effect of single doses of VPA with significant onset delay and incomplete SPR suppression. Although statistical analyses identified a VPA effect, confidence intervals overlapped placebo. Pk-Pd NONMEM analysis of the same data demonstrated good correlation with LTG effect but no effect on the PPR or SPR for single doses of VPA. Concern about stability of the SPR as a test parameter across the waking day led us to analyse 2058 PPR “placebo treatment” and “no-dose” results from EEG PPR/SPR studies. We analysed them by eye condition, time of day, continent and “placebo” or “no-dose” parameters with standard statistical and NONMEM analyses. These data represent the first large analysis of this type. They demonstrate that PPR and SPR are stable parameters over the waking day, and that optimal consistency of the PPR and SPR tests are obtained when photic stimulation is carried out “on-eye-closure”. Finally, chronic dosing studies were carried out in JME patients taking stable doses of VPA. Half were switched to LTG in a double dose, double dummy, double blind, one-way cross-over, parallel group protocol. In many patients myoclonus worsened after switching to LTG, but after the LTG dose was increased, myoclonus came back under control. This is a new finding, and although the data-set is small it represents the only blinded analysis of this type. I also demonstrated that LTG initially suppressed the SPR less effectively than VPA, but as the LTG dose was increased the SPR also diminished and this paralleled improvement in seizure control; reinforcing the theory that change in SPR represents a useful surrogate efficacy marker.
