| The first part: Optimization of contrast-enhanced transcranial Doppler in right-to-left detectionObjective: Right-to-left shunt(RLS) is likely to play a causal role in patients with ischemic stroke, migraine, decompression sickness, platypnea-orthodeoxia syndrome peripheral arterial embolism and obstructive sleep apnea syndrome. Contrast-enhanced transcranial Doppler(c-TCD) is a reliable and reproducible method for RLS detection, with high sensitivity. However, definite common standard of c-TCD protocol is not yet achieved. There are several differences in methodology. First, monitoring the middle cerebral artery(MCA) is an optimal choice, yet for patients with insufficient temporal bone windows or severe stenosis of carotid arteries, an alternative should be established. Besides, most recent study suggested that related ischemic lesions are located predominantly in the vertebrobasilar circulation, especially in patients with provoked RLS. To further establish whether c-TCD with vertebral artery(VA) monitoring could be a better alternative, we compared VA and MCA monitoring for RLS detection. Second, the adequate procedure and evaluation criterion of Valsalva maneuver are critical to the positive diagnosis of provoked RLS. Previous studies adopted conventional Valsalva maneuver for RLS detection by c-TCD used to evaluate the efficacy of VM by the reduction of the flow velocity of the MCA, ambiguously defined as 20-25% decrease. However, many patients have difficulty in understanding or executing the procedure of conventional Valsalva maneuver. Besides, percentage is inadequate for quick evaluation during the procedure. Thus, we compared the effectiveness of modified Valsalva maneuver and conventional Valsalva maneuver for RLS detection by c-TCD and further measured the change of peak systolic velocity(Vs) and mean flow velocity(Vm) during theValsalva maneuver. 1. Comparison of VA and MCA monitoring for RLS detection by c-TCD. Methods: There were totally 318 subjects came for c-TCD from February to April, 2015. We evaluated 194 consecutive subjects who met the inclusion and exclusion criteria for RLS detection with VA and MCA monitoring simultaneously. Results: 1There was no significant difference between the positive rates of VA and MCA monitoring for RLS detection, including total RLS, constant RLS and provoked RLS, all with high sensitivity and specificity. 2VA monitoring detected lower degrees of RLS compared to MCA monitoring with no statisitical difference(P = 0.079). 3 The first microbubble occurred later for VA monitoring than MCA monitoring both at rest and during Valsalva maneuver(P < 0.001). 2. Comparison of modified Valsalva maneuver and conventional Valsalva maneuver for RLS detection by c-TCD and establishment of velocity criterion in Valsalva maneuver efficacy evaluation.Methods: During November to December, 2014, we evaluated 298 consecutive subjects for RLS detection by c-TCD at rest state(RS), during the conventional Valsalva maneuver(CM) and modified Valsalva maneuver(BM: blowing into the connecting tube of a sphygmomanometer at 40 mm Hg for 10 s) in random order, and the degree of RLS along the time of the first microbubble occurrence was recorded. To further establish the velocity criterion of MCA in Valsalva maneuver efficacy evaluation, we retrospectively analyzed the monitored Doppler spectra of 114 subjects who met the inclusion and exclusion criteria and measured the change of Vs and Vm during BM.Results: 1The positive rates were 21.8%, 36.9%, and 47.3% for RS, CM, and BM, respectively(P < 0.001). BM provoked a significantly higher positive rate(P = 0.010). 2There was a significant difference between the two different methods of VM in terms of the degree of RLS detection(P < 0.001). BM detected higher degrees than CM. 3The first microbubble occurred later during BM than CM(10.22 ± 3.77 s vs. 9.44 ± 4.36 s, P <0.05). 4The change of Vs during BM was 29.82 ± 9.67 cm/s(95%CI: 28.2- 31.5). 5The change of Vm during BM was 23.56 ± 5.30 cm/s(95% CI: 22.6- 24.5).Conclusions: 1 c-TCD with VA monitoring could be an alternative for RLS detection, with high sensitivity and specificity both at rest and during the Valsalva maneuver. 2This modified maneuver is an alternative to the conventional one, especially for those who cannot perform conventional maneuver adequately, but are highly suspected to have RLS. 3The change of Vs(about 30cm/s) or Vm(about 25cm/s) might be the velocity criterion for rapid evaluation of Valsalva maneuver during c-TCD without sphygmomanometer.The second part: Evaluation of effectiveness and safety of transcatheter PFO closure for RLS related migraine(EASTFORM Trial: a prospective, non-randomized, contrast trial of patients enrolled and included in a continuous registry at a single centre in China).Objective: Over the last few decades, independent reports have hypothesized an association between PFO and migraine, and especially migraine with aura. The proposed mechanism is the arrival of agents into the cerebral circulation that are normally removed by the lungs, which subsequently triggers a migraine attacks or lowers the threshold for migraine occurrence. Observational studies have also reported reductions in the frequency of migraine attacks after transcatheter PFO closure, but it has remained controversial due to a paucity of evidence to guide patient eligibility and device selection. To date, there is a lack of prospective studies investigated PFO closure for migraine in China. Thus we aimed to evaluate the safety and longterm effectiveness of transcatheter PFO closure for migraine in a Chinese population. In the mean while, to verify the important role of c-TCD in diagnosis of RLS related migraine and follow-up of residual shunt after transcatheter PFO closure. Methods: From 2013 to 2015, this non-randomized clinical trial enrolled 258 consecutive substantial or severe migraineurs with moderate-to-large cardiac right-to-left shunt(RLS) and grouped them according to their election or refusal of PFO closure. Migraine was evaluated using headache impact test-6(HIT-6). Among 258 subjects, 130 underwent closure and aspirin was administered for 6 months, they were also requested of c-TCD follow-up at 1, 3, 6, and 12 months after the procedure. Results: 1In total, 241 participants(125 in the transcatheter closure group and 116 in the contrast group) were included in the final analysis of our study. The PFO occluder was implanted successfully in all 125 patients. Only 1 patient had cardiac tamponade, and no patients had serious complications. 2During the one year period follow up, 85.7% of patients with residual shunts who came back for c-TCD evaluation were downgraded to negative or mild shunt. 3Residual shunts and placebo effect were assumed to resolve by 12 months post-procedure. 4The impact degree of 92 migraineurs(73.6%) decreased, 31 migraineurs(24.8%) unchanged and 2 migraineurs(1.6%) increased. 5Transcatheter PFO closure was demonstrated to be effective using comparison of 12-month HIT-6 scores between transcatheter PFO closure group and contrast group(48.77 vs. 57.85, P < 0.001). 6The change score(calculated by subtracting 12-month HIT-6 score from baseline HIT-6 score) of the transcatheter closure group was significantly more than that of the contrast group(16.35 vs. 5.59, P < 0.001). 7Subgroups analyses corroborated these findings except in male and provoked RLS subgroups.Conclusions: Transcatheter PFO closure is a safe and effective approach for migraine. In the mean while, c-TCD plays an important role in diagnosis of RLS related migraine and follow-up of residual shunt after transcatheter PFO closure. Clinical trial no. NCT02127294... |
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