Investigation on clinical features, brain imaging, a number of riks factors and the value of d-dimer in diagnosis of cerebral venous thrombosis

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THE MINISTRY OF EDUCATION AND TRAINING THE MINISTRY OF DEFENCE MILITARY MEDICAL UNIVERSITY LE VAN MINH INVESTIGATION ON CLINICAL FEATURES, BRAIN IMAGING, A NUMBER OF RIKS FACTORS AND THE VALUE OF D-DIMER IN DIAGNOSIS OF CEREBRAL VENOUS THROMBOSIS Speciality: NEUROLOGY Code: 62 72 01 47 MD-PhD. THESIS SUMMARY HANOI - 2014 THE THESIS WAS COMPLETED AT MILITARY MEDICAL UNIVERSITY Supervisors: A.Prof. Dr. PHAN VIET NGA A. Prof. Dr.PHAM NGOC HOA 1st reviewer: 2nd reviewer: 3rd reviewer: The thesis will be upheld before the University Grade Thesis Examination Board at: hour on day month year . The thesis can be found at: - National library - Military medical university’s library 1 FOREWORDS Cerebral venous thrombosis (CVT) is estimated to account for 0.5% of all strokes in adults. In recent years, with the present of non-invasive and high accuracy diagnostic techniques such as magnetic resonance imaging and computed tomography, the rate of diagnosis of CVT also increases. Congenital Thrombophilia states account a high rate in white skin peoples and make up 15-30% cases of patients with venous thrombosis. D-dimer test is an inexpensive and commonly available method which has high performance in diagnosis of CVT as proven by some prospective and meta-analytic studies. Moreover, at present there is no published study on the role of D-dimer test in the diagnosis of CVT in our country. In Vietnam, there have been many studies on aspects of stroke. However, there are few studies on CVT, therefore we decided to study CVT with the following objectives: OBJECTIVES OF THE STUDY 1. To describe some clinical features and brain images of CVT. 2. To review some risk factors of CVT. 3. To determine the sensitivity, specificity, positive predictive value and negative predictive value of D-dimer test in the diagnosis of CVT. 2 NEW CONTRIBUTION OF THE THESIS 1. Our study described some clinical features and brain images of CVT. 2. Our study found some genetic and acquired risk factors of CVT. 3. Our study successfully determined the role of D-dimer test in the diagnosis of CVT. The thesis includes 115 pages, with 4 chapters, 43 tables, 16 charts, 1 diagram, 8 Vietnamese references and 83 English references. 3 pages forewords, 35 pages overview, 19 pages subjects and methods, 24 pages results, 31 pages discussion, 2 pages conclusion, 1 page recommendations. Chapter 1 - OVERVIEW 1.1. GENERAL 1.1.1. Anatomy of cerebral veins and sinous The veins of the brain have no muscular tissue in their thin walls and possess no valves as compared to other types of veins. They emerge from the brain and lie in the subarachnoid space. They pierce the arachnoid mater and the meningeal layer of the dura and drain into the cranial venous sinuses. Blood from both brain is drained by cerebral veins into dural sinuses and then into the jugular. Cerebral veins is divided into 3 important groups which are superfical cerebral veins, deep cerebral veins and posterior fossa veins. 1.1.3. Pathogenesis of cerebral venous thrombosis Causes of CVT are diverse. According to the hypothesis of Rudolf Vichow: there are 3 basic factors contributing in the formation of venous thrombosis: venous congestion; hypercoagulable state; vascular injuries. Most of the main factors causing thrombosis are venous congestion and hypercoagulable state. 