|Ahead of print publication
Study of clinical spectrum, laboratory parameters, and radiological patterns in cerebral venous thrombosis cases occurring at high altitude
AK Naik1, Jai Prakash Prasad2, Vani Singh3, SK Singh4, Barun Kumar Chakrabarty5, Jitender Sharma6, S Yadav7, AK Singh8, Vishal Jha9
1 Department of Hosp Adm, Prof and HOD, AFMC and Ex Brig Med,14 Corps, Udampur, India
2 Department of Hosp Adm, Brig AFMS(HR), O/o-DGAFMS, New Delhi, India
3 Ex SR, Department of Radiation Oncology, RIMS Ranchi & Medical Officer in charge, ECHS Polyclinic, New Delhi, India
4 Department of Medicine, Classified SPL (Med), CH (NC), India
5 Department of Pathology, Classified SPL (Path), 151 Base Hospital, Guwahati, Assam, India
6 Department of Medicine and Neurology, Classified SPL (Medicine and Neurology), CH (NC), Udampur, India
7 Department of Medicine, CH (NC), Udampur, Jammu and Kashmir, India
8 Department of Radiology, Senior ADV (Radiology), MH namkum, Ranchi, Jharkhand, India
9 Department of Medicine, GD SPL (Med), 153 GH, Leh, India
|Date of Submission||01-Jun-2020|
|Date of Decision||06-Jul-2020|
|Date of Acceptance||23-Aug-2020|
|Date of Web Publication||10-May-2021|
Department of Medicine, Classified SPL (Med), Command Hospital (NC), Udampur, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Context: The risk of cerebral venous thrombosis at particular locations and its association with high altitude is yet to be established completely. The relation between high altitude and venous thromboembolic events has been debated for many years. Cerebral venous thrombosis presenting with nonspecific symptoms like headache can be a tough challenge for primary care physicians deployed at high altitudes. Materials and Methods: Combatants going to wide areas of mountainous territories at varying altitudes presenting with persistent severe headache associated with nausea and vomiting were subjected into the study after evaluation at zonal and tertiary care hospital. Results: Over a period of 18 months from October 2018 to March 2020, 75 cases of headache were screened and evaluated. Eighteen of these patients were diagnosed to have cerebral venous thrombosis. Conclusion: The occurrence of chronic venous thrombosis in combatants who enter and remain at high altitude for the prolonged duration is very common and the gold standard for diagnosis is a clinical evaluation with radio imaging.
Keywords: Acute mountain sickness, cerebral venous thrombosis, high altitude, magnetic resonance venography, thrombophilia
|How to cite this URL:|
Naik A K, Prasad JP, Singh V, Singh S K, Chakrabarty BK, Sharma J, Yadav S, Singh A K, Jha V. Study of clinical spectrum, laboratory parameters, and radiological patterns in cerebral venous thrombosis cases occurring at high altitude. J Mar Med Soc [Epub ahead of print] [cited 2021 Jun 21]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=315779
| Introduction|| |
The human body responds differently to different environmental stresses. High altitude is one such challenge and is often attributable to many physiological and pathological responses. A number of hematological changes have been noted by various researchers on the ascent to high altitude or on simulation in hypobaric chambers, results varying with the duration of stay.,, Chronic venous thrombosis (CVT) is a relatively uncommon cause of cerebral infarction that occurs due to thrombosis of dural venous channels in the brain. Clinical presentation is frequently vague and is a diagnostic challenge in an individual presenting with sudden onset headache, vomiting and focal neurological deficits, beyond the domains of altitude sickness. However, there is still little knowledge of pathology and its contributing risk factors.
The purpose of this study is to elaborate varied clinical manifestations of CVT in high altitude in adult male patients and discuss the clinical and bedside clues that help in differentiating CVT from other mimics of high altitude illnesses. We discuss the laboratory parameters including tests for thrombophilia and neuroimaging as a cornerstone in the diagnosis of CVT. The approach to a patient with suspected CVT starts with a good history and physical examination focusing on the bedside clues as neurological symptoms may be wrongly attributed to acute mountain sickness and HACO and delay the proper treatment.
