Efficacy of 3,4-DAP treatment for LEMS
In LEMS, 3,4-DAP blocks VGCCs, prolongs the action potential depolarization of motor nerve endings, and increases the opening time of VGCC. This process leads to an increase in presynaptic calcium influx and an improvement in acetylcholine release, manifested as enhancement in muscle function.
In 1989, McEvoy and colleagues studied the effect of oral 3, 4-DAP on 12 LEMS patients, 7 of whom were cancer patients, in a double-blind RCT. This trial showed distinct improvements in neurological dysfunction scores, isometric muscle strength tests, limb strength measurements, autonomic function, and CMAP amplitude after oral 3,4-DAP of up to 100 mg compared to placebo. Oh and colleagues published a cross-over RCT of oral 3,4-DAP of up to 80 mg daily, which indicated a significant effect over the placebo in patients with LEMS. Similarly, another randomized, parallel group trial of 26 patients demonstrated significant enhancement of both QMG score and CMAP amplitude with an oral dosage of 60 mg of 3,4-DAP daily .Similar results of intravenous administration of 3,4-DAP were also reported by Wirtz and colleagues.
All primary outcome indicators of isometric muscle strength, neurological disability score and QMG score[20-23] showed significant improvements after the administration of oral or intravenous 3,4-DAP. We conducted a meta-analysis of QMG score according to the results provided in the studies by Sanders et al., Oh, Claussenet al., Oh, Shcherbakova et al.[21, 22], and Shieh et al.. The QMG rating system, with a score from 0 to 39, is a physician-rated assessment, including assessments of speech, swallowing, external ocular muscles, facial muscle strength, and all limb muscles. The QMG score is a quantitative evaluation, in which a lower score indicates better muscle function. The current meta-analysis showed a significant overall benefit (a decrease of 2.33 points, 95% CI, -2.81 to -1.85) in QMG for LEMS patients with 3,4-DAP compared to placebo. However, according to Barohn et al., only a QMG change of more than 2.6 indicates a clinically significant improvement on the basis of 5 myasthenia gravis patients and 4 controls. If Barohn’s criterion is used, no significant clinical improvement was obtained in either the study by Sanders and colleagues or this meta-analysis. As Sanders pointed out, it may be due to the fact that bulbar, ocular, and distal limb items of the QMG score are less common in LEMS than in myasthenia gravis. However, studies by both Oh et al. and Shieh et al. demonstrated that QMG score is an effective method to assess clinical enhancement in muscle strength, provided the QMG scoring system is followed[21-23].
Keogh M et al. and Maddison P et al.[28, 29] concurred that the QMG score should still remain the preferred outcome indicator of muscle strength in future LEMS treatment trials. The use of uniform primary outcome measurements and data from further tests will help to describe more specific effects of 3,4-DAP treatment. The authors also recommend that in keeping with previous studies, it is appropriate to continue to evaluate the effect of 3,4-DAP treatment by performing a QMG assessment 3-4 days after the initiation of treatment.
Sanders et al. reported that in a RCT of 26 participants with LEMS, the median resting CMAP amplitude improved by 1.3 mV (+64%) in 12 cases receiving 3, 4-DAP 60mg daily, compared with a decrease of 0.1 mV(-3%) in the placebo group (P < 0.001). This meta-analysis also showed an average improvement in the secondary outcome measure, with a resting CMAP amplitude of 1.63 mV (95% CI, 0.85 to 2.41). Therefore, the change of mean amplitude of CMAP appears to be a repeatable and objective secondary outcome for any LEMS treatment trial. The authors of this study suggest that since the duration of action of 3, 4-DAP is relatively short, the duration of action should be recorded three to six hours after taking 3, 4-DAP, and recommend that future studies record the CMAP assessment time related to the dose of the drug.
The results of six trials of 3, 4-DAP in the treatment of LEMS showed that the drug had a significant effect on LEMS, which was consistent with earlier reports of the beneficial effect of 3, 4-DAP on LEMS and reflected the current practice of symptomatic first-line treatment of LEMS patients with the drug.
Adverse events associated with 3,4-DAP treatment reported from the included trials[14, 19-23] included temporary perioral tingling and digital paraesthesiae, back pain, headache, and epigastric discomfort. In addition, Wirtz et al described one participant with cellulitis after 3,4-DAP infusion and McEvoy et al. reported a participant who suffered from epilepsy while taking 100mg of 3.4-dap daily. Of these included trials, there were no other major adverse events.
Although these RCTs and the pooled results showed significant improvement in the treatment of LEMS with 3,4-DAP, the number of RCTs studied was relatively few thereby limiting the total number of cases in this meta-analysis. In addition, not all RCTs used the same primary outcome (QMG) and secondary outcome (CMAP) measures. Finally, the follow-up time for these RCTs was limited. In future studies, large sample sizes, consistent outcome measures, and long-term follow-up RCTs are needed to further confirm the therapeutic efficacy and safety of 3,4-DAP on LEMS.