MS Global Mon, 17 Aug 2020 14:19:30 +0000 en-US hourly 1 Clinical Relevance of Evaluating Cognitive Function in Multiple Sclerosis (MS) Thu, 10 Oct 2019 21:16:16 +0000 Cognitive Impairment, an Early Marker of Poor Long-Term Outcomes The primary evaluation of disease progression in MS has largely focused on clinical symptoms and the physical function of the patient.1,2 However, the clinical relevance of cognitive impairment in MS is becoming increasingly recognized, especially in the earliest stages of disease.1,2 Nearly half of patients with […]

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Cognitive Impairment, an Early Marker of Poor Long-Term Outcomes The primary evaluation of disease progression in MS has largely focused on clinical symptoms and the physical function of the patient.1,2 However, the clinical relevance of cognitive impairment in MS is becoming increasingly recognized, especially in the earliest stages of disease.1,2 Nearly half of patients with MS experience cognitive impairment, which most frequently presents as impaired information-processing speed and impaired immediate and delayed memory. Verbal fluency and executive function can also be affected.3 Cognitive impairment may be present in a significant proportion of patients before clinical symptoms appear, sometimes years before, and can serve as an early marker of disease activity.2,4
Significant Impact on Patient Function Cognitive deficits can impose a heavy burden on the lives of patients with MS. Cognitive impairment may cause limitations in the workplace and social settings irrespective of the level of physical disability.2 Studies indicate that cognitive impairment in patients with MS is implicated in causing reduction of work responsibilities or leaving the workforce. Additionally, these patients are more likely to report higher rates of divorce, low self-esteem, and fewer social activities.6

Impact of Cognitive Impairment on Patient Function2,3,7

Pathogenesis of Cognitive Impairment Recent advances in MRI technology have revealed that grey matter damage, in addition to white matter damage, plays a significant role in the pathogenesis of cognitive impairment. 3T MRI has demonstrated in studies that T1 hypointense cortical lesions are common in patients with MS and are predictive of worse performance on neuropsychological tests. 7T MRI imaging has provided further evidence that cortical lesions have a strong association with cognitive impairment in this patient population. Recent studies have also revealed that deep grey matter volume, particularly of the thalamus, is lower in patients with MS compared with normal controls and associated with impaired processing speed, working memory, and visuospatial memory.6 Impact of Neurological Reserve on Early Cognitive Impairment While correlations between MRI findings and cognitive function are robust, the pathophysiological changes underlying cognitive impairment in patients with MS are highly variable. Only 33%–50% of the variability can be explained by MRI findings. Cognitive reserve, the capacity to compensate for pathological damage and maintain neurological function in the presence of disease, may explain individual differences in cognitive deficits and their limited correlation with MRI findings.8 Educational level correlates with levels of cognitive reserve at baseline. Individuals with high cognitive reserve maintain function despite neurological damage and thus are able to withstand greater disease burden prior to cognitive impairment compared with individuals with low cognitive reserve, who cannot compensate for an equivalent amount of neurological damage.9 Based on studies in patients with CIS and early RRMS, it is believed that early intervention against cognitive decline helps preserve intact cognitive functioning and delay impairment in cognitive function.8 Assessing Cognitive Function in Clinical Practice Initial signs of cognitive impairment are subtle, and standard components of neurological exams do not adequately detect it.2,3
  • The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, which can be completed in 15–30 minutes, is available and recommended for use by Langdon et al. It can be administered by most HCPs without requiring a specially trained or qualified professional. BICAMS is designed for international use and currently validated by 14 countries for a comprehensive cognitive assessment. BICAMS assesses information processing speed (SDMT), immediate verbal recall memory (CVLT-II), and immediate visual recall memory (BVMT-R)1,10
  • The Symbol Digit Modalities Test (SDMT) is a reliable tool that is sensitive to cognitive deficits and takes ≤5 minutes to complete. It can be completed by a trained health care professional and does not require a neurologist to administer.10 Also, robust correlations are seen with MRI metrics, specifically third ventricle widening and thalamus volume loss11
    • When completing the SDMT, the patient is presented with a page that contains a key that pairs the single digits 1–9 with 9 symbols. The patient’s task is to write or orally report the correct number in the spaces within the allotted time12

