key: cord-0717446-b774fu0a authors: Vasaghi Gharamaleki, Maryam; Habibagahi, Maryam; Hooshmandi, Etrat; Tabrizi, Reza; Arsang-Jang, Shahram; Barzegar, Zohreh; Fadakar, Nima; Reza Ostovan, Vahid; Rahimi-Jaberi, Abbas; Ashjazadeh, Nahid; Petramfar, Peyman; Poursadeghfard, Maryam; Izadi, Sadegh; Nazeri, Masoumeh; Bazrafshan, Hanieh; Bahrami, Zahra; Karimlu, Sedigheh; Shaghayegh Zafarmand, Seyedeh; Bayat, Mahnaz; Saied Salehi, Mohammad; Owjfard, Maryam; Karimi-Haghighi, Saeideh; Safari, Anahid; Shakibajahromi, Banafsheh; Lim Alvin Chew, Beng; Worral, Bradford B; Coutinho, Jonathan M.; Garcia-Esperon, Carlos; Spratt, Neil; Levi, Christopher; Reza Azarpazhooh, Mahmoud; Borhani-Haghighi, Afshin title: The hospitalization rate of cerebral venous sinus thrombosis before and during COVID-19 pandemic era: A single-center retrospective cohort study date: 2022-03-25 journal: J Stroke Cerebrovasc Dis DOI: 10.1016/j.jstrokecerebrovasdis.2022.106468 sha: 53b51ae1eb47873afe0837dabd69e25ee5230ffd doc_id: 717446 cord_uid: b774fu0a BACKGROUND: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). METHODS: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. RESULTS: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P=0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P=0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P=0.015) and malignancy (P=0.014) in pre-COVID period; and was associated with age (P=0.025), altered mental status on admission time (P<0.001), malignancy (P=0.041) and COVID-19 infection (P=0.008) in COVID-19 period. CONCLUSION: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended. Cerebral venous sinus thrombosis (CVST) is an uncommon though potentially fatal cerebrovascular disease which mainly affects the younger and female population [1, 2] . However, timely diagnosis and treatment may lead to better outcomes [3, 4] . The CVST incidence varies between 5 and 20 per million annually [5] [6] [7] [8] . The CVST is more frequent in the Middle East and southern Asia than in Western countries [1, 9] . The annual hospitalization rate of CVST was reported as 12.3 and 13.49 per million in Iran [10, 11] . Since the emergence of the Coronavirus Disease 2019 (COVID-19) pandemic, there have been rising concerns about neurological complications associated with COVID-19, particularly thrombotic events [12] . Some studies have demonstrated the predominance of venous thromboembolic manifestations, especially in the critically ill groups [13, 14] . There are growing numbers of case reports and case series investigating the association between CSVT and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection [15, 16] . The current study was designed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic era in a referral center in Iran. We also assessed the changes in the rate of mortality, disability, and epidemiological shifts in aging and sex distribution. This retrospective cohort study was conducted in the Namazi hospital, a major referral center for stroke in Shiraz with a large catchment area in the Fars province (southern Iran [17] . The National COVID-19 vaccination program was started after the recruitment time [17] . Accordingly, no recruited patient was vaccinated. As all official medical and demographic reports are presented in the Iranian calendar, which starts on 21st March, the above-mentioned dates were selected for the study periods [18] . According to the Statistical Center of Iran, the estimated > 20-year-old population of Fars province in the first and second period was 3,487,000 and 3,547,000 people, respectively, based on the National Population and Housing Census results in the year 2016 [19] . Namazi hospital covers all CVST patients from the metropolitan area of Shiraz and severe CVST patients from other parts of Fars province. The referral system from the catchment area had no change between the pre-COVID period and the COVID period. Urban and rural areas are defined according to the Statistical Center of Iran [19] . All patients with age>20year-old with the definite final diagnosis of CVST were included in our study. The diagnosis criteria of CVST was based on the presence of relevant clinical symptoms and radiological assessments of the brain (Computed Tomography -CT-, CT venography, 4 Magnetic resonance imaging -MRI-or MR venography) [20] . Patients with incomplete medical records as well as patients with indefinite diagnosis were excluded. We entered all data from patients diagnosed with CVST from the time of admission into a newly organized registry system designed by the engineering team of the Neurology Research Center of Shiraz University