|Ahead of print publication
Clinico-radiological patterns of cerebral venous thrombosis in adult males working in the mountainous region of North India - A pilot study from tertiary care hospital
J Chanderbhan1, Aditya Gupta2, Bharat Hosur3, Vivek Sharda1, Julie Sachdeva4, GS Chowdhary1, BA Muthanna2, Rajeev Saxena1, Gaurav Monga1
1 Department of Medicine, Command Hospital Chandimandir, Panchkula, Haryana, India
2 INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
3 Department of Radiodiagnosis, Command Hospital Chandimandir, Panchkula, Haryana, India
4 INHS Asvini, Mumbai, Maharashtra, India
|Date of Submission||30-Jun-2022|
|Date of Decision||24-Jul-2022|
|Date of Acceptance||05-Aug-2022|
|Date of Web Publication||11-Nov-2022|
Senior Advisor (Medicine and Neurology), Department of Medicine, Command Hospital Chandimandir, Panchkula, Haryana
Source of Support: None, Conflict of Interest: None
Introduction: Working adults in high-altitude regions (HARs) are at higher risk of developing cerebral venous thrombosis (CVT) due to multiple factors. The clinico-radiological patterns pertaining to the high altitude associated with CVT can be different compared to those without HAR exposure. Objective: We aimed to study the clinico-radiological patterns of CVT in adult males diagnosed with CVT while working in mountainous regions at an altitude higher than 8000 feet above sea level. Methodology: The study population consists of adult males aged >18 years who suffered symptomatic CVT while working in mountains at high altitudes. They were divided into groups according to the altitude at which they were working as high-altitude (8202–11,483 ft), very high-altitude (11,484–19,029 ft), and extremely high-altitude (above 19,030 ft) regions. Meticulous history, clinical examination, imaging with computed tomography, magnetic resonance imaging, and laboratory investigations including procoagulation profile were done. The outcome was classified according to the modified Rankin score at 3-month follow-up. Results: Among the forty patients with CVT, 100% had a headache, 65% had vomiting, and 20% suffered convulsions at presentation. Increasing altitude was associated with higher clot load, increasing extent of involvement within the venous sinuses, and a tendency to involve deep veins in isolation or conjunction with the sinuses. Twenty-three recovered without any deficit and 15 were symptomatic without disability at the 3-month follow-up. Conclusion: In patients of CVT who are exposed to high altitudes in mountains, the increasing altitude is associated with higher clot load, increasing extent of involvement within the venous sinuses, and a tendency to involve deep veins. Polycythemia, smoking, alcohol, and deficiency of protein C are the coexisting factors.
Keywords: Intracranial thrombosis, lateral sinus thrombosis, magnetic resonance imaging, multidetector computed tomography, sagittal sinus thrombosis
|How to cite this URL:|
Chanderbhan J, Gupta A, Hosur B, Sharda V, Sachdeva J, Chowdhary G S, Muthanna B A, Saxena R, Monga G. Clinico-radiological patterns of cerebral venous thrombosis in adult males working in the mountainous region of North India - A pilot study from tertiary care hospital. J Mar Med Soc [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=360902
| Introduction|| |
Cerebral venous thrombosis (CVT) is an uncommon disorder causing cerebral infarction in comparison to arterial stroke but has been responsible for lots of morbidity and mortality. CVT accounts for 0.5% of all strokes, and its annual incidence ranges from three to four cases per million among the general population up to seven cases per million among the youth. CVT which involves various venous channels of the brain can present with variable signs and symptoms that include headache, benign intracranial hypertension, subarachnoid hemorrhage, focal neurological deficit, seizures, unexplained altered sensorium, and meningoencephalitis., A prompt diagnosis and timely treatment of CVT are essential to reduce the risk of acute complications and long-term sequelae.
The people who are actively working in the mountains of high altitudes are at higher risk of developing serious and potentially fatal problems, such as high-altitude pulmonary edema, cerebral edema and CVT due to dehydration, vasodilation, hemoconcentration, and procoagulant state secondary to hypoxia. Another important factor responsible for high-altitude hypercoagulability is platelet dysfunction. Platelet counts are higher as is platelet adhesion which is not thrombopoietin mediated. Increased release of thromboxane from platelets, endothelial cell damage, and activation of clotting cascade have also been reported due to hypoxic stress at high altitudes. When an individual has a procoagulation disorder such as protein C deficiency, fibrinolytic enzyme deficiency, or antiphospholipid antibody syndrome, thrombosis can develop even at a moderate altitude.