Most of the cases of headache occurring at high altitude are linked with acute mountain sickness or high altitude cerebral edema. Radiological imaging, by far the diagnostic modality for CVT, is either not performed or is limited.
The present study was done to identify the cases of CVT in male individuals temporarily living at hilly terrains for a prolonged duration. Seventy-five individuals living at more than 9000 ft who had presented with acute onset persistent severe headache with associated symptoms were evaluated for the likelihood of CVT.
| Materials and Methods|| |
This descriptive, prospective, cross-sectional, and observational study was conducted on patients admitted in the medicine ward of tertiary care hospital located in the hilly terrains of the Northern part of the country for 18 months from October 2018 to March 2020. The study population involved 20–50 years' adult male individuals living at altitudes ranging between 9000 ft and 20,000 ft comprising of temporary inhabitants who had prolonged stay at high altitude for <24 months. All of our study subjects were healthy and successfully inducted in HAA after completion of proper scheduled pre induction screening and acclimatization duration of mostly more than 2 weeks. Seventy-five of these individuals who had presented with sudden onset persistent headache, associated with nausea, vomiting, seizures, impaired mental status, fever, and focal neurological deficits and were admitted to medical ward were evaluated for suspicion of CVT. All individuals were subjected for hematological, biochemical, and metabolic profile. Thrombophilia workup performed for all CVT patients. Laboratory investigations include hemoglobin, packed cell volume, prothrombin time, activated partial thromboplastin time, d-Dimers, protein C and S, serum lipid profile, liver and kidney function tests, and serum electrolytes. CVT patients were evaluated for composite thrombophilia mutation panel (comprising variant tested for Factor V [Leiden and R2], Prothrombin [G20210A], methylene tetrahydrofolate reductase [MTHFR C677T and A1298C], Factor XIII [V34 L], plasminogen activator inhibitor-1 [PAI-1 4G/5G] and endothelial protein C receptor [A4600G and G4678C] gene). Genetic testing was done at initial stage. Anticoagulation was continued in acute stage and only stopped after continuation of at least 6 months. Thrombophilia screening was done only after stoppage of oral anticoagulation which was continued for 4–6 months from case to case basis. After 6 months of oral anticoagulation therapy, all these cases were reviewed with fresh magnetic resonance imaging (MRI). Thrombophilia screening workup was sent after 4 weeks of discontinuation of oral anticoagulation therapy.
While tests for thrombophilia were investigated to aid in diagnosis and risk evaluation, evidence of CVT was confirmed on radio imaging modalities such as MRI and magnetic resonance venography (MRV). Neuroimaging, a combination of computed tomography (CT), magnetic resonance angiography and MRV,, along with T2-weighted (T2W), fluid-attenuated inversion recovery, T1W and (GRE) Gradient echo sequences were carried out in these patients. MRV along with the basic sequence show involvement of sinus, superficial cortical veins, and deep veins. Altitude variation and duration of stay were also considered.
| Results|| |
During the period from October 2018 to March 2019, a total of 75 adult male patients with persistent severe headache were admitted. The mean age of our study population was 33.6 years. Eighteen of these were diagnosed to have CVT. The mean age of patients with CVT was 33.1 years.
The patient's age was distributed between 20 and 50 years, the youngest being 21 years and oldest 49 years. Results showed higher number of cases of CVTs in the younger age group. Six out of the 18 cases were aged between 20 and 30 years, 8 individuals were between 30 and 40 and 04 others were above 40 years of age. Of these, 04 cases were individuals who were living between altitude 13,000 ft and 17,000 ft and 04 cases beyond 17,000 feet. Majority of the individuals who had presented with headache also belonged to this altitude range [Figure 1].
|Figure 1: Distribution of cases of chronic venous thrombosis with age and altitude|
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In our study, out of 75 patients who had presented with sudden onset headache also had vomiting. Out of those who were diagnosed to have CVT, 15 had presented with vomiting, 8 had presented with vision disturbances, 5 complained of paresthesia while 12 had speech disturbances. Seven patients had an episode of seizure, 5 complained of weakness in one of the limbs while 5 also developed altered sensorium. Most patients presented with more than one symptom.
