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\begin{document}

\title{Impact of MRA Echo Time on Stroke Prevention Therapy in Pediatric
Patients with Sickle Cell Disease}



\author[1]{Parmpreet Dhillon}%
\author[1]{Kerry Morrone}%
\author[1]{Kevin Hsu}%
\author[2]{William Gomes}%
\author[3]{Ellen Silver}%
\author[1]{Daniel Lax}%
\author[1]{Qi Peng}%
\author[1]{Seon Kyu Lee}%
\author[1]{Deepa Manwani}%
\author[3]{William Mitchell}%
\affil[1]{Montefiore Medical Center}%
\affil[2]{Westchester Medical Center}%
\affil[3]{Yeshiva University Albert Einstein College of Medicine}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Flow artifact, intrinsic to Magnetic Resonance Angiography
(MRA), is dependent on technical parameters and can lead to
overinterpretation of stenosis. Degree of cerebrovascular stenosis in
pediatric patients with sickle cell anemia (SCA) informs need for
chronic transfusion therapy, which may have significant risks. The
primary objective of this study was to document any change in stroke
prevention therapy that could be attributed to the implementation of a
standardized MRA scanning protocol. Procedure: A standardized MRA
scanning protocol with an echo time of \textless{}5 msec was implemented
at Montefiore Medical Center in May 2016. Retrospective chart review
identified 29 patients [?] 21 years with SCA cerebral vasculopathy and an
MRA head pre- and post-May 2016. Level of arterial stenosis on MRA, echo
time, and treatment plans were documented both pre- and
post-implementation. McNemar analysis determined the significance of
change in treatment plans before and after implementation of the
standardized scanning protocol. Results: Previously seen stenosis was
re-classified to a lower degree in 12/29 patients (41\%). Notably, 6
patients had a reclassification of vasculopathy leading to
discontinuation of chronic transfusion therapy whereas 0 patients
required escalation of therapy to chronic transfusions. McNemar analysis
showed this difference to be statistically significant (p = 0.042).
Conclusion: Minimizing flow artifact with echo time \textless{}5msec
improves accurate interpretation of true cerebrovascular disease and
ensures appropriate treatment plans are in place for stroke prevention.
This is especially important when trying to implement ``TCD With
Transfusions Changing to Hydroxyurea (TWiTCH)'' clinical trial results
in the real-world setting.%
\end{abstract}%



\sloppy


\textbf{Impact of MRA Echo Time on Stroke Prevention Therapy in
Pediatric Patients with Sickle Cell Disease}

\emph{Authors:} Parmpreet Dhillon, MD\textsuperscript{1}, Kerry Morrone,
MD\textsuperscript{2}, Kevin Hsu, MD\textsuperscript{3}, William Gomes,
MD, PhD\textsuperscript{4}, Ellen Silver, Ph.D\textsuperscript{5},
Daniel Lax MD\textsuperscript{1}, Qi Peng, PhD\textsuperscript{6}, Seon
Kyu Lee MD, PhD\textsuperscript{3}, Deepa Manwani,
MD\textsuperscript{2}, William Mitchell, MD\textsuperscript{2}

\textsuperscript{1}Division of Child Neurology, Department of Neurology,
Montefiore Medical Center / Albert Einstein College of Medicine

\textsuperscript{2} Division of Hematology/Oncology, Department of
Pediatrics, Children's Hospital at Montefiore, Albert Einstein College
of Medicine

\textsuperscript{3}Division of Neuroradiology, Department of Radiology,
Montefiore Medical Center / Albert Einstein College of Medicine

\textsuperscript{4}Division of Neuroradiology, Department of Radiology,
Westchester Medical Center and New York Medical College

\textsuperscript{5}Division of Academic General Pediatrics, Children's
Hospital at Montefiore, Albert Einstein College of Medicine

\textsuperscript{6}Department of Radiology, Montefiore Medical Center /
Albert Einstein College of Medicine

Conflict of Interest Statement: The authors have no conflicts of
interest to disclose

