INTRODUTION

                Cerebral venous thrombosis (CVT) is an infrequent variety of cerebrovascular disease with a wide spectrum of clinical presentations and modes of onset leading to great diagnostic difficulties. The most frequent symptom is headache, which may be isolated but is more commonly associated with other signs such as focal deficits, seizures, disorders of consciousness, and papilledema, which occur in highly variable combinations^{1, 2, 3}. Because of this great variability, CVT is frequently clinically suspected but confirmed only rarely by the expensive neuroimaging investigations including Magnetic resonance venography (MRV) which is considered the gold standard for its diagnosis¹. Therefore, it would be of great practical interest to have a test that would be easy to perform in emergency care and would confidentially rule out CVT⁴.

Plasma D-dimer is a marker of endogenous fibrinolysis, being cross-linked fibrin degraded by plasmin, may be a good candidate for the diagnostic approach of CVT⁴, Particularly on emergency basis, because of its well established usefulness in the diagnosis

of deep venous thrombosis. High D-dimer values are very sensitive markers for deep venous thrombosis and pulmonary thromboembolism whereas low values (<500 ng/mL) have a high negative predictive value^{5, 6}. However some debate surrounds the usefulness of D-dimer in the diagnosis or the exclusion of CVT^{7, 8,9,10}.

                Thus, the aim of this study is not only to establish the usefulness of D-dimer assessment in diagnosis of CVT but also to detect if negative D-dimer assay confidentially rules it out.

PATIENTS AND METHODS

Twenty one consecutive patients with definite cerebral venous sinus thrombosis with mean age 36.2±11.9 years, 8 male and13 females, were selected to be enrolled in this study out of 104 patients presented with acute headache in the emergency unit of neurology department of Zagazig University hospitals during the period from August 2006 to July 2009. The remaining 83 patients were considered as a control group. 

Careful medical history was obtained including history of oral contraceptive pills (OC) intake, previous thromboembolic events, or other risk factors for developing CVT such as pregnancy, puerperium, malignancy, infections and dehydration. Only patients admitted within 30 days of symptoms onset and had a D-dimer measurement at entry, before starting heparin or other anticoagulant therapy were included.

All patients were subjected to the following:

A)     Full history with complete general and neurological examination focusing on; headache either isolated or with symptoms of increased intracranial pressure (nausea/vomiting, papilledema, visual disturbance, disturbance of consciousness), focal motor deficit, cranial nerve palsy, or seizure. The patients were clinically subdivided into three subgroups namely those with isolated headache, intracranial hypertension or encephalic signs.

B)     All cases underwent cerebral MRI using (0.5 TESLA GENERAL ELECTRIC SIGMA CONTOUR SYSTEM). Positive MRI brain images were defined according to the site, extent, and nature of the abnormality.  The three dimensional time of flight (3D-TOFL) magnetic resonance vengoraphy (MRV) technique was used. In the TOF MR vengoraphy gradient echo sequence with flow compensation was used with the following parameters: Repetition time = 30-70 msec, time to echo= 4-10 msec, flip angle = 25-45, number of excitation 1-2, field of view 18-22 cc, matrix size 256 x 256 and slice thickness 0.8-1 mm. Reconstruction was done using maximum intensity projection algorithm in multiple planes.

C)     D-dimer levels were measured at entry using Liatest (Diagnostica Stago), a rapid and sensitive assay^6,11,12 Blood plasma was separated, frozen at –80°C, and sent on dry ice to the study center. This test has been validated for exclusion of deep venous thrombosis, pulmonary embolism as well as CVT with an exclusion cut-off value of 500 ng/mL^{9,10,13,14,15}.

Statistical Analysis

                SPSS software and Epi info 2000 were applied for statistical analysis. Student t test, chi square and Fisher exact test were used for evaluation of variables relationship with CVT occurrence. The sensitivity, specificity, negative and positive predictive values were calculated by Fisher exact test. To assess agreement between the diagnostic capacities of D-dimer test and radiologically confirmed diagnosis, kappa statistic was applied.

