Multiple Sclerosis

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

Hidden behind all of the new drugs and breakthroughs reported at the 2024 ECTRIMS meetings was one paper that caught my attention.

It was that, after several years of study, simvastatin had no benefit for multiple sclerosis.

Statins for MS (and for Alzheimer’s disease) have been bandied about for some time, with arguments based on theoretical ideas, and small studies, that they’d have a beneficial effect on the disease – maybe from anti-inflammatory and other properties. In addition, they offered the benefit of being widely available and comparatively inexpensive.

Because of those studies, 15-20 years ago I used them off label for MS in a handful of patients – sometimes as an adjunct to their current treatment (limited at that point to interferons and Copaxone), or in patients who couldn’t afford the FDA-approved drugs. Although not without their drawbacks, the statins are relatively well understood and tolerated.

At some point, for reasons I’ve long forgotten, they all came off of them (at least for MS purposes). Maybe for side effects, or lack of benefit, or because new medications, with much clearer efficacies, were rolling out.

Now it seems pretty clear that statins don’t work for MS.

So was it a bad idea to try? No. Without asking questions we don’t find answers. If they’d worked out it would have been great, another tool on the neurology workbench to reach for in the right situation. It might also have led us to new avenues in MS treatment.

But it didn’t, and that’s fine. Although they don’t get the attention, we learn as much (sometimes more) from negative studies as we do from positive ones. If we put people on every drug that initially showed promise for their conditions, my patients would have a pretty huge medication list. For Alzheimer’s disease alone I remember studies that once suggested ibuprofen, statins, estrogen, nicotine, and several vitamins might be effective (“might” being the key word). Today we’re looking at the PDE5 inhibitors and semaglutide. The jury is still out on them, but whichever way it goes we’ll still learn something.

The statins are good drugs. Their benefits in cardiac and cerebrovascular disease can’t be disputed (I’m sure someone would, but that’s not the point of this piece). But, like all drugs, they don’t work for everything.

Just like other sciences, everything we do now in medicine is based on both the successes and failures of what came before. We learn from both and keep moving forward.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Hidden behind all of the new drugs and breakthroughs reported at the 2024 ECTRIMS meetings was one paper that caught my attention.

It was that, after several years of study, simvastatin had no benefit for multiple sclerosis.

Statins for MS (and for Alzheimer’s disease) have been bandied about for some time, with arguments based on theoretical ideas, and small studies, that they’d have a beneficial effect on the disease – maybe from anti-inflammatory and other properties. In addition, they offered the benefit of being widely available and comparatively inexpensive.

Because of those studies, 15-20 years ago I used them off label for MS in a handful of patients – sometimes as an adjunct to their current treatment (limited at that point to interferons and Copaxone), or in patients who couldn’t afford the FDA-approved drugs. Although not without their drawbacks, the statins are relatively well understood and tolerated.

At some point, for reasons I’ve long forgotten, they all came off of them (at least for MS purposes). Maybe for side effects, or lack of benefit, or because new medications, with much clearer efficacies, were rolling out.

Now it seems pretty clear that statins don’t work for MS.

So was it a bad idea to try? No. Without asking questions we don’t find answers. If they’d worked out it would have been great, another tool on the neurology workbench to reach for in the right situation. It might also have led us to new avenues in MS treatment.

But it didn’t, and that’s fine. Although they don’t get the attention, we learn as much (sometimes more) from negative studies as we do from positive ones. If we put people on every drug that initially showed promise for their conditions, my patients would have a pretty huge medication list. For Alzheimer’s disease alone I remember studies that once suggested ibuprofen, statins, estrogen, nicotine, and several vitamins might be effective (“might” being the key word). Today we’re looking at the PDE5 inhibitors and semaglutide. The jury is still out on them, but whichever way it goes we’ll still learn something.

The statins are good drugs. Their benefits in cardiac and cerebrovascular disease can’t be disputed (I’m sure someone would, but that’s not the point of this piece). But, like all drugs, they don’t work for everything.

Just like other sciences, everything we do now in medicine is based on both the successes and failures of what came before. We learn from both and keep moving forward.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Hidden behind all of the new drugs and breakthroughs reported at the 2024 ECTRIMS meetings was one paper that caught my attention.

It was that, after several years of study, simvastatin had no benefit for multiple sclerosis.

Statins for MS (and for Alzheimer’s disease) have been bandied about for some time, with arguments based on theoretical ideas, and small studies, that they’d have a beneficial effect on the disease – maybe from anti-inflammatory and other properties. In addition, they offered the benefit of being widely available and comparatively inexpensive.

Because of those studies, 15-20 years ago I used them off label for MS in a handful of patients – sometimes as an adjunct to their current treatment (limited at that point to interferons and Copaxone), or in patients who couldn’t afford the FDA-approved drugs. Although not without their drawbacks, the statins are relatively well understood and tolerated.

At some point, for reasons I’ve long forgotten, they all came off of them (at least for MS purposes). Maybe for side effects, or lack of benefit, or because new medications, with much clearer efficacies, were rolling out.

Now it seems pretty clear that statins don’t work for MS.

So was it a bad idea to try? No. Without asking questions we don’t find answers. If they’d worked out it would have been great, another tool on the neurology workbench to reach for in the right situation. It might also have led us to new avenues in MS treatment.

But it didn’t, and that’s fine. Although they don’t get the attention, we learn as much (sometimes more) from negative studies as we do from positive ones. If we put people on every drug that initially showed promise for their conditions, my patients would have a pretty huge medication list. For Alzheimer’s disease alone I remember studies that once suggested ibuprofen, statins, estrogen, nicotine, and several vitamins might be effective (“might” being the key word). Today we’re looking at the PDE5 inhibitors and semaglutide. The jury is still out on them, but whichever way it goes we’ll still learn something.

The statins are good drugs. Their benefits in cardiac and cerebrovascular disease can’t be disputed (I’m sure someone would, but that’s not the point of this piece). But, like all drugs, they don’t work for everything.

Just like other sciences, everything we do now in medicine is based on both the successes and failures of what came before. We learn from both and keep moving forward.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

COPENHAGEN — Serum glial fibrillary acidic protein (sGFAP) is quickly maturing as a biomarker to predict disability in patients with multiple sclerosis (MS), but it will add information to, not compete with, serum neurofilament light chain (sNFl) levels, according to multiple independent studies.

The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.

This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
 

A New Biomarker for MS Disability Progression

Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.

In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.

On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.

Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.

It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.

The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.

Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.

Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).

Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
 

Comparing sGFAP and sNFl

This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.

The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.

However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.

Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”

So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.

Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.

“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.

Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.