Dynamic Expansion and Contraction of Multiple Sclerosis T2-Weighted Hyperintense Lesions Are Present below the Threshold of Visual Perception

Graphical Abstract

Recognition of longitudinal imaging changes of MS lesions has substantial implications for clinical management, but changes may remain below the resolution of human perception. In this study, the authors demonstrated that T2-weighted hyperintense lesions undergo dynamic change on MRI, with predominantly enlarging or contracting characteristics, more frequently seen in untreated individuals.

Abstract

BACKGROUND AND PURPOSE:

The study of T2-weighted hyperintense lesions resulting from autoimmune inflammatory injury and associated volumes within the CNS remains fundamental to the diagnosis and disease surveillance of MS. We investigated the dynamic changes of individual T2-weighted hyperintense MS lesions on MRI and hypothesized that variations may be present below the threshold of visual perception when evaluating longitudinal data.

MATERIALS AND METHODS:

A retrospective study was performed of people with MS, incorporating data from 3 consecutive MRI time points acquired within a single academic center. All included MRI studies lacked formal imaging interpretations of newly enlarging or contracting T2-weighted hyperintensities. Well-defined, noncoalescing, individual T2-weighted hyperintense lesions were targeted. A total of 8–12 lesions were randomly selected in a blinded fashion at MRI time point 1 and 3D lesion volumes were followed over MRI time points 2 and 3. The impact of treatment on lesion expansion and relationship to brain MRI advancement, patient-reported progression of disease, and physician-identified progression was also studied.

RESULTS:

The study cohort comprised 115 people (81 (70.4%) women; mean disease duration of 9.36 years [standard deviation: 7.72 years]) who were primarily White (79.1%). A total of 1426 focal T2-weighted hyperintense MS lesions were identified on MRI time point 1 and longitudinally followed over MRI time points 2 and 3. In the evaluation of raw changes in individual T2-weighted hyperintense lesion volumes from MRI time point 1 to MRI time point 2, a similar number of individuals were observed with predominantly expanding (49/115; 42.6%) or contracting (51/115; 44.3%) lesions. However, most lesions expanded in volume (48/115; 41.7%) versus those that contracted (45/115; 39.1%) when evaluating MRI time point 3 to time point 1. Those individuals not on active treatment had a 67.15% reduction in the odds of more individual lesions predominantly contracting in volume relative to those on low-efficacy disease modifying therapy treatment (95% CI = [−83.89% to −33.01%], P = .0008) and 74.02% reduction relative to high-efficacy treatment individuals (95% CI = [−87.37% to −46.56%], P < .0001).

CONCLUSIONS:

Dynamic changes in T2-weighted hyperintense lesions are abundant, occurring below the threshold of visual perception and are present more frequently in untreated individuals.

SUMMARY

PREVIOUS LITERATURE:

The study of newly enlarging T2-weighted hyperintense lesions has been a cornerstone in MS clinical trials and routine clinical practice for disease surveillance. The appreciation of such changes on longitudinal imaging are dependent upon the review of data in grayscale and perceptions of luminance gradients supported by visual processing within lateral inhibitory optic neurons. As a result, the expansion or contraction of T2-weighted hyperintense lesions over time may occur, however, these changes may remain below the resolution of human perception. The recognition of such changes has significant implications for clinical management.

KEY FINDINGS:

Most T2-weighted hyperintense lesions expanded in volume in people (41.7%) versus contracted (39.1%) from MRI time point 3 to 1. Nonactively treated individuals had a 67%–74% reduction in odds of more individual lesions predominantly contracting in volume based on treatment exposure to low-efficacy or high-efficacy disease-modifying therapies.

KNOWLEDGE ADVANCEMENT:

Dynamic changes in T2-weighted hyperintense lesions associated with MS occur with expanding and contracting characteristics. These transformations appear to be more frequent in untreated individuals and occur below our visual perception, limiting our ability to effectively discern gray-scale differences.

