On Cave Paintings and Shallow Waters—The Case for Advancing Spinal Cord Imaging in Multiple Sclerosis

On Cave Paintings and Shallow Waters—The Case for Advancing Spinal Cord Imaging in Multiple Sclerosis
Artículos Médicos - December 14th, 2020 by Admin

Modern magnetic resonance imaging (MRI) provides a magnificent window into the brain of individuals with multiple sclerosis (MS), allowing visualization of periventricular, juxtacortical, and infratentorial brain lesions with remarkable precision. Yet, despite the great advances in clarity, brain MRI identifies MS lesions that do not correlate well with current or progressive longterm MS disability outcomes (eg, ambulation). Rather, it is MS disease burden in the spinal cord that raises such prognostic concerns. Reviewing spinal cord imaging in clinical practice, however, oftenentails peering at a fuzzy and inscrutable abstraction, leading us to speculate as to the presence and number of spinal cord lesions based on just a couple of T2-bright pixels. Unfortunately, far from the photorealism of brain MRIs, spinal cord MRIs remain about as veridical as cave paintings. We judge this disease by what we are able to see; indeed, the fundamental concept thatMS is a whitematter disease was amended to include gray matter pathology only once imaging technology revealed it. Yet, MS remains a heterogenous and unpredictable disease. Perhaps the most prognostically important MS lesions are still hiding in plain sight, just below the limit of radiographic detection (Figure). The presence of numerous lesions on brain MRI in the absence of signs and symptoms has been termed the clinical radiologic paradox. Although new brain lesions are used as a radiographic surrogate marker of MS disease activity, most new brain lesions do not bring patientswithMS to theemergency departmentwith symptoms of relapse. It is rather a partial myelitis (newonset hemiparesis or paraparesis) that is often most clinically significant and disabling. Two factors help to resolve the clinical radiologic paradox: lesion localizationand neurological reserve. The topographical model of MS1 integrates these factors by depicting the specific association between subclinical lesion burden and variable reserve. In this framework, the central nervous system is visualized as a pool of reserve with increasing depth, with the spinal cord and optic nerves at the shallow end and the cerebral hemispheres constituting the deep end. The depth of the water in this visual model corresponds with the degree of reserve intrinsic to these different regions: from the least redundancy and capacity for plasticity in the optic nerve and spinal cord to the greatest such structural and functional reserve in the cerebral hemispheres.1 Lesions in the spinal cord—that shallow pool of reserve—are more likely to yield acute relapses of clinically apparent pyramidal, sensory, and bowel and bladder symptoms and lead to long-term disability.2,3 Bothspinalcordlesionsandatrophyareprognostically importantbutdifficult toidentifyandquantify radiographi-cally.Accelerated central nervous systematrophy inMS is hypothesized to reflect the loss of the compensatory mechanisms thatconstituteneurological reserve.Atrophy in thecervicalcordspecifically,orlossof reservein thiscrucial region, is associatedwith the development of disease progression.4Long-termcohortshavedemonstratedeven 1criticallylocatedlesionin thespinalcordisassociatedwith disabilityaccumulationandevolutiontosecondaryprogressive MS.3 It is striking that such long-term clinical correlationswith spinalcordlesionshavebeendemonstrateddespite the relatively poor resolution of current-generation spinalcordimaging.The realparadoxis that themostprognostically important localization is where imaging is least sensitive. Brain imaging has been the primary focus of neuroimaging advancements. National and international meetings feature a plethora of novel, cutting-edge brain MRI techniques5 : paramagnetic rims, proton spectroscopy, sodium imaging, neurite orientation dispersionand density imaging, functional MRI connectomic imaging, etc. These techniques would require radiologic expertise, software, and ultra–high-field 7-Tmagnets not generally found outside of academic centers. I would argue these brain MRI techniques are not just potentially inaccessible and difficult to translate into the clinical routine but also topographically misguided. Localization matters, and we are looking in the wrong place.6 Perhaps we should expend less time, effort, and funding on further refining brain MRI in MS when the advancement of cord imaging could yield so many more crucial insights. The importance of assessing spinal cord damage with MRI is being increasingly recognized,7 and updated guidelines on the use of spinal cord imaging have been included in the 2021 Magnetic Resonance Imaging in Multiple Sclerosis–Consortium of Multiple Sclerosis Centres–North American Imaging in Multiple Sclerosis consensus recommendations.8However, these recommendations continue to minimize the role of spinal cord imaging, consigning axial sequences as optional at MS diagnosis and finding not enough evidence to recommend spinal cord MRI for routine monitoring.8 Moving forward to fill these data gaps, cervical cord imaging should be included in all MS clinical trials; grants lookingatimagingcorrelatesofdisabilityandprognosis;and all longitudinal MS cohorts. Indeed, spinal cord MRI is alreadystarting tobeusedasanimagingoutcomeinMSclinical trials.9 Thisisan opportunity tocollect data thatcaninform how these MRI findings should influence treatment decisions.Effortsshouldbedirected towardincreasing the qualityof spinalcordimagingand radiologicaleducationin spinal cord imaging interpretation to be commensurate with theprognosticimportanceof thislocalization.The return on investment could be enormous.

