INVESTIGATION ON CLINICAL FEATURES, BRAIN IMAGING, a NUMBER OF RIKS FACTORS AND THE VALUE OF d DIMER IN DIAGNOSIS OF CEREBRAL VENOUS THROMBOSIS

CLINICAL Clinical symptoms of CVT are diverse, non-specific and thesymptom onset in cerebral venous thrombosis is usually subacute2 days to 1 month, in some cases it can be acute 2 days

AND TRAINING DEFENCE

MILITARY MEDICAL UNIVERSITY

LE VAN MINH

INVESTIGATION ON CLINICAL FEATURES, BRAINIMAGING, 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

MEDICAL UNIVERSITY

Supervisors:

A.Prof Dr PHAN VIET NGA

A Prof Dr.PHAM NGOC HOA

Cerebral venous thrombosis (CVT) is estimated to accountfor 0.5% of all strokes in adults In recent years, with the present ofnon-invasive and high accuracy diagnostic techniques such asmagnetic resonance imaging and computed tomography, the rate ofdiagnosis of CVT also increases

Congenital Thrombophilia states account a high rate in whiteskin peoples and make up 15-30% cases of patients with venousthrombosis D-dimer test is an inexpensive and commonly availablemethod which has high performance in diagnosis of CVT as proven

by some prospective and meta-analytic studies Moreover, at presentthere is no published study on the role of D-dimer test in thediagnosis of CVT in our country

In Vietnam, there have been many studies on aspects ofstroke However, there are few studies on CVT, therefore wedecided 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 valueand negative predictive value of D-dimer test in the diagnosis ofCVT

NEW CONTRIBUTION OF THE THESIS

1 Our study described some clinical features and brain images ofCVT

2 Our study found some genetic and acquired risk factors of CVT

3 Our study successfully determined the role of D-dimer test in thediagnosis of CVT

The thesis includes 115 pages, with 4 chapters, 43 tables, 16 charts,

1 diagram, 8 Vietnamese references and 83 English references 3 pagesforewords, 35 pages overview, 19 pages subjects and methods, 24pages results, 31 pages discussion, 2 pages conclusion, 1 pagerecommendations

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 thinwalls 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 thedura and drain into the cranial venous sinuses Blood from bothbrain is drained by cerebral veins into dural sinuses and then intothe jugular Cerebral veins is divided into 3 important groupswhich are superfical cerebral veins, deep cerebral veins andposterior fossa veins

1.1.3 Pathogenesis of cerebral venous thrombosis

Causes of CVT are diverse According to the hypothesis ofRudolf Vichow: there are 3 basic factors contributing in theformation of venous thrombosis: venous congestion; hypercoagulablestate; vascular injuries Most of the main factors causing thrombosisare venous congestion and hypercoagulable state

1.2 CLINICAL

Clinical symptoms of CVT are diverse, non-specific and thesymptom 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 isolatedintracranial hypertension like brain tumor, the onset of symptoms an

be chronic Depending on the location of the thrombosis and thecollateral blood flow, and patient’s age, the range of clinicalsymptoms associated with cerebral venous thrombosis isastonishingly varied, and its clinical presentation is extremelyvariable and unspecific The progression of deep CVT may begradually severe or variable depending on the status of intracranialpressure with or without accompanied seizures Besides, CVT isoften symmetry and hemorrhagic transformation of the lesion is quitefrequent

1.3 LABORATORYL

1.3.2 Magnetic resonance imaging

1.3.2.1 Magnetic resonance imaging (MRI)

Magnetic resonance imaging in combination with magneticresonance venography (MRV) imaging provide a best non-invasivetechnique for the diagnosis of CVT which is considered as a goldstandard and can replace invasive conventional cerebral angiographyand is used as a leading mean of diagnosis in case with clinicalsuspicion of cerebral venous thrombosis Advantages of magneticresonance imaging are it can survey the blood flow and allow us to

see the direct imaging of the venous sinous thrombosis and brainparenchymal 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 aclot is fibrinated After the formation of a clot, the hemolytic path

is triggered with plasminogen is activated to plasmin Then plasmincut fibrin at E-D bonds to form separate D-D segments called D-dimer (2D)

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 diagnosedwith CVT at the Department of Neurology, Cho Ray Hospital fromJanuary 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 ofthe following criteria:

- Abnormal headache with acute, subacute or chronic onsetand a history did not relate to cluster headache, migraineheadache or muscle tension headache

- Atypical headache accompanying vomiting and did notreponse to conventional treatment methods

- Clinical signs of brain injury (focal neurological signs,seizures, disorders of consciousness)

- Images of ischemic stroke on computerized tomography filmshowed atypically distribution along cerebral artery

b) Found images of CVT by using routine magnetic resonanceimaging in combination with magnetic resonance imaging ofvein and/or routine magnetic imaging in combination withcomputerized tomography of cerebral vein and/or cerebralangiography with DSA technique