At presentation, of the 18 who were later diagnosed with CVT, 7 had high blood pressure, who were not previously hypertensive, 8 had tachycardia while 4 had bradycardia. Twelve had tachypnea, 12 of these patients had signs of dehydration while 4 had papilledema on fundus examination. Apart from central nervous system (CNS), other systemic examination was relatively normal [Table 1].
Relevant clinical parameters are shown in [Table 2]. Thirty-two patients out of 75 who had presented with headache had polycythemia. Out of the 18 diagnosed CVT cases, two third were found to have polycythemia. D-dimers were raised in 5 out of the 18 CVT cases. Other hematological and biochemical parameters were almost normal.
|Table 2: Details of studied parameters of the chronic venous thrombosis patients at the time of admission|
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In our study, one patient tested positive for both Factor V Leiden and MTHFR, 1 was heterozygous for both MTHFR and Factor XIII polymorphism, 2 were found heterozygous for PAI-1 mutation. One patient had both prothrombin and PAI-1 polymorphism, 1 patient was protein C deficient and heterozygous for PAI-1 [Table 3].
|Table 3: Thrombophilic mutations in diagnosed chronic venous thrombosis patients|
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In our study, gold standard for diagnosis remains radio-imaging modalities like MRI and MRV to visualize the thrombosed vessel and detect the nonvisualization of the same vessel, respectively. [Figure 2] and [Figure 3] demonstrate few of the basic findings in a patient detected to have CVT. Majority of these patients had the involvement of superior sagittal sinus, followed by transverse, sigmoid, and straight sinus. Few of the patients showed the involvement of cerebral parenchyma in the form of venous hemorrhagic infarct [Figure 2] and [Figure 3].
|Figure 2: Gradient echo sequences of magnetic resonance imaging shows blooming due to magnetic susceptibility. Artefacts of superficial cortical veins suggestive of thrombosis of superficial cortical veins|
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|Figure 3: (a) Magnetic resonance venography shows attenuated right transverse sinus with nonvisualization of right sigmoid sinus suggestive of thrombosis of right transverse and sigmoid sinus. (b) Magnetic resonance venography of another patient shows thrombosis of middle one-third of superior sagittal sinus, correlated with base sequences with findings of loss of flow void on T2-weighted and fluid-attenuated inversion recovery and hyper intense on T1-weighted. (c) T1-weighted sagittal image on right shows hyper intense anterior and middle one-third superior sagittal sinus. Magnetic resonance venography on left shows nonvisualization of anterior one-third with attenuated middle one-third superior sagittal sinus|
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| Discussion|| |
Manifestations of high altitude thrombosis are extremely variable but all may result to significant morbidity and mortality. Other than CVT high altitude thrombosis can manifests as occlusive hypertensive disease, deep vein thrombosis, pulmonary thrombo-embolism, cerebrovascular accident, mesenteric or splenic, or portal vein thrombosis, retinal or peripheral arterial thrombosis. The occurrence of CVT in individuals serving at high altitude areas is relatively more common and due to varied clinical spectrum of signs and symptoms, reaching a diagnosis is a challenge for physicians working at medical institutions at high altitudes.
The relation between high altitude and thrombosis has been studied for many years and a definite link between the two is still the area of research. The overall risk of venous thrombotic manifestations is reported to be increased at least 30 times at high altitude areas. Various factors suggested playing role in CVT with increasing altitude resulting hypobaric hypoxia. Preexisting prothrombotic states, hypothermia, dehydration, smoking, prolonged immobilization, secondary polycythemia, hemostatic changes, endothelial injury, hyperhomocysteinemia, and lack of exercise have shown increased risk of thrombotic events. Certain comorbidities such as coronary artery disease (CAD), hypertension, diabetes, dyslipidemia, pregnancy, previous history of strokes, CVTs, and other thrombotic events are independent risk factors. In the young- to middle-aged adult, the incidence is more in women than men but the scenario found to be reversed in high altitude areas. The cause for this gender variation may be due to variation in physical activity and physiological changes. It is also observed that there is higher rate of CVT incidences reported from developing countries, than the developed world. Our study group comprised of temporarily migrated properly acclimatized healthy male individuals who were screened for any underlying comorbidity such as CAD, hypertension, diabetes, dyslipidemia, and other chronic ailments prior to their induction to high altitude.
