Quantitative d-dimer level and anticoagulant therapy in idiopathic intracranial hypertension

Abstract

Background

Idiopathic intracranial hypertension (IIH) is a syndrome characterized by elevated intracranial pressure (ICP) of unknown etiology

Aim of the work

The aim of this research is to study the quantitative d-dimer level and the role of anticoagulant therapy in absence of occlusive sinus thrombosis in patients with IIH.

Methodology

Twenty-four patients with IIH according to the modified Dandy criteria were enrolled. Headache impact test (HIT6), ophthalmological assessment including Frisen classification for papilledema, visual acuity, visual field, and visual evoked potentials were performed to the patients. Serum quantitative d-dimer level was measured using the enzyme-linked immunosorbent assay (ELISA) technique for the patients and for 24 healthy matched controls. Patients were divided into two groups: group (1) received acetazolamide and low molecular weight heparin (LMWH) in a prophylactic dose for 2 weeks while group (2) received acetazolamide only. Both groups continued on acetazolamide for 6 months. We followed the patients after 1 and 6 months later through the HIT6 test and the ophthalmological assessment.

Results

d-dimer level was statistically higher among the cases compared to the controls. Also, a statistically significant improvement was recorded in the ophthalmological assessment after 6 months among both groups; more evident in group (1).

Conclusion

The elevated d-dimer level and the visual improvement in IIH patients receiving LMWH added to acetazolamide suggest the presence of an underlying unrecognized non-occlusive venous cerebral microthrombi impeding the cerebrospinal fluid (CSF) drainage.

Trial registration

ClinicalTrials,gov on 22/5/2019, NCT03963336.

Introduction

Idiopathic intracranial hypertension (IIH) is a syndrome characterized by elevated intracranial pressure (ICP) in the absence of intracranial disorder, a meningeal process or cerebral venous thrombosis [1]. The common clinical manifestations are headache and visual dysfunction in the form of blurring of vision, field defects, and binocular diplopia [2].

The pathophysiology underlying the raised ICP still remains obscure but there are some proposed mechanisms such as increased brain water content, excessive cerebrospinal fluid (CSF) production or reduced absorption, and increased cerebral venous pressure. It was noticed that obese young women and patients having bilateral transverse sinus stenosis are predisposed to develop increased ICP. Endocrinal changes, hypercoagulable state, or specific medications may trigger the increased venous pressure [3].

Moreover, a prothrombotic state with an elevated d-dimer level has been observed in obese IIH patient [4]. The d-dimer is considered the smallest fibrinolysis-specific degradation product in the circulation and it is an exquisite sensitive test to intravascular thrombosis [5].

The aim of our study was to measure the serum quantitative d-dimer level in IIH patients and to investigate the role of anticoagulation added to the routine treatment as a possible effective therapy.

Patients and methods

This is a prospective case control study. We recruited 24 consecutive IIH patients of both sexes fulfilling the modified Dandy criteria [6] from the Neurology department, Fayoum University Hospitals in the period from January to October 2017.

We excluded patients with disturbed conscious level, focal neurological signs, seizures, cerebral venous sinus thrombosis or stenosis, deep venous thrombosis or pulmonary embolism, malignancy, and acute nephritic syndrome. Patients with signs of disseminated intravascular coagulopathy and septic sinus thrombosis and patients with history of cerebral granuloma or infection, cerebrovascular stroke, head trauma, or surgery were excluded. Finally, pregnant females or those who terminated their pregnancy in the last 4 weeks were also excluded.

The study population was divided into two groups randomly; patients with odd number were included in group (1) while those with even number were fitted in group (2). Group (1) received acetazolamide and low molecular weight heparin (LMWH) in a prophylactic dose 1 mg/kg/day for 2 weeks, while group (2) received acetazolamide only. Both groups continued on acetazolamide (1–2 g/day) for 6 months.

Twenty-four age, sex, and body mass index (BMI) matched healthy volunteers were selected as a control group. They were the patients’ relatives visiting the Neurology clinic.

All patients were subjected to thorough history taking and full neurological examination. We assessed the headache severity using the headache impact test (HIT6) that is a six-item test used to provide a global measure of the adverse headache impact. The final HIT-6 score is obtained from simple summation of the six items and ranges between 36 and 78, with lower scores reflecting lower impact [7]. There is no Arabic validated translated version for the HIT-6 test up till now; we translated it and we referred to the score present in the original one. Patients were evaluated for headache severity at baseline then after 1 and 6 months.