of Medical Sciences (Iran ministry of health registry code: 9001013381). All neurologists who work in our center were affiliated to this registry and actively enrolled CVT patients. To ensure full entry of patients in the registry system, using the international classification of diseases 10th version (ICD-10), we searched all medical records with primary ICD-10 diagnostic codes of G08 for "Intracranial and intraspinal phlebitis and thrombophlebitis", O87.3 for "Cerebral venous thrombosis in the puerperium", I63.6 for "Cerebral infarction due to cerebral venous thrombosis, nonpyogenic", I67.6 for "Non-pyogenic thrombosis of the intracranial venous system" and I61.9 for "Non-traumatic intracerebral hemorrhage". Thereafter, miscoded patients were excluded by a vascular neurologist. Disability or death at the time of discharge and three-month follow-up was assessed according to the modified Rankin Scale (mRS) score. Poor outcome is defined as mRS ≥ 3 at discharge and three-month after the index event. Analysis was performed on the data using IBM SPSS Statistics for Windows, Version 16.0. Armonk, NY: IBM Corp. The P-value<0.05 is considered significant in all analyses. The crude hospitalization rate per 1,000,000 population in the two periods was the dependent variable. The quantitative variables are shown using mean ± standard deviation (SD) or median with interquartile range (IQR) according to the distribution pattern. The qualitative variables are reported using numbers with percentages (%). A Chi-Square test was used to compare the 5 hospitalization rate change between pre-covid-19 and COVID-19 periods. Besides, independent variables (e.g., predisposing risk factors and main demographic variables) were compared using Chi-Square tests. Due to the non-normally distributed pattern of our data, we applied the Mann-Whitney test to compare the age of participants between pre-COVID19 and COVID-19 periods. In addition, using Cox Proportional Hazards regression analysis, we compared the adjusted Hazard ratio (aHR) of mortality between mentioned periods. To evaluate the trend of crude hospitalization rate of CVST, aggregated monthly hospitalization of CVST was used. Bayesian interrupted time series was used to examine the change of hospitalization rate across the study period. The BSTS package was used to perform time series analysis in the R 4.1 environment. The final time series model was fitted with adjusting the effects of age and male to female ratio variables. The 95% Credible Intervals (CrI) were used to report the Bayesian time series model results. The institutional review board and the Ethics Committee of Shiraz University of Medical Sciences (SUMS) approved the study protocol (IR.SUMS.REC.1399.098). This study follows the ethical standards of the institutional and national research committee and with the Helsinki Declaration or comparable ethical standards [22] . Data can be shared with other centers upon the approval of the Ethics Committee. 50 and 77 adult CVST cases were registered in the pre-COVID and COVID-19 periods, respectively. Therefore, the estimated crude hospitalization rate of CVST increased from 14 6 During the COVID-19 pandemic period, the female-to-male ratio changed from 3:1 to 2:1, although it was not significant (P=0.305) compared to the pre-COVID period. In addition, the median age of CVST patients increased from 40. 5 [29, 45.25 ] to 41 [35.5, 55 .5] during the study period (P =0.037) and the proportion of the patients > 50-year-old, increased in the COVID-19 pandemic era (P=0.042). The most common presentation was a headache in both intervals, including 88 and 81.8 % of patients in the first and second periods. Other symptoms were visual symptoms (34 % and 31.2%), seizure (40% and 33.8%), motor involvement (30% and 37.7%), paresthesia (14% and 9.1%), slurred speech (30 % and 19.5%) and cranial nerve palsy (14% and 7.8%). Table 2 represents the comparison of clinical characteristics of CVST patients between the mentioned periods. Sex-specific risk factors-pregnancy, puerperium ,and oral contraceptives-comprised the largest etiological group representing 56 % of all cases (73.7% of female patients) in the pre-COVID period and 42.9% (61.5% of female patients) in the COVID-19 period had at least one of these risk factors. There was a high proportion of infectious causes in the COVID-19 period; however, this was not statistically significant (8% vs. 19.5% in period 2, P=0.076). SARS-CoV-2 PCR test was done in 38 patients (49.3%) out of all COVID-19 period patients who were positive in 5 patients (6.5%). Overall, there was no difference regarding the