Standardization of MRI in Multiple Sclerosis Management Consensus by the Czech Expert Radiology-Neurology Panel

Summary

In MS, MRI has an irreplaceable role. The unification of MRI management across different institutions is crucial for maximal use of the potential of this method, i.e., for early and accurate diagnosis with the determination of prognostic markers, early signal of ineffectiveness of therapy or safety problem, but also for availability of adequate care for all patients. At the same time, communication between the radiologist and neurologist and the associated standardization of both the referral form and MRI description are essential. In addition to improving the quality of care for the individual patient, a uniform MRI data format would also lead to the possibility of national data collection. This would allow for structured information for research as well as the use of MRI data in negotiations with healthcare providers. For this purpose under the patronage of the Section of Clinical Neuroimmunology and Liquorology of the Czech Neurological Society, this consensus of the Czech Expert Radiology-Neurology Panel is published based on the international Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) recommendations. It proposes recommendations for a basic and extended diagnostic, monitoring and safety MRI protocol, specifies the frequency of individual examinations, the necessary information on the MRI referral form and presents a standardized description of diagnostic and monitoring MRI in patients with suspected or confirmed diagnosis of MS.

Keywords:

diagnostic criteria – Safety – Multiple sclerosis – magnetic resonance imaging – monitoring protocol – recommendations – prognostic markers – diagnostic protocol – referral form – standardized description

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

The role of MRI is absolutely crucial in MS patients, even at the time of disease diagnosis. Therefore, it has been incorporated into the international McDonald diagnostic criteria and its role is gradually being strengthened in subsequent revisions (the most recent revision of the criteria is from 2017 [1]). The MRI protocol used in the diagnosis of the disease must reflect the mentioned criteria, allow to differentiate MS from other diseases, and above all to reach a diagnosis as quickly as possible. Adequate therapy initiated as early as possible is crucial for the patient's prognosis [2-8].

However, self-diagnosis is not the only role of MRI in the management of new MS patients. The course of the disease is highly variable from patient to patient and the prognosis is uncertain at the time of diagnosis. Therefore, a correct evaluation of predictive indicators is essential for setting the next treatment strategy, especially because of the possibility of early deployment of more effective therapy, even at the cost of a higher risk of adverse effects of this treatment [9]. The basic, and thus key, predictive indicator is the finding on the initial MRI scan [10]. Therefore, we consider the optimal situation to be the evaluation of these important indicators already in the diagnostic imaging. A worse prognosis is predicted by a larger number and volume of lesions [11,12], infratentorial location [13,14], intramedullary localization of lesions [15,16] and enhancement demonstrating active inflammation with a breached blood-brain barrier [16]. We must not forget the presence of early signs of atrophy and black holes already at the initial examination [17]. Large foci of involvement in the cortex are also an unfavourable predictor of cognition and overall disability (according to the Kurtzke Expanded Disability Status Scale [EDSS]) [18].

Once therapy is initiated, it is equally important to monitor its effectiveness and safety and to change the therapeutic strategy in time if necessary. The main clinical and practically measurable outcome is the level of clinical disability assessed by the EDSS. However, when disability progresses, it is often too late to intervene effectively enough. A paraclinical marker capable of capturing subclinical MS activity is essential for early effective therapy change, and this is mainly MRI. This is also reflected in the current European and Czech treatment standards, which mention the concept of No Evidence of Disease Activity (NEDA) as one of the main treatment goals. A patient who achieves NEDA-3 does not have clinical relapses, does not progress on the EDSS scale and does not show active inflammatory lesions or new or enlarged T2 lesions [19-21]. Achieving NEDA-3 leads to a significantly lower risk of long-term progression [22]. However, in addition to indication criteria based on medical evidence, treatment in the Czech Republic is also governed by reimbursement criteria. These also take into account MR parameters. Currently, these include the evaluation of negative prognostic markers in the MR image, that is, the presence of infratentorial and intramedullary foci, the total number of foci and the presence of enhancing lesions. Furthermore, treatment can be escalated based on MR image activity alone -⁠ when three or more new or enlarged lesions are present. Given the proven importance of MR in detecting subclinical activity, further expansion of treatment regimens based on MR findings can be anticipated.