3 1.2. CLINICAL Clinical symptoms of CVT are diverse, non-specific and the symptom onset in cerebral venous thrombosis is usually subacute (2 days to 1 month), in some cases it can be acute (2 days or less) and simulate arterial stroke (20-30%). In patients presenting isolated intracranial hypertension like brain tumor, the onset of symptoms an be chronic. Depending on the location of the thrombosis and the collateral blood flow, and patient’s age, the range of clinical symptoms associated with cerebral venous thrombosis is astonishingly varied, and its clinical presentation is extremely variable and unspecific. The progression of deep CVT may be gradually severe or variable depending on the status of intracranial pressure with or without accompanied seizures. Besides, CVT is often symmetry and hemorrhagic transformation of the lesion is quite frequent 1.3. LABORATORYL 1.3.2. Magnetic resonance imaging 1.3.2.1. Magnetic resonance imaging (MRI) Magnetic resonance imaging in combination with magnetic resonance venography (MRV) imaging provide a best non-invasive technique for the diagnosis of CVT which is considered as a gold standard and can replace invasive conventional cerebral angiography and is used as a leading mean of diagnosis in case with clinical suspicion of cerebral venous thrombosis. Advantages of magnetic resonance imaging are it can survey the blood flow and allow us to 4 see the direct imaging of the venous sinous thrombosis and brain parenchymal injuries. 1.3.4. D-dimer in diagnosis of cerebral venous thrombosis 1.3.4.1. Biochemical characteristics of D-dimer D-dimer, the final product of plasma in-mediated degradation of fibrin-rich thrombi. It is a small protein chain in blood after a clot is fibrinated. After the formation of a clot, the hemolytic path is triggered with plasminogen is activated to plasmin. Then plasmin cut fibrin at E-D bonds to form separate D-D segments called Ddimer (2D). 1.4. RISK FACTORS These risk factors are often related to Virchow's triad. The markers such as: antithrombin, protein C, protein S, V Leiden factor or activated protein C are considered as point markers of congenital thrombophilia. The deficiency of antithrombin (AT), protein C (PC) or protein S (PS) or the present of V Leiden factor (FVL) will increase the risk of thrombosis, each factor is listed hereunder. Chapter 2: SUBJECTS AND METHODS OF THE STUDY 2.1. SUBJECTS OF THE STUDY 2.1.1. Group of patients with cerebral venous thrombosis We chose patients ≥ 16 years old who had been diagnosed with CVT at the Department of Neurology, Cho Ray Hospital from January 2010 to May 2012 based on the following inclusion criteria: INCLUSION CRITERIA patients had all criteria as follows: a) Clinically suspected to have CVT: when the patients got one of the following criteria: 5 - Abnormal headache with acute, subacute or chronic onset and a history did not relate to cluster headache, migraine - headache or muscle tension headache. Atypical headache accompanying vomiting and did not - reponse to conventional treatment methods. Clinical signs of brain injury (focal neurological signs, - seizures, disorders of consciousness). Images of ischemic stroke on computerized tomography film showed atypically distribution along cerebral artery. b) Found images of CVT by using routine magnetic resonance imaging in combination with magnetic resonance imaging of vein and/or routine magnetic imaging in combination with computerized tomography of cerebral vein and/or cerebral angiography with DSA technique. EXCLUSION CRITERIA 1. Patients using anticoagulants. 2. Patients were diagnosed with deep vein thrombosis or pulmonary embolism and/or calf vein thrombosis. 3. Patients with signs of disseminated intravascular coagulation. 4. Patients had experienced major surgery or severe trauma within 3 months. 5. Patients did not agree to participate in the study. 2.1.2. Control group We chose 57 people who came for periodic health examination at Cho Ray Hospital and they voluntarily participated in 6 the study. All these cases were carefully clinically examined and tested. Protein S, Protein C, ATIII, V Leiden factor, D-dimer. 2.2. METHODS OF THE STUDY This is a prospective, cross-sectional descriptive study with control group. 2.2.1. Clinical study All patients were clinically evaluated risk factors according to a common data collection form and were treated according to a unique regime at the Department of Neurology, Cho Ray Hospital. 