Speculative Insights into the McDonald 2024 Criteria for MS

As a neurologist who is not directly involved in the development of the upcoming McDonald 2024 criteria but who follows MS research closely, I find myself speculating about what changes could be made in the diagnostic framework for multiple sclerosis (MS). At this moment, the official criteria are not publicly available, and I have no conflict of interest in sharing my predictions. The updated criteria will be presented at ECTRIMS 2024 in Denmark this year—the largest MS conference in the world, where MSologists, NMOSD specialists, people with MS or NMOSD, their families, and carers all gather together.

On the last day of the congress, September 20th, there will be a Patient Community Day—an event that’s very close to my heart, especially with the work I do through my BeewellwithMS www.beewellwithms.com project. While I won’t be able to attend in person due to my dad’s birthday, rest assured, in spirit and in heart, I will be with you all. I’ll be there for the rest of the conference from September 18th, and I look forward to all the incredible insights and conversations to come.

In the meantime, I’d like to share my thoughts and encourage discussion in the comments. Of course, if you’re involved in creating the new McDonald criteria, I understand that this information remains confidential for now!

My predictions are based on recent advances in early MS diagnosis, neuroimaging, biomarker research, and the growing interest in early intervention for conditions like Radiologically Isolated Syndrome (RIS), Clinically Isolated Syndrome (CIS), and Smouldering (non-relapsing Secondary Progressive MS). With the goal of diagnosing MS earlier and initiating treatment as soon as possible, I believe the McDonald 2024 criteria may include the following updates...

The proposed 2024 updates to the McDonald criteria reflect a significant shift towards earlier diagnosis and personalised management of Multiple Sclerosis (MS). While the advancements are valuable, there are a few potential areas of concern that could be further explored or addressed:

Reliability of Neurofilament Light Chain (NFL) as a Biomarker:

?The prediction emphasises the inclusion of NFL as a biomarker for neurodegeneration and progression. However, the specificity of NFL in distinguishing MS from other neurological conditions remains a challenge. NFL is also elevated in a variety of other neurodegenerative diseases. The reliance on NFL might lead to over-diagnosis or confusion with other conditions if not used cautiously alongside clinical and MRI findings.

Role of Advanced Imaging Techniques:

While advanced MRI techniques such as myelin imaging and grey matter lesion detection are promising, the widespread availability of such imaging modalities could be an issue, especially in resource-limited settings. Additionally, the interpretation of these advanced imaging techniques requires highly specialised expertise, and there may be variability in how different canters implement these technologies, leading to inconsistent diagnoses.

Inclusion of Radiologically Isolated Syndrome (RIS):

?The potential reclassification of RIS as early MS based on high-risk features (spinal cord lesions, oligoclonal bands, gender, and age) is intriguing but also somewhat controversial. The management of RIS remains debated, and treating patients with RIS preemptively could lead to unnecessary treatments, as not all RIS patients progress to clinical MS. Balancing treatment benefits against the risks of exposing patients to disease-modifying therapies (DMTs) is a concern that warrants further clinical trials.

Non-relapsing Secondary Progressive MS (nrSPMS):

?The predicted McDonald 2024 criteria could define nrSPMS using advanced imaging or biomarkers. However, there's an inherent difficulty in distinguishing between progressive MS and active inflammation in such cases. If not carefully handled, the use of biomarkers and imaging to define nrSPMS might blur the lines between relapsing and progressive forms of the disease. This could lead to treatment dilemmas, as some therapies are more effective in relapsing than in progressive disease.

Artificial Intelligence (AI) and Machine Learning:

?The mention of AI and machine learning in assisting with differential diagnoses raises concerns about the validation of these tools. While AI can enhance diagnostic precision, there are risks of over-reliance on algorithms that may not yet be adequately validated across diverse populations. AI tools should be viewed as supportive, not definitive, in the diagnosis and management of MS, and clinicians must maintain a central role in decision-making.

Exclusion of NMOSD and Other MS Mimics:

?The exclusion of neuromyelitis optic spectrum disorder (NMOSD) and other autoimmune demyelinating diseases is appropriate, but the diagnostic overlap between these diseases and atypical MS presentations remains tricky. It's critical to ensure that more precise imaging definitions and biomarkers do not lead to misclassification, especially in regions where access to testing for specific NMOSD antibodies (e.g., AQP4, MOG) is limited.

Potential Over-Diagnosis:

?The broader diagnostic criteria, including emphasis on early biomarkers and advanced imaging, might increase the likelihood of over-diagnosing MS in patients who may not require immediate treatment. While early intervention is important, the long-term impact of unnecessary DMTs must be carefully considered, particularly when balancing benefits with side effects and patient quality of life.

