Abstracts

Serum blood levels, a standard measure tracking the therapeutic effects of antiepileptic drugs (AEDs), do not always reflect brain levels, or provide direct information on cortical excitability. Transcranial magnetic stimulation (TMS) is a non-invasive technique that allows accurate measures of this parameter. The purpose of this study is to test the hypothesis that TMS measures of cortical excitability will correlate with serum blood levels of AEDs, and reflect clinical effects directly.
Subjects were assigned to either of two drugs, carbamazepine (CBZ) or lamotrigine (LTG). Six healthy normal volunteers aged 21 to 48 years (mean 38 yrs, 4 for CBZ, 2 for LTG) have been recruited so far. Measures of cortical excitability were performed using TMS in various drug treatment phases: at baseline (before drug intake); during the AED induction period (days 3, 7, 10, 17), after 3 and 10 days of drug intake at the maximum dosage (days 24, 31); and 3, 6, and 12 half-lives after (days 35, 38, 44), and finally three weeks after abrupt drug withdrawal (day 54). Indices for TMS cortical excitability were obtained including motor threshold for 50[mu]V MEP in resting state (r-MT) and for 1mV MEP (1mV MT), recruitment curve with stimulus intensities from 100 to 140%, paired pulse inhibition at 2ms of interstimulus interval (ISI) and paired pulse facilitation at 15ms of ISI. Blood sampling for drug levels and drug adverse events profiles were obtained at each TMS study. Differences from baseline measurements were compared to the serum drug level (total, free and epoxide levels for CBZ, and total serum level for LTG). Regression analysis and repeated measures ANOVA were used for statistical analysis.
In the CBZ group, the elevation in r-MT and 1mV MT increased with increasing drug levels. Total CBZ levels showed a positive relationship with changes in r-MT and 1mV MT (p[lt]0.001 for both, y=-1.036+1.403x, vs.-1.763+2.008x). After acute drug withdrawal, blood levels decreased abruptly, but r-MT and 1mV MT fluctuated, remaining elevated 3 weeks after drug withdrawal in one subject. In another, 1mV MT fell to subnormal level 14 half lives after withdrawal, then returned to baseline. Free CBZ levels showed a similar positive relationship with r-MT and 1mV MT changes (p=0.01 for both, y=1.020+4.104x, vs.0.452+6.496x), but epoxide levels did not (p=0.31 and 0.19). In the LTG group, MTs showed similar positive relationships with serum drug levels, significant in r-MT (p=0.02 vs. p=0.21 for 1mV MT).
The positive relationship between MT changes and serum blood levels suggests that TMS measures might be an alternative quantitative method to guide AED treatment. Preliminary data suggest that AED effects on cortical excitability may persist after blood levels are undetectable in some people, but show rebound effects in others.
[Supported by: NINDS competitive postdoctoral fellowship award (H.W. Lee)]