Corresponding Author: Parmpreet Dhillon, MD

1410 Pelham Pwy South - Kennedy 316 Bronx, N.Y. 10461

Phone: 718-430-2447

Fax: 216-208-1053

pampreetdhillonmd@gmail.com

Running Title: Impact of MRA TE on SCD Stroke Prevention Therapy

Tables: 2 Figures: 4

MeSH Index Terms: Magnetic Resonance Angiography, artifacts, stroke,
sickle cell, cerebrovascular disease\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviation & Full term\tabularnewline
\midrule
\endhead
MMC & Montefiore Medical Center\tabularnewline
MRI & Magnetic Resonance Imaging\tabularnewline
MRA & Magnetic Resonance Angiography\tabularnewline
SCD & Sickle Cell Disease\tabularnewline
SCA & Sickle Cell Anemia\tabularnewline
\bottomrule
\end{longtable}

Word Count Abstract: 250 Word Count Main Text: 2465 Reference Count: 17

\textbf{Abstract}

\textbf{Background:}

Flow artifact, intrinsic to Magnetic Resonance Angiography (MRA), is
dependent on technical parameters and can lead to overinterpretation of
stenosis. Degree of cerebrovascular stenosis in pediatric patients with
sickle cell anemia (SCA) informs need for chronic transfusion therapy,
which may have significant risks. The primary objective of this study
was to document any change in stroke prevention therapy that could be
attributed to the implementation of a standardized MRA scanning
protocol.

\textbf{Procedure:}

A standardized MRA scanning protocol with an echo time of \textless{}5
msec was implemented at Montefiore Medical Center in May 2016.
Retrospective chart review identified 29 patients [?] 21 years with SCA
cerebral vasculopathy and an MRA head pre- and post-May 2016. Level of
arterial stenosis on MRA, echo time, and treatment plans were documented
both pre- and post-implementation. McNemar analysis determined the
significance of change in treatment plans before and after
implementation of the standardized scanning protocol.

\textbf{Results:}

Previously seen stenosis was re-classified to a lower degree in 12/29
patients (41\%). Notably, 6 patients had a reclassification of
vasculopathy leading to discontinuation of chronic transfusion therapy
whereas 0 patients required escalation of therapy to chronic
transfusions. McNemar analysis showed this difference to be
statistically significant (p = 0.042).

\textbf{Conclusion:}

Minimizing flow artifact with echo time \textless{}5msec improves
accurate interpretation of true cerebrovascular disease and ensures
appropriate treatment plans are in place for stroke prevention. This is
especially important when trying to implement ``TCD With Transfusions
Changing to Hydroxyurea (TWiTCH)'' clinical trial results in the
real-world setting.

\textbf{Introduction}

In pediatric patients with sickle cell anemia (SCA), stroke is a major
cause of morbidity and mortality with an estimated 1.9-11\% risk of
stroke by the age of 20 (1-7). Specific screening and treatment
guidelines aimed at both primary and secondary prevention have
successfully reduced the incidence of overt strokes in this high-risk
population (4). The Stroke Prevention Trial in Sickle Cell Anemia (STOP)
trial showed significant primary stroke prevention by reducing the risk
of first stroke by 90\% with chronic transfusions in those patients at
increased risk as determined by Transcranial Doppler (TCD) (4). This
study lead to a national recommendation to conduct annual TCD screening
for all children with SCA between the ages of 2-16 years (8).

Patients with SCA who have conditional or abnormal TCDs or neurologic
symptoms may undergo regular neuroimaging with Magnetic Resonance
Imaging (MRI) and Magnetic Resonance Angiogram (MRA) to confirm cerebral
vasculopathy and stratify stroke risk. Risk stratification using MRA is
recommended by the American Society of Hematology in selection of a
stroke prevention treatment plan (9). Current recommendations based on
the multicenter, randomized controlled trial TWiTCH (TCD with
Transfusions Changing to Hydroxyurea) suggest that a child aged 2-16
with abnormal TCD results who has been receiving transfusion therapy for
at least 1 year with low-risk MRA imaging can be transitioned off
transfusions and onto hydroxyurea treatment (9, 10). Determination of
low-risk or high-risk requires MRA grading of vasculopathy, highlighting
the importance of accurate MRA assessment.

