Remote ischemic conditioning for the treatment of ischemic moyamoya disease

Abstract Aims This study investigated the safety and efficacy of remote ischemic conditioning (RIC) on ameliorating the sequelae of ischemic moyamoya disease (iMMD). Methods A total of 30 iMMD patients underwent long‐term RIC and were followed up at 0.5, 1, and 2 years for clinical outcomes, including frequency of stroke recurrence, Patient Global Impression of Change (PGIC) scale, peak systolic velocities (PSV), and cerebral perfusion. Results During the whole RIC treatment process, no RIC‐related adverse event occurred. Only one of 30 patients suffered a onetime infarction (3.3%), and the ratios of acceptable PGIC were 88.2%, 64.3%, and 92.3% at 0.5, 1, and 2 years follow‐up. Kaplan‐Meier analysis showed the frequency of stroke recurrence was significantly reduced after RIC (P = .013). The frequency of TIA per week was 1.1 (0.6, 2.8) prior to RIC and 0.1 (0.0, 0.5) post‐RIC (P < .01). Compared to baseline, PSV values were significantly reduced after RIC treatment (P = .002 at 0.5, P = .331 at 1, and P = .006 at 2 years). In patients undergoing perfusion studies, 75% obtained improvement on followed‐up SPECT and 95% on followed‐up PET maps. Conclusions Remote ischemic conditioning may be beneficial on controlling iMMD‐induced ischemic events, relieving symptoms, and improving cerebral perfusion, without incidence of complications in this case series.

and decrease the incidence of stroke. 2 Although refined with modern microsurgical techniques, surgical treatment is not without risk and potential complications. 3 Hyperperfusion syndrome, described in 21%-50% of MMD revascularization patients, can occur from sudden changes in cerebral hemodynamics and places patients at a risk for perioperative hemorrhage and postoperative neurological deficits. 4,5 Considered one of the most technically demanding procedures in neurosurgery, inadequate training and insufficient experience in bypass surgery of MMD-due to the inherent paucity of the disease in most clinical settings-can lead to increased rates of operative failure and morbidity, resulting in disability and even death. 3 Thereby, more safe and effective treatment strategies of MMD are warranted.
Recently, remote ischemic conditioning (RIC) has garnered great attention due to its efficacious therapeutic benefit on atherosclerotic intracranial arterial stenosis (ICAS). [6][7][8] It has been demonstrated that RIC can increase the tolerance to cerebral ischemia, reduce stroke recurrence, improve cerebral perfusion, and promote compensatory collateral network formation. [9][10][11] Moreover, RIC is a noninvasive, easyto-use, and low-cost strategy in comparison with revascularization surgery. [6][7][8] Herein, we hypothesized that RIC may yield a safe and effective treatment strategy to patients with ischemic MMD (iMMD), a modality that is hitherto undescribed for this disease entity.

| Interventions and assessment
All of the iMMD patients enrolled underwent bilateral upper limb RIC intervention three times daily, consisting of five cycles alternating between 5 minutes of ischemia (induced by inflating tourniquets with the pressure of 200 mm Hg) and 5 minutes reperfusion (inflating pressure was 0 mm Hg). 10 The RIC was achieved through an electric auto-control device that has been delineated in our previous study (patent number ZL200820123637.X, China). 10 Meanwhile, routine treatment, such as antiplatelet therapy, was as the same as the traditional medical treatment prior to RIC.  Table S1). 1 Regional cerebral blood flow was assessed with technetium-99m ethylene cysteine dimer ( 99m Tc-ECD) on SPECT and 13 N-Ammonia on PET. SPECT scan was conducted at the 30th minute after IV 99m Tc-ECD (25 mCi) bolus injection, and PET scan was performed at the 5th minute after IV 13 N-ammonia (8 mCi) bolus injection. Original images were reconstructed as perfusion maps in a 128 × 128 matrix and presented in coronal, axial, and sagittal planes by the Butterworth filtering function.

