"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
No one knows exactly how the chronic demyelinating disorder multiple sclerosis (MS) begins, but two opposing viewpoints known as the "outside-in" or "inside-out" debate remain the subject of contention.
Inside-out vs Outside-in
The outside-in theory holds that MS is a disease that starts in the immune cells circulating in the bloodstream, which then enter the brain and/or spinal cord or central nervous system (CNS) and attack. Conversely, in the inside-out theory, damage begins within the CNS and triggers the immune system to cause further destruction.
In a 2020 review, Stephen D. Miller, PhD, and colleagues at Northwestern University Feinberg School of Medicine in Chicago summarized the inside-out hypothesis as consisting of oligodendrocyte injury and destabilized myelin as the primary pathogenesis and subsequent reactive inflammatory response and further myelin degradation as a secondary pathogenesis. For the outside-in hypothesis, the team said, the primary pathogenesis is autoimmune inflammation, while myelin degradation is the secondary pathogenesis.
Much of the scientific work on this issue has been performed in mouse models. "The outside-in experimental autoimmune encephalomyelitis models initiated by myelin-specific autoreactive CD4+ T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents," Miller and co-authors wrote. "The inside-out mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS."
After reviewing the current models, the group concluded that a combination of both paradigms may explain the onset of MS better than either paradigm alone due to the heterogeneous nature of MS pathology.
In a , Antonio Luchicchi, MD, of Vrije University in Amsterdam, and colleagues noted that, when viewed through the lens of genetic factors, dysregulation of immune responses, promoted by one's genetic background and potentially triggered by environmental factors, could represent the main mechanism in MS onset and progression.
Regarding the role of the immune system, the editorialists said, "both autophagy and complement production could be equally supportive of either a primary immune attack against myelin or a primary response to a CNS cytodegenerative process, paving the way for future experiments that can potentially unveil the real cause of MS."
Additionally, mitochondria instability could be a primitive trigger of MS pathology, Luchicchi and colleagues wrote. One possibility involves the role of oxidative stress-derived mitochondrial impairment, while another is the possible interplay between mitochondria and Ca2+-dependent cysteine proteases.
After considering all these possible mechanisms, the editorialists pointed to "a complex picture where a dichotomy between outside-in/inside-out theories is replaced by a more integrated vision where both theories might equally apply according to the specific condition."
The group also argued for "the need for a re-evaluation of cellular processes, previously regarded as pure indicators of an immune attack (e.g., complement), in combination with the individual (genetic) variability of MS patients, and the development of highly predictive experimental models/accurate biomarkers to unravel the unknown cause of the MS in the coming years."
Epstein-Barr Virus
Epstein-Barr virus (EBV) has long been postulated to play a role in the pathogenesis of MS, but that connection received a solid boost in 2022, when Alberto Ascherio, MD, DrPH, of Harvard T. H. Chan School of Public Health in Boston, and co-authors published a longitudinal analysis in that revealed the strongest link yet between the two conditions. The team analyzed data from a cohort of 10 million people who served in the U.S. military from 1993 through 2013, evaluating EBV antibodies in serum from the 801 individuals in the cohort who developed MS.
Of the 801 cases, 35 were initially EBV seronegative, and 34 became infected with EBV before the onset of MS. EBV seropositivity was "nearly ubiquitous" at the time of MS development, with only one of 801 MS cases being EBV seronegative at the time of MS onset.
"These findings provide compelling data that implicate EBV as the trigger for the development of MS," William H. Robinson, MD, PhD, and Lawrence Steinman, MD, both of Stanford University in California, wrote in an .
About 95% of healthy people demonstrate increased serum antibodies to EBV and never develop MS, so what is the mechanism in at-risk individuals? Robinson and Steinman suggest four possible mechanisms:
- Molecular mimicry by EBV nuclear antigen 1
- B cell transformation through latent membrane protein 1
- Induction of B cell trafficking to the CNS
- Other unknown mechanisms
The study by Ascherio and co-authors has already had a significant impact among neurologists: "That study is about as good as it gets in observational data coming close to proving causality," Lindsay Ross, MD, of the Cleveland Clinic, told 鶹ý. "They've eliminated potential biases, obeyed all the rules, and done a beautiful study."
Role of Gray Matter in Early Disease
Gray matter has also been a focal point of MS pathogenesis research. As early as 2008, Jeroen Geurts, PhD, of Vrije University in Amsterdam and Frederik Barkhof, MD, of University College London posited in that gray matter damage starts early in the disease and substantially affects cognitive functioning, although the causes of gray matter damage remained unclear.
Another that helped establish that gray matter is targeted in first-attack MS/clinically isolated syndrome appeared in PLOS One in 2013. Steven E. Schutzer, MD, of Rutgers University New Jersey Medical School in Newark, and colleagues used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients compared with established relapsing-remitting MS and control individuals.
The team found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (i.e., axon, neuron, and synapse). Myelin components did not distinguish these groups. "The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation," the researchers wrote.
"At this point, there is broad consensus that gray matter is involved early in the disease course," Ross said. "And while we have historically been able to see the white matter disease on imaging, it seems to be the gray matter that tracks with disease duration and disability."
Read Part 1 of this series: Early Diagnosis Can Mean Better Outcomes in Multiple Sclerosis