Standard non-contrast MRA is accomplished with a 3-dimensional time of
flight technique and allows assessment of the patency and caliber of
intracerebral arterial vessels (11). Technical artifacts can influence
the appearance of arterial structures on MRA (12), especially in regions
of arterial tortuosity or bifurcation, sites commonly affected in
patients with SCA. These technical artifacts can lead to the erroneous
interpretation of arterial stenosis, and thereby lead to inappropriate
risk stratification and treatment selection for primary stroke
prevention, such as initiation or continuation of chronic transfusion
therapy or transition to hydroxyurea. While chronic transfusion therapy
can significantly lower stroke risk (13), it has notable risks including
iron overload, alloimmunization, and infection (14-16).

Investigators in the Stroke with Transfusions Changing to Hydroxyurea
(SWiTCH) trial developed standardized scanning protocols for their entry
and exit brain MRI, MRA, and TCD studies. The SWiTCH MRA scanning
protocol specified an echo time of \textless{}5 msec (12). Echo time or
TE, describes the time between application of radiofrequency excitation
pulse and peak of the signal induced in the coil, measured in
milliseconds (msec). While SWiTCH primary objective was to compare
standard transfusion therapy to hydroxyurea in preventing recurrent
stroke and quantitative liver iron content (12), the standardized
imaging scanning protocols developed provide an opportunity for further
study of flow artifact and its clinical importance. These MRA scanning
protocols were also utilized in the TWiTCH trial to grade vasculopathy
as low and high risk and guide treatment decisions. The generalizability
and real-world application of the results of the TWiTCH trial could
potentially depend on close adherence to study MRA protocols. Few
reports have mentioned minimizing TE to \textless{}5 msec to limit
flow-related artifact (5, 6, 17), however, no prior studies have
reported the clinical implications of these protocols.

The primary objective of our study was to document any change in stroke
prevention therapy, particularly discontinuation of chronic
transfusions, that could be attributed to the implementation of the
standardized MRA scanning protocol based on the SWiTCH protocol. We
hypothesized that the implementation of a standardized MRA protocol
would lead to re-classification of the level of cerebral stenosis and
impact treatment plan for a subset of patients.

\textbf{Methods}

At Montefiore Medical Center (MMC), a standardized MRA scanning protocol
with TE \textless{}5 msec based on the SWiTCH protocol was implemented
in May 2016. This study was approved by the Albert Einstein College of
Medicine and MMC Institutional Review Board as a retrospective chart
review that included the following criteria i) patients [?]21 years old at
the time of implementation of the scanning protocol in May 2016 ii)
sickle cell disease (genotypes SS, S\selectlanguage{greek}β\selectlanguage{english}0thalassemia, S\selectlanguage{greek}β\selectlanguage{english}+thalassemia, SC),
iii) established hematology care at CHAM for at least one year (defined
as having at least one outpatient clinic visit), and iv) MRA performed
at MMC prior to May 1\textsuperscript{st} 2016 AND after May
1\textsuperscript{st} 2016.

Clinical Looking Glass (CLG), a patented software tool designed by MMC
for practitioners to use medical and administrative data as a means for
continued quality improvement, was used to identify study population.
Inclusion criteria applied to CLG were ICD diagnoses for sickle cell
disease, age [?]21, date range of 2014-2018, and procedure codes for MRI.
Studies performed on MRI machines from any vendors and any MMC sites
were included. Exclusion criteria included incomplete records and
patients with only one MRA. Twenty-nine patients were identified with
any degree of cerebral vasculopathy on the pre-May 2016 images and
included in this study. Patient assembly including ICD codes is
illustrated in Figure 1.

A dedicated neuroradiologist with expertise in interpreting vasculopathy
in sickle cell patients reviewed all images as part of institutional
hematology-neuroradiology rounds that are performed as a routine
component of clinical care. After data collection and prior to analysis,
a separate blinded neuroradiologist reviewed key images for patients in
question. Level of arterial stenosis on MRA, TE, and treatment plans
were documented both pre- and post-May 2016 for each patient. Other
technical factors such as magnet field strength, repetition time (TR)
and slice thickness were also noted.

