MRI methods are widely used to follow the pathological evolution of multiple sclerosis in life and its modification by treatment. To date, measures of the number and volume of macroscopically visible lesions have been studied most often. These MRI outcomes have demonstrated clear treatment effects but without a commensurate clinical benefit, suggesting that there are other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis pathology, whether it arises in macroscopic lesions or in the normal appearing tissues. An International Workshop recently considered the measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss of these structures, especially axons, although variable effects on tissue volumes may also arise from glial cell proliferation or loss, gliosis, inflammation and oedema. Significant correlations found between brain volume and other putative MR neuronal markers also indicate that atrophy reflects axonal loss. Numerous methods are available for the measurement of global and regional brain volumes and upper cervical cord cross-sectional area that are highly reproducible and sensitive to changes within 6-12 months. In general, 3D-T(1)-weighted acquisitions and largely automated segmentation approaches are optimal. Whereas normalized volumes are desirable for cross-sectional studies, absolute volume measures are adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis, developing gradually following the appearance of inflammatory lesions. This probably reflects both inflammation-induced axonal loss followed by Wallerian degeneration and post-inflammatory neurodegeneration that may be partly due to failure of remyelination. One component of atrophy appears to be independent of focal lesions. Existing immunomodulatory therapies have had limited effects on progressive atrophy, concordant with their modest effects on progressive disability. Atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti-inflammatory, remyelinating or neuroprotective therapies.

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Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance

Summary About 10–15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

Primary-progressive multiple sclerosis

Objective To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS). Background Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined. Design We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measureN-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging. Results We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P Conclusion Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

https://jamanetwork.com/journals/jamaneurology/articlepdf/778355/noc00100.pdf

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability.

The dissociation between magnetic resonance imaging (MRI) and permanent disability in multiple sclerosis (MS), termed the clinicoradiological paradox, can primarily be attributed to the lack of specificity of conventional, relaxivity-based MRI measurements in detecting axonal damage, the primary pathological correlate of long-term impairment in MS. Diffusion tensor imaging (DTI) has shown promise in specifically detecting axonal damage and demyelination in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). To quantify the specificity of DTI in detecting axonal injury, in vivo DTI maps from the spinal cords of mice with EAE and quantitative histological maps were both registered to a common space. A pixelwise correlation analysis between DTI parameters, histological metrics, and EAE scores revealed a significant correlation between the water diffusion parallel to the white matter fibers, or axial diffusivity, and EAE score. Furthermore, axial diffusivity was the primary correlate of quantitative staining for neurofilaments (SMI31), markers of axonal integrity. Both axial diffusivity and neurofilament staining were decreased throughout the entire white matter, not solely within the demyelinated lesions seen in EAE. In contrast, although anisotropy was significantly correlated with EAE score, it was not correlated with axonal damage. The results demonstrate a strong, quantitative relationship between axial diffusivity and axonal damage and show that anisotropy is not specific for axonal damage after inflammatory demyelination.

https://www.jneurosci.org/content/jneuro/29/9/2805.full.pdf

Axial Diffusivity Is the Primary Correlate of Axonal Injury in the Experimental Autoimmune Encephalomyelitis Spinal Cord: A Quantitative Pixelwise Analysis

Objective: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. Methods: A follow-up study was conducted to reassess patients from a phase III trial of interferon β-1a (IFNβ-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. Results: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. Conclusions: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

Eight-year follow-up study of brain atrophy in patients with MS

We investigated various magnetic resonance MRI parameters for both brain and spinal cord to see if any improved the clinicoradiological correlation in multiple sclerosis. Ninety-one multiple sclerosis patients (28 relapsing-remitting, 32 secondary progressive and 31 primary progressive) were imaged using conventional T1, proton density- and T2-weighted MRI of the brain and spinal cord. Focal brain and spinal cord lesion load was scored, as were diffuse signal abnormalities, brain ventricular volume and spinal cord cross-sectional area. Clinical measures included the expanded disability status scale (EDSS), the functional systems score and a dedicated urology complaint questionnaire. Secondary progressive patients differed from relapsing-remitting and primary progressive patients by a larger number of hypointense T1 lesions in the brain, ventricular enlargement and spinal cord atrophy. Primary progressive patients more often had diffuse abnormalities in the brain and/or spinal cord than did relapsing-remitting and secondary progressive patients. In the entire study population, EDSS correlated with both brain and spinal cord MRI parameters, which were independent. The urological complaint score correlated only with spinal cord MRI parameters. In relapsing-remitting and secondary progressive multiple sclerosis, the correlation between MRI and clinical parameters was better than in the entire population. In this subgroup EDSS variance could be explained best by T1 brain lesion load, ventricle volume and spinal cord cross-sectional area. In the primary progressive subgroup the clinicoradiological correlation was weak for brain parameters but was present between spinal cord symptoms and spinal cord MRI parameters. In conclusion, the different brain and spinal cord MRI parameters currently available revealed considerable heterogeneity between clinical subtypes of multiple sclerosis. In relapsing-remitting and secondary progressive multiple sclerosis both brain and spinal cord MRI may provide a tool for monitoring patients, while in primary progressive multiple sclerosis the clinicoradiological correlation is weak for brain imaging.

Brain and spinal cord abnormalities in multiple sclerosis : Correlation between MRI parameters, clinical subtypes and symptoms

We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy'.

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Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis.

PURPOSE
To compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions.


METHODS
Twenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions.


RESULTS
Eighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images.


CONCLUSION
Triple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.

G J Nijeholt

Papers

Brain and spinal cord abnormalities in multiple sclerosis : Correlation between MRI parameters, clinical subtypes and symptoms

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis.

Single-Dose Gadolinium With Magnetization Transfer Versus Triple-Dose Gadolinium in the MR Detection of Multiple Sclerosis Lesions