Reversible Cerebral Vasoconstriction Syndrome Clinical Trial
Official title:
Association Between Reversible Cerebral Vasoconstriction Syndrome and Herpes Zoster Infection
Among patients with thunderclap headache who were admitted to the four participating hospitals, who has diffuse segmental vasoconstriction on CT angiography or MR angiography will be eligible for the study. Participants who meet the definition of RCVS will be enrolled as the case-patients and others will be enrolled as control-patients. The RCVS group will be defined when two or more neurologists agree by the clinical features and angiographic findings. The result of tests for varicella zoster virus titer will not be opened to neurologists until the end of the study. For case and control patients, tests for varicella zoster virus infection are (1) Pre-existing virological markers (ex. VZV-IgG, IgM, and VZV PCR in CSF or Skin lesion if present) (2) VZV-specific cell mediated immune response (CMI) at the time of admission and one month later (3) VZV in blood measured by quantitative test of viral load with real-time PCR and digital PCR for latent viral load (4) Quantitative test of viral load with real-time PCR in saliva at time of admission and one month later. Reactivation or infection of VZV of patients with RCVS and controls will be compared.
In the previous pilot study, reactivation of VZV was confirmed in 63.6% of the patients as
having RCVS by cell mediated immune response (CMI) test and 18.2% by Saliva PCR. None of
patients who were simply stressed showed reactivation of VZV. Considering about 20% had false
negative results in angiographic findings of RCVS, we set the effect size as 0.63 in group of
subjects and 0.12 in group of controls. Using alpha values of 0.05 and beta values of 0.2, we
calculated the target number of the study. If the ratio of cases to controls is 1:2, 9
case-patients and 18 control-patients were needed and if the ratio is 1:3, 8 case-patients
and 24 control-patients were needed. We expect to enroll 10 case-patients and 20 to 30
control-patients within two years, considering the drop rate of 10~20%.
Baseline clinical information regarding age, sex, smoking history and medical comorbidities
including hypertension (treated, systolic blood pressure ≥140 mmHg or diastolic blood
pressure ≥90 mmHg at discharge), diabetes (treated, fasting blood glucose ≥126 mg/d),
hyperlipidemia (treated, total cholesterol level ≥200 mg/dl or low‐density lipoprotein level
≥140 mg/dl) and coronary artery disease will be collected on admission. Laboratory tests,
including complete blood count, blood chemistry, c-reactive protein and erythrocyte sediment
rate wil be performed. Images of brain MRI, MR angiography, CT angiography or digital
substraction angiography will be gathered if present.
Tests for VZV specific antibody responses and T-cell mediated immune response will be
performed by VZV specific ELISA and IFN-γ ELISPOT, respectively. Result for T cell responses
will be shown as spot number per 10^6 PBMCs. On the day of blood sample collection, plasma
will be isolated and freezed (-80℃). Peripheral mononuclear cells will be separated from the
remaining blood samples and keep freezed (-190℃). Melt the frozen peripheral mononuclear
cells and inoculate them on a plate (T-Track human IFN-γ, Lophius) with anti-human IFN-γ
antibody and inoculate VZV lysate (Microbix) 50 ug/mL on them. After incubating 24 hours, the
staining will be performed and the spot will be read in a automated ELISPOT reader (ELR07
reader system, Autoimmune Diagnostika GmbH).
For statistical analysis, patients with thunderclap headache will divided into two groups
according to the presence of RCVS. Among them, the rate of infection with varicella zoster
virus will be compared and analyzed. Fisher's exact test, Mann-Whitney test, Pearson
correlation will be performed. Also, logistic regression analysis will be used, and
covariates will be adjusted if needed. Sensitivity and specificity of tests for reactivation
of VZV and RCVS will be analyzed too.
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