A McNemar analysis was performed to determine whether there was a
significant change in treatment plan after implementation of the
standardized MRA scanning protocol.

\textbf{Results}

Baseline demographics and treatment plans for the 29 patients with
sickle cell CNS vasculopathy prior to implementation of the MRA scanning
protocol in May 2016 are listed in Table 1. Indications for chronic
transfusion therapy included primary stroke prevention for 7 patients,
secondary stroke prevention for 17 patients, and chronic pain for 2
patients.

MRAs were performed for routine screening, symptoms including headache,
or focal neurologic findings. Pre- May 2016, 16/29 patient studies used
TE \textless{}5msec whereas post May 2016, 26/29 patient studies used TE
\textless{}5msec.

For 12 of the 29 patients (41\%), some or all stenosis that was
previously seen on pre- May 2016 MRA imaging was not identified on MRA
imaging done post- May 2016. Figures 2 and 3 show examples of MRAs in
two patients in whom vasculopathy was no longer visualized. In six
patients, there was a decrease in the classification of CNS
vasculopathy, however, their treatment was not impacted. These patients
were not on disease modifying therapy, already had significant stenosis
requiring transfusions, or had undergone curative bone marrow
transplant.

In six patients (21\%) there was complete resolution of previously seen
CNS vasculopathy that lead to a change in treatment plan; all six
patients were on chronic transfusion therapy for primary stroke
prevention and after review of newer imaging showing no vasculopathy,
this therapy was discontinued. Two patients had an increase in the
degree of classification of stenosis, suggestive of the commonly seen
progression of sickle cell CNS vasculopathy, without change in their
treatment plan.

As seen in Figure 4, 24 patients (83\%) were on chronic transfusion
therapy prior to May 2016, while this number decreased to 18 (62\%)
after May 2016. For the McNemar analysis (Table 2), clinical treatment
plans were categorized as ``Transfusions'' or ``Not transfusions'' both
pre- and post- implementation of the scanning protocol. 18 patients
remained in the same category of requiring transfusion therapy pre- and
post- implementation. While six patients on chronic transfusion therapy
were able to discontinue transfusion therapy, 0 patients required
escalation in treatment plan (starting chronic transfusion therapy).
Five patients with CNS vasculopathy remained off chronic transfusion
therapy. The proportion of patients with change in treatment plan after
the implementation of scanning protocol with TE \textless{} 5msec was
found to be statistically significant (p = 0.0412).

\textbf{Discussion}

Accurate diagnosis of large vessel narrowing has clinical implications
for stroke risk stratification and the initiation of and escalation of
clinical interventions such as transfusions and surgical procedures
(e.g. encephaloduroarteriosynangiosis) in pediatric patients with SCA.
While there are many imaging techniques to examine the intracranial
vasculature, MRA imaging without gadolinium is preferred as first line
as it is noninvasive, avoids ionizing radiation and iodinated or
gadolinium contrast, compared to Computed Tomography Angiography (CTA),
catheter angiography, and contrast-enhanced MRA(18). Non-contrast MRA
provides visual assessment of flow-related enhancement within the
intracranial arteries as compared to velocity assessment with TCD,
however it is uniquely subject to flow-related MRI artifact, which can
lead to misidentification of stenosis when it is not truly present, or
exaggeration of existing stenosis.

One disadvantage of noncontrast MRA is the potential loss of
flow-related signal in regions of arterial tortuosity and/or branching,
which are commonly present in patients with SCA, and the possibility for
this artifact to simulate arterial stenosis. The possibility of
artifactual stenosis is especially problematic in SCA, as the regions
typically affected by artifact on noncontrast MRA overlap with the
regions typically affected by sickle-cell related vasculopathy. Use of
short-TE MRA techniques (ideally less than 5msec), can limit the
artifactual loss of flow-related signal and thereby more accurately
assess the true patency of intracerebral arterial vessels.

