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 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. 1 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 2 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. 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) 3 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 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 D-dimer (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. 4 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: - 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. 5 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 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: 6 - 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 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 7 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 Location Number of patients Percent (%) 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 8 [...]... in studies of Kosinski (1286), Crassard (938), and Ghaffarpour (920) Overall, the difference in D- dimer concentration of our study to studies of other authors might be due to the following reasons: First, because the nature of D- dimer concentration is to indirectly evaluate the fibrin breakdown of thrombosis, while clinical characteristics of thrombosis are varied then D- dimer concentration also varying... The study of Ghaffarpour obtained low sensitivity (83.1%) as compared to other authors in table 4.43 and specificity was 95.2% respectively In summary, due to the epidemiological, clinical and imaging characteristics of CVT are very varied and the D- dimer concentration fluctuates greatly because it depends on many factors as mentioned then it's hard to avoid the difference of diagnostic cut off between... followed by decreased protein C, decreased protein S and decreased ATIII Due to limitation of sample size then the author calculated general OR = 6 for 3 factors decreased protein C, decreased protein S and decreased ATIII Thus, percents of factors of primary thrombophilia in our study were higher than results of other studies of domestic and foreign authors, this may relate to recial characteristics of Asians... 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... 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 of the study of Le Van Thinh and Trinh Tien Luc with headache accounted 88% In general,... varying greatly; second, CVT is a rare disease then sample sizes in these studies were not large enough leading to representative for patients was not high; third, D- dimer concentration may change depending on patient's age, testing time, accompanied diseases and used techniques 4.5.2 Identify the cut off of D- dimer test 23 In our study, as showed in table 3.35, the cut off of Ddimer concentration (µg/L)... limitation of sample size 21 According to the study of Tran Thanh Tung, among 21 female patients with deep vein thrombosis, the percent of patients related to administration of oral contraceptive drugs was 13.8%, percent of abortions was 10.3%, no case was recognized as relating to pregnancy and hormone replacement therapy According to the study of Dentali, this was a meta-study of previous studies,... 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 study of Ferro, among 624 patients there was only 29% of patients < 65 years old and 14% of patients ≥ 65 16 years old had this symptom, ranked after... OF THE AUTHOR’S PUBLISHED INVESTIGATIONAL WORKS RELATING TO THE THESIS 1 2 Le Van Minh, Phan Viet Nga, Pham Ngoc Hoa, Tran Thanh Tung (2013), “study the value of d- dimer measurement in diagnosis of cerebral venous thrombosis , Journal of Viet Nam Medicine, 408(1), PP.90-95 Le Van Minh, Phan Viet Nga, Pham Ngoc Hoa, Tran Thanh Tung (2013), “study clinical features and some risk factors of cerebral venous. .. CHARACTERISTICS OF PATIENTS 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 12 study of Tanislav, among 39 patients . 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. 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. 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