MS is a complex condition with a wide disease spectrum that may result in permanent neurologic injury in susceptible individuals.¹ Fundamental to the diagnosis and disease surveillance of MS is the evaluation of distinct T2-weighted hyperintensities on MRI studies of the brain and spinal cord, features that are reflective of CNS autoimmune inflammatory injury.² Disease-modifying therapies (DMTs) are prescribed to prevent the development of new gadolinium-enhancing lesions, new T2-weighted hyperintense lesions, and to reduce the risk of future disability. As MRI relapses commonly outnumber clinical relapses by a substantial amount, longitudinal imaging studies are performed to monitor for disease advancement.³ These data are also used to evaluate the recrudescence of disease activity in the absence of immunomodulatory or immunosuppressive treatment, but more commonly to assess the DMT treatment response.

In clinical practice, repeat MRI studies are commonly performed, and clinicians rely on both the formal interpretation of the findings coupled with their direct impressions of any change. The appreciation of the interval development of a gadolinium-enhancing lesion or new T2-weighted focus is straightforward. More difficult is recognizing subtle changes that may remain below the resolution of the human perception.⁴ These changes may inform on a subgroup of focal white matter lesions pathologically corresponding to slowly expanding lesions and chronic active inflammation⁵ or even improvement. However, techniques capable of detecting such characteristics are technically complex and often unavailable. These results would be of great value not only to the health care team in providing direction for the most ideal treatment plan but, more importantly, to the patient.

Although incorporated as an essential metric within randomized clinical trials in MS, the definitions of “enlarging” T2 foci used within these studies are not always readily disclosed.^6-9 Moreover, uniform definitions are lacking, and typically, a percent change in volume is applied as a threshold (eg, 20%–40% volume increase), which may vary considerably from study to study. Interestingly, as all DMTs have a mechanism of action that is principally anti-inflammatory, the inverse definition of “shrinking” is not applied. Instead, measures involving the observation of a new T2-weighted hyperintense lesion or change in T2-weighted lesion volume is determined.

The ability to deliver accurate imaging results when longitudinal MRI data are acquired is essential as findings may reveal disease advancement, stability, or even improvement at the individual lesion level. Identifying if lesion size, location, or treatment influences individual lesion behavior is also important. In this retrospective study, we evaluated the dynamic changes of T2-weighted hyperintense lesions over 3 MRI time points in the context of formal imaging reports by neuroradiologists. The study of lesion dynamics by location within the CNS and the relationship to future radiologic and clinical measures of disease progression was also explored.

MATERIALS AND METHODS

Research Participants

In this retrospective study, all research participants were obtained from The University of Texas Southwestern (UTSW) Medical Center and were seen in the Multiple Sclerosis and Neuroimmunology Clinic. Inclusion criteria comprised 1) male or female patients ≥ 18 years of age; 2) an established diagnosis of relapsing-remitting MS after a comprehensive medical evaluation by fellowship-trained MS specialists; 3) 3 MRI time points containing a 3D T2-FLAIR sequence; 4) formal neuroradiology interpretation of MRI studies lacking the description of ≥1 enlarging/contracting T2-weighted hyperintense lesions or the presence of gadolinium-enhancing lesions at baseline or during follow-up; 5) no change in DMT or treatment course within the prior 6 months to each MRI; and 6) no exposure to oral or intravenous glucocorticosteroid treatment within the past 30 days of each MRI. Exclusion criteria included 1) MRI scans with low image quality due to motion artifacts or other causes that hindered effective registration or lesion segmentation or 2) incomplete medical records. The methodology proposed in the Strengthening the Reporting of Observational Studies in Epidemiology Checklist was followed for this study (Online Supplemental Data).

The protocol was approved by the UTSW institutional review board who granted a waiver for consent.

