MRI in Multiple Sclerosis: How Imaging Helps Diagnose and Predict the Disease

Table of Contents

• Key Points
• Background: Why This Research Matters
• Basic Principles of MRI Techniques
• Diagnostic Criteria for MS
• Promising MRI Measures for MS Diagnosis
• MRI for Prognosis: Predicting Disease Course
• Special Populations and Diagnostic Challenges
• New Technologies: Artificial Intelligence and Automated Tools
• Recommendations and Clinical Implications
• Limitations and What the Study Could Not Prove
• Frequently Asked Questions
• Source Information

Key Points

• MRI is crucial for diagnosing MS because it detects specific damage in the brain and spinal cord with high accuracy.
• The 2017 McDonald criteria allow earlier diagnosis and treatment, but they are more sensitive and less specific than the 2010 criteria, so careful exclusion of other conditions is essential.
• Emerging markers such as cortical lesions, the central vein sign, paramagnetic rim lesions, and optic nerve involvement may improve diagnostic accuracy.
• Advanced MRI techniques can help predict disability progression, and lesion number and location in the brainstem and spinal cord may predict long-term outcomes in early MS.
• Standardized brain and spinal cord MRI protocols and interpretation by qualified neuroradiologists are essential worldwide.

Background: Why This Research Matters

Multiple sclerosis (MS) is a disease in which the immune system attacks the protective covering of nerve fibers in the brain and spinal cord. In most patients, MS begins with reversible episodes of neurological dysfunction. These episodes are often followed by irreversible clinical disability.

Accurate diagnostic criteria and prognostic markers are critical. They allow doctors to diagnose MS early and to correctly identify patients who are at increased risk of disease progression. Early diagnosis allows earlier treatment, which can limit the buildup of permanent disability.

The diagnosis of MS requires evidence of a symptomatic demyelinating syndrome (an episode of neurological symptoms caused by damage to the myelin sheath). It also requires objective neurological signs. Doctors must evaluate clinical and paraclinical findings to demonstrate a focal demyelinating pathology. This pathology must affect at least two distinct areas of the central nervous system (CNS). This is called dissemination in space (DIS). The damage must also occur at separate times, which is called dissemination in time (DIT).

Doctors must also exclude alternative diagnoses. MRI was formally included in the diagnostic algorithm for patients presenting with a clinically isolated syndrome (CIS) suggestive of MS in the 2001 McDonald criteria. These criteria have been revised several times, most recently in 2017. The criteria rely on standardized MRI protocols to assess the number, size, and location of brain and spinal cord lesions typical of MS.

Recently, uncommon groups within the MS population have gained increased attention. These groups include primary progressive (PP) phenotypes, pediatric MS, late-onset MS, and radiologically isolated syndrome (RIS). New potential MRI features for MS diagnosis and prognostication have also been proposed. These features include the assessment of optic nerve involvement, the detection of cortical lesions (CLs), the central vein sign (CVS), and chronic active lesions.

Basic Principles of MRI Techniques

Clinical MRI relies on the resonance signal of hydrogen (1H) spins of the intra- and extracellular tissue water. It offers different sequences and techniques to visualize changes in the microstructural environment of these water compartments.

In MS, most pathophysiological features are associated with an increase in T2 relaxation time. These features include inflammation, edema, demyelination, and axonal loss. A T2-weighted spin echo sequence therefore is the most sensitive approach to depict MS lesions as hyperintense signal intensities (bright spots).

Improved conspicuity of T2 lesions can be achieved with a fluid-attenuated inversion recovery sequence (FLAIR). This is especially true with three-dimensional (3D) acquisitions. FLAIR sequences suppress the cerebrospinal fluid (CSF) by an inversion radio frequency pulse. A delay time follows that corresponds to zero-magnetization of the CSF during T1 relaxation.

T1 contrast is considered a more sensitive marker for demyelination and axonal loss. This is because these processes result in T1 prolongation. T1 contrast can be achieved with a short echo time spin echo sequence and a repetition time that corresponds to T1 of white matter (WM). At higher field strengths, it is advantageous to use gradient echoes with shorter repetition times. This permits true 3D imaging with improved T1 contrast and high signal-to-noise ratio.

3D T1-weighted sequences with isotropic resolution are also crucial when assessing brain volume and atrophy. T1-weighted sequences are still the only way to reliably identify active lesions after gadolinium (Gd)-based contrast administration. Gadolinium produces a strong paramagnetic moment leading to significant T1 shortening. Consequently, active lesions where the blood–brain-barrier becomes leaky appear bright on post-Gd T1-weighted images.

