Understanding the “gray area” in multiple sclerosis treatment.

One of the most significant issues with which our multiple sclerosis patients must cope and that we treat in our neurology practice is the resulting cognitive impairment that occurs in nearly two-thirds of patients and is often present in even those who are newly diagnosed.

While the available drugs for MS all claim to delay cognitive impairment, we must fully consider their degree of efficacy as it appears they actually do very little to help in the loss of gray matter, which is what gives us our information processing abilities.

The human brain is made up of two types of tissue: gray matter, which contains most of the neuronal cell bodies, and white matter, which is composed of bundles of nerve fibers that connect nerve cells in different areas of the brain and carry messages or nerve impulses between them. In years past, MS was considered a disease of the white matter, but we now know that both the white and gray matter are affected.

Deciding then how to best treat this cognitive decline in MS, as well as other neurodegenerative diseases, we must first look at this “gray area” to best understand the origination of the symptoms as we also look to science to guide our practices.

A paradigm shift in categorizing MS.
A recent publication in JAMA Neurology (June 2020) reported on findings of an investigation to examine the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of two treatments. The study explained that MS “is characterized by relapses with or without residual worsening and/or steady progression independent of relapses. A consensus statement suggested using the term disability worsening to describe a stepwise increase in disability in patients with relapsing MS (RMS) while reserving the term disability progression for patients in the progressive phase of MS, when disability accumulation occurs more continuously and independently of relapse activity.”1

Results showed that disability accumulation in remitting multiple sclerosis (RMS) is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis.

We can now see that MS progression is clearly tied to what is going on in the gray matter. Another published study from the Annals of Neurology, “Deep gray matter volume loss drives disability worsening in multiple sclerosis” revealed that gray matter atrophy becomes more widespread and severe in secondary (SPMS) and primary progressive MS (PPMS). In some patients, it may manifest as a dramatic acceleration, but also can be smoldering even in newly diagnosed cases.2

The MS drugs designed to reduce the inflammatory mechanisms thought to drive MS are called immunomodulating therapies as they alter and may sometimes suppress the immune system. Gray matter atrophy, especially cortical atrophy, can be demonstrated very early in patients with clinically isolated syndrome (CIS) and rapidly progresses during the relapsing-remitting (RRMS) disease course. This becomes particularly evident in the frontal, temporal, and parietal lobes; in other words, we see gray matter atrophy early and it may even pre-date the first clinical manifestations of MS!

Understanding the gray zone of MS pathology.
In MS, a misdirected immune response targets myelin, which is located in the white matter of the brain, spinal cord and optic nerves. The areas where the myelin is damaged are called plaques or lesions, which results in altered electrical conduction of the nerves. This is considered the inflammatory stage of MS followed by cumulative damage that results in a neurodegenerative stage whereby the lines of communication are broken (e.g. myelinated axons) and neuronal cell bodies in the brain’s gray matter start to die.   

In the last few years, this bifurcated theory of disease mechanism and progression in MS has become quite the “gray zone” as far as there being a consensus of thought.  A strong inflammatory immune attack also may be underway in MS, autonomously affected the gray matter. There are many other molecules that have yet to be discovered that comprise the targets of adaptive immunity in MS in the white and gray matter.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688852/

In addition, mechanisms that drive gray and white matter changes may be very different. In MS, meningeal inflammation, the presence of follicle-like structures in the meninges, and a unique lymphatic system adjacent to the meninges all point to greater effects on cortical gray matter pathology rather than on white matter. The thalamus, a deep gray matter structure, is affected significantly, perhaps because of its prominent bidirectional connections with the cortical gray matter and because of its close proximity to the choroid plexus, a site of immune cell entry into the CNS.

Unfortunately, standard magnetic resonance imaging (MRI) does not detect brain volume loss until it is often far along in its course. However, NeuroQuant, a software technology that analyzes a brain MRI to improve the early detection and treatment of dementia, Alzheimer’s disease, traumatic brain injury, multiple sclerosis and epilepsy, can precisely  measures brain atrophy. Its unique capabilities can look at structural volumes and the patient’s results to compare to someone of the same age and gender with no identified disease. And NeuroQuant uses no gadolinium (a contrast agent) and requires much less time in the scanner, which is definitely a benefit for many patients.  https://www.cortechslabs.com/products/neuroquant/

Do MS drugs work to prevent cognitive decline?
Researchers at Kessler Foundation conducted a comprehensive review of pharmacologic agents used in the treatment of multiple sclerosis, seeking evidence for efficacy for the cognitive dysfunction experienced by more than half of affected individuals.3 Study investigators identified 87 articles, using the PubMed and PsycINFO databases and the 2017 American Academy of Neurology (AAN) criteria for therapeutic trials; review of the studies of disease-modifying therapies failed to support effectiveness for treating cognitive deficits.