Clinical Relapses, MRI Advancement, Physician-/Patient-Reported Progression

A clinical relapse was defined as a new neurologic symptom consistent with CNS demyelination or worsening of a prior symptom, persisting for >24 hours, that occurred in the absence of fever or acute illness. MRI advancement was defined as the development of a new T2-weighted hyperintense lesion described within the formal neuroradiology reports. Physician-reported disease progression was based on findings documented on neurologic examination. Patient-reported disease progression included personal opinions about changes in mobility, physical functioning, sensory experiences, challenges with memory, fatigue, and quality of life.

MS DMTs

High-efficacy DMTs included alemtuzumab, natalizumab, ocrelizumab, ofatumumab, and oral cladribine. Low-efficacy DMTs comprised weekly or thrice-weekly interferon β-1 α, dimethyl fumarate, fingolimod, glatiramer acetate, monomethyl fumarate, ozanimod, and teriflunomide.

Image Acquisition

All imaging studies were performed on an Ingenia 3T MRI scanner (Philips Medical Systems) by using a 32-channel phased- array coil for reception and body coil for transmission at UTSW. Uniformity corrections were applied for all included scans during the acquisition phase. A 3D T2-FLAIR sequence (1.1 × 1.1 × 1.1 mm³, TE/TR/TI = 350/4800/1600 ms, flip angle 90°, 250 × 250 × 180 mm³ FOV, NEX = 1163 slices, duration: 5:02 minutes) was used for the analysis.

The formal neuroradiologic impressions for each study were reviewed to ensure that included subjects lacked descriptors of enlarging/contracting T2-weighted hyperintense lesions.

Lesion Segmentation

Quality assurance measures were incorporated, including the evaluation of movement along with the presence of artifacts at each MRI time point. Individual lesions were selected if they had well-defined borders and measured at least 3 mm². Single lesions that coalesced with others were excluded. Of the lesions fulfilling these criteria, approximately 8–12 T2-weighted hyperintense lesions were randomly selected on MRI time point 1 by a single reviewer (D.T.O.) with additional details captured, including location, lobe, and hemisphere. The reviewer was blinded to baseline demographic and clinical information. The range of lesions targeted in each individual allowed for proper sampling across different CNS locations and enabled the reasonable study of a meaningful number of lesions across many individuals. This facilitated an adequate comparison of changes in lesion dynamics based on their spatial dissemination characteristics. Targeted lesions were segmented by using an in-house fully automated platform utilizing expert supervision implemented in prior studies, MedIP.^4,10-15 The MRIs for the 3 time points were initially registered based on structural positioning and intensity in which the second and third MRI time points were registered to the first time point (Fig 1). MRI studies were aligned by using the Insight Toolkit (Version 5.1.1; Kitware) multiresolution rigid registration with Mattes Mutual Information Metric.¹⁶ To ensure proper intensity alignment, histogram matching of intensities involving regions of interest was incorporated through linear transforms and ordered correspondence on a set of match points computed from the quantiles of each histogram. After positional and local intensity alignment, segmentations were performed by implementing geodesic active contouring methodology (Fig 1).¹⁷

FIG 1.

A, Axial T2-FLAIR brain images from 3 MRI time points. MRI time point 1 was registered to MRI time point 2 and MRI time point 1 was registered to MRI time point 3 before lesion segmentations. B, Example of T2-weighted hyperintense lesion segmentations by time point. Boxes in solid yellow demonstrate lesion selections at MRI time point 1 (left, circled in green) and MRI time point 2 (right, circled in blue). Dashed yellow line boxes show selections from MRI time point 1 (left, circled in green) and MRI time point 3 (right, circled in red).

Lesion Threshold Determination

A centile curve was fit by using a λ, μ, and σ (LMS) method to estimate the standard deviation (SD) of the rate of volume change per year as a function of the lesion volume at the prior time point.^18,19 The centile curve specifies a time-dependent variance so that at time $t_j$, the SD is estimated to be ${\sigma }_j$. Lesion expansion was defined to be an increase in the rate of volume change greater than $c\times {\text{σ}}_{\text{j}}$, a reduction if the rate of volume change was less than $-c\times {\text{σ}}_{\text{j}}$, and stable otherwise, such that c serves as a scalar value controlling the magnitude of the threshold.