Last but not least, the monitoring of neurodegeneration responsible for the accumulation of disability, or in particular progression independent of relapse activity (PIRA), which according to available data is already present at the beginning of the disease and starts to dominate with time, is a very topical issue [23,24]. PIRA is caused by inflammation smouldering behind the closed blood-brain barrier. This inflammation is typically localized at the margins of pre-existing foci and is mediated mainly by activated microglia [25,26]. The detection of chronically active foci, either in the form of slowly evolving lesions (SEL) or foci with a ring-shaped hyposignal border on susceptibility-weighted imaging, the so-called paramagnetic rim lesion (PRL), has been applied to monitor this phenomenon on MRI. To predict disease severity, it is ideal to monitor both SEL and PRL, as a greater increase in disability has been described in patients with lesions positive for both features [27]. Progressive atrophy is also evident [25]. PIRA monitoring is gaining clinical relevance, especially as phase III clinical trials of several Bruton's tyrosine kinase inhibitors with the ability to penetrate the CNS and affect, among other things, microglia and thus smoldering inflammation are nearing completion [28-34]. The ever-expanding portfolio of therapeutic options as well as improving MRI methods are also leading to new therapeutic targets, with the NEDA-3 concept becoming widely accepted in addition to the aforementioned NEDA-4 concept taking into account atrophy monitoring [35].

MRI has been the most important biomarker in MS since its introduction and its importance has increased. Firstly, due to the possibility of deploying highly effective treatment based on MR findings, and secondly, due to the possibility of escalation in subclinical activity based on MR progression. Unification of protocols across departments is crucial for maximal use of the potential of this method, i.e. for early and accurate diagnosis with identification of prognostic markers, early signal of therapy ineffectiveness or safety problem, but also for availability of adequate care for all patients. Standardization leads to greater specificity and sensitivity of MR examinations. At the same time, the quality of communication between radiologist and neurologist and the related standardization of both the request form and the evaluation of the MR examination, or the standardization of its description, is equally important. In addition to improving the quality of care for the individual patient, a uniform format of MR data will also enable data collection at the national level [36] and better negotiating conditions when dealing with healthcare payers. To this end, recommendations for standardized protocols according to Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) and the Consortium of Multiple Sclerosis Centers are published regularly [37]. The recent trend is then to consolidate optimization at the national level. The Czech Republic is also moving in this direction, and under the auspices of the Section of Clinical Neuroimmunology and Neurology (SKNIL) of the Czech Neurological Society, this consensus of the Czech expert radiology-neurology panel is published and modified according to MAGNIMS [37-39].

 

Standardization of MRI diagnostic protocol in adult patients

The basic minimum diagnostic protocol for brain examination established by the consensus of the Czech expert radiology-neurology panel, following the MAGNIMS model [37], is preferably performed on a 3T machine, if available. It includes (Table 1, Figs. 1, 2):

Sagittal 3D fluid attenuated inversion recovery (FLAIR) -⁠ key sequence (possibly with fat signal suppression);

T2-weighted image in the transverse plane (turbo spin echo [TSE] or fast spin echo [FSE]; slice thickness less than or equal to 3 mm) -⁠ the FLAIR sequence and T2-weighted image can be performed postcontrast to avoid prolonging the scan time and to maintain the postcontrast scan interval;

Postcontrast T1-weighted 2D transverse plane image or 3D (it is important to maintain an interval of 5-10 min between contrast agent administration and scanning to maximize enhancement detection);

    Diffusion weighted image (DWI) -⁠ can help in differential diagnosis, e.g. It can help in the diagnosis of vascular lesions, vasculitis, inflammatory changes (typical MS lesions do not have diffusion restriction), but it is necessary to keep in mind that hyperacute plaques may have diffusion restriction (one week before the appearance of enhancement) [40] + T1 weighted 3D image (with isotropic voxel and high resolution, native) -⁠ it is recommended to be added during the diagnostic examination, if possible, as a baseline for the possibility of measuring brain atrophy and SEL in the future.

In line with current knowledge on the importance of cortical lesion detection, an extension of the protocol is recommended for consideration (Figure 2):

        Double inversion recovery (DIR) -⁠ this sequence is very sensitive for the detection of cortical foci, which are counted according to the current diagnostic criteria for dissemination in space (DIS). Cortical foci are more specific for MS than white matter foci. In contrast, they are not typical of neuromyelitis optica and its broader spectrum disorder (neuromyelitis optica spectrum disorder; NMOSD), and do not occur in migraine patients or healthy volunteers -⁠ however, there may be a small white matter lesion in these groups. The problem may be the prolonged examination time and evaluation, which is more time consuming and requires some specialist erudition. For higher detection it is advisable to include DIR in 3D.