Inversion recovery (IR) can suppress tissue with a specific T1 relaxation time. Double inversion recovery (DIR) is used to highlight a specific tissue while suppressing all other magnetization. The DIR sequence provides excellent contrast for the cortex. It was therefore introduced to detect cortical MS lesions with improved sensitivity. The DIR sequence is usually performed with fast spin echo readout and provides the best sensitivity when performed in 3D acquisition mode.

Magnetic susceptibility reflects the ability of tissue to become magnetized when placed in a magnetic field. Brain tissue is weakly diamagnetic (nonmagnetizable), which corresponds to the magnetic properties of water as its main component. In contrast, iron can induce paramagnetic shifts and accentuate MS-related features. These features include lesions with central veins and iron rims, and iron accumulation in the basal ganglia. These features can be detected with susceptibility-based imaging, which is performed with T2*-weighted gradient echo sequences.

Among susceptibility-based imaging, quantitative susceptibility mapping (QSM) includes imaging techniques that allow quantification of the absolute concentrations of specific elements. These elements include iron, calcium, and myelin. This is achieved by assessing their alterations in local magnetic susceptibility. QSM may offer a better contrast-to-noise ratio for specific tissues and structures when compared to T2*-weighted magnitude images.

Magnetization transfer (MT) imaging and diffusion weighted imaging (DWI) are optional sequences that provide quantitative measures of microstructural tissue changes. MT imaging is based on the magnetization exchange between 1H spins bound to macromolecules and surrounding tissue water. The MTR is specific for myelin content, even though it correlates with other pathological substrates, such as axonal density.

The mobility of intra- and extracellular tissue water is driven by Brownian motion and restricted by cellular structures. This leads to anisotropic diffusion, particularly in the intracellular cytoplasm of the axons. DWI can pick up alterations in water mobility. Diffusion tensor imaging (DTI) is a fitting model that can assess orientational features such as fiber orientation and the degree of diffusion anisotropy. Complex diffusion models are also able to assess the diffusion properties for intra- and extracellular water separately.

Diagnostic Criteria for MS

In the 2017 revision of the McDonald MRI criteria, DIS can be demonstrated by at least one T2-hyperintense lesion in at least two of four typical areas of the CNS. These four areas are periventricular, cortical/juxtacortical, infratentorial, and spinal cord.

DIT can be demonstrated by the simultaneous presence of Gd-enhancing and non-enhancing lesions at any time. DIT can also be demonstrated by a new T2-hyperintense and/or Gd-enhancing lesion on follow-up MRI.

The modifications introduced in this last revision included the removal of any distinction between symptomatic and asymptomatic lesions. They also combined cortical lesions and juxtacortical lesions to expand the concept of juxtacortical involvement. Furthermore, in patients with typical CIS suggestive of MS fulfilling clinical or radiological DIS, the presence of CSF-specific oligoclonal bands (OCBs) supports DIT.

The 2017 McDonald criteria exhibit higher sensitivity, lower specificity, and similar accuracy compared with the previous 2010 revision. This applies to predicting the second clinical attack (i.e., clinically definite MS) both in adults and pediatric CIS patients.

Moreover, the 2017 McDonald criteria substantially shorten time to MS diagnosis. More CIS patients are diagnosed with MS already at the time of the first clinical manifestation and with a single MRI scan. In 785 CIS patients, the 2017 McDonald criteria were found to reduce the median time to diagnose MS by 4.6 years in comparison to the clinical criterion alone (i.e., Poser criteria). Additionally, they allowed diagnosis of MS 10 months before the 2010 McDonald criteria (3.2 vs 13.0 months).

An early diagnosis allows starting earlier commencement of disease-modifying therapies (DMTs). This limits the accumulation of irreversible clinical disability. In 1174 CIS patients, the median time from CIS to treatment initiation reduced by 82% from the Poser criteria to the 2017 McDonald criteria periods. This was associated with a significantly lower risk of reaching an Expanded Disability Status Scale (EDSS) score of 3.0 or higher for patients diagnosed with the most recent diagnostic criteria.

However, the inappropriate application of MRI diagnostic criteria may increase the risk of misdiagnosis. This is especially true in the context of atypical clinical presentations. To minimize misdiagnosis, standardized MRI protocols are crucial. Careful determination of which imaging patterns constitute "typical" or "atypical" MS features is also crucial. Guidelines for a proper interpretation of imaging findings are essential.