Statistical Analysis

Baseline demographic and clinical data were summarized as the mean and SD when continuous and count and percentage when categoric. Linear regression was used to estimate the average T2-weighted hyperintense lesion volume at MRI time point 1 by lesion location. Tukey pair-wise comparisons were used to estimate differences in the average T2-weighted hyperintense lesion volumes between lesion locations within the CNS. The P values obtained from Tukey pair-wise comparisons were adjusted by using the single-step approach.²⁰

To classify lesions as expanding or contracting, a 1 SD threshold ( $c\hspace{0.17em}=\hspace{0.17em}1)$ was determined based on the LMS curve such that if the rate of change in T2-weighted hyperintense lesion volume was greater than ${\sigma }_j$, it was classified as expanding. Similarly, if the rate of change in T2-weighted hyperintense lesion volume was less than $-{\sigma }_j$, a lesion was classified as contracting. Then, for the $i$-th subject, let $n_{i,expand}$, $n_{i,contract}$, and $n_{i,stable}$ denote the number of lesions expanding, contracting, and stable (within $\pm {\sigma }_j$), respectively. A subject was then designated as improving overall if $n_{i,contract}\hspace{0.17em}>\hspace{0.17em}{n}_{i,expand}$, progressing overall if $n_{i,contract}\hspace{0.17em}<\hspace{0.17em}{n}_{i,expand}$, and stable otherwise. Logistic regression was then used to determine if there was a change in likelihood of overall improvement ( $n_{i,contract}\hspace{0.17em}>\hspace{0.17em}{n}_{i,expand}$) for those receiving high-efficacy therapy or no therapy relative to those receiving low-efficacy therapy, controlling for time from first symptoms and body mass index (BMI). Last, logistic regression was performed to test for differences in the odds of brain MRI advancement, patient-reported progression of disease, and physician-identified progression when an enlarging lesion is present in a particular region.

All analyses were performed in R (Version 4.3.2). A P value < .05 was considered significant.

RESULTS

The study cohort comprised 115 people with relapsing-remitting MS, with a mean age of 41.3 years (SD: 10.4 years) and mean disease duration of 9.36 years (SD: 7.72 years). The median time between MRI time point 1 and 2 was 1.2 years (range: 0.6–4.7 years), and from MRI time points 2 to 3, 1.1 years (0.6–4.1 years). Most people studied were treated with low-efficacy treatments (49.6%), followed by high-efficacy (27.8%), or no treatment (22.6%) (Table 1). A total of 1426 focal T2-weighted hyperintense MS lesions were identified on MRI time point 1 and longitudinally followed over MRI time points 2 and 3.

Table 1:

Baseline demographic and clinical data for the study cohort

N	115
Mean (SD) age (years)	41.3 (10.4)
Race (%)
White	91 (79.1)
Black or African American	22 (19.1)
Native American	2 (1.7)
Sex at birth (%)
Woman	81 (70.4)
Man	34 (29.6)
Mean (SD) height (inches)	66.4 (4.07)
Mean (SD) weight (kilograms)	80.1 (20.9)
Mean (SD) time from first symptom(s) (years)	9.36 (7.72)
Mean (SD) time from diagnosis (years)	6.62 (6.68)
Median (range) time: MRI time point 1 to 2 (years)	1.2 (0.6–4.7)
Median (range) time: MRI time point 2 to 3 (years)	1.1 (0.6–4.1)
Treatment (%)
Low-efficacy	57 (49.6)
High-efficacy	32 (27.8)
None	26 (22.6)
Mean (SD) treatment duration (years)	2.1 (2.3)

In the evaluation of raw changes in T2-weighted hyperintense lesion volumes within an individual from MRI time point 1 to MRI time point 2, a similar number of individuals were observed with predominantly expanding lesions (49/115; 42.6%) as compared with contracting (51/115; 44.3%). Only 15 individuals (13.0%) were identified with an equal number of expanding and contracting lesions within this period. When evaluating MRI time point 3 changes relative to MRI time point 1, more individuals were identified as having a majority of lesions that expanded in volume (48/115; 41.7%) versus those that contracted (45/115; 39.1%) with 22 individuals (19.1%) having an equal number of expanding and contracting lesions.