Of the 29 patients initially identified with sickle cell CNS
vasculopathy, our study identified 12 patients (41\%) in whom the level
of cerebral stenosis was re-classified to a lower degree after
implementation of the standardized MRA protocol. Clinically, an
improvement in the level of arterial stenosis is not expected in
patients with SCA, even for those on disease modifying therapy such as
chronic transfusion therapy. This suggests that previously identified
areas of stenosis were a result of artifact rather than true
vasculopathy.

In six patients (21\%) this reclassification led to a de-escalation of
the stroke prevention plan and discontinuation of chronic transfusion
therapy. In these six patients, the initially identified stenosis was
noted to be most often in A1 branch of the anterior cerebral artery or
supraclinoid segments of the internal carotid artery. Additionally, one
patient was newly identified to have stenosis and one patient was
determined to have an increased classification of stenosis, suggesting a
progression of stenosis due to SCA.

As a retrospective chart review, this study has limitations in assessing
whether the TE of the scanning protocol is responsible for leading to
the decreased appearance of artifact and thus clinical change in
treatment plan. After May 2016, MRA in three patients had TE
\textgreater{}5msec, suggesting that the standardized scanning protocol
was not uniformly implemented at our institution in May of 2016. For the
six patients in which the degree of CNS stenosis was re-classified and
treatment was de-escalated, two patients had TE \textgreater{} 5msec on
their post May 2016 imaging. While TE was the major parameter
standardized in this protocol, MRA time of flight angiography phase
dispersions may also be dependent on other technical parameters. For
example, a greater slice thickness or TR will make the contrast between
stationary tissue and blood less obvious. To evaluate this, TR, matrix
size, and slice thickness were reviewed for several patients and were
not noted to be significantly different.

Our analysis included 29 patients; however, our initial chart sample
identified 136 patients with only one MRA; reanalysis of all MRA exams
done prior to May 2016 or with a high TE may identify other patients in
which the stenosis can be re-classified.

Aside from the presence of MRI artifacts, interpretation of MRA imaging
may be partially dependent on the interpreting neuroradiologist. To
minimize this variability, a blinded expert neuroradiologist reviewed
the pre-May 2016 images for the six patients that had a change in
treatment plan. This reader agreed with previous MRA reports regarding
the appearance of stenosis in five of the six patients, however for one
patient this reader did not identify any stenosis on the pre-May 2016
imaging. This raises the question regarding variability of expert
neuroradiologist interpretation of stenosis versus artifact in scans
with higher TE and implications on clinical management.

To elucidate these results further, next steps could include a focused
comparative analysis of TCD and MRA findings on a larger sample size,
which may require a multicenter project to identify patients with CNS
arterial stenosis identified using a higher TE and prospectively
re-image them with a lower TE. Further analysis could also include other
factors that might decrease the degree of artifact (slice thickness,
matrix, contrast mechanisms, etc.), comparison to other vessel imaging
techniques, long term follow up of patients identified in this study,
and addressing the impact of MRI parameters in patients with other
vascular conditions.

\textbf{Conclusion}

Implementing a standardized, SCA-specific MRA scanning protocol, using
short-TE techniques, allowed for re-classification of previously seen
stenosis in 12/29 patients (41\%). This reclassification resulted in
discontinuation of chronic transfusion therapy, which has potentially
significant side effects, in six out of 24 patients. Implementation of
the TWiTCH trial results is dependent on accurate classification of the
grade of vasculopathy on MRA and if low grade, allows the patients to
transition to hydroxyurea. Optimizing MRA echo time to \textless{}5msec
can minimize flow artifact, improve accurate interpretation of true
cerebrovascular disease, and impact treatment plans put in place for
stroke prevention for pediatric patients with sickle cell anemia.