Careful exclusion of other neurological disorders is essential in the MS diagnostic work-up. The range of diseases mimicking clinical manifestations and MRI features of MS is wide. A few MS mimics, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-associated disease (MOGAD), have been more accurately characterized in recent years.

Moreover, small-vessel disease (SVD) is a condition associated with aging. SVD is frequently observed in smokers and in patients with cerebrovascular risk factors such as hypertension, diabetes, and dyslipidemia. SVD may represent the most common differential diagnosis for brain WM hyperintensities. This is especially true in older patients, who tend to have a greater prevalence of underlying comorbidities.

Promising MRI Measures for MS Diagnosis

Recently, more distinctive MRI features have been proposed to improve the specificity and accuracy of the MS diagnostic work-up. These features include cortical lesions (CLs), the central vein sign (CVS), and chronic active lesions.

Cortical Lesions (CLs)

Cortical involvement is an extremely specific hallmark of MS and is highly clinically relevant. CLs are present from the early phases of MS, and they accumulate over time. Several studies confirmed their role in the diagnostic work-up. This is especially true in differentiating MS from other MS mimics. These studies supported the inclusion of CLs in the recent revision of the diagnostic criteria.

Imaging of CLs, especially subpial lesions, is technically challenging. This is mainly because of their characteristics, size, and location. Many CLs are still not detected by any MRI technique. However, 7.0 T MRI detects more CLs with respect to the best performing 3.0 T MRI. Imaging protocols may substantially improve their in vivo detection. These protocols include DIR and phase-sensitive inversion recovery (PSIR). These protocols also include magnetization prepared rapid gradient echo (MPRAGE). These protocols also include magnetization prepared two rapid acquisition gradient echo (MP2RAGE). These protocols also include fluid and white matter suppression (FLAWS) sequences.

The Central Vein Sign (CVS)

Perivenous demyelination is a distinctive pathological feature that is specific of demyelinating disorders of the CNS, especially MS. The association between brain WM venules and MS lesions (i.e., "CVS") can be efficiently visualized in susceptibility-based MRI at varying MRI field strengths and across scanner manufacturers. This takes advantage of the T2*-shortening effect of deoxyhemoglobin, with improved detection after Gd-based contrast.

The presence of the CVS may improve the accuracy of MS diagnosis. A threshold of WM lesions showing the CVS between 35% and 50% has been established as the best cutoff to separate MS and non-MS mimics. These mimics include SVD, migraine, NMOSD, MOGAD, and other inflammatory CNS disorders. To facilitate their assessment, a few studies proposed a threshold of 3 or 6 CVS-positive lesions. This threshold has shown a high sensitivity and good specificity for MS diagnosis.

Paramagnetic Rim Lesions (PRLs)

Histopathologically, several MS lesions show a smouldering inflammatory profile which continues after the acute inflammatory phase. Chronic active lesions typically exhibit a combination of ongoing myelin breakdown, remyelination attempts, and infiltrating immune cells, such as lymphocytes and macrophages. They can be visualized with susceptibility-based imaging as lesions showing an hypointense rim (i.e., paramagnetic rim lesions [PRLs]). This is because they are usually surrounded by activated microglia, which are rich in iron.

PRLs are specific to MS and their assessment can potentially improve the differentiation of MS from other conditions. They have been described in patients with CIS suggestive of MS, but not in MS mimics, including NMOSD, Susac syndrome, and SVD.

The presence of at least one PRL was found the optimal cut-off to distinguish CIS/MS patients from MS mimickers and old healthy subjects. This cut-off had a high specificity (99.7%) but low sensitivity (24.0%) and area under the curve (AUC) of 0.71. Of note, the presence of at least one PRL or at least four lesions with CVS improved the sensitivity (57.9%) and AUC (0.83), preserving the specificity (90.6%).

Among CIS patients, fulfilling the "CVS" criteria predicted MS conversion within three years. The "CVS" criteria are at least 3 lesions or 40% threshold of lesions with the CVS. Having at least one chronic active lesion also predicted MS conversion within three years. This prediction had good sensitivity (up to 90.4%) and specificity (up to 85.7%). Notably, none of the patients who remained with a CIS diagnosis after three years exhibited any chronic active lesion.

QSM has also been applied to identify PRLs. Recent studies showed that QSM may be superior to phase and susceptibility-weighted images in detecting PRLs, with a prevalence of PRLs ranging from 4.2% to 10.6%.