Common causes of CVT are inherited or acquired prothrombotic states, infections like mastoiditis, sinusitis, meningitis, collagen vascular diseases like systemic lupus erythematous, sarcoidosis, drugs like oral contraceptives and physiological states like pregnancy and dehydration.
Majority of the patients had presented with subtle symptoms of headache and vomiting while a few who presented with seizure, loss of consciousness, and focal neurological deficits developed catastrophic outcomes with residual lifelong morbidity. Similar case studies have shown varied clinical presentation of CVT at high altitude ranging from throbbing headache, vomiting, visual field narrowing, diplopia, gait disturbances, speech disturbances and paresthesias to seizure, loss of consciousness, altered sensorium, and focal neurological deficits.,,,
In addition, cold stress, dehydration, physical inactivity and hypoxia-induced vascular endothelial injury further predispose to thrombosis. Twelve out of the 18 diagnosed CVT patients had signs of dehydration at presentation while 4 among them were severely dehydrated. The relative incidence of dehydration is common at high altitude areas due to reduced water intake, abrupt augmentation of physical exertion, and acute mountain illness induced vomiting and diarrhea. Dehydration may lead to reduction of cerebral perfusion, increase blood viscosity and hypercoagulability resulting preponderance of thrombotic phenomenon. Studies have shown the association of CVT with polycythemia that occurs as an adaptation to high altitude., In our study, more than one-third patients had polycythemia. High altitude polycythemia is a well-known chronic disease among inhabitants at high altitude. The overall prevalence of polycythemia vera has been reported approximately 22 cases per one lakh population with male preponderance. There is reported lower prevalence of polycythemia (5%–18%) in permanent highlander population than temporary lowlander migratory inhabitants in high altitude. Polycythemia results due to the rise in blood hemoglobin and hematocrit levels with rise in altitude to compensate for the hypoxia that occurs. This leads to an increase in blood viscosity, platelet, and flow dysfunction which in turn leads to a hypercoagulable state.,
The term thrombophilia has been used to describe familial or acquired disorders of the hemostatic mechanisms which are likely to predispose to thrombosis. Various inherent and acquired defects of coagulation are independent risk factors. Tyagi et al. demonstrated that increased Caplain activity leading to platelet activation and activation of coagulation cascade. Certain factors when in excess like Factor 7, 8, 9, elevated homocysteine and fibrinogen levels whereas certain deficient states like factor V Leiden deficiency, plasminogen deficiency, protein C and S deficiency lead to a hypercoagulable state. Out of the diagnosed CVT patients, 2 were protein S deficient while 1 was protein C deficient. In our study, we found 2 patients who were positive for factor V Leiden mutation. Polymorphisms in or methylenetetrahydrofolate MTHFR gene result in reduced enzymatic activity of MTHFR which lead to increased levels of homocysteine.,, Thrombophilic profile of CVT cases revealed 2 cases who were heterozygous positive for MTHFR gene. Numerous works have indicated an increased PAI-1concentration in some diseases with an elevated prothrombotic risk, and PAI-1 has become an important inhibitor of natural fibrinolysis., Two of the 18 CVT patients were heterozygous PAI-1 mutation.
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. High altitude ascent found to be associated with augmentation of D-dimer levels, prolongation of prothrombin time, and results in activated protein C resistance. 27.8% of our patients had elevated D-dimer levels. D-dimer levels are often correlated with diagnosis of venous thrombotic incidences; however, it exhibited high negative predictive value.
The most common symptoms in a patient developing CVT are also commonly associated with acute high altitude illnesses, strokes or symptoms of raised ICT which may cause delay in diagnosis and can have serious outcomes. Many clinical conditions such as dehydration, hypoplasia/aplasia of dural sinus, giant arachnoid granulations, and acute SDH may mimic CVT on neuroimaging to further complicate the scenario. Nevertheless, till date, radio-imaging modalities such as MRI and MRV are the gold standard for the diagnosis of CVT but their use is limited by their high cost of installation and management, lack of workforce, and technical skills to operate them.