Susceptibility weighted imaging (SWI) -⁠ this imaging may increase the specificity of MR imaging as it is able to visualize perivenular demyelination by showing the central venule passing through the lesion. This sequence should be used where differential diagnostic problems are expected, e.g. in elderly patients to differentiate postischemic changes. If a higher percentage of lesions with central venule signs are present, then it is likely to be MS and not a disease mimicking it. The disadvantage of this sequence is that acquisition has not yet been standardized and there are higher demands on erudition in its evaluation. Another problem is the lack of a defined cut-off value. However, according to the available literature, RS is clearly distinguished from other diseases with white matter deposits by a minimum of 50% of deposits with the presence of a central venule [41]. Some authors suggest to choose a certain minimum number of foci with the presence of a central venule, e.g. the rule of three or six foci [42-44]. SWI can also image chronically active foci, that is, foci that have hyposignal borders. We detect activated microglia at the periphery of the lesion or its elevated iron content (PRL). Foci are found in relapsing-remitting as well as, to a greater extent, in progressive MS [45,46]. Their occurrence is reported in 20-40% of patients [44,47-49]. Comparison of foci with hyposignal borders on MRI with histopathological findings has shown that they are chronically active foci (SEL) that are destructive in the centre (axonal loss) and have smoldering inflammation and demyelination at the margins [48]. The problem here is similar to that in the evaluation of central venule symptoms; the sequence is not standardized (different for different time to echo [TE] devices; lower sensitivity for the 1.5T device) and the evaluation of the foci requires expert erudition and is time consuming.

 

The basic minimum diagnostic protocol includes examination of the spinal cord in the sagittal plane with a maximum thickness of 3 mm without gaps, at least up to vertebral body Th4-5. It always contains two sequences out of three (Table 2, Fig. 3):

T2 weighted image;

    protondensity weighted display;

T2-weighted image with fat suppression using short tau inversion recovery (STIR) technique (T2 STIR sequence for spinal cord imaging should be performed before contrast agent application due to possible contrast suppression of any confluent lesions).

Since contrast agent is applied during diagnostic MRI to show enhancement of lesions in brain tissue, it is recommended to perform post-contrast examination of the spinal cord -⁠ in the sagittal plane of the section (although the incidence of enhancement of intramedullary lesions is an order of magnitude lower than intracerebral).

The MRI scan of the spinal cord can be extended with additional sequences:

                T2-weighted image in the transverse plane -⁠ can help with confirmation of the lesion (e.g. in case of loading of sagittal sections with artefacts), it is of great importance in increasing specificity; RS lesions are typically localized laterodorsally in contrast to central localization in NMOSD and diseases with positivity of antibodies against myelin oligodendrocyte glycoprotein (MOGAD).

 

Standardization of MRI monitoring protocol in adult patients

The basic, non-submissive MR protocol for monitoring MS established by the consensus of the Czech expert radiology-neurology panel, following the MAGNIMS model [37], includes (Table 1, Figure 4):

                Sagittal 3D FLAIR -⁠ key sequence (with reconstructions in the transverse plane tilted according to the corpus callosum, possibly with fat suppression), in case of lower quality it is advisable to add T2 weighted image in the trans -⁠ versal plane;

DWI.

 

If possible, supplementation is recommended for standardized measurement of atrophy:

T1 weighted 3D image (with high-resolution isotropic voxel).

 

Standardization of the MRI security monitoring protocol

In patients at risk of developing progressive multifocal leukoencephalopathy (PML), a subset of the monitoring protocol must be defined, namely the safety protocol. According to the consensus of the radiology-neurology panel, this should include (table 1):

sagittal 3D FLAIR -⁠ key sequence (with reconstructions in the transverse plane folded according to the corpus callosum);

    T2 weighted image in the transverse plane;

    DWI.

 

Standardization of MRI application and monitoring logistics

In addition to the actual protocols, the timing of the MR examination is also crucial with regard to disease dynamics and therapeutic response. The Czech expert radiology-neurology panel recommended:

                Examination frequency (Figure 5) -⁠ MRI of the brain and spinal cord should be performed in the diagnostic protocol before starting therapy (optimally no more than 3 months before starting therapy). Rebaseline MRI of the brain on the same device in the monitoring protocol is recommended to be performed subsequently every 6 months after starting/changing therapy. Further monitoring should be performed every 12 months. With regard to spinal cord imaging, the request for inclusion in the monitoring protocol must be indicated by the neurologist on the claim form based on individual consideration. It is recommended especially for spinal cord symptoms, also according to MAGNIMS [37]. The inclusion of spinal cord MRI (partial after Th4) in regular monitoring is also to be considered, albeit with a longer interval (e.g. à 2-3 years) [50].