2.2.2. Subclinical study All patient with clinical signs of CVT were examined the MRI tests: - Investigation on features of CVT images using magnetic - resonance imaging. Investigation on rick factor protein S. Investigation on risk factor protein C. Investigation on ATIII risk factor. Investigation on V Leiden risk factor. Investigation on blood D-dimer concentration. Chapter 3 - RESULTS OF THE STUDY 3.1. SOME GENERAL CHARACTERISTICS OF PATIENTS There were 59 patients with cerebral venous thrombosis (experimental group) and 57 people in the control group. The 7 male/female ratio in the experimental group was 1/0.78, and in the control group was 1/0.72. The percent of patients aged 21 to 50 accounted a majority of both groups, wherein, the experimental group had 47 patients (82.46%), and the control group had 41 patients (71.93%). The percent of patients aged less than 20 was mostly equivalent between both groups (6.78% vs 7.02%). In the experimental group, the percent of patients with subacute onset was 79.7%, patients with acute onset was 11.8% and patients with chronic onset was 8.5%. 3.2. CLINICAL CHARACTERISTICS 3.2.1. Symptoms Table 3.7: Clinical symptoms on admission Symptom Number of patients Percent (%) Headache 58 98.31 Motor deficit 34 57.63 seizures 30 50.85 Altered consciousness 22 37.29 Cranial nerve palsy 19 32.2 Papilledema 18 30.5 Sensorial deficit 5 8.47 Aphasia 5 8.47 Meningeal signs 3 5.08 Vertigo 3 5.08 3.3. IMAGING CHARACTERISTICS 3.3.2. Location of cerebral venous thrombosis Table 3.16: Characteristics on location of cerebral venous thrombosis of 57 patients tested by magnetic resonance imaging 8 Location Number of Percent (%) patients Superior sagittal sinus 43 75.44 Transverse sinus 37 64.91 Sigmoid sinus 36 63.1 Inferior sagittal sinus 3 5.26 Cavernous sinus 2 3.51 Straight sinus 8 14.04 Deep cerebral veins 4 7.02 Internal jugular veins 5 8.77 Cortical veins 23 40.35 ≥ 2 veins had blood clots 41 71.93 Comment: The location of cerebral veins mostly affected by thrombosis on the images obtained by magnetic resonance imaging was superior sagittal sinuses with 43 cases (75.54%), next to transverse sinuses with 37 cases (64.91%). 3.3.3. Brain parenchymal abnormalities on magnetic resonance imaging Among 57 patients with CVT, patients with hemorrhagic transformation accounted the highest percent (36.84%), followed by patients with infarction alone (22.81%), and hemorrhage (21.05%). Subarachnoid hemorrhage accounted smallest percent (10.53%). 3.4. RISK FACTORS OF CVT 3.4.1. Risk factors of primary thrombophilia Table 3.20: Prevalence of primary thrombophilia Risk factors Protein S Protein C Number of patients 16/53 14/57 Percent (%) 30.2 24.5 9 ATIII 11/57 19.3 V Leiden factor 23/47 48.9 ≥ 2 risk factors 29/57 33.3 ≥ 3 risk factors 5/56 8.9 4 risk factors 0 3.4.2. Factors of acquired thrombophilia 0 Table 3.25: Status of administration with oral contraceptive drugs in female patients contraceptiv Number of patients Experimental group Control group e drugs Yes 10 3 No 23 28 Total 33 31 2 = 4.2; p = 0.04; OR = 4.05 (CI 95%, 0.88-25.1) Total 13 51 64 Table 3.26: Status of pregnancy in female patients Pregnancy Yes No Total Number of patients Experimental group Control group 1 0 32 27 33 27 2 = 1.06 ; p = 0.361 Total 1 59 60 Comment: There was no statistically significant difference on CVT between pregnancy group and non-pregnancy group with p = 0.361. Table 3.27: Puerperium characteristics on female patients Puerperium Yes No Total Number of patients Experimental group Control group 8 0 25 27 33 27 Total 8 52 60 10 2 = 7.5 ; p = 0.006 Comment: There was a statistically significant difference on number of patients with CVT between Puerperium group and control group. 