The average periventricular T2-weighted hyperintense lesion volume at the initial scan was significantly greater than lesions located in juxtacortical/cortical (P < .0001), subcortical (P < .0001), deep white matter (P < .0001), paraventricular (P < .0001), and thalamic/deep gray matter (P = .0001) structures. Table 2 summarizes the observed differences in volume by location within the brain from MRI time point 1.

Table 2:

Differences in T2-weighted hyperintense lesion volumes (mm³) from MRI time point 1 between lesion locations within the brain

Comparison	Estimate	P Value
Infratentorial – deep white matter	−28.01	1.00
Juxtacortical/cortical – deep white matter	−2.50	1.00
Paraventricular – deep white matter	−30.64	.21
Periventricular – deep white matter	105.10	<.0001
Subcortical – deep white matter	−3.65	1.00
Thalamic/deep white matter – deep white matter	−9.71	1.00
Juxtacortical/cortical – infratentorial	25.50	1.00
Paraventricular – infratentorial	−2.64	1.00
Periventricular – infratentorial	133.11	.33
Subcortical – infratentorial	24.36	1.00
Thalamic/deep gray matter – infratentorial	18.30	1.00
Paraventricular – juxtacortical/cortical	−28.14	.47
Periventricular – juxtacortical/cortical	107.61	<.0001
Subcortical – juxtacortical/cortical	−1.15	1.00
Thalamic/deep gray matter – juxtacortical/cortical	−7.20	1.00
Periventricular – paraventricular	135.75	<.0001
Subcortical – paraventricular	26.99	.40
Thalamic/deep gray matter – paraventricular	20.94	.97
Subcortical – periventricular	−108.75	<.0001
Thalamic/deep gray matter – periventricular	−114.81	.0001
Thalamic/deep gray matter – subcortical	−6.06	1.00

Note:—All T2-weighted hyperintense lesions measured at least 3 mm² having an MRI appearance highly suggestive of multiple sclerosis. Lesion location definitions were as follows. Juxtacortical/cortical lesions were defined as T2-weighted hyperintense lesions having physical contact with the cortex with subcortical lesions defined as having a position below the cortex without apparent physical contact. Deep white matter lesions involved deeper regions of the white matter within the brain, away from the cortical/subcortical and periventricular/paraventricular regions. Periventricular lesions had direct contact with the ventricle and paraventricular lesions were positioned near the ventricle without physical connection. Thalamic/deep gray matter lesions had direct contact with the thalamus or basal ganglia. Infratentorial lesions involved structures below the tentorium cerebelli.

Fig 2 demonstrates the results from the LMS curve, estimating the standard deviation of the volume change rate per year as a function of the lesion volume at the prior MRI time point. Data points above the shaded region represent T2-weighted hyperintense lesion expansion, while data points below signify contraction, with those falling within the shaded region remaining stable based on the defined threshold.

FIG 2.

Estimated LMS curve for the rate of volume change per year, with shaded region representing ± 1 SD change.

Utilizing this threshold for T2-weighted hyperintense lesion volume change and when evaluating MRI time point 1 to MRI time point 2, 27.8% and 13.0% of individuals were classified as having predominantly expanding and contracting lesions, respectively. Between these 2 time points, most (59.1%) were observed with equal numbers of expanding and contracting lesions or no expanding or contracting lesions. When evaluating MRI time point 1 to MRI time point 3, more people (76.5%) had equal or no expanding and contracting lesions, while 12.2% and 11.3% had a majority of expanding lesions or contracting lesions, respectively. The number and frequency of expanding, contracting, and stable lesions by location within the brain are provided in Table 3.