    Pregnancy and lactation -⁠ in pregnancy, MRI is not performed in the first trimester; in the second or third trimester, MRI can be performed, but always without the administration of contrast medium (due to transfer to the fetal circulation). After delivery, there are no restrictions on MR monitoring or contrast agent administration. A negligible amount enters the breast milk, and the current recommendations of the European Society of Urogenital Radiology no longer provide the earlier instruction to interrupt lactation for 24 h after gadolinium contrast agent administration [51]. In the case of delivery, a rebaseline MRI scan should be performed up to 3 months apart.

    Safety monitoring: imaging in the safety monitoring protocol should be performed in patients with John Cunningham virus (JCV) antibody index positivity at 3-month intervals.

Contrast agent administration (Fig. 5) -⁠ contrast agent administration must be performed before the start of treatment within the diagnostic protocol described above (except in patients with contraindications for gadolinium contrast agent administration or in case of completely negative lesion findings), then only in specific cases according to the agreement of the radiologist and neurologist. The neurologist has to indicate the administration of contrast agent in the monitoring, the indication has to be adequately justified on the application form (e.g. when planning escalation of treatment or suspecting a coincidence with another disease), then MRI with contrast agent will be performed with the radiologist's consent, unless there are contraindications.

    Consistency -⁠ the MRI scan should optimally be performed on the same machine for each patient, with the same protocol and parameters being maintained.

    Appointment management -⁠ the monitoring of appointments is the responsibility of the neurologist, the request must be delivered as soon as possible in order to be able to schedule MRI examinations in advance.

    Standardization of information on the MRI request form -⁠ in order to streamline the cooperation between neurologist and radiologist, but also to enable the use of relevant standardized protocols, it is essential to include all necessary information on the request form. The suspicion of MS, or already established diagnosis of MS, including phenotype, treatment and clinical activity should be noted on each request form. In the case of a request for a safety protocol, information about the high risk of PML + possibly the presence of an atypical clinical symptom should be included.

 

Standardisation of the description

A final, but equally important, point of consensus is the importance and form of standardized MR descriptions within both diagnostic and monitoring protocols (Tables 3, 4). Standardization of descriptions and their conclusions is a trend across disciplines and countries. It allows radiologists to speed up their work and neurologists to make therapeutic decisions more easily based on knowledge of all the essential information from MRI needed to determine prognosis and appropriate treatment [52,53]. In particular, indicating the presence of DIS and dissemination over time (DIT) and the presence of negative prognostic markers (multiple foci, presence of infratentorial, intramedullary, but also cortical lesions, enhancement, black holes, degree of atrophy) is essential. The number of new and enlarging lesions in individual locations and overall (Figure 6) should not be neglected (also with regard to diagnostic and reimbursement criteria). However, a semi-quantitative evaluation according to the following scheme seems to be sufficient: 1, 2, 3, > 3, > 20, reflecting also the MAGNIMS recommendations [37]. For the evaluation of MR monitoring, the use of automated postprocessing techniques is advantageous, which speed up and unify the evaluation of active foci. Software is available within scanner manufacturers' evaluation consoles (e.g., 3D coregistrated fusion with subtraction), freely available software (e.g., ITK-SNAP [University of North Carolina, Charlotte, NC, USA]) [54], or academic software developed at individual departments (Figure 6) [55].

 

Conclusion

In MS, particularly in the last decade, there have been significant advances in the understanding of aetiopathogenesis and in therapeutic, diagnostic and monitoring advances. MRI has played a fundamental role. In order to maximise the use of this imaging modality to improve patient prognosis, it is necessary to standardise it at all levels -⁠ from a properly selected diagnostic and monitoring protocol, to monitoring on the same machine, to adherence to recommended examination intervals, to standardised radiological descriptions and claims. Correct and timely indication of MR can help to initiate therapy quickly as well as modify it if necessary and significantly reduce disability at an individual level across all MS centres. At the same time, standardized MR data will then enable analysis of large cohorts and advance science leading to further improvements in care. This consensus of the Czech expert radiology-neurology panel, supported by SKNIL, provides the first steps towards establishing a unified approach across the Czech Republic. The next necessary step is its implementation into routine clinical practice.

 

Grant support

The work was supported by the grant of the Ministry of Health of the Czech Republic-RVO-VFN64165; the Cooperatio, neuroscience research program of Charles University and the project of the National Institute for Neurological Research (EXCELES Program, ID: LX22NPO5107) -⁠ Funded by the European Union -⁠ Next Generation EU.

 

Conflict of interest

The authors declare that they have no commercial interests in the subject of the study.

 

Table 1. Standard protocols for brain examination.