RESULTS

The characteristics of the patients included in this study were; Six (28.5%) patients with isolated headache, Five (23.8%) with isolated intracranial hypertension, and encephalic signs were found in Ten (47.5%) patients concerning the site of thrombosis according To MRI and MRV; single sinus involvement was found in 15 patients (71.4%) (Lateral sinus: 7, Superior sagittal sinus: 6; and straight sinus: 2 patients), multiple sinus involvement was found in 6 patients (28.6%) Parenchymal lesions were found in (3) (14.3%) patients (venous infarction or edema in (2) patients) and parenchymal hemorrhage in one patient. Figure 1 shows cerebral MRV showing superior sagittal sinus thrombosis.

Risk factors were reported as follows  pregnancy and postpartum (obstetric causes) 5 patients, systemic diseases and malignancies 3 patients, infections 3 patients, dehydration 2, oral contraceptive pills intake 6 and no risk factors were found in 2 patients. (Table1)

                The mean D-dimer values were significantly higher in patients with CVT (1290±410) compared with patients without CVT (375±215) (p<0.05) (Table 2).

                The D-dimer level was +ve in (85.7%) of patients with CVT and in (14.5%) of patients without CVT and this was statistically significant (p<0.05). Agreement between D-dimer test with final diagnosis with Kappa statistic (Kappa value =0.61, p value = 0.000); sensitivity = 85.7% specificity = 85.5%, Negative predictive value = 95.9%, positive predictive value =60% (p<0.05) (Table 3).

                The relation between (-ve) D- dimer value and patients characteristics revealed that a negative D-dimer was more in younger age group of less than 35 years (18.1%) compared with older group(10%) and in females(15.3%) more than males (12.5%), but the difference did not reach a significant level. Isolated headache was significantly correlated with a negative D-dimer level. Among 6 patients with isolated headache 3 (50%) had a negative D-dimer level <500 ng/ml (p<0.05).Two patients with a negative D-dimer had history of  headache of more than 7 days duration suggesting a possible correlation between the duration of the disease and negative D-dimer level. Negative D-dimer was found in (20%) of patients with one sinus involvement as well as in those without parenchymal involvement on first neuroimaging study (Table 4).

Table 1. Characteristics of CVT Patients included in this study.

CVT cerebral venous thrombosis, MRI magnetic resonance imaging, MRV magnetic resonance venography, SD standard deviation

Data are expressed as mean (standard deviation)

Table 2. Mean values of D-dimer in patients with and without CVT.

CVT cerebral venous thrombosis, SD standard deviation

* Significant at p< 0.05.

Table 3. The D-dimer values in patients with and without CVT.

CVT cerebral venous thrombosis

* Significant at p< 0.05.

Table 4. Relation Between negative D-dimer values and the characteristics of patients with CVT.

CVT cerebral venous thrombosis, MRI magnetic resonance imaging, MRV magnetic resonance venography

* Significant at P value < 0.01.

Figure 1. Cerebral MRV showing superior sagittal sinus thrombosis.

DISCUSSION

The diagnosis of cerebral venous thrombosis (CVT) is a challenge because its clinical presentation is variable, brain CT may be normal, and MRI can not be used on emergency basis. A specific challenge for early diagnosis of CVT is patients who present with headaches that are not accompanied by any focal neurological abnormalities, in one series, 20 out of 35 patients having CVT, focal neurological signs were absent¹⁰. Because measurement of D-dimer "a marker of endogenous fibrinolysis" has been demonstrated to be helpful in excluding deep vein thrombosis and pulmonary thromboembolism, the aim of this study is to investigate whether D-dimers would be also sensitive enough to diagnose or exclude CVT. In the present series of 21patients with a recent CVT, 85.7% of the patients had +ve D-dimmer values (>500ng/ml) which is in agreement with the result of ^1,2,4, however false passivity of D-dimer test have been reported with some inflammatory disease such as Rheumatoid arthritis¹⁶. Only three patients (14.3%) had D-dimer levels<500 ng/mL (according to Liatest).We used this cut off value of (500 ng/ml), because it is usually used in deep venous thrombosis and in studies related to CVT. Liatest was chosen because it is feasible on an emergency basis  and has sensitivity comparable to that of ELISA^6,9,15.