We aimed to study the clinico-radiological patterns of CVT in adult males working in mountainous regions at altitudes higher than 8000 feet above sea level.
| Materials and Methods|| |
This was a descriptive study, conducted at a tertiary care hospital in North India, approved by the hospital ethics committee. The study population consists of working adult males (aged >18 years) who suffered symptomatic CVT at high altitudes (8202 feet or more above sea level). They were admitted with clinical and radiological computed tomography/magnetic resonance (CT/MR-angiogram) features suggestive of CVT. Exclusion criteria were age <18 years, stroke due to arterial thrombosis, intracranial space-occupying lesions of any type, secondary CVT due to malignancy, infection, and trauma. These patients were further divided into high altitude (8202–11,483 ft), very high altitude (11,484–19,029 ft), and extremely high altitude (above 19030 ft). Meticulous history, clinical examination, and laboratory investigations were carried out in all cases of CVT. The diagnosis was confirmed by noncontrast CT, CT-venogram of head, and/or MR imaging (MRI) with 3D time-of-flight MR-venogram. A detailed history was taken which included the date and time since induction at high altitude, acclimatization history, and clinical symptoms and signs. Demographic variables considered were personal and family history, drug history, and habits/addictions. Along with baseline investigations, procoagulation workup was done which included prothrombin time/activated partial thromboplastin time, serum homocysteine, antithrombin III, protein C, protein S, anticardiolipin and antiphospholipid antibody, factor V Leiden mutation, lupus anticoagulant, and antinuclear antigen. The outcome was classified according to the modified Rankin score (mRS): complete recovery (mRS 0–1), partial recovery, independent (mRS 2), dependent (mRS 3–5), and death (mRS 6). The primary outcome was death or dependence (mRS >2) at the end of the follow-up period. The secondary outcomes were death or dependence at 3 months of follow-up. The quantitative data were presented as mean and standard deviation (median and interquartile range in violation of normality). Qualitative variables were summarized as ratios and proportions.
| Results|| |
A total of forty patients who were deployed in the mountainous terrain and were diagnosed with CVT met the inclusion criteria of the study. These patients were at high-altitude (17.5%), very high-altitude (80%), and extremely high-altitude (2.5%) regions, respectively, prior to hospitalization [Table 1]. All patients were males and their mean age was 34.8 years. It was observed that 30% of the patients were each in the age group of 20–30 years and 40–50 years as compared to 40% in the age group of 30–40 years.
The most cardinal features of CVT were headache (100%) and vomiting (82.5%, 33/40). The site of the headache was frontal-temporal (39%), diffuse (28%), temporal (19%), and occipital (14%), respectively. Convulsions, as presenting features, were noticed in 20% of them. The history of smoking and alcohol intake was elicited in 22.5% and 47.5%, respectively. History and clinical findings did not elicit the features of dehydration or the presence of fever in any patient at the time of admission. None of the patients reported any family history of the CVT as well.
The patients from very high-altitude region (VHAR) and extremely high altitude region (EHAR) presented with seizures, more frequent vomiting, and worse headaches compared to the patients from a high-altitude region (HAR) [Table 2]. The neurodeficits in the form of limb paresis (25%, 10/40) were also discernible at presentation only in the patients of VHAR and EHAR cohorts. On imaging, isolated involvement of superior sagittal sinus (60%) or unilateral transverse/sigmoid sinus (67%) was the most common phenotype in HAR patients [Figure 1]. The extent of thrombus in patients from VHAR and EHAR was more with involvement of bilateral transverse/sigmoid sinus (50%) or unilateral transverse/sigmoid sinus (37.5%) in conjunction with the superior sagittal sinus [Figure 2]. Occlusion of the deep veins and straight sinus in isolation were found in four patients from VHAR, while one patient from EHAR showed extensive involvement of all the cerebral venous sinuses as well as the deep venous system [Figure 3].