Acknowledgements: Prince Dhillon, DMD, MD for guidance on figure
creation

Sources of Funding: none

Disclosures: none

\textbf{Figure 1. Flowchart of patient sample identification}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Table 1. Baseline (pre-May 2016) clinical characteristics of 29
patients with sickle cell CNS vasculopathy}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Variable & Value\tabularnewline
\midrule
\endhead
Age \textbf{median (range), y} & 12 (5-21)\tabularnewline
\textbf{Sex} & \textbf{n (\%)}\tabularnewline
Male & 12 (41)\tabularnewline
Female & 17 (59)\tabularnewline
\textbf{Genotype} & \textbf{n (\%)}\tabularnewline
HgbSS & 29 (100)\tabularnewline
\textbf{Clinical treatment plan} & \textbf{n (\%)}\tabularnewline
Hydroxyurea & 2 (7)\tabularnewline
Chronic transfusion therapy & 19 (66)\tabularnewline
Previous Bone Marrow Transplant & 1 (3)\tabularnewline
Previous Bone Marrow Transplant + chronic transfusions & 5
(17)\tabularnewline
EDAS* + chronic transfusions & 2 (7)\tabularnewline
\textbf{Degree of objective neurologic disease} & \textbf{n
(\%)}\tabularnewline
None & 8 (27)\tabularnewline
TIA (clinically) & 2 (7)\tabularnewline
Silent infarct & 18 (62)\tabularnewline
Symptomatic stroke & 11 (38)\tabularnewline
\bottomrule
\end{longtable}

* Encephaloduroarteriosynangiosis

\textbf{Figure 2.} ~\textbf{Example patient images}

Axial 3D time of flight (TOF) MRA head and corresponding maximum
intensity projection (MIP) images before (A, B) and after (C, D) the
protocol change in the same patient.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Before - Images A and B taken with a higher echo time show focal
diminished flow related signal in the right greater than left internal
carotid artery supraclinoid segment (outlined grey arrow and arrowhead).

After - Images C and D taken with a lower echo time show vessel patency
after protocol change (white arrow and white arrowhead).

\textbf{Figure 3. Example patient images}

Axial 3D time of flight (TOF) MRA head and corresponding maximum
intensity projection (MIP) images before (A, B) and after (C, D) the
protocol change in the same patient.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Before - Images A and B taken with a higher echo time show focal
diminished flow related signal in the A1 segment of the left anterior
cerebral artery (outlined grey arrow and arrowhead).

After - Images C and D taken with a lower echo time show vessel patency
after protocol change (white arrow and white arrowhead). 

\textbf{Figure 4. Treatment plans for 29 patients with sickle cell CNS
vasculopathy pre and post implementation of a standardized MRA scanning
protocol}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

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Data available on request due to privacy/ethical restrictions

\emph{Figure Legend}

\emph{Figure 1.} Flowchart of patient sample identification

\emph{Table 1.} Baseline (pre-May 2016) clinical characteristics of 29
patients with sickle cell CNS vasculopathy

\emph{Figure 2.} ~Example patient images

Axial 3D time of flight (TOF) MRA head and corresponding maximum
intensity projection (MIP) images before (A, B) and after (C, D) the
protocol change. Before - Images A and B taken with a higher echo time
show focal diminished flow related signal in the right greater than left
internal carotid artery supraclinoid segment (outlined grey arrow and
arrowhead). After - Images C and D taken with a lower echo time show
vessel patency after protocol change (white arrow and white arrowhead).

\emph{Figure 3.} Example patient images

Axial 3D time of flight (TOF) MRA head and corresponding maximum
intensity projection (MIP) images before (A, B) and after (C, D) the
protocol change. Before - Images A and B taken with a higher echo time
show focal diminished flow related signal in the A1 segment of the left
anterior cerebral artery (outlined grey arrow and arrowhead). After -
Images C and D taken with a lower echo time show vessel patency after
protocol change (white arrow and white arrowhead). 

\emph{Figure 4.} Treatment plans for 29 patients with sickle cell CNS
vasculopathy pre and post

implementation of a standardized MRA scanning protocol

\emph{Data Availability}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{Hosted file}

\verb`Tables Impact of MRA Echo Time on Stroke Prevention Therapy in Pediatric Patients with Sickle Cell Disease.docx`  available at \url{https://authorea.com/users/473807/articles/563870-impact-of-mra-echo-time-on-stroke-prevention-therapy-in-pediatric-patients-with-sickle-cell-disease}\selectlanguage{english}
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