CVT is a multifactorial condition with a wide clinical presentation with variable etiologies and prognosis and warrant high index of suspicion to diagnose. The presenting features of CVT usually depend on the sinuses involved, speed of occlusion, and involvement of cortical veins with presence of collaterals. The headache of CVT is moderate to severe in intensity and often bilateral with associated vomiting and may mimic as thunderclap headache of subarachnoid hemorrhage. Several infective and noninfective CNS disorder presenting with headache can be differential diagnosis. Common serious diseases presenting as headache can be primary brain tumor, metastatic brain tumor, intracerebral hemorrhage, meningitis, temporal arteritis, hydrocephalus, glaucoma, subdural hematoma, migraine, and pseudotumor cerebri. Infective etiology like meningitis (viral/bacterial/tuberculosis) will have a history of fever and diagnostic cerebrospinal fluid will help to point out the diagnosis. Migraine headache will present with prodome, aura and postdome phase and mostly unilateral only. Cluster headache strikes abruptly, without any aura, around and behind one eye. While there are some known factors that may lead to the development of CVT, there's still a vast horizon to be covered. In this study, we have identified high altitude as one of the risk factors, especially in individuals with no prior exposure to high altitudes, our study also revealed that certain inherited or acquired defects of coagulation may add up to the risk of developing venous thromboembolic event.
It is almost impossible to prognosticate who will develop thromboembolic events before their exposure to high altitude. However, people with prior history of such events should not be deployed at high altitude. Prior thrombophilia screening of individual should be done wherever indicated and possible. Certain stressors at high altitude like dehydration can simply be tackled by adequate fluid intake. Our management comprised of decongestive therapy with Mannitol and Furosemide, anticonvulsants, oxygen and fluid correction with general supportive measures. In addition, our patients were started on anticoagulation with heparin (LMWH) along with oral anticoagulant to achieve a target INR of 2.5–3.0. Once therapeutic INR was achieved LMWH was withheld. Early diagnosis may help manage a case of CVT promptly and prevent associated morbidity and mortality.
Unusual thrombotic episodes such as CVT warrant a complete thrombophilia workup as it can have a bearing on anticoagulation therapy which is often long term in cases of life endangering episodes and recurrent thrombotic events. Prophylactic anticoagulation is indicated when these patients are faced with any of the high risk situations mentioned earlier.
There are still giant holes in our knowledge of the disease that need to be filled, however, we can make judicial use of our knowledge, treatment and diagnostic resources and make evidence-based guidelines to tackle such health hazards.
| Conclusion|| |
It takes a colossal effort to recruit, train, and prepare a combatant and to lose them to ailment like CVT can only be viewed as a despicable loss of precious resource and is demoralizing to medical fraternity. The occurrence of CVT in individual who remain at high altitude for prolonged duration is very common and should be suspected whenever individual present with sudden headache, vomiting, and focal neurological defects at high altitude. Our study has focused on the bedside clues which help the physician in solving the diagnostic conundrum of high altitude-related illness which are commonly encountered in high altitude areas with its protean manifestations in the critical care setting. With our enhanced clinical awareness and the help of radiological techniques such as CT, MRI, and CT or MRI angiography, CVT can be reliably diagnosed and properly managed and can reduce morbidity and prevent death.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Singhal S, Bhattachar SA, Paliwal V, Malhotra VK, Addya K, Kotwal A. Pulmonary embolism in young natives of high altitude. Heart Views 2016;17:62-5.
] [Full text]
Siebenmann C, Robach P, Lundby C. Regulation of blood volume in lowlanders exposed to high altitude. J Appl Physiol (1985) 2017;123:957-66.
Gambhir RP, Anand V, Khatana SS, Bedi VS. A brief review of high altitude thrombosis. Indian J Vasc Endovasc Surg 2014;1:20. [Full text]
Huertas A, Guignabert C, Barberà JA, Bärtsch P, Bhattacharya J, Bhattacharya S, et al
. Pulmonary vascular endothelium: The orchestra conductor in respiratory diseases: Highlights from basic research to therapy. Eur Respir J 2018;51:1700745.
Keyes LE. Hormonal contraceptives and travel to high altitude. High Alt Med Biol 2015;16:7-10.
