Reversible Cerebral Vasoconstriction Syndrome and Varicella Zoster Virus

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Association Between Reversible Cerebral Vasoconstriction Syndrome and Herpes Zoster Infection

Conditions
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Varicella-zoster Virus Infection, Reversible Cerebral Vasoconstriction Syndrome

Intervention / Treatment
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* Diagnostic Test: VZV-specific antibody response from blood


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with thunderclap headache and suspicious of intracranial vascular lesion by computed tomographic angiography (CTA) or magnetic resonance angiography (MRA). Exclusion Criteria: Patients with life threatening medical condition Pregnant or scheduled for pregnancy Unwilling or unable to give informed consent Patients who confirmed vasculitis Patients with genetic disease for vascular disorder

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Subject (RCVS)<br>Patients who meet the definition of RCVS. (1) acute and severe headache with or without focal deficits or seizures, (2) uniphasic course without new symptoms more than 1 month after clinical onset, (3) segmental vasoconstriction of cerebral arteries shown by computed tomography angiography (CTA), magnetic resonance angiography (MRA) or transfemoral cerebral angiography (TFCA),(4) normal or near normal cerebrospinal fluid analysis and (5) complete or substantial normalisation of arteries shown by follow-up angiography within 12 weeks. | Diagnostic Test: VZV-specific antibody response from blood<br>* Check VZV-specific antibody response, VZV specific T-cell mediated immune response by IFN-γ ELISPOT assay from blood, and real-time PCR results from saliva<br>* Other names: VZV-specific T cell response from blood, viral load from saliva;|
| Control<br>Patients with thunderclap headache and intracranial stenosis, but not diagnosed as RCVS. | Diagnostic Test: VZV-specific antibody response from blood<br>* Check VZV-specific antibody response, VZV specific T-cell mediated immune response by IFN-γ ELISPOT assay from blood, and real-time PCR results from saliva<br>* Other names: VZV-specific T cell response from blood, viral load from saliva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection or reactivation of varicella zoster virus (VZV) | Compare prevalence of infection or reactivation of VZV in case-patients and control-patients. | At the time of enrolled. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reversible cerebral vasoconstriction syndrome, Herpes zoster, Varicella-zoster virus infection