3.5. CHARACTERISTICS OF D-DIMER TEST 3.5.1. Comparison of mean D-dimer concentration between two groups Table 3.29: D-dimer concentration (µg/L) of patients D-dimer(µg/L) Mean value Standar deviation Number of Experimental group 1890.92 309.03 Control group 146.19 15.55 58 57 investigated patients KTC 95% 1272.5 - 2509 115.03 - 177.35 Non-uniform variance T-test t = -5.63; p = 0.000 3.5.3. Identify the cut off of D-dimer test Table 3.31: Cut off of D-dimer concentration Cut off (µg/L) Sensitivity Specificity PPV (%) NPV (%) Area under ROC ≥256 93.1 80.7 83.08 92 0.869 ≥280 93.1 82.46 84.38 92.16 0.877 ≥302 91.33 89.47 89.83 91.07 0.904 ≥424 79.3 98.25 97.87 82.35 0.887 ≥502 74.14 98.25 97.73 78.87 0.861 ≥604 62.07 98.25 97.3 71.79 0.801 Chapter 4 - DISCUSSION 4.1.SOME GENERAL CHARACTERISTICS OF PATIENTS 11 In all 59 cases with CVT, we diagnosed based on clinical criteria and had CVT images obtained using magnetic resonance imaging, computerized tomography and DSA. Sex In our study, the percent of female patients with CVT was higher than percent of male patients with CVT (55.93% vs 44.7%), with the female/male ratio was 1/0.78. According to the study of Tanislav, among 39 patients with CVT, the percent of female patients was significantly higher than the percent of male patients (71% vs 29%). According to the study of Khealani, among 109 patients, the percent of female patients was higher than the percent of male patients (53% vs 47%). Overall, our study was similar to other studies of other authors with the percent of female patients with CVT was higher than the percent of male patients, especially female patients in childbearing age, this suggested that the risk of CVT may relate to pregnancy, puerperium and birth control drugs. Age Mean age of patients in our study was 37.8, wherein percent of patients aged from 21 to 50 was 82.46%, percent of patients aged > 50 was 13.56%. According to the study of Nguyen Ngoc Hung on 37 patients with CVT, the mean age was 38.7. A retrospective study on 48 patients with CVT of Terazzi et al. in 2004 showed that the mean age 12 of CVT patients was 44.8. According to the study of Ferro, in 624 patients with CVT, there was 92.8% of patients < 65 years old. Thus, according to above stated studies, the mean age of adult patients with CVT was 32.7 to 44.8. Result of mean age in our study was also withing this range and was not significantly different to other studies of other authors worldwide. Onset time and diagnosis time In our study, the number of patients with subacute onset accounted the highest percent (79.7%) followed by acute onset. According to Paciaroni, onset of CVT is commonly subacute (2 days to 1 month) with 50-80% of all cases, but sometimes it suddenly occurs with acute onset (< 2 days) like stroke (20-30% of all cases). In some cases, the clinical symptoms of CVT are similar to cerebral tumors, and there are few cases CVT occurs with clinical signs are increased intracranial pressure, and chronic symptoms at the onset (>1 month), 10-20%. According to the study of Terazzi, in 48 patients with CVT, the percent of patients with acute onset was 44%, subacute onset was 35% and chronic onset was 21%. In general, the onset characteristics of CVT are varied, but the majority of patients have cubacute onset and our study data was equivalent to the result of Paciaroni's study. 4.2. CLINICAL CHARACTERISTICS 4.2.1. Symptoms and onset time Headache: In our study, the headache was most common with a rate of 98.31% of all cases. This result is similar to the result 13 of the study of Le Van Thinh and Trinh Tien Luc with headache accounted 88%. In general, it is like other studies of other authors, headache was most common and presented with highest rate in these studies. Paraparesis: Similar to results of other studies of other authors, our study found that the symptom of paraparesis ranked the 2nd position after headache with a percent of 57.63%. Signs of this symptom were mainly 4th degree (25.5%), 3rd degree (13.5%), 2nd degree (10.6%). According to the study of Tanislav et al., this symptom also ranked the 2nd position after headache (69%) with a rate of 44%. In general, the percent of patients with paraparesis symptom in our study was equivalent to results from others studies of other authors and the similar point is this symptom ranked that 2nd or 3rd position among other clinical signs. Seizures: In our study, the percent of seizures symptom ranked a 3rd position after headache and paraparesis. According to the study of Le Van Thing and Trinh Tien Luc, seizures symptom accounted 32%, ranked