Protocol		Diagnostic	Monitoring	Security
T2 FLAIR 3D* (SAG)	isotropic voxel 1≤ ×  1 × 1 mm from vertex to max spinal cord	+	+	+
T2 FLAIR (TRA)	≤ 3mm, subcallous inclination	+ (-*)	+ (-*)	+ (-*)
T2 TSE (TRA)	≤ 3mm, subcallous inclination	+	+ (± *)	+
T1 3D isotropic	isotropic voxel≤  1 × 1 × 1 mm from vertex to max spinal cord	±	±	-
DWI (TRA)	≤ 5mm	±	±	+
T1 + KL	2D /3D interval 5-10 min	+	±	±
DIR	2D/3D	±	±	-
SWI		±	-	-

*when 3D FLAIR cannot be performed or when 3D FLAIR is not of sufficient quality

DIR, double inversion recovery; DWI, diffusion weighted images; FLAIR, fluid attenuated inversion recovery; KL, contrast agent; SAG, sagittal; SWI, susceptibility weighted imaging; TRA, transverse; TSE, turbo spin echo

 

 

Table 2. Standard protocols for spinal cord examination.

Protocol		Diagnostic	Monitoring	Security
T2	≤ 3mm, 0 gap	+*	±	-
T2 STIR	≤ 3mm, 0 gap	+*	±	-
PDW	≤ 3mm, 0 gap	+*	±	-
T1 3D	isotropic voxel≤  1 × 1 × 1 mm	±	±	-
T2 TSE (TRA)	≤ 5mm	±	±	-
T1 SAG + KL	interval 5-10 min	+	±	-
T1 SAG		±	±	-
T1 TRA + KL		±	±	-

*2 sequences of 3 (T2/T2 STIR/PD)

KL, contrast agent; PDW, proton density weighted imaging; TSE, turbo spin echo; TRA, transverse; SAG, sagittal; STIR, short tau inversion recovery

 

 

Table 3. Standard diagnostic description of MRI.

MR protocol: diagnostic

supratentorial (number of foci): periventricular: 0, 1, 2, 3, more subcortical: 0, 1, 2, 3, more cortically: 0, 1, 2, 3, more bearings in central grey: 0, 1, 2, 3, more

infratentorially (numbers of foci): cerebellum: 0, 1, 2, 3, more mesencephalon: 0, 1, 2, 3, more pons: 0, 1, 2, 3, more Oblong: 0, 1, 2, 3, more

spinal cord -⁠ examined after vertebral body... intramedullary foci: 0, 1, 2, 3, more diffuse changes: no/yes

atrophy cortical atrophy none/mild/moderate/severe regional atrophy yes/no, area

Kl applied: no/yes, bearing enhancement: no/yes, number of

flush bearings: yes/no

total number of bearings (exactly up to 20, others to be considered, estimate 20-50, 50-100, can't count):

finding typical for MS: yes/no a finding more typical of another disease

incidental finding: no/yes -⁠ which one

Conclusion: MRI of the brain shows quite a few... deposits. The finding meets DIS yes/no. The finding meets DIT yes/no. Negative prognostic markers are present -⁠ yes/no, infratentorial foci -⁠ number, intramedullary foci -⁠ number. Violated HEB is present no/yes, number of enhancing foci. The finding is typical for MS/ the finding is more typical for other diseases.

DIT -⁠ dissemination in space; HEB -⁠ blood-brain barrier; CI -⁠ contrast agent

 

 

Table 4. Standard monitoring description of MR.

MR protocol: monitoring

supratentorial (number of foci): periventricular: 0, 1, 2, 3, more subcortical: 0, 1, 2, 3, more cortically: 0, 1, 2, 3, more bearings in central grey: 0, 1, 2, 3, more

infratentorially (numbers of foci): cerebellum: 0, 1, 2, 3, more mesencephalon: 0, 1, 2, 3, more pons: 0, 1, 2, 3, more Oblong: 0, 1, 2, 3, more

spinal cord -⁠ examined after vertebral body... intramedullary foci: 0, 1, 2, 3, more diffuse changes: no/yes

atrophy cortical atrophy none/mild/moderate/severe regional atrophy yes/no, area

Kl applied: no/yes, bearing enhancement: no/yes, number of

flush bearings: yes/no

total number of bearings (exactly up to 20, others to be considered, estimate 20-50, 50-100, can't count):

incidental finding: no/yes -⁠ which one

Conclusion: brain MRI shows MRI ne/ano activity -⁠ total number of foci, localization of foci. Atrophy (mild/moderate/severe) is present. (If KL was administered, in the description: HEB no/yes, number of enhancing foci is visible.) Is there a secondary finding no/yes -⁠ what is it.

HEB -⁠ blood-brain barrier; CI -⁠ contrast agent