Hassan WU, Syed MJ, Alamgir W, Awan S, Bell SM, Majid A, et al
. Cerebral venous thrombosis at high altitude: Analysis of 28 cases. Cerebrovasc Dis 2019;48:184-92.
Syed MJ, Alamgir W, Wasay M. Cerebral venous thrombosis at high altitude. Pak J Neurol Sci (PJNS) 2018;13:44-51.
Zavanone C, Panebianco M, Yger M, Borden A, Restivo D, Angelini C, et al
. Cerebral venous thrombosis at high altitude: A systematic review. Rev Neurol (Paris) 2017;173:189-93.
Hull CM, Rajendran D, Barnes AF. Deep vein thrombosis and pulmonary embolism in a mountain guide: Awareness, diagnostic challenges, and management considerations at altitude. Wilderness Environ Med 2016;27:100-6.
Kim JH, Kim SJ, Kim HY. Right hand weakness and headache during ascent to Mount Everest: A case of cerebral venous infarction. Neurologist 2017;22:98-100.
Algahtani FH, AlQahtany FS, Al-Shehri A, Abdelgader AM. Features and incidence of thromboembolic disease: A comparative study between high and low altitude dwellers in Saudi Arabia. Saudi J Biol Sci 2020;27:1632-6.
Khattar NK, Sumardi F, Zemmar A, Liang Q, Li H, Xing Y, et al
. Cerebral venous thrombosis at high altitude: A retrospective cohort of twenty-one consecutive patients. Cureus 2019;11:e4940.
Dash UK, Karmarkar AA, Dangi MS. A study of high-altitude-associated conditions in soldiers less than 50 years of age admitted in the ICU of a tertiary care military hospital operating in a counter insurgency operation area. J Mar Med Soc 2017;19:138. [Full text]
Zhao Y, Zhang Z, Liu L, Zhang Y, Fan X, Ma L, et al
. Associations of high altitude polycythemia with polymorphisms in EPAS1
in Chinese Han and Tibetan populations. Oncotarget 2017;8:86736-46.
Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res 2019;181:77-83.
Yanamandra U, Bhattachar SA, Das SK, Yanamandra S, Kumari VK, Ayekappam A, et al
. Hematological parameters in native highlanders of ladakh aged 4-19 years. Indian J Hematol Blood Transfus 2018;34:731-8.
Tyagi T, Ahmad S, Gupta N, Sahu A, Ahmad Y, Nair V, et al.
Altered expression of platelet proteins and calpain activity mediate hypoxia – Induced prothrombotic phenotype. Blood 2014;123:1250-60.
Ooi QX, Wright DF, Tait RC, Isbister GK, Duffull SB. A joint model for vitamin K-dependent clotting factors and anticoagulation proteins. Clin Pharmacokinet 2017;56:1555-66.
Zhao P, Hou J, Wu H, Zhong M. Analysis of genetic polymorphism of methylenetetrahydrofolate reductase in a large ethnic Hakka population in Southern China. Medicine (Baltimore) 2018;97:e13332.
Min SK, Kim YH, Joh JH, Kang JM, Park UJ, Kim HK, et al
. Diagnosis and treatment of lower extremity deep vein thrombosis: Korean practice guidelines. Vasc Specialist Int 2016;32:77-104.
Sam NB, Zhang Q, Li BZ, Li XM, Wang DG, Pan HF, et al
. Serum/plasma homocysteine levels in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Clin Rheumatol 2020;39:1725-36.
Lawrence DA, Ginsburg D. Gene Expression and Function of Plasminogen Activator lnhibitor-1. Fibrinolysis in Disease-The Malignant Process, Interventions in Thrombogenic Mechanisms, and Novel Treatment Modalities. Vol. 2. Boca Raton, FL:CRC Press;2019. p. 21-9.
Zhu J, Wan Y, Xu H, Wu Y, Hu B, Jin H. The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: Friend or foe? Cell Mol Life Sci 2019;76:1489-506.
Komro J, Findakly D. Cerebral venous sinus thrombosis in adults with prothrombotic conditions: A systematic review and a case from our institution. Cureus 2020;12:e7654.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]