The ophthalmological assessment included a fundus examination with grading of papilledema according to Frisen classification [8]. Also, visual acuity was assessed using the Snellen’s chart. The results obtained were converted into the logarithm of minimum angle of resolution (log MAR) for analysis [9]. Finally, visual field assessment was performed by the automated perimetry (SBP, 3000S) that measures the visual field mean deviation (MD). An MD of 0 to 2 dB indicates a normal value, while a negative value represents a deviation [10]. All patients were subjected to these ophthalmological tests at baseline and at follow up after 1 and 6 months in the Ophthalmology Department.

Visual evoked potentials (VEPs) using the Nicolet Viking IV equipment was performed. The latency and the amplitude of P100 wave was measured. Responses were considered abnormal if the P100 latency exceeded 110.85 ms in any eye or if the response amplitude was absent [11].

Serum quantitative d-dimer level (normal level up to 200 ng/dl) was assessed using the enzyme-linked immunosorbent assays (ELISA) technique. Venous blood samples (2 cm) were obtained from the patients and the controls to be centrifuged immediately. The separated plasma was stored at 2–8 °C. The ELISA Kit is based on the principle of competitive binding. Patient samples, standards, and controls were acidified and neutralized before starting the procedure’s steps. The micro titer wells were coated with a monoclonal antibody directed toward the d-dimer molecule. The pre-treated sample was incubated at room temperature with the conjugate biotinylated d-dimer. The wells were washed then incubated with the enzyme complex streptavidin-horse radish peroxidase (HRP). After adding the substrate solution, the concentration of the d-dimer was calculated in a reverse proportional manner to the intensity of the color developed.

Ethical consideration

The study was approved by the Research Ethical Committee of the Faculty of Medicine, Fayoum University. All the participants either patients or controls signed an informed and detailed consents after explaining for them the aim and the procedures of the study. The confidentiality of their data and their right not to participate in the study were respected.

Statistical analysis

Statistical package for social sciences (SPSS) version 18 for Microsoft Windows was used for data management and analysis. The sample size was calculated according to Epi Info 2000. A sample size of 24 was calculated using a special formula at a confidence interval of 95% and precision of (2%). Simple descriptive analysis in the form of numbers and percentages was performed for qualitative data and arithmetic means such as central tendency measurement. Standard deviation (SD) was used as a measure of dispersion for quantitative parametric data and inferential statistic test. For quantitative parametric data, independent student t test was used to compare measures of two independent groups while paired t test was used to compare between two dependent groups. For qualitative data, we applied Chi-square test to compare two of more than two qualitative groups and general linear model to compare repeated measures. A p value ≤ 0.05 was considered statistically significant.

Results

The present study included 24 IIH patients and 24 controls. Their demographic data are shown in Table 1.

Table 1 Demographic data of IIH patients and controls

There was neither statistically significant difference between cases and controls nor between IIH groups regarding the age, sex, and BMI (p > 0.05).

The d-dimer serum level was high in all IIH patients ranging from 100 to 310 ng/dl (mean 232.4 ± 54.5) while in controls it ranged from 100 to 250 ng/dl (mean 186.1 ± 22.7). There was a statistically significant difference between the two groups (p < 0.001). Meanwhile, group (1) had a mean of d-dimer level 233.4 ng/dl and group (2) had a mean of 231.4 ng/dl with no statistically significant difference between the two groups.

The HIT6 score improved in all the patients on follow up as shown in Table 2. Statistically significant differences were found in HIT6 score after 1 and 6 months follow up with low mean in group (2) as shown in Table 3.

Table 2 HIT6 score at baseline, after 1 and 6 months

Table 3 Comparisons of HIT6 score at baseline, after 1 and 6 months follow up between IIH groups

Regarding the ophthalmological assessment, 58.3% of the patients presented with papilledema grade 2 at baseline and they improved gradually on follow up reaching grade 1 (41.7%) at 6 months. The log-MAR was 0.30–0.60 in 41.7% of the patients at baseline and improved at 6 months follow up reaching 00.00–0.30 in 66.7% of the patients. Also, 85.4% presented with mild to moderate field defect at baseline while at 6 months follow up 83.3% had mild to normal field defect.

No significant differences were found between IIH groups at baseline visual assessment. A statistically significant difference was found with improvement in papilledema’s grade between the baseline assessment and after 6 months between IIH groups; p value in group (1) was less than 0.001 while in group (2) the p value was 0.009. Similarly, a statistically significant difference was found in log-MAR between the baseline assessment and 6 months follow up; in group (1) (p = 0.003) and group (2) (p value = 0.02).

A statistically significant improvement was found in visual field between the baseline assessment and 6 months follow up in group (1) (p = 0.009), while there was no statistically significant difference in visual field between the baseline and 6 months follow up in group (2) (p = 0.2). Also, no statistically significant difference was found between both groups from the baseline to 6 months follow up (p value was 0.8 and 0.4 respectively). A statistically significant decline in VEP latencies and a statistically significant increase in VEP amplitudes were found between the baseline assessment and 6 months follow up between both IIH groups as shown in Fig. 1 and (Table 4).