Optic Nerve Involvement

Optic nerve involvement is another promising marker. Studies focusing on acute optic neuritis patients report rates of optic nerve enhancement on contrast-enhanced T1-weighted sequences from 34% to 78%. These rates depend on time elapsed since the onset of optic neuritis, and on corticosteroid use.

Importantly, in the acute phase, lesion length (but not Gd-enhancement characteristics) was associated with poorer visual recovery 12 months after visual symptom onset.

MRI for Prognosis: Predicting Disease Course

The number and location of white matter lesions in the brainstem and spinal cord may predict long-term outcomes in early phases of MS. Advanced MRI techniques can further predict disability progression during the disease course. These techniques include cortical lesions, chronic active lesions, atrophy, and brain microstructural abnormalities.

Primary progressive MS is characterized by gradual progression. In this form, diagnostic emphasis is on cerebrospinal-fluid-specific oligoclonal bands and spinal cord lesions.

Late-onset MS after 45–50 years may pose diagnostic challenges. This is due to comorbidities and a more severe course.

Special Populations and Diagnostic Challenges

Uncommon groups within the MS population have gained increased attention. These groups include primary progressive (PP) phenotypes, pediatric MS, late-onset MS, and radiologically isolated syndrome (RIS).

For progressive-onset MS (PPMS), the diagnosis requires one year of disability progression (retrospectively or prospectively determined) independent of clinical relapse. The diagnosis also requires at least two out of three of the following criteria:

• At least one T2-hyperintense lesion in at least one area in the brain characteristic of MS (periventricular, cortical/juxtacortical, or infratentorial), with no distinction between symptomatic or asymptomatic lesions
• At least two T2-hyperintense WM lesions in the spinal cord, with no distinction between symptomatic or asymptomatic lesions
• Presence of CSF-specific OCBs

For relapse-onset MS (CIS), the diagnostic approach depends on the number of clinical relapses and the number of lesions with objective clinical evidence. The criteria specify when no additional data are needed, when DIS must be demonstrated, when DIT must be demonstrated, and when both DIS and DIT must be demonstrated. Some patients have atypical CIS suggestive of MS fulfilling DIS criteria. For these patients, there is no better explanation for the clinical presentation. In these patients, the demonstration of CSF-specific OCBs substitutes for the requirement of fulfilling DIT. This allows a diagnosis of MS, even if the clinical and MRI findings do not meet the criteria for DIT.

New Technologies: Artificial Intelligence and Automated Tools

The article explores the potential of new technologies, such as artificial intelligence and automated quantification tools, to support clinicians in the management of patients. These tools may help with the consistent application of MRI protocols and the interpretation of results.

However, to ensure consistency and improvement in the use of MRI in MS diagnosis and patient follow-up, it is essential that standardized brain and spinal cord MRI protocols are applied. It is also essential that interpretation of results is performed by qualified (neuro)radiologists in all countries.

Recommendations and Clinical Implications

The 2021 MAGNIMS–CMSC–NAIMS international consensus recommendations offer updated guidelines on the utilization of MRI for diagnosing, prognosticating, and monitoring treatment in MS patients.

For patients, the key implications are:

1. MRI is crucial for diagnosing MS because it detects specific pathological processes with high accuracy.
2. The 2017 McDonald diagnostic criteria accurately predict a second MS attack in patients with typical clinically isolated syndromes, even in pediatric patients. This enables early diagnosis and treatment.
3. However, these criteria should be used cautiously after ruling out other potential diagnoses.
4. Emerging imaging markers like optic nerve involvement, cortical lesions, lesions with the central vein sign, and chronic active lesions may improve the accuracy of diagnostic criteria.
5. Primary progressive MS is characterized by gradual progression, with diagnostic emphasis on cerebrospinal-fluid-specific oligoclonal bands and spinal cord lesions.
6. Late-onset MS after 45–50 years may pose diagnostic challenges due to comorbidities and a more severe course.
7. The number and location of white matter lesions in the brainstem and spinal cord may predict long-term outcomes in early phases of MS.
8. Advanced MRI techniques, including cortical lesions, chronic active lesions, atrophy, and brain microstructural abnormalities, can further predict disability progression during the disease course.

To ensure consistency and improvement in the use of MRI in MS diagnosis and patient follow-up, standardized brain and spinal cord MRI protocols must be applied. Interpretation of results must be performed by qualified (neuro)radiologists in all countries.