predisposing factors between pre-COVID and COVID-19 periods. The monthly crude hospitalization rate of CVST in the two periods is illustrated in Figure-1 period, but it was insignificant (95% CrI: -2.2, 5.14). The estimated expected and observed trend of hospitalization rate from the time series model is shown in supplemental Figure- 1. The 28-day crude mortality rate of CVST was 6% in the pre-COVID period and 14.3% in the COVID-19 period, a non-statistically significant difference (P=0.145). Excluding COVID-19 associated CVST patients, the 28-day mortality rate was 11.1% in the COVID-19 period. Moreover, COVID-19 associated CVST patients had higher 28-day mortality than the other patients in the COVID-19 period (60% vs. 11.1%, P=0.019). This higher non-significant mortality rate in COVID-19 period could be due to secondary infections [23] . While in the pre-COVID period, head and neck infections including mastoiditis and sinusitis were the most common predisposing infections (8%), COVID 19 (6.5%), mucormycosis (3.9%), meningitis, and sepsis (2.6%) struck the patients in the COVID-19 period, as well as head and neck infections (6.5%). The Cox proportional analysis after adjusting for age and sex did not show a statistically Poor outcome at three month-follow-up in the pre-COVID period was associated with age (P=0.015) and malignancy (P= 0.014). In contrast, in the COVID-19 period, it was associated with higher age (P=0.025), altered mental status on admission time (P-value <0.001), malignancy (P=0.041), and COVID-19 infection (P=0.008). However, it was not associated with gender, intracranial hemorrhage, thrombosis of the deep venous system, and comatose status on admission in none of the two periods. In our study, the crude hospitalization rate of CVST patients older than 20 increased significantly from the pre-COVID period to the COVID-19 period. Although, after age and sex adjustment, 8 the incremental trend was not significant. During the COVID-19 era, the median age of the CVST patients increased as compared to the pre-COVID period. No predisposing risk factor was different between mentioned periods. COVID-19 associated CVST patients had higher 28-day mortality than the other patients in the COVID-19 period. There have been several case series and case reports of association of CVST and COVID-19 infection [15, [24] [25] [26] [27] [28] . In a systematic review, CVST frequency was 0.08% among hospitalized COVID-19 patients [29] . A retrospective cohort study using electronic health records of 537,913 patients with COVID-19 infection demonstrated the incidence of CVST in two weeks after a COVID-19 diagnosis was 42.8 per million people, which was significantly higher than in a matched cohort of people who received an mRNA vaccine and patients with influenza [30] . However, asymptomatic COVID-19 infection might trigger thrombosis, particularly in patients with predisposing risk factors [31] . About 16% of patients with SARS-COV-2 infection might be asymptomatic [32] . If these patients refer to the hospital more than 14 days after SARS-COV-2 infection, there is a high probability for nasopharyngeal COVID-19 RT-PCR to be negative [33] . Therefore, the underestimation of COVID-19 cases among CVST patients is possible in our study. We found that the older population was more affected in the COVID-19 than in the pre-COVID period. This is contrary to previous pre-pandemic reports illustrating younger patients' predominance [6, 34] . Similar to the results of the current study, a multicenter study indicated COVID-19 related CVST was more prevalent among the elderly in comparison with previously reported CVST cases [35] . In the retrospective cohort study on COVID-19 hospitalized patients, a male preponderance and average age of 49 years were reported. [36]. The 28-day mortality rate and 3-month poor outcome -mRS ≥3had no significant change from pre-COVID to COVID-19 period. Although, a higher 28-day mortality rate was seen among COVID-19 patients. Our results are consistent with the other studies representing high inhospital mortality in COVID-19 associated CVST patients [16, 29, 37] . However, this finding was not universal. In a multinational case series, poor outcome and in-hospital mortality among COVID-19 associated CVST patients did not differ significantly compared to control CVST patients without COVID-19 infection [15] . 