the 3rd position after headache and cranial nerve paralysis. According to the study of Ferro, seizures symptom accounted 39% in patients < 65 years old, and 45% in patients >= 65 years old. Consciousness disorders: In our study, percent of patients with consciousness disorcers accounted 37.29%, ranked the 4th position among other symptoms. Wherein, mild consciousness disorders was most common with 30.5% while severe consciousness disorders accounted 6.8%. According to the study of Bruijin in 59 14 patients with CVT (equal to the number of patients in our study), the percent of patients with consciousness disorders was 39%. Wherein, mild consciousness disorders accounted 23.7%, and severe symptom accounted 15.3%. Overall, the percent of CVT patients with consciousness disorders symptom in the studies of domestic and foreign authors was not as high as other symptoms, from 21% to 39%, the percent of our study was within this range and similar to results of other authors. Cranial nerve palsy: In our study, the percent of patients with cranial nerve palsy was 32.2%. According to the study of Le Van Thinh and Trinh Tien Luc, the percent of patients with cranial nerve palsy was 48%. According to the study of Paciaroni, the percent of patients with cranial nerve palsy was 12%, this symptom commonly occurred in III, IV, V, VI, VII, VIII, IX, X and XI.These nerves could be injured separately or link to other nerves. Almost authors did not recognize cranial nerve analysis in their studies, might be due to small sample size then they only recognized that patients had focal neurological dificits, such as in the study of Fink, this author only general recorded that 60% of patients had focal neurological dificits. Overall, the cranial nerve palsy symptom on patients with CVT was not as common as other symptoms and accounted from 12% to 48%, the percent in our study was 32.2%. Papilledema: According to the results of our study, the percent of patients with papilledema was 30.5%. This symptom varied depending on studies of other authors (table 4.39). According to the study of Stolz, papilledema accounted 40%. According to the 15 study of Ferro, among 624 patients there was only 29% of patients < 65 years old and 14% of patients ≥ 65 years old had this symptom, ranked after headache and positioning nerve sign and seizures. Overall, the percent of patients with papilledema in our study was smaller than results from studies of other authors, this could be due to the percent of patients exhibited increased cranial pressure in our study was higher than results from studies of other authors. 4.3. IMAGING CHARACTERISTICS 4.3.2. The location of the venous sinous thrombosis Because in our study patients were diagnosed by magnetic resonance imaging then we only discuss and compare our study results to other authors based on this group (57 patients). The location of the venous sinous thrombosis system which was highest percent was superior sagittal sinuses (75.54%), followed by transverse sinuses (64.91%), sigmoid sinuses (63.1%), and cortical veins (40.35%). The remaining veins and sinus were less common such as: straight sinuses 14.4%, juglar veins 8.77%, deep cerebral veins 7.02%, inferior sagittal sinuses 5.26% (3 cases), cavernous sinuses 2% (2 cases). The number of patients with ≥ 2 veins or sinouses thrombosis accounted 41/57 cases (71.93%). According to the study of Zubkov, among 59 patients diagnosed by routine magnetic resonance imaging in combination with magnetic resonance veinography, there were 34% (19 cases) of all patients had images of brain parenchymal injuries on the magnetic resonance images and this author compared the percent of patients 16 with thrombisis on 2 groups of patients. Among patients with brain parenchymal injuries, thrombosis were most common in transverse sinuses with 78.9% (15 cases), followed by superior sagittal sinuses 57.8% (11 cases), sigmoid sinuses 47.3% (9 cases), straight sinuses 26.3% (5 cases), Galen veins 26.3% (5 cases), other position thrombosis were not significant. Among 37 patients without