|Figure 1: Cranial CT images of a 27-year-old male, deployed in a high-altitude region, with noncontrast images (top row - a, b, c) and corresponding contrast-enhanced CT-venograms (bottom row - d, e, f) in the axial plane. The hyperdense thrombus (white arrows) within the superior sagittal sinus and left sigmoid sinus appearing as luminal hyperdensity is seen as filling defects (black arrows) in the corresponding venograms. There are no associated infarcts or neuroparenchymal hemorrhage, CT: Computed tomography|
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|Figure 2: Cranial CT images of a 33-year-old male, deployed in a very high-altitude region, with noncontrast images (top row - a, b, c) and corresponding contrast-enhanced CT-venograms (bottom row - d, e, f) in axial and coronal planes. The hyperdense thrombus (white arrows) involving the left sigmoid sinus is seen as filling defects (black arrows) in the corresponding venograms. Furthermore, there is a left frontoparietal intracerebral hemorrhage (white arrowhead) with midline shift and perilesional edema, CT: Computed tomography|
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|Figure 3: Cranial CT images of a 24-year-old male, deployed in an extremely high-altitude region, with noncontrast images (top row - a, b, c) and corresponding contrast-enhanced CT-venograms (bottom row - d, e, f) in axial, sagittal, and coronal planes, respectively. The hyperdense thrombus (white arrows) distending the internal cerebral veins, straight sinus, and superior sagittal sinus is appearing as filling defects (black arrows) in the corresponding venograms. Furthermore, there is an associated left thalamic infarct (white arrowhead) with no neuroparenchymal hemorrhage, CT: Computed tomography|
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|Table 2: Clinico-radiological variables of the patients with high-altitude-related cerebral venous thrombosis|
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The laboratory investigations revealed that polycythemia (Hb more than 18.5 g/dl) was present in 27.5% of the patients [Table 3]. The packed cell volume (PCV) was abnormally high at 67.5%. The homocysteine was also found to be high at 72.5%. There were lower levels of protein C in 28% of patients and 70% had lower limits of protein S. The rest of the coagulation factors remained insignificant. All patients were treated with low-molecular-weight heparin acutely and were subsequently shifted to oral anticoagulants during the course in the hospital depending on their clinical improvement. Twenty-three patients (58%) were not having any symptoms during the 3-month follow-up, whereas 15 (38%) were not having any disability despite symptoms [Table 4]. One patient who had extensive CVT involving sinuses, as well as deep veins with hemorrhagic venous infarct and mass effect, died in the hospital due to expanding hematoma and its recalcitrant mass effects.
|Table 3: Procoagulation profile of the patients with high-altitude-related cerebral venous thrombosis|
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|Table 4: Follow-up of the patients at 3 months of treatment as per the modified Rankin Scale|
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| Discussion|| |
CVT is one of the rare cerebrovascular disorders, which constitutes around 1% of all strokes in developed nations.,, A higher incidence of stroke was found in the population staying at a higher altitude above sea level for a longer duration. The afflictions related to intravascular thrombosis during ascent to high altitude are not unknown; deep vein thrombosis (DVT), pulmonary thromboembolism, and hemiplegia as the impact of cerebral thrombosis in mountain climbers are well known. Literature on the details of the CVT in the context of high altitude is scarce, especially concerning young adults with prior acclimatization.
The CVT is often overlooked or difficult to diagnose at the early stage as presenting clinical symptom in most cases is a headache. This headache usually develops acutely and is very often indistinguishable from headaches found in mountain sickness, common at higher altitudes. In our study, headache was one of the presenting complaints in all the patients, commensurate with the extant literature. In our study, 13% of the patients had an altered level of consciousness at presentation, which is comparable with the findings of Wasay et al. The cause of altered sensorium can be attributed to cortical involvement, raised intracranial pressure, postictal states, and CVT afflicting the deep venous system.
The prothrombotic state is the most common risk factor identified for unprovoked CVST in published literature throughout the world. In an International Study on Cerebral Venous Thrombosis (ISCVT) cohort, 34% of patients had prothrombotic conditions, and 22% had underlying genetic prothrombotic states. Recently, Pai et al. and Narayan et al. reported thrombophilia as a risk factor for CVST in 18% and 12.3% of patients, respectively., In our study, 29/36 (77%) of the unprovoked CVST patients had predisposing thrombophilic conditions. The protein C, protein S, and antithrombin III levels could be low because of acute illness and need to be repeated after 03 months to ascertain the procoagulable state.