Example CVLT-II Stimuli13

  • The California Verbal Learning Test-II (CVLT-II) assesses verbal memory, while the Brief Visuospatial Memory Test-Revised (BVMT-R) assesses visuospatial memory. Both tests are associated with high sensitivity with good age- and sex-adjusted normative data available and can be completed in 5–10 minutes1,13
    • When completing the CVLT-II, patients are provided with a list of 16 words, with four items belonging to each of four categories, arranged randomly. The list is read aloud five times in the same order to the patient. Patients are required to recall as many items as possible, in any order, after each reading of the list13

A Scored Version of the SDMT12

    • When completing the BVMT-R, patients are asked to inspect a 2 x 3 stimulus array of abstract geometric figures. The array is removed, and the patient is required to draw the array from memory, with the correct shapes in the correct position13

Example BVMT-R Stimuli13

Additional batteries to assess cognitive function are also available; however, the time and resources it takes to administer them remains a limiting step for their adoption in clinical practice.6
  • Brief Repeatable Battery of Neuropsychological tests (BRB-N) for MS is a battery that takes 1 hour or less to be administered. It can distinguish between MS patients with cognitive impairment versus intact cognition with a sensitivity of 71% and specificity of 94%. There are some limitations to this battery, as some researchers have found this battery to lack measurements of visuospatial ability and executive function. Therefore, other tests are often added to this battery for a more comprehensive assessment6
  • The Minimal Assessment of Cognitive Function in MS (MACFIMS) was developed to include tests that the BRB-N lacks, ensuring a more comprehensive assessment but increasing the test duration to 1.5–2 hours. Although not included in the battery, the panel of experts who developed this test recommended that premorbid cognitive ability, generalized fatigue, and mood disorders, specifically depression, also be measured, as these factors can affect performance on objective cognitive measures6
  • The Paced Auditory Serial Addition Test (PASAT), which is included as part of both BRB-N and MACFIMS batteries, measures cognitive processing speed and working memory. The PASAT stimuli is auditory and utilizes and audio cassette to conduct the test. While this test can be completed in 10–15 minutes, it is associated with several limitations for cognitive monitoring in clinical practice, including limited reliability and poor tolerability by patients1,14
Overcoming Limitations to Adoption of Cognitive Monitoring in Clinical Practice Practice effects, defined as poorer performance in patients when first tested due to lack of familiarity with the task, have been observed with available cognitive tests, including the SDMT, CVLT-II, BVMT-R, and PASAT.14-17 Computerized testing may serve as an alternative to traditional paper-and-pencil assessments and aim to overcome some limitations associated with them. The Processing Speed Test (PST) is a tablet-based test modeled after the SDMT that enables electronic data from tablet-based tasks to be integrated with electronic medical records. Tools like the PST may help promote cognitive monitoring as standard care for better detection of cognitive decline, develop large datasets from representative samples to advance understanding of prevalence, time course, and risk factors for decline, and promote feasibility of postmarketing studies of the effects of disease-modifying therapies on cognition.1 Observational research has also identified modifiable lifestyle factors that may protect against cognitive decline, such as mental activity, physical exercise, and stress management. However, these treatments are most effective when they are integrated into the context of the patient’s life. Interventions for cognitive rehabilitation may be most effective when tailored to the underlying cause of a patient’s specific deficit, which may differ within the same cognitive domain (eg, memory deficit secondary to diffuse white matter lesions versus focal thalamic lesions). A holistic approach to treatment is necessary to ensure optimal outcomes for each patient in practice and research.1 Conclusions Cognitive impairment is increasingly recognized and accepted as one of the earliest clinical symptoms of MS, with a significant impact on patient function and overall quality of life.2,6 Cognitive function is not captured using current assessments, such as disability progression (generally measured using the EDSS) as well as no evidence of disease activity-4 (NEDA-4), which includes an assessment of clinical relapses, MRI activity, disability progression, and brain volume loss.18,19 Early and ongoing cognitive assessment using validated tests and management may therefore help improve long-term outcomes. Because cognitive impairment may be missed in a standard neurological exam, early baseline screening and reassessment with the SDMT is recommended.2 Effective use of cognitive assessments, including computerized tests, has the potential to improve clinical outcomes and preserve long-term patient function.1

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Maximising the Potential of Advanced MRI Techniques to Assess Grey Matter Pathology Thu, 10 Oct 2019 21:15:51 +0000 Importance of Assessing Grey Matter Pathology, in Addition to White Matter Multiple sclerosis (MS) has long been characterised by the well-known focal inflammatory, demyelinating lesions that are typically seen in the white matter. While white matter lesions and inflammation are certain to contribute to clinical deficits in MS, recent evidence suggests that neurodegeneration and consequent […]