cerebral injuries, blood clots were most common in veins of transverse sinuses with 86.4% (32 cases), sigmoid sinuses 43.2% (16 cases), superior sagittal sinuses 24.3% (9 cases), straight sinuses 8.1% (3 cases). Overall, we recognized that: Location of thrombosis occurred with highest percent in superior sagittal sinuses (36% to 97.8%); followed by transverse sinuses and sigmoid sinuses (43% to 83%); cortical veins accounted a high varied percent range (3% to 43.2%), this might be due to the previous studies did not apply GRE pulse sequence then the possibility of false negative results was relatively high. Percent of straight sinuses with blood clots ranged from 8.1% to 34.4%; deep cerebral veins ranged from 7.02% to 25.3%. Other rare veinous sinouses thrombosis were not mentioned in studies of other authors are cavenous sinuses, inferior sagittal sinuses and jugular veins. In most cases, when occurred CVT, cases with just one vein or sinous thrombosis were rare, percent of cases with ≥ 2 position thrombosis ranged from 54.7% to 71.93%. Thus, percent of venous sinous thrombosis in our study was within the range of other authors. 17 4.3.3. Brain parenchymal abnormalities on magnetic resonance imaging Based on the images obtained by magnetic resonance imaging, we found that the percent of patients with CVT accompanied parenchymal injuries was 84.21%, hemorrhagic infarction accounted a highest percent 36.84%, followed by infarction (22.81%); parenchymal hemorrhage 21.05%, subarachnoid hemorrhage 10.53%. According to the results from the study of Terazzi in 48 patients with CVT, among 44 patients were tested by computerized tomography, there were 9 cases (21%) suspected to have CVT (empty Delta sign, rope sign), 11 patients (25%) were completely normal on imeges of computerized tomography, 24 patients (55%) had signs of cerebral hemorrhage or ischemic injuries. Among 19 patients were tested again by computerized tomography, there were 5 cases had signs of CVT. Also, in this study, there were 42 cases diagnosed with CVT by magnetic resonance imaging, wherein 12 cases (29%) had signs of CVT alone, 15 cases (36%) related to parenchymal hemorrhage and infarction. 12 cases (29%) had parenchymal hemorrhage or infarction alone. Overall, by comparing to results of studies of domestic and foreign authors, we found that our study results were relatively equivalent to results of other authors. Wherein, percent of patients with infarction ranged from 19.4% to 70%; parenchymal hemorrhage ranged from 10.2% to 57%; subarachnoid hemorrhage ranged from 18 8% to 10.53%. However, percent of patients with subarachnoid hemorrhage in our study was higher than results from other studies, this might be due to the diversity of injuries in CVT. 4.4. RISK FACTORS OF CEREBRAL VENOUS THROMBOSIS 4.4.1.Factors of primary thrombophilia According to results of our study, in patients with primary thrombophilia, V Leiden factor accounted the highest percent, followed by decreased protein S, decreased protein C, decreased ATIII. Compared to control group, we found that OR of protein C was highest, followed by V Leiden factor, ATIII. We could not calculate OR of protein S because there was no case with decreased protein S in control group. According to the study of Bombeli [10], when analyzed 51 patients with CVT among 260 patients with venous thrombosis (cerebral veins, portal veins, retinal veins, upper limb veins, lower limb vein) and 120 healthy controls, he recognized that V Leiden factor accounted the highest percent 13.7% with OR 2.1 (CI 95%: 0.7-6), percent of decreased protein S was 2% with OR 2.4 (CI 95%: 0.1-38.3); percent of decreased protein C and ATII was 2%, he could not calculate OR of protein C and ATIII due to limitation of sample size. According to the study of Martinelli in 121 patients with CVT, the percent of V Leiden factor was highest with OR = 4.7 (CI 95%: 1.8-11.8), followed by decreased protein C, decreased protein S and decreased ATIII. Due to limitation of sample size then the author
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