| Outcome measurements
Safety-related outcome endpoints consisted of signs of tissue or vascular injury such as local edema, erythema, skin lesions, allergy, or intolerance for RIC. Other suspected events related to RIC were also recorded.
The incidence of recurrent ischemic events and overall treat- scores. The measurement aforementioned at follow-up was compared with those at admission in order to uncover the effectiveness of RIC on patients with iMMD. According to the diagnosis criteria of cerebral arterial stenosis via TCD, PSV of >120 cm/s in ACA and MCA were considered abnormal, reflecting on stenosis seen on MRA or CTA. 15 Based on the signal intensity presented by the SPECT map, perfusion status was categorized into six intensity scales (0 = 0%, 1 = 0%-25%, 2 = 25%-50%, 3 = 50%-75%, 4 = 75%-100%, and 5 = 100%). The arterial territories comprised of the bilateral frontal, parietal, occipital, and temporal lobes; basal ganglia; and cerebellum. The difference of the total signal intensities pre-and post-RIC was assessed. Furthermore, the overall perfusion improvement and deterioration rates were also recorded.
The definition of perfusion improvement referred to the total signal intensity scale increase by two or more and deterioration referred to the total signal intensity scale decrease by two or less.
The perfusion status on PET map was evaluated by the ratio of impaired lobe vs cerebellum perfusion that was presented as the 13 N-ammonia uptake index. SPSS 19.0 was used for analysis in this study. Continuous data following a Gaussian distribution were presented as mean ± standard deviation and analyzed with Student's t test; otherwise, the data were presented as median (interquartile range, IQR) and analyzed with a Mann-Whitney U test. Categorical data were expressed as n (%) and were processed by chi-square test (for dichotomous variable)

| Statistical analysis
or Mann-Whitney U test (for ordinal dependent variable). Kaplan-Meier curve and log-rank test (Mantel-Cox) were used to compare the stroke recurrence frequency between pre-and post-RIC treatment; P < .05 was indicative of statistical significance.  Table 1.

| Safety outcomes
No RIC-related adverse events occurred during RIC intervention. All patients in this study tolerated to RIC strategy and completed the whole study. No major discomfort as a result of RIC treatment was reported.

| Primary outcomes
One (3.3%) patient reported having a new infarction at follow-up.  was analyzed with Kaplan-Meier analysis (Figure 2), which showed a significant recurrent stroke frequency reduction after RIC, log-rank test (Mantel-Cox) P = .013. Twelve patients manifested with TIA.

| Neurological dysfunction and arterial PSV in TCD
The NIHSS and mRS scores were used to evaluate permanent neu-

| D ISCUSS I ON
The steno-occlusion of the circle of Willis leads to a reduction of CBF in the territory irrigated by the affected vessels. As a result, compensatory collateral networks depicted as a "puff-of smoke" from the deep thalamoperforating and lenticulostriate perforating arteries are formed extensively in an attempt to maintain adequate CBF.
The smoke-like vessels are fragile and thin, resulting in thrombosis However, the risks of revascularization surgery are not eliminated, even in experienced hands; the rate of morbidity ranges from 3.5% to 4%, and death has been estimated to be at 0.7% per treated hemisphere. [21][22][23][24][25][26] A recent meta-analysis declared that bypass surgery significantly reduces stroke events compared with conservative treatment for iMMD. 21 Meanwhile, some studies have also reported a lack of clear benefit in the surgical arm for the treatment of iMMD. 22,23 Furthermore, bypass surgery in China costs approximately 30 000 USD or more. Whereby, if a noninvasive strategy is applied in iMMD patients, it can help patients who are not surgical candidates or can even serve as an adjunct to surgery.
Remote ischemic conditioning strategy has been suggested to treat both acute ischemic stroke and intracranial atherosclerosis (ICAS). [6][7][8][9][10][11] Our previous study indicated that RIC reduced the incidence of stroke recurrence in ICAS patients from 26.7% to 7.9% after 300 days continuous intervention. 10 Likewise, another study also verified the safety and efficacy of RIC on patients with ICAS. 11 As the abnormality of hemodynamics in both ICAS and iMMD stems from large artery stenosis, thereby we hypothesized that RIC can also be effective to patients with iMMD. To the best of our knowledge, this is the first report studying the efficacy and safety of longterm RIC in MMD.
The primary outcomes in this study demonstrated that the incidence of iMMD-induced stroke recurrence and TIA events after long-term RIC was significantly lower than that prior to RIC in the same cohort of patients. Furthermore, almost all patients reported that their symptoms were ameliorated after RIC treatment. Chronic cerebral circulation insufficiency in iMMD always causes nonfocal neurological deficits such as headache, dizziness, and insomnia; as a result, the subjective feelings from patients are of great importance. Therefore, PGIC scales, which reflected the emotional and patient-subjective status, were used as the indicator for symptom amelioration in this study. 14,19,27   Nevertheless, long-term observation still needed to find more reliable results. The perfusion improvement was likely to be a prodromal sign for excellent long-term outcomes in this cohort.

| CON CLUS IONS
Remote ischemic conditioning may be a promising noninvasive method for iMMD control. It contributed to both symptoms relieving and incidence reducing of iMMD-mediated stroke recurrence and improved cerebral perfusion status as well as at a low cost and safety. Considering the aforementioned limitations, a multicenter, large sample size, and well-designed prospective clinical trial is ongoing.