Table 4 Comparisons of VEP latency and amplitude at baseline and after 6 months follow up between IIH groups

Fig. 1

Comparisons of visual acuity (log-MAR) (up and left); papilledema’s grade (up and right); visual field (down) at base line, and follow up between IIH groups

Discussion

The IIH is a syndrome of elevated ICP with obscure etiology. An underlying prothrombotic state would explain at least a part of its pathogenesis [12]. The d-dimer is a by-product of fibrinolysis and has an already established role in the diagnosis of venous thromboembolism and disseminated intravascular coagulation [13].

Our results showed a statistically significant higher mean of d-dimer among the cases compared to the controls. This result agrees with Kesler A. et al. 2010 [4]

Headache is the most common presenting symptom in IIH [2]. The HIT6 score improved statistically in all the patients on follow up after 1 and 6 months which agrees with Friedman D. and his colleagues who used the acetazolamide as a treatment for IIH [14].

Statistically significant differences were found in HIT6 score after 1 and 6 months follow up with lower mean in group [2] indicating that the headache improved much more in patients who did not receive anticoagulant therapy. This discrepancy between both groups in headache improvement can be explained by the fact that the present headache could be associated with tension type headache, depression, or psychosomatic symptoms. Nevertheless, the HIT6 score is a subjective evaluating method and not objective.

Regarding the ophthalmological assessment, our results showed a statistically significant improvement in papilledema’s grade at 6 months follow up among both groups which agrees with Wall M [15] who explained that the acetazolamide works by inhibition of carbonic anhydrase leading to reduction in sodium ions transport across the choroid plexus epithelium. There was a statistically significant decrease in papilledema after 6 months among patients who received anticoagulant treatment with acetazolamide while no statistically significant difference between both treatment groups after 1 month may be because the papilledema takes time to resolve.

Concerning the visual acuity, there was a statistically significant improvement in log-MAR after 6 months among both groups of patients which agrees with Wall M 15]. The improvement was more noticed in patients who received anticoagulant therapy.

Visual field assessment was considered the main criterion to assess the clinical improvement in IIH patients [16]. There was a statistically significant improvement in visual field after 6 months among patients who received anticoagulant therapy and acetazolamide. On the other hand, there was no difference in visual field follow up among patients who did not receive anticoagulation which disagrees with Wall M. [15] who found an improvement in visual field after 6 months among IIH patients who received acetazolamide added to low sodium diet. Moreover, Celebisoy N. and co-authors [16] showed visual field improvement on either acetazolamide or topiramate considering that the two medications exert their effect through the carbonic anhydrase inhibition. Nevertheless, Koc F and his colleagues 2018 [17] showed in their recent study that the weight reduction combined with acetazolamide significantly improve the visual field in IIH patients. The discrepancy in the results could be attributed to different methodology applied in the studies.

Finally, the VEPs results showed a statistically significant decrease in latency and significant increase in amplitude after 6 months among both groups with more improvement among the group who received anticoagulant therapy. This result was in accordance with Hamurcu M. and co-authors [18] who reported that the papilledema initially does not disrupt the function of the optic nerve and retinal nerve fiber layer (RNFL), but it may lead to an elongation of the p100 latency in VEP test and an increase in RNFL. After elimination of the effect of edema, changes in the optic nerve and RNFL improve. When papilledema is not treated and becomes chronic, ischemic symptoms may occur with the effect of pressure on the nerve fibers and RNFL. Therefore, early diagnosis and treatment are extremely important.

Up to our knowledge, this study is the first to investigate the quantitative d-dimer serum level in IIH patients and to study the role of anticoagulant therapy in IIH cases. The results obtained prove the possibility of an unrecognized non-occlusive venous cerebral thrombus impeding the CSF drainage as described in previous studies [3, 4]. We can assume that the anticoagulant therapy disrupted these microthrombi and improved the CSF drainage which was manifested by the improvement of the papilledema, visual field, visual acuity, and the VEPs results.

The limitations of this study were the small sample size and the absence of objective instrumental findings demonstrating the presence of unrecognized non-occlusive venous cerebral thrombus impeding the CSF drainage.

To conclude, our study demonstrated the presence of high serum quantitative d-dimer levels among the IIH patients and showed an improvement in visual assessment after 6 months in both groups of patients; more apparent in the cohort who received anticoagulant therapy added to the acetazolamide. Routine screening of d-dimer level is recommended in patients with IIH. Further studies are warranted for objective instrumental findings able to detect this unrecognized non-occlusive venous cerebral thrombus. Also, larger studies are needed to establish guidelines for the use of anticoagulation in IIH patients.