Table 3:

Number of expanding, contracting, or stable T2-weighted hyperintense lesions by location within the brain based on a defined threshold in volume change from the prior MRI time point

Location	N	Expansion (%)	Contraction (%)	Stable (%)
All	1426	103 (7.22)	62 (4.35)	1261 (88.43)
Juxtacortical/cortical	184	14 (7.61)	10 (5.43)	160 (86.96)
Subcortical	410	36 (8.78)	19 (4.63)	355 (86.59)
Deep white matter	630	47 (7.46)	21 (3.33)	562 (89.21)
Periventricular	68	4 (5.88)	7 (10.29)	57 (83.82)
Paraventricular	96	0 (0.00)	1 (1.04)	95 (98.96)
Thalamic/deep gray matter	34	2 (5.88)	4 (11.76)	28 (82.35)
Infratentorial	4	0 (0.00)	0 (0.00)	4 (100.00)

Note:—All T2-weighted hyperintense lesions measured at least 3 mm² having an MRI appearance highly suggestive of multiple sclerosis. Lesion location definitions were as follows: Juxtacortical/cortical lesions were defined as T2-weighted hyperintense lesions having physical contact with the cortex with subcortical lesions defined as having a position below the cortex without apparent physical contact. Deep white matter lesions involved deeper regions of the white matter within the brain, away from the cortical/subcortical and periventricular/paraventricular regions. Periventricular lesions had direct contact with the ventricle and paraventricular lesions were positioned near the ventricle without physical connection. Thalamic/deep gray matter lesions had direct contact with the thalamus or basal ganglia. Infratentorial lesions involved structures below the tentorium cerebelli.

Regarding the impact of treatment on individual T2-weighted hyperintense lesion volume changes over the study period, no significant differences were observed between individuals exposed to high-efficacy DMTs versus low-efficacy DMTs (P = .35). Individuals not on active treatment had 67.15% reduction in the odds of more lesions contracting than expanding relative to those on low-efficacy treatment (95% CI = [−83.89% to −33.01%], P = .0008) and a 74.02% reduction in the odds of more lesions contracting than expanding relative to those on high-efficacy treatment (95% CI = [−87.37% to −46.56%], P < .0001) after controlling for disease duration and BMI. There was also no significant impact of enlarging lesions on MRI advancement, patient-reported progression of disease, and physician-identified progression.

DISCUSSION

In this study, we demonstrated that MS lesions on MRI undergo dynamic change with more than 40% of individuals having predominantly enlarging or contracting T2-weighted hyperintense lesion characteristics. Importantly, these dynamic changes remained below the threshold of visual perception and therefore were not recognized or described within formal neuroradiology reports. Our findings appear to be consistent with dynamic changes in lesion behavior observed previously.^4,13,21 The extent of lesion contraction was influenced by low- and high-efficacy DMT use compared with no treatment. The location of lesions within the CNS, disease duration, and BMI did not appear to influence volume change and the expansion of lesions and were not associated with clinical or MRI relapses or self-reported progression, findings that may have been influenced by the timeframe that individuals were followed.

The use of total T2-weighted lesion volumes, or burden of disease has been a key metric in clinical trials. The importance of the time course of T2-weighted lesion volume accumulation has been shown to impact disability measures at 20 years.²² Prior imaging techniques involving T2 subtraction demonstrated the ability to recognize occult changes from non-3D imaging sequences.²³ More recently, 3D conformational efforts have revealed the dynamic characteristics of MS lesions in orthographic view with lesions exhibiting deformation, or changes in shape, and displacement, changes in the original location, over time.⁴ Quantitative susceptibility mapping, myelin water fraction, and neurite attenuation index maps have also provided insights into lesion age.²⁴ Slowly expanding and nonexpanding T2-weighted hyperintense lesions may also exhibit specific directional patterns and 85% of enlarging lesions have been associated with increases in T1-hypointense lesion volume.¹³ Stable lesions were also recognized in this work, however, the absence of reporting changes in lesion volume when truly present may create a misleading impression of disease stability.