Substantialimprovementin thecapabilityofdetecting spinalcord lesions and atrophy have already occurred, including new sequences (eg, short tauinversion recovery,Amira)andopen-source toolboxes.10 While somemayargue that thereare no fundamentalmethodological limitations to spinal cord imaging, there remain myriad practical and technical hurdles that need to be addressed to further refine it. Brain imaging techniques cannot always be readily repurposed to visualize thespinalcord,a regionwithdistinctimagingconstraints—asmallstructure, surrounded by fluidandencased in bone,withartifacts frommotion,breathing,and theheartbeat.7 Scanning thespinalcordis timeconsuming,andstandardization remainsachallenge.Theseare reasonsspinalcordimagingwasnothistoricallyincorporatedintoMSpivotal trials, whichhasled togapsindata thathaveallowed thismodality tolanguish in clinical practice. It must be noted that directing resources to spinal cordimagingwouldincreaseexpenseandduration of the scans,which couldinturndecreasepatientcomplianceinobtainingthem.Thesepractical limitations offer current and future researchers a great opportunity to fulfill an unmet need: to optimize the efficiency and signal-tonoise ratio of spinal cord imaging and bring it up to parwith that of the brain. Brain MRIs once looked like cave paintings, too. This Viewpoint does not address other traditionally invisible sources of MS-associated disability, such as cognitive dysfunction, language ability, and fatigue. These are indeed important, and brain imaging will no doubt continue to shed light on their pathogenesis and localization. But looking for the drivers of progressive disability, such as an Expanded Disability Status Scale score of 6 or 7 (the need for a cane or a wheelchair) on a brain MRI is a fool’s errand. Those correlates are not there, obscured by the brain’s deep resources of neuroplasticity and reserve. It is time we redirect the search to more shallow waters.

ARTICLE INFORMATION Published Online: November 22, 2021. doi:10.1001/jamaneurol.2021.4245 Conflict of Interest Disclosures: Dr Krieger reports consulting or advisory work with Biogen, EMD Serono, Genentech, MedDay, Novartis, Octave, Sanofi, Teva, and TG Therapeutics and nonpromotional speaking with Biogen, EMD Serono, Genentech, and Novartis, as well as grant and research support from Biogen and Novartis outside the submitted work.


1. Krieger SC, Cook K, De Nino S, Fletcher M. The topographical model of multiple sclerosis: a dynamic visualization of disease course. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e279. doi:10.1212/NXI.0000000000000279

2. Arrambide G, Rovira A, Sastre-Garriga J, et al. Spinal cord lesions: a modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor. Mult Scler. 2018;24(3): 301-312. doi:10.1177/1352458517697830

3. Keegan BM, Kaufmann TJ, Weinshenker BG, et al. Progressive motor impairment from a critically located lesion in highly restricted CNS-demyelinating disease. Mult Scler. 2018;24(11): 1445-1452. doi:10.1177/1352458518781979

4. Rocca MA, Valsasina P, Meani A, et al; MAGNIMS Study Group. Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS. Neurology. 2019;93(20):e1852-e1866. doi:10.1212/ WNL.0000000000008466

5. Cortese R, Collorone S, Ciccarelli O, Toosy AT. Advances in brain imaging in multiple sclerosis. Ther Adv Neurol Disord. 2019;12:1756286419859722. doi:10.1177/1756286419859722

6. Krieger SC, Lublin FD. “Location, location, location”. Mult Scler. 2018;24(11):1396-1398. doi:10. 1177/1352458518790385

7. Rocca MA, Preziosa P, Filippi M. What role should spinal cord MRI take in the future of multiple sclerosis surveillance? Expert Rev Neurother. 2020; 20(8):783-797. doi:10.1080/14737175.2020.1739524

8. Wattjes MP, Ciccarelli O, Reich DS, et al; Magnetic Resonance Imaging in Multiple Sclerosis study group; Consortium of Multiple Sclerosis Centres; North American Imaging in Multiple Sclerosis Cooperative MRI guidelines working group. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021;20(8): 653-670. doi:10.1016/S1474-4422(21)00095-8

9. Moccia M, Valsecchi N, Ciccarelli O, Van Schijndel R, Barkhof F, Prados F. Spinal cord atrophy in a primary progressive multiple sclerosis trial: improved sample size using GBSI. Neuroimage Clin. 2020;28:102418. doi:10.1016/j.nicl.2020.102418

10. SCT Contributors. Spinal Cord Toolbox release v5.3.0. Updated 2020. Accessed August 23, 2021. https://spinalcordtoolbox.com/en/latest/

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