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Importance of Assessing Grey Matter Pathology, in Addition to White Matter Multiple sclerosis (MS) has long been characterised by the well-known focal inflammatory, demyelinating lesions that are typically seen in the white matter. While white matter lesions and inflammation are certain to contribute to clinical deficits in MS, recent evidence suggests that neurodegeneration and consequent volume loss of the grey matter also play an important role in driving disease progression.1,2

Using MRI Markers to Assess Ongoing Disease Activity in MS

While the assessment of whole brain volume loss is an invaluable marker of disease activity, grey matter volume loss in particular has recently been identified as contributing much of that loss and, increasingly, shown to be associated with clinical outcomes in MS.3,4 Because grey matter loss is shown to be present in the earliest stages of the disease and progresses throughout the course of the disease, accurate measurement of grey matter volume loss is important to better understand MS pathology and quantitatively characterise its effects in patients.2,5

Select Correlations Between Brain Volume Loss and Patient Outcomes6-12

Limitations of Conventional MRI Conventional magnetic resonance imaging (MRI), such as T2-weighted imaging and GdE T1-weighted imaging, is limited in its ability to assess grey matter damage, due to both technical challenges and patient factors.4,5,7,13 The grey matter/white matter border, as seen on conventional MRI, is generally not as distinctive as the brain/cerebrospinal fluid (CSF) border, and cortical grey matter lesions may be small and difficult to detect on conventional MRI.4,7 Cortical lesions, which make up a significant portion of grey matter damage, are often undetectable on conventional MRI using standard field strength, mainly due to their small size, the anatomical lack of myelin in the cortex generating little MRI contrast upon demyelination, and the partial volume effects from adjacent CSF and white matter. In addition, in contrast to white matter lesions, cortical grey matter lesions lack focal infiltration of immune cells, complement deposition, and blood brain barrier damage that can be seen on conventional MRI.2 Brain volume measurements are also affected by differences in MRI hardware (eg, scanner), scan quality, and analytical software.14 Due to time constraints during routine visits, the spatial resolution and coverage of MRI scans may also be limited compared with scans taken as part of clinical studies.15 Most MRI technology used in general clinical practice uses 1.5 Tesla (T) field strength further limiting the sensitivity of damage that can be observed.16 In addition to technical factors, patient-specific factors such as age, genetics, lifestyle (eg, alcohol, smoking, dehydration), and comorbidities (eg, diabetes, hypertension) can affect the accuracy of brain volume measurements. Pseudoatrophy, in which the resolution of inflammation is thought to decrease water content in the brain with no associated loss of cell structure, can complicate the interpretation of brain volume changes over time.7,8 To account for these physiological confounding factors, normative brain volume changes need to be established, both for healthy individuals and for patients with MS.7 In addition, MRI scans should be obtained at baseline (pretreatment) and within 6 months of treatment initiation to ensure that the treatment has taken effect. Follow-up brain MRI scans should be performed and then compared with the re-baseline reference MRI scan.17 Addressing Challenges of Measuring Grey Matter Volume Loss and Pathology With Advanced MRI Techniques In recent years, advancements in MRI technology have significantly contributed to identifying the true extent and clinical impact of grey matter involvement in MS. Advanced MRI techniques allow quantification of several pathological processes in vivo and offer insights into MS pathophysiology beyond white matter lesions.1,2 By revealing what is happening beneath the visible surface of MS pathology, these techniques allow early measurement of functional and structural abnormalities and have the potential to delay permanent damage.18