EXCLUSION CRITERIA

1 Patients using anticoagulants

2 Patients were diagnosed with deep vein thrombosis orpulmonary embolism and/or calf vein thrombosis

3 Patients with signs of disseminated intravascular coagulation

4 Patients had experienced major surgery or severe traumawithin 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 healthexamination at Cho Ray Hospital and they voluntarily participated inthe study All these cases were carefully clinically examined andtested Protein S, Protein C, ATIII, V Leiden factor, D-dimer

2.2 METHODS OF THE STUDY

This is a prospective, cross-sectional descriptive study withcontrol 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 aunique regime at the Department of Neurology, Cho Ray Hospital

- 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 Themale/female ratio in the experimental group was 1/0.78, and in thecontrol group was 1/0.72

The percent of patients aged 21 to 50 accounted a majority ofboth groups, wherein, the experimental group had 47 patients(82.46%), and the control group had 41 patients (71.93%) Thepercent of patients aged less than 20 was mostly equivalent betweenboth groups (6.78% vs 7.02%) In the experimental group, thepercent of patients with subacute onset was 79.7%, patients withacute 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 (%)

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

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 Number of patients Percent (%)Protein S

30.224.519.348.933.38.90

3.4.2 Factors of acquired thrombophilia

Table 3.25: Status of administration with oral contraceptive drugs in

female patientscontraceptiv

e drugs

Experimental group Control group

2 = 4.2; p = 0.04; OR = 4.05 (CI 95%, 0.88-25.1)

Table 3.26: Status of pregnancy in female patients

Experimental group Control group

2 = 1.06 ; p = 0.361 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

Experimental group Control group

Yes 8 0 8

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) Experimental group Control group

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) ≥256 ≥280 ≥302 ≥424 ≥502 ≥604Sensitivity 93.1 93.1 91.33 79.3 74.14 62.07Specificity 80.7 82.46 89.47 98.25 98.25 98.25

PPV (%) 83.08 84.38 89.83 97.87 97.73 97.3

Area under ROC 0.869 0.877 0.904 0.887 0.861 0.801

Chapter 4 - DISCUSSION

4.1.SOME GENERAL CHARACTERISTICS OF PATIENTS

In all 59 cases with CVT, we diagnosed based on clinicalcriteria and had CVT images obtained using magnetic resonanceimaging, computerized tomography and DSA

Sex

In our study, the percent of female patients with CVT washigher 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 ofTanislav, among 39 patients with CVT, the percent of female patientswas significantly higher than the percent of male patients (71% vs29%) According to the study of Khealani, among 109 patients, thepercent of female patients was higher than the percent of malepatients (53% vs 47%)

Overall, our study was similar to other studies of otherauthors with the percent of female patients with CVT was higher thanthe percent of male patients, especially female patients inchildbearing age, this suggested that the risk of CVT may relate topregnancy, 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 patientswith CVT, the mean age was 38.7 A retrospective study on 48patients with CVT of Terazzi et al in 2004 showed that the mean age

of CVT patients was 44.8 According to the study of Ferro, in 624patients with CVT, there was 92.8% of patients < 65 years old

Thus, according to above stated studies, the mean age ofadult patients with CVT was 32.7 to 44.8 Result of mean age in ourstudy 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 onsetaccounted 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 suddenlyoccurs with acute onset (< 2 days) like stroke (20-30% of all cases)

In some cases, the clinical symptoms of CVT are similar to cerebraltumors, and there are few cases CVT occurs with clinical signs areincreased intracranial pressure, and chronic symptoms at the onset(>1 month), 10-20% According to the study of Terazzi, in 48patients with CVT, the percent of patients with acute onset was 44%,subacute onset was 35% and chronic onset was 21% In general, theonset characteristics of CVT are varied, but the majority of patientshave cubacute onset and our study data was equivalent to the result ofPaciaroni's study

4.2 CLINICAL CHARACTERISTICS

4.2.1 Symptoms and onset time

Headache: In our study, the headache was most commonwith 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 headacheaccounted 88% In general, it is like other studies of other authors,headache was most common and presented with highest rate in thesestudies.

Paraparesis: Similar to results of other studies of otherauthors, our study found that the symptom of paraparesis ranked the2nd position after headache with a percent of 57.63% Signs of thissymptom were mainly 4th degree (25.5%), 3rd degree (13.5%), 2nddegree (10.6%) According to the study of Tanislav et al., thissymptom also ranked the 2nd position after headache (69%) with arate of 44% In general, the percent of patients with paraparesissymptom in our study was equivalent to results from others studies ofother authors and the similar point is this symptom ranked that 2nd or3rd position among other clinical signs

Seizures: In our study, the percent of seizures symptomranked a 3rd position after headache and paraparesis According tothe study of Le Van Thing and Trinh Tien Luc, seizures symptomaccounted 32%, ranked the 3rd position after headache and cranialnerve paralysis According to the study of Ferro, seizures symptomaccounted 39% in patients < 65 years old, and 45% in patients >= 65years old

Consciousness disorders: In our study, percent of patientswith consciousness disorcers accounted 37.29%, ranked the 4thposition among other symptoms Wherein, mild consciousnessdisorders was most common with 30.5% while severe consciousness