One of our recent scientific articles might explain, too, why the MS drugs don’t work as well as they should. Much like we’ve discovered in Alzheimer's disease treatments and akin to the “36 holes in the roof” described by Dr. Dale Bredesen in his extensive body of work, pharmaceutical approaches are simply not addressing all or enough of the mechanisms of neurodegeneration. MS must be seen as a tertiary disease resulting from the downstream effect of many, many different mechanisms and as such cannot be expected to respond to any one drug or single approach.

But what about IVIg as a neuroprotective component in brain health?

Intravenous immoglobulin (IVIg) has exhibited a diverse array of beneficial effects, including B and T cell trafficking, neutralization of autoantibodies, modulation of the complement cascade, and cytokine production, which are the body’s signaling cells that mediate and regulate things like immunity and inflammation. In animal models, IVIg has shown improvement in spinal cord injury and stroke and was shown to be profoundly neuroprotective.  It attenuates immune cell infiltration, promotes an anti-inflammatory environment and enhances tissue preservation and functional recovery after injury. In addition to targeting microglia as resident immune cells of the CNS as well as immune cells from the systemic immune compartment and endothelial cells, IVIg can also help shear up the leaky blood-brain barrier (BBB).4 And as a treatment protocol in Alzheimer’s disease, IVIg was shown to reduce cortical atrophy. So there is unquestionably a host of applications for which the use of IVIg may be considered in the treatment of not only neurological disease, but other inflammatory and autoimmune conditions.

A case for integrative medicine.

Certainly the drugs available for MS can be very helpful to many patients. But we also believe that there is strong evidence for employing neuroplasticity strategies, comprehensive programs such as the Bredesen Protocol™, the Wahls Protocol and, as always, a vigorous search for the root cause of disease in all MS treatment paradigms. This integrative medicine approach that includes a myriad of scientific resources, research and advanced technological methods would be invaluable and potentially life-changing for so many patients as well as their loved ones.

We’ll be writing more about some of these innovations in the field so please continue to stop by and visit our blog section as well as our social media pages for regular updates! And don’t hesitate to reach out if you have questions or would like to schedule an appointment.

In health and hope,
Dr. Suzanne Gazda

1 Kappos L, Wolinsky JS, Giovannoni G, et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. Published online June 08, 2020. doi:10.1001/jamaneurol.2020.1568
https://jamanetwork.com/journals/jamaneurology/fullarticle/2766801

2 Eshaghi, A., Prados, F., Brownlee, W.J., Altmann, D.R., Tur, C., Cardoso, M.J., De Angelis, F., van de Pavert, S.H., Cawley, N., De Stefano, N., Stromillo, M.L., Battaglini, M., Ruggieri, S., Gasperini, C., Filippi, M., Rocca, M.A., Rovira, A., Sastre‐Garriga, J., Vrenken, H., Leurs, C.E., Killestein, J., Pirpamer, L., Enzinger, C., Ourselin, S., Wheeler‐Kingshott, C.A.G., Chard, D., Thompson, A.J., Alexander, D.C., Barkhof, F., Ciccarelli, O. and (2018), Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol., 83: 210-222. doi:10.1002/ana.25145
https://onlinelibrary.wiley.com/doi/full/10.1002/ana.25145

3 Chen MH, Goverover Y, Genova HM, DeLuca J. Cognitive Efficacy of Pharmacologic Treatments in Multiple Sclerosis: A Systematic Review. CNS Drugs. 2020;34(6):599-628. doi:10.1007/s40263-020-00734-4

4 Chio, J.C.T., Wang, J., Badner, A. et al. The effects of human immunoglobulin G on enhancing tissue protection and neurobehavioral recovery after traumatic cervical spinal cord injury are mediated through the neurovascular unit. J Neuroinflammation 16, 141 (2019). https://doi.org/10.1186/s12974-019-1518-0
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1518-0#citeas