The percentage of negative D-dimer in our study (14.3%) is more than the average which is around (3%) in patients with recent CVT in the four previous studies^7-10. In the three largest published studies^8-10, none of the patients with a recent CVT (<3- to 4-week duration) had D-dimer<500 ng/mL, and only 2 of the 5 patients reported by Talbot et al.⁷ had a recent CVT and a normal D-dimer. We agree with Lalive and his associates⁹ who studied 54 consecutive patients with headaches suggestive of CVT. D-dimer levels were tested for all patients in the emergency room before brain CT or MRI was performed. Twelve of the 54 patients in their study had CVT, 10 of these 12 patients had D- dimer level of >500 ng/mL. Two patients with confirmed CVT and D-dimer of <500 ng/mL had a history of chronic headache of >30 days’ duration. In the 42 patients without confirmed CVT, only 4 patients had D-dimer level of >500 ng/mL. D-dimer test is useful in the diagnosis of acute CVT. A value below 500 ng/mL makes acute thrombosis unlikely⁹.

In the present study we found that the only variable significantly associated with a negative D-dimer assay was isolated headache at presentation. No patients presenting with other symptoms had low values, whereas among patients presenting with isolated headache, 50 %had low D- dimer values.

Only one patient out of 35 patients in the study of Kosiniski and his collegues¹⁰ had CVT with D-dimer levels <500 ng/ml. It is interesting that this patient reported headaches for >3 weeks before diagnosis¹⁰. Other groups have described normal D-dimer levels in CVT patients with rather chronic headaches lasting for >3 weeks¹⁷. It is known that in acute deep venous thrombosis of the legs, initially raised D-dimer levels may decline to normal within the first week. If this is also the case in CVT, D-dimers levels might be inversely correlated with duration of symptoms¹⁷.

The present study showed high frequency of CVT presenting with isolated headache (28.5%), and a negative D-dimer assay was found  in (50%) of them (P<0.05). This result agrees with one study that showed that 10% of patients with CVT had negative D-dimer, 26% of them presenting with isolated headache¹⁸. The high frequency of negative assay raises the question of the neuroimaging diagnosis of CVT, particularly because half of the patients with isolated headaches had only one sinus involved. However, it seems unlikely that CVT was overdiagnosed  because  various magnetic resonance techniques was to carefully rule out low flow, hypoplasia, and stenosis, which may be difficult to differentiate from lateral sinus thrombosis⁸. It is of interest that the 2 patients reported by Talbot et al with acute CVT and normal D-dimer levels also had unilateral lateral sinus thrombosis, but, in contrast to our patients, they presented with encephalopathic  signs rather than isolated headache⁷. Because there is a correlation between isolated headache and both a limited sinus involvement and a negative D-dimer assay, it is suggested that the most important factor is the extension of thrombosis. In DVT, D-dimer levels are significantly higher in patients with proximal thrombosis than in those with thrombosis below the knee, and they are correlated with clot volume and surface as shown using thrombus MRI¹². In CVT, Kosiniski and his collegues¹⁰ also found an association between elevated D-dimer values and the extent of thrombosis¹⁰. Our study showed significant association between a limited sinus involvement and a negative assay, as the three negative D-dimer patients had only one sinus involved.

Thus, our results showed that in recent CVT, when there is a high index of clinical suspicion, a negative D-dimer assay is relatively rare.  The sensitivity of D-dimer test was 85.7% and the specificity was 85.5% (p<0.05) in the present study. These results are in agreement with most previous reports on CVT¹⁰. In this setting, a negative D-dimer assay is of great clinical utility because it makes the presence of CVT very unlikely.  However, when the degree of clinical suspicion for CVT is low because of isolated headache, particularly in the absence of cause other than oral contraceptive use, a negative D-dimer does not confidently rule out CVT. This contrasts sharply with deep venous thrombosis, where a combination of low clinical probability and a negative D-dimer assay safely excludes the diagnosis¹⁷.