Limitations and What the Study Could Not Prove

This Series article discusses the current role of MRI in the diagnosis and prognosis of MS. It also examines promising MRI markers, which could serve as reliable predictors of subsequent disease progression. These markers could help optimize the management of individual patients with MS.

However, novel imaging markers are still emerging. Rigorous validation and standardization is still needed before they can be incorporated into clinical practice. Many cortical lesions are still not detected by any MRI technique. The inappropriate application of MRI diagnostic criteria, especially in the context of atypical clinical presentations, may increase the risk of misdiagnosis.

The article notes that the 2017 McDonald criteria exhibit higher sensitivity but lower specificity compared with the previous 2010 revision. This means the criteria are better at identifying patients who have MS, but may be less accurate at ruling out patients who do not have MS. This is why careful exclusion of other neurological disorders is essential.

Frequently Asked Questions

How does MRI help diagnose multiple sclerosis?

MRI detects the damage to myelin in the brain and spinal cord that is typical of MS. It shows lesions in areas such as around the ventricles, in the cortex or near it, in the brainstem and cerebellum, and in the spinal cord. It can also show that damage has occurred at different times, which supports the diagnosis.

What are the 2017 McDonald criteria and why do they matter?

The 2017 McDonald criteria are a set of rules that use MRI findings to diagnose MS. They allow doctors to diagnose MS earlier than older criteria. In a study of 785 patients with a first episode, the 2017 criteria reduced the time to diagnosis by 4.6 years compared with clinical criteria alone, and by 10 months compared with the 2010 criteria.

Can MRI predict how my MS will progress?

Yes, MRI can help predict the course of MS. The number and location of lesions in the brainstem and spinal cord may predict long-term outcomes in early MS. Advanced MRI techniques, such as measuring cortical lesions, chronic active lesions, brain atrophy, and microstructural abnormalities, can further predict disability progression during the disease.

What is the central vein sign and how is it used?

The central vein sign is a marker seen on special MRI scans. It shows a small vein running through an MS lesion. A threshold of 35% to 50% of lesions with this sign has been established as the cutoff to separate MS from other conditions that mimic it. A threshold of 3 or 6 such lesions has shown high sensitivity and good specificity for MS.

What are paramagnetic rim lesions and what do they mean?

Paramagnetic rim lesions are chronic active MS lesions with a dark rim on special MRI scans, caused by iron-rich immune cells. They are specific to MS. In one study, having at least one such lesion distinguished MS from mimics with high specificity (99.7%) but low sensitivity (24.0%). Having at least one also predicted conversion to MS within three years.

Can MRI be used to diagnose primary progressive MS?

Yes. For primary progressive MS, diagnosis requires one year of disability progression independent of relapses, plus at least two of three criteria: one or more typical brain lesions, two or more spinal cord lesions, or specific antibodies in the spinal fluid called oligoclonal bands. MRI is used to find these lesions.

What are the risks of using MRI to diagnose MS?

The main risk is misdiagnosis if the MRI criteria are applied inappropriately, especially in people with atypical symptoms. The 2017 criteria are more sensitive but less specific than the 2010 version, meaning they are better at finding MS but may be less accurate at ruling it out. Careful exclusion of other conditions is essential.

I was just diagnosed with multiple sclerosis after one MRI scan — when should I get a second opinion on my diagnosis?

The 2017 McDonald criteria can diagnose MS at the first clinical episode with a single MRI, and they are more sensitive but less specific than earlier criteria, so misdiagnosis is possible when they are applied inappropriately, especially in atypical presentations. A second opinion is reasonable when imaging patterns are not clearly typical, when alternative conditions such as small-vessel disease, NMOSD or MOGAD have not been excluded, or when the diagnosis rests on one scan. Review of the original images by a qualified neuroradiologist using standardized brain and spinal cord protocols is central. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Current and future role of MRI in the diagnosis and prognosis of multiple sclerosis

Authors: Maria A. Rocca, Paolo Preziosa, Frederik Barkhof, Wallace Brownlee, Massimiliano Calabrese, Nicola De Stefano, Cristina Granziera, Stefan Ropele, Ahmed T. Toosy, Àngela Vidal-Jordana, Massimiliano Di Filippo, and Massimo Filippi

Publication: The Lancet Regional Health–Europe, 2024; volume 44, article 100978. Published online 22 August 2024.

DOI: https://doi.org/10.1016/j.lanepe.2024.100978

Copyright: © 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This patient-friendly article is based on peer-reviewed research.