Guidance on Differential Diagnosis:

?More detail is needed on how to differentially diagnose MS from conditions like NMOSD, ADEM, or other CNS inflammatory diseases. The 2024 speculated update appears to rely heavily on biomarkers, but more precise guidelines on using clinical history, symptomatology, and imaging in combination with these biomarkers could further enhance diagnostic accuracy.

Final Thoughts and a Call for Discussion

These predictions for the McDonald 2024 criteria aim to emphasise earlier and more precise diagnosis of MS, with the goal of starting treatment sooner to reduce long-term disability. By integrating AI, biomarkers like NFL, GFAP, and advanced MRI techniques, I believe that the criteria will reflect the latest advances in MS research. Additionally, the formal inclusion of RIS as an early form of MS, with the potential for early intervention, could be a ground-breaking shift in how we approach pre-symptomatic MS.

As I mentioned, these are only predictions, and I encourage you to share your thoughts! Do you agree with these speculations, or do you think the criteria will take a different direction? Are you particularly excited (or sceptical) about the role of AI or biomarkers like NFL? Please share your insights in the comments below. And if you happen to be involved in creating the McDonald criteria, I understand that you may need to stay neutral until the official criteria are presented at ECTRIMS 2024! See you soon!

If this article resonated with you or if you believe it can inspire someone else on their MS journey, I encourage you to like, comment, and share it with your community.

#Multiplesclerosis #Lifestyle #Mcdonaldcriteria #autoimune #chronic

? dr Agne Straukiene

References:

1.?????????? Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J, et al. A Lymphocyte–microglia–astrocyte Axis in Chronic Active Multiple Sclerosis. Nature. 2021;597(7878):709-14.

2.?????????? Absinta M, Sati P, Gaitán MI, Maggi P, Cortese I, Filippi M, et al. Seven‐tesla Phase Imaging of Acute Multiple Sclerosis Lesions: A New Window Into the Inflammatory Process. Annals of Neurology. 2013;74(5):669-78.

3.?????????? Aldosh M. The Effectiveness of MRI Techniques in Evaluating Multiple Sclerosis Patients. International Journal of Current Science Research and Review. 2021;04(01).

4.?????????? Amezcua L. Progressive Multiple Sclerosis. Continuum Lifelong Learning in Neurology. 2022;28(4):1083-103.

5.?????????? Ammitzb?ll CG, Dyrby TB, B?rnsen L, Schreiber K, Ratzer R, Christensen JR, et al. NfL and GFAP in Serum Are Associated With Microstructural Brain Damage in Progressive Multiple Sclerosis. Multiple Sclerosis and Related Disorders. 2023;77:104854.

6.?????????? Banwell B, Bennett JL, Marignier R, Kim HJ, Brilot F, Flanagan EP, et al. Diagnosis of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: International MOGAD Panel Proposed Criteria. The Lancet Neurology. 2023;22(3):268-82.

7.?????????? Bebo BF, Allegretta M, Landsman D, Zackowski KM, Brabazon F, Kostich W, et al. Pathways to Cures for Multiple Sclerosis: A Research Roadmap. Multiple Sclerosis Journal. 2022;28(3):331-45.

8.?????????? Benard-Seguin E, Costello F. Optic Neuritis: Current Challenges in Diagnosis and Management. Current Opinion in Neurology. 2022.

9.?????????? Beynon V, George IC, Elliott C, Arnold DL, Ke J, Chen H, et al. Chronic Lesion Activity and Disability Progression in Secondary Progressive Multiple Sclerosis. BMJ Neurology Open. 2022;4(1):e000240.

10.???????? Dal‐Bianco A, Gr?βner G, Kronnerwetter C, Weber M, H?ftberger R, Berger T, et al. Slow Expansion of Multiple Sclerosis Iron Rim Lesions: Pathology and 7?T Magnetic Resonance Imaging. Acta Neuropathologica. 2016;133(1):25-42.

11.???????? Filippi M, Preziosa P, Meani A, Ciccarelli O, Mesaro? ?, Rovira à, et al. Prediction of a Multiple Sclerosis Diagnosis in Patients With Clinically Isolated Syndrome Using the 2016 MAGNIMS and 2010 McDonald Criteria: A Retrospective Study. The Lancet Neurology. 2018;17(2):133-42.

12.???????? Filippi M, Rocca MA, Ciccarelli O, Stefano ND, Evangelou N, Kappos L, et al. MRI Criteria for the Diagnosis of Multiple Sclerosis: MAGNIMS Consensus Guidelines. The Lancet Neurology. 2016;15(3):292-303.

13.???????? Giovannoni G, Popescu VA, Wuerfel J, Hellwig K, Iacobeus E, Mb J, et al. Smouldering Multiple Sclerosis: The ‘Real MS’. Therapeutic Advances in Neurological Disorders. 2022;15:175628642110667.

