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Three Part Question

Does a [normal D-dimer] [rule out cerebral venous sinus thrombosis (CVST)] in [patients presenting to ED]?

Clinical Scenario

A 32 year old female with presents to the emergency department with an occipital headache and intermittent blurred vision for the past 3 weeks. D-dimer performed on admission is within normal range. Can you safely rule out cerebral venous sinus thrombosis?

Search Strategy

NICE Healthcare interface

Medline 1966-November 2016

[d-dimer.ti,ab] AND [exp INTRACRANIAL EMBOLISM/ OR exp INTRACRANIAL THROMBOSIS/ OR exp SINUS THROMBOSIS, INTRACRANIAL/ OR exp CAVERNOUS SINUS THROMBOSIS/ OR exp INTRACRANIAL EMBOLISM AND THROMBOSIS/ OR exp LATERAL SINUS THROMBOSIS/ OR exp SAGITTAL SINUS THROMBOSIS/ OR (cerebral AND venous AND sinus AND thrombosis).ti,ab/ OR (sinus AND thrombosis).ti,ab] AND [exp DIAGNOSIS/ OR (rule AND out).ti,ab/ OR exclu*.ti,ab/ OR normal.ti,ab/ OR negative.ti,ab/ OR sensitivity.ti,ab/ OR diagnosis.ti,ab]

Search Outcome

71 papers identified of which 52 were irrelevant and 7 were of insufficient quality for inclusion.
12 papers were included for use in final review. This included 2 systematic reviews which covered 8 of the previously identified papers.
Therefore, these 2 systematic reviews, along with the remaining 2 studies are detailed in this BET.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Dentali F, Squizzato A, Marchesi C, Bonzini M, Ferro JM, Ageno W. April 2012 Italy	1134 patients with suspected or confirmed CVST, diagnosed by CT venography/magnetic resonance imaging (MRI)/ magnetic resonance venography (MRV)/angiography.	Systematic review and meta-analysis	D-dimer level in CVST	10/155 CVST cases had normal (<500 ng/mL) D-dimer. 93.9% sensitivity (95% CI 87.5-97.1)	Variable study design of included studies e.g D-dimer assays used, exclusion of certain patients with risk factors (pregnancy, OCP). Low number of included studies. Low quality of included studies: no randomised controlled trials, only retrospective/prospective studies.
Imanda M.E. Alons, Korné Jellema, Marieke J.H. Werner and Ale Algra January 2015 The Netherlands	636 patients with isolated headache and normal neurological examination. D-dimer was determined at presentation and the presence of CVT examined with CT venography/ MRI or both.	Systematic review and meta-analysis	D-dimer level in CVST cases	45/636 CVST cases, 1 had normal (<0.5 μg/ml) D-dimer. Sensitivity: 97.8%. Negative predictive value: 99.8%	6 potential articles excluded from meta-analysis due to incomplete/missing data. Assays used to determine D-dimer level varied between studies. Normal neurological examination is subjective and assessment may vary between clinicians. The authors have not specified what they define as "normal". Study only looks at "low risk" patients i.e those with isolated headache and normal neurological examination. Higher risk patients with additional neurology may have been excluded but would have still been relevant to the BET question.
Hiltunen S, Putaala J, Haapaniemi E, Salonen O, Tatlisumak T April 2013 Finland	71 patients from Helsinki University central hospital discharge register from 1987 to 2010, with radiologically-confirmed CVST and D-dimer measured before initiation of anticoagulant treatment.	Retrospective	D-dimer level in CVST cases	9/71 CVST cases had normal D-dimer (<0.5mg/L). Sensitivity: 87.3%. Negative predictive value: >95%.	Retrospective nature of study led to exclusion of half of patients with CVST due to inclusion criteria. Study only looked at patients presenting to Helsinki hospital, this group may not be representative of the general global population.
Hui Fang Wang, Chuan Qiang Pu, Xi Yin, Cheng Lin Tian, Ting Chen, Jun Hong Guo and Qiang Shi July 2016 China	139 patients with CVST presenting to their hospital between 1st January 2004 and 1st August 2014. CVST confirmed with magnetic resonance imaging (MRI)/ magnetic resonance venography (MRV) or digital subtraction angiography (DSA). D-dimer was measured within 24 hr of presentation.	Prospective	D-dimer level in CVST cases	74/139 CVST cases had normal D-dimer. Sensitivity: 46.8%	The study excluded patients with CVST with a family history of thrombosis. This could skew the data and make the results less applicable to the general population.

Comment(s)

CVST is a relatively rare disease with high morbidity and mortality if undiagnosed. The array of imaging techniques available has increased CVST incidence, however it remains a diagnostic challenge for clinicians due to the wide, sometimes vague spectrum of symptoms with which it can present. D-dimer is an inexpensive, readily-accessible test which is already used to rule out deep vein thrombosis with high sensitivity. If D-dimer could be similarly utilised to rule out CVST, it has the potential to aid clinical diagnosis, whilst avoiding unnecessary costly imaging studies. There are a lack of high quality data to assess the role of D dimer in predicting CVST. Studies are observational in nature and as a result their design varies widely. In addition, a relatively low number of patients have been studied, which may reflect the rarity of the disease. Although not directly relevant to my BET question, it is noteworthy that the included studies have suggested that a number of clinical variables affect D-dimer level. These include: symptom duration, signs/symptoms, and the number of sinuses affected. Symptoms of >30d duration had statistically lower D-dimer levels than acute and subacute presentations. In addition, isolated headache and single, rather than multiple sinus involvement were significantly associated with a lower D-dimer level.

Editor Comment

CF

Clinical Bottom Line

A normal D-dimer does not safely rule out CVST. However, the research suggests D-dimer level may help predict the risk of CVST when combined with other factors, such as clinical presentation and risk factors for thrombosis. This could negate the need for further imaging in low-risk patients. Therefore, there is potential for D-dimer to be used as part of a pre-imaging probability score in the context of CVST. To answer this question, larger, higher quality studies would need to be performed.

References

1. Dentali F, Squizzato A, Marchesi C, Bonzini M, Ferro JM, Ageno W. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. Journal of Thrombosis and Haemostasis 2012 Apr; 582-9
2. Imanda M.E. Alons, Korné Jellema, Marieke J.H. Wermer and Ale Algra D-dimer for the exclusion of cerebral venous thrombosis: a meta-analysis of low risk patients with isolated headache. BMC Neurology 2015; 15:118 p1-7
3. Hiltunen 1, Putaala J, Haapaniemi E, Salonen O, Tatlisumak T. D-dimer and clinicoradiologic features in cerebral venous thrombosis. Journal of the Neurological Sciences 15;327(1-2)
4. Hui Fang Wang, Chuan Qiang Pu, Xi Yin, Cheng Lin Tian, Ting Chen, Jun Hong Guo and Qiang Shi D dimers (dd) in CVST International Journal of Neuroscience