Optimizing diagnosis of cerebral vein thrombosis with MR Direct Thrombus Imaging (MRDTI)

Cerebral vein thrombosis (CVT), i.e. thrombosis of the intracranial veins and
sinuses, is a rare but lethal type of cerebrovascular disease, with 1-month
mortality rates of approximately 5.6%, mainly due to cerebral herniation. The
clinical presentation of patients with CVT is highly variable and nonspecific,
which makes the diagnosis of CVT more difficult than other types of stroke.
There is no validated clinical algorithm and there are no specific laboratory
tests for the diagnosis of CVT. Fort instance, D-dimer tests cannot safely
exclude CVT, due to false negative test results. Thus the diagnosis of CVT
mainly relies on neuroimaging tests.
Conventional angiography used to be the gold standard for the diagnosis of CVT,
but is rarely used nowadays due to its invasive nature. Computed tomography
(CT) is generally the first line imaging test, especially in the acute setting,
because of its wide availability. Non-contrast CT, however, is normal in 25-30%
of patients with CVT and is therefore mainly used to rule out other conditions
such as stroke, tumours or brain abscess.CT combined with CT venography (CTV)
enhances the diagnostic accuracy, although its sensitivity is dependent on the
thrombus site and is especially poor in the detection of cortical vein
thrombosis. Furthermore, CTV requires administration of a iodinated contrast
agent with potential renal toxicity or allergic reactions as well as the use of
ionizing radiation. Contrast-enhanced magnetic resonance (MR) combined with
venography is commonly considered the 'gold standard' for the diagnosis of CVT.
MRI is superior to CT for detecting small cortical venous thrombosis and
parenchymal lesions. However, this modality has some limitations with false
positive results due to flow artefacts and appearances that can vary depending
on the age of thrombosis. Thus, even with the combination of MRI and magnetic
resonance venography (MRV), the diagnosis may still be difficult. Because of
the better availability of CTV, this has become the diagnostic test of first
choice in many, but not all, centers and depending on local preference MRV is
often mainly performed in patients with contraindications to CTV, i.e.
pregnancy or contrast allergies or for the evaluation of possible other
parenchymal lesions. Contrast-enhanced MRV is often only performed in patients
with inconclusive CTV and high suspicion for CVT. Importantly, differentiation
between old and new thrombosis in patients with a history of CVT is often not
possible with current imaging tests. Furthermore, the diagnosis of CVT,
especially of cerebral cortical veins, is often delayed because the
non-specific symptoms, confirmation of diagnosis relaying on the combination of
different imaging tests or requires multiple imaging tests due to
non-conclusive results. This delays treatment which potentially may result in
death or permanent disability. On the other hand, anticoagulation initiated for
a false positive diagnosis may cause major bleeding.

An alternative imaging technique for more accurate diagnosis of CVT is MR
Direct Thrombus Imaging (MRDTI)/MR Black Blood Imaging (MRBTI). This technique
is in an advanced stage of development (Theia study, NCT02262052) and is close
to implementation in clinical practice. The method is based on the formation of
methemoglobin in a fresh thrombus leading to shortening of the T1 signal. It
does not require contrast administration. Both the diagnostic accuracy
(sensitivity 97-100%, specificity 100%) as well as the inter-observer agreement
of MRDTI for first and recurrent DVT of the leg were reported to be excellent
(kappa 0.89-0.98). Moreover, it was shown to accurately differentiate acute
from chronic thrombosis. In previous studies, a high sensitivity (100%) and
specificity (95.8-100%) of MRDTI/MRBTI for CVT was reported, as compared to CT,
MR and MRV. Importantly, in these two studies the diagnosis of CVT was clearly
confirmed or ruled out by the CT, MR and/or MRV and patients with
non-diagnostic test results were not evaluated. As stated above, due to
variation in venous anatomy, artefacts or difficult to visualize small veins, a
final diagnosis often remains unclear even after performing CT(V) and MRI/MRV.
In addition to the general advantage of not using ionizing radiation and
contrast agents, the added value of MRDTI/BTI for the diagnostic management of
CVT lies within this latter patient category. Therefore, we plan to evaluate
MRDTI/BTI in patients suspected for first or recurrent CVT and referred for
MRI/MVR in the setting of routine clinical practice.

The primary objective is to assess diagnostic accuracy of MRDTI/BTI for first
and recurrent CVT in patients referred for MRI/MRV in the setting of routine
clinical setting. The secondary objectives are to optimize MRDTI/BTI sequences
for imaging CVT and to assess interobserver agreement of MRDTI/BTI for
suspected CVT.

This study is a prospective diagnostic proof of concept study to assess
diagnostic accuracy of MRDTI/BTI for patients suspected of (recurrent) CVT and
referred for MRI/MRV. Since 1) previous studies has shown that MRDTI/BTI scan
may be valuable in the diagnosis of CVT, 2) the sequence can be performed
without contrast and 3) the sequence only takes a few minutes of extra scanning
time, MRDTI/BTI will be added to the standard MR image procedure in patients
with suspected CVT referred for MRV. In the first 5 patients scanned with this
updated protocol, an expert laboratory technician will optimize the MRDTI/BTI
scan sequences. The final diagnosis and treatment plan is left to the
discretion of the treating physician. After the study is completed, the
MRDTI/BTI images will be read and adjudicated as *positive* or *negative* by
two expert reviewers in an imaging core lab, blinded to other radiological
examinations, clinical diagnosis and clinical outcome. The diagnostic standard
is the aggregate diagnosis by the same expert reviewers based on all available
cerebral imaging (without MRDTI/BTI images), clinical outcome and follow up.

This is an observational study; patients do not have direct benefits of
participating in this study other than helping in increasing our knowledge of
the subject under study. The burden of the study is very limited and includes a
telephonic follow up that will take only 5-15 minutes. Patients are
not expected to experience harm from study participation.