In conclusion, D-dimer measurement is a useful guide within the diagnostic dilemma of patients with suspected CVT.  Normal D-dimers make the presence of CVT very unlikely. However, in patients presenting with isolated headache, negative D-dimer assay does not reliably exclude diagnosis of CVT. Future larger and multicenter studies are recommended before confidential approval of D-dimer assay as a useful biomarker in the diagnostic approach of acute CVT.

REFERENCES

1.          Bousser MG. cerebral venous thrombosis. Diagnosis and management. J Neurol. 2000; 247: 252-8.

2.          Stam J. Thrombosis of the cerebral veins and sinuses. N   Engl  J Med. 2005; 352: 179-8.

3.          Cakmak S, Derex L, Berruyer M, Nighoghossian N, Philippeau F ,Adeleine P, et al. Cerebral venous thrombosis clinical outcome and systemic screening of prothrombotic factors. Neurology. 2003; 60:1175-8.

4.          Misra UK, Kalita J, Bansal V. D-dimer is useful in the diagnosis of cortical venous sinus thrombosis. Neurol India 2009; 57:50-4.

5.          Brill-Edward SP, Lee A. D-dimer testing in the diagnosis of acute venous sinus thrombo-embolism. Thromb Haemost. 1999; 82: 688-94

6.          Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004; 140: 589–602.

7.          Talbot K, Wright M, Keeling D. Normal D-dimer levels do not exclude the diagnosis of cerebral venous sinus thrombosis. J Neurol. 2002; 249: 1603–1604 17 

8.          Tardy B, Tardy-Poncet B, Viallon A, Piot M, Garnier P, Mohamedi R, Guyomarc’h S, Venet C. D-dimer levels in patients with suspected acute cerebral venous thrombosis. Am J Med. 2002; 113: 238–41.

9.          Lalive PH, de Moerloose P, Lovblad K, Sarasin FP, Mermillod B, Sztajzel R. Is measurement of D-dimer useful in the diagnosis of cerebral venous thrombosis? Neurology. 2003; 61: 1057–60

10.       Kosinski CM, Mull M, Schwarz M, Koch B, Biniek R, Schlafer J, et al. Do normal D-dimer levels reliably exclude cerebral sinus thrombosis. Stroke. 2004; 35: 2820–5.

11.       Houbouyan-Reveillard LL, Mihoubi A, Houdijk WP, Qanadli S, Joseph T, Courret JP, et al. Preliminary evaluation of two new rapid immunoturbidimetric D-dimer assays in patients with clinically suspected venous thromboembolism (VTE). Thromb Haemost. 2000; 84: 770–4.

12.       Escoffre-Barbe M, Oger E, Leroyer C, Grimaux M, Le Moigne E, Nonent M, et al. Evaluation of a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer). Am J Clin Pathol. 1998; 109: 748–53.

13.       D’Angelo A, D’Alessandro G, Tomassini L, Pittet JL, Dupuy G, Crippa L. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis. Thromb Haemost. 1996; 75: 412–6.

14.       Duet M, Benelhadj S, Kedra W, Vilain D, Ajzenberg C, Elkharrat D, et al. A new quantitative D-dimer assay appropriate in emergency: reliability of the assay for pulmonary embolism exclusion diagnosis. Thromb Res. 1998; 91: 1–5.

15.       Oger E, Leroyer C, Bressollette L, Nonent M, Le Moigne E, Bizais Y, et al. Evaluation of a new, rapid and quantitative D-dimer test in patients with suspected pulmonary embolism. Am J Respir Crit Care Med. 1998; 158: 65–70.

16.       Becham JC, Caldwell DS, Peterson BL, Pippen AM, Currie MS, Keefe FJ, et al. Disease severity in rheumatoid arthritis: Relationships of plasma tumor necrosis factor alpha, soluble inter-leukin 2-receptor, neopterin and fibrin D-dimmer to traditional severity and functional measures. J Clin Immunol. 1992; 12: 353-61.

17.    Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ. 2004; 329: 821–4.

18.    Isabelle C,Claudine S,Christophe T. A negative D-dimer assay does not rule out cerebral venous   thrombosis: A series of seventy-three patients. Stroke. 2005; 36: 1716-9.