Investigating Subclinical Disease Activity in MS19-21

Grey Matter Volume Loss Measurement Techniques There are currently commercially available, sophisticated methods to measure regional grey matter volume loss in the brain. Grey matter volume loss, typically characterised by volume decrease of subcortical grey matter structures and volume or thickness decrease of cortical regions, can be measured using standard 3D T1-weighted images acquired by MRI or automated methods, such as FreeSurfer. For measurement of cortical volume, methods such as Jacobian integration and SIENAX (cross-sectional pipeline of SIENA; Structural Image Evaluation using Normalization of Atrophy) can be used.1
  • Jacobian integration is a method that quantifies longitudinal grey matter or white matter volume changes by measuring the total net amount of contraction or expansion of a selected region in an image during an accurate nonlinear registration between the images of the first and last time points. Jacobian integration applied to longitudinal grey matter volume loss analysis has been shown to reduce variability related to measurement error compared to other commonly used methods1
  • FreeSurfer contains a fully automated structural imaging system that allows visualisation of structural MRI data to calculate cortical thickness. FreeSurfer also includes volumetric segmentation of deep grey matter structures. FreeSurfer has a longitudinal pipeline with improved reliability of volume change measurements for analysis of changes over time1
  • SIENAX estimates partial volume fractions of grey matter, white matter, and CSF. The longitudinal SIENA only quantifies overall brain volume change (based on the shift of the parenchyma-CSF border over time), and therefore does not measure grey matter or white matter volume change separately. Extensions of SIENAX to perform specific analysis of grey matter volume loss have recently been developed1
Grey Matter Lesion Measurement Techniques While it remains unclear whether it could be possible to translate these methods into routine clinical practice, recent improvements in the detection of cortical lesions have been achieved through the introduction of several advanced MRI techniques.2
  • Cortical lesions can be visualised, at 1.5T and 3T, with specific sequences that enhance the contrast between normal-appearing grey matter and focal grey matter lesions. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) imaging suppresses the signal from CSF and white matter, thus achieving a superior delineation between grey and white matter. These techniques can be used to detect MS cortical pathology, with PSIR showing a higher sensitivity3,22
  • An ultra-high MR field (7T) has further demonstrated that cortical lesions are strongly correlated with disability status and cognitive impairment3,22

Axial DIR Sequences From 4 Different Patients With RRMS2

Several cortical lesions are highlighted; intracortical lesions, leucocortical lesions, and subpial cortical lesions. DIR are red colored to better highlight some cortical lesions.
  • Magnetisation transfer (MT) MRI provides an index, called the MT ratio (MTR), whose values reflect the efficiency of the magnetisation exchange between protons in tissue water and those bound to the macromolecules. MTR maps are sensitive to changes in myelin content in all brain tissues, and although the MTR signal can be influenced by factors such as axonal loss, inflammation, and oedema, their impact is less pronounced in the cortex, supporting its use in investigating myelin loss and repair in cortical areas22
  • Delayed high-resolution postcontrast T2 fluid-attenuated inversion recovery (FLAIR) MRI can be used to visualise leptomeningeal immune cell accumulation, which is often associated with cortical lesions. These infiltrates preferentially involve the subpial cortical layers, are closely associated with subpial demyelination and cortical volume loss, and are present in ~20% of patients with relapsing-remitting MS. They are not exclusively observed in MS, but their relationship with cortical volume loss and lesions appears to be highly specific22
  • Advanced 7T MRI allows detection of several underlying mechanisms that drive pathogenesis in grey matter, including a gradient of subpial cortical abnormalities, strictly associated with increased severity of demyelination, neuronal loss, and microglia activation in the outermost cortical layers. Furthermore, the use of MRI techniques such as 3D DIR has recently shown that cortical lesion susceptibility maps can highly reproduce the heterogeneous activity features of grey matter damage, even at an individual level2
Conclusions Grey matter pathology has been shown to occur early and extensively throughout all stages of MS disease course, thus influencing the long-term prognosis of the disease.4 Therefore, improving the ability to detect these changes may provide insight on disease management at the earliest phases of disease.4 With MRI measures that are more specific and sensitive to disease pathological substrates, advances in MRI technology promise to improve monitoring of MS, even in the earliest phases of the disease.18 MRI has traditionally been used as a robust tool to monitor lesion load and new disease activity in clinical practice. However, the implementation of a standardized postprocessing protocol for the evaluation of brain volume is not yet feasible.23 The sensitivity associated with advanced MRI techniques is also not currently ideal and therefore, caution is required before presence of grey matter lesions can be reliably assessed.23 The MAGNIMS consortium developed MRI guidelines in 2015 recommending that new T2 lesion count requires high-quality, comparable MRI scans, and must be interpreted by highly qualified, trained readers to minimize observer variability. MRI subtraction facilitates recognition of changes in focal lesions over time, thus increasing the power of serial imaging, and automated subtraction improves accuracy and sensitivity for identifying new and/or enlarged T2 lesions.17 Routine monitoring should be conducted every 3–12 months using at least 1.5 T, depending on patient characteristics such as disease duration, comorbidities and current treatment.17 While advanced MRI techniques have become more commonly used for secondary outcomes in clinical trials in recent years, there are ongoing efforts to make these techniques more widely available and feasible for everyday clinical practice and to reach comparable results between different centres. This will help to achieve personalised patient care and manage various pathological mechanisms that may drive MS disease progression.18,23

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