If distinct regions of the brain were associated with greater lesion dynamics, these data may be of value in the clinical monitoring of individuals or the study of molecules aimed at altering the biology and subsequent imaging properties of lesions. In the evaluation of raw changes in individual T2-weighted hyperintense lesion volume, periventricular lesions were found to increase in volume more than those within the juxtacortical/cortical, subcortical, deep white matter, and paraventricular regions, along with thalamic/deep gray matter. This may be due to the location of the lesions, having direct contact with the ependymal surface of the ventricle, along with the choroid plexus volume that may influence periventricular lesion volume.²⁵ Therefore, the characteristics of lesion dynamics in specific brain regions may be more effective for monitoring disease progression.

For the segmentation platform utilized in this study, we identified measures that deviated by a maximum of 0.82% when the same lesion is resampled up to 20 times. Similarly, when individuals were scanned and rescanned, repeat measures only deviated maximally by 1.2%. The findings reported here are of importance as the formal interpretation of brain MRI studies in untreated individuals described “stable” features without the report of newly enlarging T2-weighted hyperintense features. Comparing T2-weighted characteristics between MRI time points may truly reveal stable findings (Fig 3). However, remarkable lesion expansions (Fig 4) may also be observed even when T2-weighted findings appeared unchanged. The reason for this may relate to our perception of the intricate spectrum of subtle gradations between black and white on MRI, altering our perspective of size estimation and change.^26-28 Skewed perceptions of brightness peaks (maxima) and valleys (minima) at edges of luminance gradients occur due to the relative nature of visual processing in lateral inhibitory optic neurons,²⁹ which are responsible for contrast enhancement edge sharpening of visual stimuli and have been known to cause misinterpretation in other radiologic mediums.³⁰ In the primitive visual cortex, the brightness of surfaces is similarly responsive to contrast cues in surrounding scenery.^31,32 The brain is also designed to “fill-in” missing information (perceptual interpolation) to make sense of the 3D world on a 2D plane. As a result, certain changes may only be appreciated in a 3D configuration.³³ The combination of these limiting factors in 2D imaging comprehension by humans suggests that focusing on the dynamic properties of lesions in 3D without strictly adhering to 2D properties may offer a more accurate approach toward better characterization of lesion dynamics.

FIG 3.

A, 2D MR axial T2-FLAIR images of a single MS lesion (yellow circle) from 3 MRI time points each performed a year apart. Observe the presence of the lesion throughout all slices within the MRI sequence. The T2-weighted lesion volumes were identified to be consistent between MRI time points: MRI time point 1, 41.8 mm³, MRI time point 2, 41.1 mm³, and MRI time point 3, 41.3 mm³. B, Visual models represented in 3D space depicting stable volumes over all 3 MRI time points (time point 1: solid white, time point 2: yellow mesh, time point 3: red mesh).

FIG 4.

A, Axial 2D T2-FLAIR MR images of a single MS lesion (yellow circle) from 3 MRI time points (1 year between each time point). Note the presence of the lesion throughout all slices within the MRI sequence. Despite the similar appearance of the lesion on MRI, a volume difference of 58.2% was observed when comparing MRI time point 1 to 2, and a 51.3% volume difference when comparing MRI time point 2 to 3. B, Visual models represented in 3D space illustrating the dynamic expansion of the lesion between MRI time point 1 (solid white), MRI time point 2 (yellow mesh), and MRI time point 3 (red mesh) that is not appreciated on the 2D axial MRI view.

