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 [5–8].
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 . Some studies have demonstrated the predominance of venous thromboembolic manifestations, especially in the critically ill groups [13, 14].
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). The study periods are defined as a) pre-COVID period [21th March 2018 to 20th March 2019] and b) COVID-19 period [20th March 2020 to 20th March 2021].
Iran reported its first confirmed case of COVID-19 on 19th February 2020 . The National COVID-19 vaccination program was started after the recruitment time.  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 .
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 .
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 .
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 (headache, focal neurological syndromes, mental status disturbance, etc.) and radiological assessments of the brain (Computed Tomography -CT-, CT venography, Magnetic resonance imaging -MRI- or MR venography) . Patients with incomplete medical records as well as patients with indefinite diagnosis were excluded.
COVID-19 attributed investigations were done for patients if any clinical relevance was found. COVID-19 is considered in patients with positive reverse transcriptase-polymerase chain reaction (RT-PCR) from the oro- or naso-pharynx . Patients who developed COVID-19 infection as a nosocomial infection was excluded.
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.
The precipitating risk factors of CVST are grouped in the following categories: Sex-specific risk factors -pregnancy, puerperium and oral contraceptive pills-, malignancy, infection, thrombophilia, hematologic, rheumatologic, mechanical, dehydration, miscellaneous and unrecognized.
The superficial sinus venous system was defined as superior and inferior sagittal, transverse, sigmoid, occipital, and cavernous sinuses and all attributed superficial veins (Trolard, Labbe, superficial middle cerebral vein, etc.). The deep system was defined as straight sinus, the vein of Galen, the basal vein of Rosenthal, internal cerebral veins, and all attributed veins (septal, thalamostriate, etc.).
Crude hospitalization rate
A total of 50 and 77 adult CVST cases were registered in the pre-COVID and COVID-19 periods, respectively. The estimated crude hospitalization rate of CVST increased from 14.3 per million in the pre-COVID period to 21.7 per million per year during the COVID-19 period (P=0.021). Excluding COVID-19 associated CVST patients- 5 patients- from the second period shows that the non-COVID-19 associated CVST hospitalization rate increased from 14.33 in the pre-COVID period to 20.29 per million, which was not significantly different (P=0.058) (Table 1).
|Pre-COVID period||COVID-19 period||P-value|
|< 50-year-old population||17.84||21.44||0.362|
|≥ 50-year-old population||5.18||22.30||0.001*|
During the COVID-19 pandemic, 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] years 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 headache in both periods (88% in the first and 81.8% in the second period). Other symptoms described 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).
Predisposing risk factors
Sex-specific risk factors 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). 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%). 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 which is illustrated in Table 3.
|Predisposing risk factor||Pre-COVID periodN=50||COVID-19 periodN=77||P-value|
|Sex-specific risk factors||28 (56%)||33 (42.9%)||0.188|
|Infection||4 (8%)||15 (19.5%)||0.076|
|Malignancy||2 (4%)||10 (13%)||0.124|
|Hematology||11 (22%)||25 (32.5%)||0.201|
|Thrombophilia||4 (8%)||3 (3.9%)||0.432|
|Mechanical||3 (6%)||6 (7.8%)||1.00|
|Dehydration||5 (10%)||5 (6.5%)||0.514|
|Miscellaneous||8 (16%)||8 (10.4%)||0.352|
|Unrecognized||8 (16%)||11 (14.3%)||0.791|
Temporal trend of hospitalization rate of CVST
The monthly crude hospitalization rate of CVST in the two periods is illustrated in Figure 1. During the COVID-19 period, the hospitalization rate of CVST had an average value of 1.67 patients per month. Although, it was 1.07 [95% CI: 0.77, 1.37] at pre-COVID-19 period. The estimated rising in hospitalization rate was +56% [95%CI: +28%, +84%]. A significant increase in hospitalization rate was observed by 21.65 (P=0.002). However, without COVID-19, we expected a value of about 13.85 [95% CI: 9.98, 17.82].
Including confounder variables to the Bayesian interrupted time series model, a stable trend of hospitalization rate was observed (Posterior Beta of time*period interaction=0.05; 95% CrI: -0.28, 0.17). In addition, the hospitalization rate raised by 1.4 times in the COVID-19 period compared to the pre-covid-19 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).
The Cox proportional analysis after adjusting for age and sex did not show a statistically significant difference in adjusted HR of mortality during the COVID-19 pandemic [aHR: 1.83, 95%CI: (0.51, 6.62)] (Figure 2).
Among the discharged patients, 42 patients in the pre-COVID period and 63 in the COVID-19 period were recruited in Three-month follow-up either by face-to-face interview or telephone interview. 3-month mRS scores of patients are illustrated in Figure 3.
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 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 . 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.
REFERENCE LINK : https://www.researchsquare.com/article/rs-1290632/v1