In this study, hypertension findings were found in 5 patients. A study conducted by the Indian Council of Medical Research showed that hypertension, diabetes mellitus, tobacco, and low hemoglobin level concentration were reported to be important risk factors for ischemic stroke. Atherosclerosis, as one of the major causes of cerebral ischemia, is seen much less commonly in young patients with stroke. None of the patients was found to have the findings of hypercholesterolemia or lipid abnormality in our study cohort. Higher concentrations of hemoglobin levels induce increased viscosity along with problems of inadequate blood flow. Increased blood viscosity, along with the abnormal vascular endothelium, is found to activate the platelets, thereby further accelerating the thrombotic process. In our study, hemoglobin values above 18.5 g/dL were seen in only 6 out of 40 cases of CVT, all of whom were from VHAR.
Investigations to rule out most inherited prothrombotic conditions showed a deficiency of protein C and S in 28% and 70% of patients, whereas a study of risk factors for thrombosis in nonembolic cerebrovascular disease in young Indian patients showed that activated protein C resistance (also factor V Leiden) was the most common defect (21.62%), followed by antithrombin III deficiency and the presence of anticardiolipin antibodies (5.6% each)., However, in patients not exhibiting the clinical features of a prothrombotic state, the yield of testing for protein C, S, and AT III deficiency is otherwise found to be low. Another study by Saxena et al. stated that of 56 young Indian patients with DVT, none of the subjects had protein C or S deficiency. Therefore, routine screening for protein C and S deficiency before going to high altitude is probably not practical and is not recommended.
In the ISCVT study, hyperhomocysteinemia was found in just 4.5% of cases (28/624) compare to our study where hyperhomocysteinemia was found in 29 cases. There was found a strong association between hyperhomocysteinemia and CVT among elderly males. Another study conducted in Italy which specifically evaluated the role between raised homocysteine level and CVT found hyperhomocysteinemia in 27% of patients with CVT compared to controls where it was found in only 8% of patients and concluded that it is associated with a four-fold increased risk of CVT.
Imaging by noncontrast CT and CT-venogram, as done in most of our patients, provides the pace, accuracy, and definitive diagnosis in patients with CVT. The hyperdensity of the thrombus within the distended sinus and/or deep veins on the noncontrast CT is seen as the delta/cord sign. The same thrombus appears as a filling defect on the CT-venogram performed using the iodinated contrast agents, identified by the “empty-delta sign.” MRI and MR-venogram save the patient from contrast-related and radiation hazards at the cost of time, postprocessing, and infrastructural requirements. Higher clot load, increasing extent of involved cerebral venous sinuses, and tendency to involve deep veins in isolation or conjunction with venous sinuses with exposure to higher altitude have been demonstrated in our study [Figure 4]. To the best of our knowledge, this imaging pattern based upon the increasing altitudinal exposure is not reported in the literature.
|Figure 4: The graphical representation of the variation of clinico-radiological parameters among CVT patients from the very high-altitude region in the form of a line chart. Patients presenting with convulsions (blue line), patients presenting with weakness (red line) and the average number of sinuses involved on imaging (yellow line) are plotted with whole numbers on the Y-axis and the duration of high-altitude exposure (months) on the X-axis, CVT: Cerebral venous thrombosis|
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In the present study, the majority of patients had good clinical outcomes (95%) who had a score of 0–1. Good prognosis has also been reported in other case studies reported from high altitudes.,,,
There were no matched controls to study the effects of high altitude in detail. A case–control study may be needed to study the etiological factors contributing to the CVT at higher altitudes better. All the patients were working males; hence the results cannot be generalized across the age and gender barriers. The present study had a small sample size and the follow-up duration was only 3 months.
| Conclusion|| |
Exposure to high altitude is associated with a higher risk of stroke among young and physically fit adult males without any prior comorbidity. Increasing altitude was associated with higher clot load, increasing extent of involvement within the venous sinuses, and a tendency to involve deep veins in isolation or conjunction with the sinuses. Polycythemia, smoking, alcohol, and deficiency of protein C could be the additional risk factors noted among these patients. A further study of various factors incriminated in coagulation disorders in the normal individual would be ideal to derive definite conclusions on the role of coagulation disorders in high-altitude CVT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
All the authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]