The use of high-efficacy DMTs did not significantly reduce individual T2-weighted hyperintense lesion volumes over time as compared with lower efficacy alternatives. Within key MS pivotal trials, even classic lower efficacy DMTs were found to be effective in suppressing the development of new and or newly enlarging T2-weighted hyperintense lesions.^34-37 All participants in this study had a history of continued use of higher efficacy treatments beyond 6 months of the first MRI time point. In routine clinical practice, repeat MRI studies are performed 6 months after the start of a new treatment, representing new baseline MRI data. This time period allows for the prescribed treatment to achieve a full therapeutic effect. Therefore, the window for detecting any remarkable radiologic treatment benefit may have already elapsed. Alternatively, the observation of no difference between groups may have been due to different pathologic mechanisms not influenced by the anti-inflammatory nature of the treatments being used—whether high- or low-efficacy—or compartmentalized inflammation, because CNS penetrance is modest among the available treatments in comparison to the recently studied Bruton tyrosine kinase inhibitors.^38,39 The lack of change over time may have also resulted from lesion age.^40,41 In addition, observed expansion may reflect continued microglia activity at the lesion edge, at times yielding a hypointense rim that has been observed on susceptibility-sensitive imaging techniques.⁴² Fluctuations in T2-weighted hyperintense lesion volume may also have been influenced by self-repair or remyelination mechanisms, aspects not impacted by DMTs.^43-45

The study of randomly selected individual T2-weighted hyperintense lesions has benefits over assessing total T2-lesion volume. First, the study of individual lesions offers a higher level of precision for care as the study of total volumes may encompass the inclusion of nonspecific white matter lesions. Second, the use of total T2-weighted lesion volumes may mischaracterize the extent of disease. Advancing disease may lead to new and enlarging T2-weighted lesions coupled with contraction of prior lesions within the same individual, resulting in a net result of minimal change. Third, greater insights into the biology of disease may be identified. For example, how do we interpret the findings of 1 T2-weighted hyperintense lesion expanding in size in the setting of 6 that have contracted, as the former is an established metric for disease advancement in current MS clinical trials? Conversely, recent ¹⁸F-DPA-714 PET revealed the presence of an unexpectedly high proportion of MS lesions with a smoldering component.⁴⁶ Lastly, the approach may reflect simpler methods of studying disease burden across sites and may be of value within clinical trials, especially if future studies are able to demonstrate an association with future clinical/radiologic attacks or disability outcomes.

The provided work should be viewed in the context of limitations. First, not all lesions within the MRI studies were included in the analysis, which may have affected outcomes and only a single reviewer was used for the selection of T2-weighted hyperintense lesions. However, the sampling of a meaningful number of lesions across many people and the inclusion of 3 MRI time points per subject enhanced this work. Second, the threshold for an expanding, contracting, or stable lesion was defined based on the volume fluctuations for all the lesions studied. This threshold may be different if a much larger sample set is used within the analysis. Third, the study of an equal number of lesions by location was not performed. Therefore, a study involving a larger number of lesions may identify a propensity for T2-weighted hyperintense lesions to change more actively than described. Fourth, most people studied were White and including a more diverse group of individuals may reveal lesion dynamic patterns that differ from the results presented here. Fifth, the findings reported here were generated from retrospective data and a prospective study may yield different findings. Lastly, all individuals included in this study were acquired from a tertiary care center and the included subjects based on the MRI study criteria may not be generalizable to a larger group of people with MS.

CONCLUSIONS

Dynamic changes in T2-weighted hyperintense lesions are abundant, occurring below our visual perception of effectively discerning between shades of gray on MRI, and are present more frequently in untreated individuals. Our findings suggest that provided counseling involving results from surveillance MRI studies may be inaccurate and incomplete, failing to properly notify individuals of the benefit or inadequacies of their current DMT. Whether greater changes can be appreciated in those with progressive clinical courses is currently unclear. For now, recognizing these dynamic characteristics may offer a new perspective into the effective surveillance and subsequent management for those with MS.

ABBREVIATIONS:

BMI

body mass index

DMT

disease-modifying therapy

LMS

λ, μ, and σ

SD

standard deviation

UTSW

The University of Texas Southwestern