14.???????? Gloor M, Andelova M, Gaetano L, Papadopoulou A, Burguet Villena F, Sprenger T, et al. Longitudinal Analysis of New Multiple Sclerosis Lesions With Magnetization Transfer and Diffusion Tensor Imaging. European Radiology. 2023;34(3):1680-91.

15.???????? Hardy TA, Reddel SW, Barnett M, Palace J, Lucchinetti CF, Weinshenker BG. Atypical Inflammatory Demyelinating Syndromes of the CNS. The Lancet Neurology. 2016;15(9):967-81.

16.???????? H?gel H, Rissanen E, Barro C, Matilainen M, Nylund M, Kühle J, et al. Serum Glial Fibrillary Acidic Protein Correlates With Multiple Sclerosis Disease Severity. Multiple Sclerosis Journal. 2018;26(2):210-9.

17.???????? Jendretzky KF, Bajor A, Lezius L-M, Hümmert MW, Konen FF, Grosse GM, et al. Clinical and Paraclinical Characteristics of Optic Neuritis in the Context of the McDonald Criteria 2017. Scientific Reports. 2024;14(1).

18.???????? Kim J-S. Protein Biomarkers in Multiple Sclerosis. Encephalitis. 2023;3(2):54-63.

19.???????? Lackey E, Reinke S, Luo S, Laskowitz D, Eckstein C, Gregory SG. Exploring Plasma Cell Motility and Extracellular Matrix Protein Biomarkers for Primary Progressive Multiple Sclerosis: A Pilot Study. 2024.

20.???????? Levin LA, Lessell S. Risk of Multiple Sclerosis After Optic Neuritis. Jama. 2003;290(3):403.

21.???????? Miki Y. Magnetic Resonance Imaging Diagnosis of Demyelinating Diseases: An Update. Clinical and Experimental Neuroimmunology. 2019;10(S1):32-48.

22.???????? Minden SL, Kinkel RP, Machado HT, Levin J, Rosenthal MB, Iezzoni LI. Use and Cost of Disease-Modifying Therapies by Sonya Slifka Study Participants: Has Anything Really Changed Since 2000 and 2009? Multiple Sclerosis Journal - Experimental Translational and Clinical. 2019;5(1):205521731882088.

23.???????? Okuda DT. Radiologically Isolated Syndrome Should Be Treated With Disease-Modifying Therapy – Yes. Multiple Sclerosis Journal. 2017;23(14):1818-9.

24.???????? Okuda DT, Kantarci OH, Lebrun-Frénay C, Sormani MP, Azevedo C, Bovis F, et al. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Annals of Neurology. 2022;93(3):604-14.

25.???????? Rebbah S, Delahaye D, Puechmorel S, Nicol F, Maréchal P, Berry I. A Combined MRI Biomarker Approach Using a Non-Standard Multiple Factor Analysis. 2018.

26.???????? Rosenthal J, Hoffman B, Tyor WR. CNS Inflammatory Demyelinating Disorders: MS, NMOSD and MOG Antibody Associated Disease. Journal of Investigative Medicine. 2020;68(2):321-30.

27.???????? Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, D?umer M, et al. The Natural History of Multiple Sclerosis, a Geographically Based Study 10: Relapses and Long-Term Disability. Brain. 2010;133(7):1914-29.

28.???????? Schneider R, Brand-Arzamendi K, Reynold Lim T, Lee LE, Guenette M, Suthiphosuwan S, et al. Plasma Glial Fibrillary Acidic Protein Levels Correlate With Paramagnetic Rim Lesions in People With Radiologically Isolated Syndrome. Multiple Sclerosis Journal. 2023;30(2):156-65.

29.???????? Thompson AJ, Banwell B, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria. The Lancet Neurology. 2018;17(2):162-73.

30.???????? Tur C, Carbonell‐Mirabent P, Cobo‐Calvo á, Otero‐Romero S, Arrambide G, Midaglia L, et al. Association of Early Progression Independent of Relapse Activity With Long-Term Disability After a First Demyelinating Event in Multiple Sclerosis. Jama Neurology. 2023;80(2):151.

31.???????? Wattjes MP, Ciccarelli O, Reich DS, Banwell B, Stefano ND, Enzinger C, et al. 2021 MAGNIMS–CMSC–NAIMS Consensus Recommendations on the Use of MRI in Patients With Multiple Sclerosis. The Lancet Neurology. 2021;20(8):653-70.

32.???????? Ziemssen T, Hoffmann O, Klotz L, Schreiber H, Weber M, Rauser B. Gaining First Insights on Secondary Progressive Multiple Sclerosis Patients Treated With Siponimod in Clinical Routine: Protocol of the Noninterventional Study AMASIA. Jmir Research Protocols. 2020;9(7):e19598.

?Note: The infographics and descriptions are fictional suggestions to give you an idea of what visuals might accompany the article. Created by AI under my commands.