Understanding the implications in cognitive-dominant MS.

While multiple sclerosis (MS) is often considered a disease that presents with impaired motor function, a recent presentation at the ACTRIMS 2021 virtual conference shared an analysis of two ongoing studies and the degree to which signs of cognitive dysfunction in cases of relapsing-remitting MS (RMSS) may precede any motor issues.

Study reviewers noted that cognitive-dominant MS “may present a diagnostic and therapeutic challenge, particularly when other neurodegenerative disease states may be under differential consideration as well.” 
 
Their conclusion: Findings in an early cohort of relapsing MS suggest disease-related risk for cognitive impairment in the absence of physical dysfunction, and suggest that pathological changes within the left versus right hemisphere are more related to cognitive (versus physical) functioning in early MS. A replication analysis is planned in the MEM CONNECT cohort to explore if this relationship is preserved in a cohort with longer-standing MS.1
 
This is significant in that while practitioners may expect to see cognitive impairment develop post-motor dysfunction, in some instances patients may during initial MS episodes already have changes to their brain structures that potentially could be under identified. I would add as well that in my many years of treating MS patients, the most difficult symptom to monitor is memory or cognitive function, which compounds the challenges of diagnoses when mobility issues may have not yet observably manifested.   
 
And there’s much more research… 
 
In this study, APOE ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for APOE ε4 heterozygosity or APOE ε2 carrier status.2 Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance.
 
Other research has suggested that "just looking” at lesion load on magnetic resonance imaging (MRI) may not show objective measures of atrophy, which on the other hand can be seen early with the concurrent use of NeuroQuant®technology.3
 
Additionally, the study performed on a large group of clinically isolated syndrome (CIS) patients (the earliest stage of MS)  demonstrated that regional gray matter (GM) atrophy is present right after the first clinical event of multiple sclerosis and mainly affects the deep GM and the limbic system. Although multiple sclerosis (MS) is mainly known as a chronic inflammatory and demyelinating white matter (WM) disease, it also exhibits extensive GM involvement.4,5,6
 
Concerns such as thalamic atrophy, one of the earliest brain changes seen in patients with MS and associated with cognitive impairment, is another disease status that is better visualized with NeuroQuant®. Patients with thalamic atrophy at baseline were at a higher risk for 5-year Expanded Disability Status Scale (EDSS) increase than patients with no identified brain atrophy. So having brain volume measurements at a single point in time could help predict disability progression in MS and complement both clinical and routine MRI evaluation in therapeutic decision-making. And this is something achievable if we incorporate NeuroQuant enhanced imaging technology in our comprehensive assessment protocols.7

Thoughts on available therapies.
 
Although we cannot expect a pharmaceutical alone to prevent brain deterioration in MS or any other neurological disease, there may be value in some medications as part of an integrative or other approach. We have previously written about memantine for MS, which as a suppressor of glutamate signaling has been used in treating Alzheimer’s disease. Although not shown to be effective beyond one year in most cases, a number of studies have looked at use of this drug for MS to reduce cognitive dysfunction as well as spasticity, fatigue and disability.8
 
Glutamate, an excitatory neurotransmitter, has been implicated in the autoimmune demyelination seen in excess levels in MS patients and lowers the levels of N-acetylaspartate (NAA), a process that likely leads to the loss of brain volume. This seems to indicate that glutamate might be a driver of neuronal cell death and disease progression in MS and a potential target of new therapies to improve disease symptoms.
 
Several studies have been facilitated to look at the use of memantine in MS; while present results do not appear to have significant benefit, I don’t believe we should completely eliminate it from our protocol considerations in cases where it may be appropriate depending on a patient’s condition or other health specifics. 
 
You can read more about memantine, suggested dosing and other facts at: https://www.suzannegazdamd.com/scientifically-speaking1/is-there-support-for-the-efficacy-of-memantine-in-ms
 
And visit https://www.suzannegazdamd.com/blog/the-relationship-between-glutamate-and-gaba to understand the role of glutamate and ways we can help reduce excess levels naturally. 
 
Remember that no single medication or action can on its own prevent cognitive deterioration. In this day and age, our brain essentially is under assault from so many impacts and from all sides. Enhanced assessment resources such as the use of NeuroQuant alongside standard MRI can help identify issues ideally at an earlier stage. But we should try to follow the pillars of good health in our lifestyle, diets, sleep and more to put us ahead of the “destructive brain game” and truly give our neurological wellbeing a fighting chance to thrive.
 
In hope and health,
Dr. Suzanne Gazda 
 
For nutritional approaches in MS you can download our helpful guide at:
https://www.suzannegazdamd.com/uploads/3/8/3/4/38341157/nutritional_approaches_in_ms.pdf
 
References:
 
1 Riley, C.S. Cerebral/Cognitive-Predominant MS. ACTRIMS FORUM 2021. (2/27/2021)
https://www.abstractsonline.com/pp8/#!/9245/presentation/32
 
2 Engel, Sinah & Graetz, Christiane & Salmen, Anke & Muthuraman, Muthuraman & Toenges, Gerrit & Ambrosius, Björn & Bayas, Antonios & Berthele, Achim & Heesen, Christoph & Klotz, Luisa & Kümpfel, Tania & Linker, Ralf & Meuth, Sven & Paul, Friedemann & Stangel, Martin & Tackenberg, Björn & Bergh, Florian & Tumani, Hayrettin & Weber, Frank & Sclerosis. (2020) Is APOE ε4 associated with cognitive performance in early MS?. Neurology - Neuroimmunology Neuroinflammation. 7. e728. 10.1212/nxi.0000000000000728.
 
 
3 Eshaghi A, Marinescu RV, Young AL, et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain. 2018;141(6):1665-1677. doi:10.1093/brain/awy088
 
4 Calabrese, M., Favaretto, A., Martini, V., & Gallo, P. (2013). Grey matter lesions in MS: from histology to clinical implications. Prion, 7(1), 20–27. https://doi.org/10.4161/pri.22580
 
5 Lin A, Chen F, Liu F, et al. Regional gray matter atrophy and neuropsychologcal problems in relapsing-remitting multiple sclerosis. Neural Regen Res. 2013;8(21):1958-1965. doi:10.3969/j.issn.1673-5374.2013.21.004
 
6 Eshaghi A, Marinescu RV, Young AL, et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain. 2018;141(6):1665-1677. doi:10.1093/brain/awy088
 
7 Hänninen K, Viitala M, Paavilainen T, et al. Thalamic Atrophy Predicts 5-Year Disability Progression in Multiple Sclerosis. Front Neurol. 2020;11:606. Published 2020 Jul 15. doi:10.3389/fneur.2020.00606
 
8 Mehta LR, McDermott MP, Goodman AD, Schwid SR. A randomized trial of memantine as treatment for spasticity in multiple sclerosis. Mult Scler. 2010;16(2):248-251. doi:10.1177/1352458509355462