9 This study has some limitations. It should be stressed that the single-centered design and small sample size of the current study decrease our findings' generalizability. To solve this issue, this study should carry on in a large-scale multi-center study [25] . The small number of deaths also prevented multivariate analysis for the detection of the determinants of mortality. Moreover, only clinically suspected CVST patients had been tested for COVID-19 infection during the pandemic, and asymptomatic COVID-19 patients might be missed in this study. As a drawback, the number of patients with indirect evidence of recent SARS-COV-2 infection such as increased D dimer but negative COVID-19 RT-PCR was not determined in the current study. In addition, in patients with severe COVID infection and decreased level of consciousness, CVT might have been overlooked. In addition, mild cases of CVST might not have been referred to the hospital due to COVID-19 phobia, similar to other mild cerebrovascular diseases [38] . Our center covers all mild to severe CVST patients from the metropolitan area of Shiraz and severe CVST patients from other parts of Fars province. Therefore, mild cases of other parts of this province might not be included in our study. However, the referral and admission system of our center did not change between 2018 and 2020. Nevertheless, we believe our registry system, which included all hospitalized CVST patients in our setting, was our study's strength. In conclusion, we observed a significant increase in crude CVST hospitalization rate but not in sex and age-adjusted CVST hospitalization rate. In line with several previous studies, we found higher mortality and worse three-month disability in COVID-19 associated CVST. This highlights the importance of a high index of suspicion for this diagnosis among COVID-19 positive patients to allow early diagnosis and treatment. As many CVST patients present with isolated headache and headache can also be a presentation of SARS-CoV-2 infection, progressive headache even in the absence of neurologic deficits should be evaluated vigilantly in this regard [27] . In addition, as the elderly became more affected during the pandemic period, we strongly recommend considering CVST as an important differential diagnosis in this population. To re-examine our findings, similar studies should be carried out on a large-scale multi-center basis. Asian Study of Cerebral Venous Thrombosis Changes in trend of cerebral venous sinus thrombosis The study of intermediate-term survival of the patients with cerebral venous sinus thrombosis Diagnosis and management of cerebral venous thrombosis Cerebral venous sinus thrombosis incidence is higher than previously thought: a retrospective population-based study The incidence of cerebral venous thrombosis: a cross-sectional study Journal Club: Trends in Incidence and Epidemiological Characteristics of Cerebral Venous Thrombosis in the United States Cerebral venous thrombosis: an update Incidence and epidemiology of cerebral venous thrombosis Cerebral vein and dural sinus thrombosis in adults in Isfahan, Iran: frequency and seasonal variation Thrombosis of the Cerebral Veins and Sinuses in Hamadan, West of Iran Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis Cerebral venous sinus thrombosis associated with SARS-CoV-2; a multinational case series Cerebral venous sinus thrombosis associated with COVID-19: a case series and literature review COVID-19 in Iran: What was done and what should be done Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the WHO (2020) 2019-nCoV/Surveillance_Case_Definition World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects complicated by rhino-orbital-cerebral mucormycosis presenting with neurovascular thrombosis: a case report and review of literature Atypical Deep Cerebral Vein Thrombosis with Hemorrhagic Venous Infarction in a Patient Positive for COVID-19 Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE) Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis Cerebral venous thrombosis and portal vein thrombosis: A retrospective cohort study of 537,913 COVID-19 cases Long lasting hypercoagulability after subclinical COVID-19 Proportion of asymptomatic coronavirus disease 2019: A systematic review and meta-analysis How should a positive PCR test result for COVID-19 in an asymptomatic individual be interpreted and managed? Cerebral venous thrombosis Cerebral Venous Thrombosis Associated with COVID-19 Infection: An Observational, Multicenter Study Cerebral Venous Thrombosis in COVID-19: A New York Metropolitan Cohort Study Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry First case of Covid-19 presented with cerebral venous thrombosis: a rare and dreaded case The authors would like to thank the Vice-Chancellor of Treatment Affairs of Shiraz University of Medical Sciences for their assistance.