Multiple Sclerosis--The Infection Connection--Part 1

Are we driving full speed in the wrong direction? Could it be time for a left-turn?

Over the years I’ve been asked the same question by lots of patients, “With all the money that’s gone into MS research, why hasn’t it been solved yet?” —Maybe they’re looking in all the wrong places. This is the info I wish my MS patients had years before they met me.

Since opening my doors in 1996, my medical practice focus has been chronic illness, with my continued goal being to find and treat cause(s), rather than only treating symptoms—Most people don’t know that many chronic infections underlie and cause a range of chronic illnesses. And the data supporting this for multiple sclerosis is compelling. Treating infections early leads to better outcomes—If there are infectious causes to MS, it’s likewise a time-sensitive issue, to treat the infection before disability sets in. This is counter to the prevailing autoimmune dogma, so this post will be a trip down the rabbit hole and back up, exploring these infections and ultimately showing how they weave together into the autoimmune tapestry.

This post is divided into 2 parts. Part 1 reviews the standard view of MS & why I think it needs a re-write. Part 2 looks at the potential infectious drivers of this illness.

The Basics

MS is a chronic neurologic condition that can cause considerable disability, sometimes early death. Over 2.8 million people have it worldwide, almost 1 million of whom live in the US. With prevalence increasing, if you don’t know someone with MS, you probably will soon.

Most MS patients fall into two categories. The first, relapsing-remitting MS, is the most common, accounting for about 85% of cases. As the name suggests, it’s hallmarked by attacks of neurologic symptoms, followed by quieter periods when symptoms improve or even resolve. About 5-10% of them, called benign MS, don’t progress to disability even without any treatment over 15 years. The rest worsen over time, albeit with with ups and downs, until ultimately their course converts to continued progression without remissions, called secondary progressive MS.

The second category is primary progressive MS, which is not characterized by attacks or remissions, but rather a slow steady progression of neurologic symptoms over time. It’s associated with fewer brain and spinal cord lesions yet results in generally more severe disability. Of note, patients who first get MS in middle-age, called late-onset MS, tend to progress to disability more quickly, regardless of their initial MS classification.

Epidemiology of MS

There are gender and hereditary factors in MS, with women getting it 2-3 times more often than men, and people of northern European ancestry at highest risk. But genetics tell just part of the story, as identical twins both get MS only about 24% of the time.

MS occurs more commonly in temperate to cooler climates, consistent with speculation that higher vitamin D blood levels from sunshine may help prevent MS. And this may be true. Accumulating evidence shows that healthy vitamin D levels are associated with better MS outcomes. Of note, there’s a sweet spot for 25-hydroxy vitamin D blood levels—about 55 ng/ml—too much vitamin D can be toxic.

There’ve been many statistically improbable clusters of MS, suspicious for an environmental cause. What occurred in the Faroe Islands, in the North Atlantic Ocean between Norway and Iceland, is probably the most famous example. MS hadn’t been present in their population until 1943, when it abruptly appeared in patients over several epidemic waves. The British, many of whom were from the Scottish Highlands, an area where MS is common, had occupied the Faroe Islands from 1940-1945, raising suspicion that they may have introduced an insidious infection which is asymptomatic in most, but causes MS in some. After peaking in 1945, the prevalence of MS in the Faroe Islands at first moderated, then gradually increased over the following decades, becoming endemic, with rates similar to the rest of nearby Europe.

These epidemiologic clues lead me to ask, are we missing the boat on a possible infectious cause to MS?

The Descriptive Dilemma

Does having a diagnosis answer all the important questions? MS is a purely descriptive diagnosis, which means that it’s defined by a characteristic set of signs, which includes demyelinating lesions in the brain and spinal cord, inflammation of the nerves attaching the eyes to the brain, and spinal fluid abnormalities. (Demyelinating means that the normal insulation around nerves, called myelin, breaks down due to attack by the immune system.)

The elephant in the room is that a descriptive diagnosis doesn’t bring us any closer to the root cause of the illness, leading us to the reasonable and singular question: How can you cure an illness when you don’t know its cause?

Standard MS Treatments & Their Outcomes

There are many drugs for MS, called disease modifying treatments, which largely consist of immunosuppressants. A variety are FDA-approved for relapsing-remitting MS, but only one, Ocrevus, is approved for primary progressive MS. Many studies show partial efficacy to these drugs, but some fail to demonstrate benefits.

In 2021, Physician’s Weekly ran a news story about a major medical journal article which summed up how MS patients have been responding to these treatments over the past 15 years. Here’s the headline:

“MS Disease-modifying Therapy Shows Reduced Disability Accrual Over 15 Years”

They’re referring to a large multicenter study by 59 authors, and published in the prestigious medical journal Neurology. They followed MS patients over 15 years to summarize the effects of treatment. Out of the many medical journal articles on this topic, I chose this study to analyze because it can reasonably be considered cream of the crop.

Warning: What follows, in the next however many paragraphs leading up the Study Funding section, is a technical review of the MS study—possibly bordering on boring for the less analytical among us—(Note to self: Way to go Steve, great way to build an audience!!)—but written specifically for the science-minded or the MS patient reading this. It’s what I’d want my MS patients to know, so in fairness I have to make it available to MS patients everywhere.

The authors wrote:

“Prevention of long-term disability accrual is currently the main goal of multiple sclerosis (MS) treatment.”

And here, included in the abstract, is what they found:

“Continued treatment with MS immunotherapies reduces disability accrual by 19%–44% (95% CI 1%–62%)”

For those who’ve never taken a statistics class—you didn’t miss much—but the following might be a little tough: “CI” is an abbreviation for confidence interval, which is a range of statistically significant answers to the studied question being asked, in this case about preventing disability. So the true reduction of disability accrual from these MS treatments, based on the statistics designed into the study, fell anywhere between 1% and 62%. If the confidence interval had included zero or a negative number, then the treatments would have failed to show statistical benefit for preventing disability. Having the lower end of the confidence interval at 1, being so close to a zero reduction, indicates that these treatments likely barely demonstrated statistically significant benefits in preventing disability accrual, which is of concern considering that it’s explicitly described as “the main goal of multiple sclerosis (MS) treatment.”

The authors grouped both primary progressive and secondary progressive MS together in a single progressive MS category, rather than performing separate treatment outcome analyses:

“Two analyses evaluated the effect of immunotherapy among patients with relapsing-remitting and progressive (primary and secondary) disease forms separately.”

And there was no treatment benefit to the grouped progressive forms.

“the analysis in progressive disease forms did not find any differences in disability accumulation (HR 0.92, 95% CI 0.81–1.05, p = 0.22) or improvement (HR 1.38, 95% CI 0.85–2.26, p = 0.19) between the treated and untreated pseudocohorts”

Why didn’t the authors separately evaluate treatment outcomes for secondary progressive MS? Many MS treatments are FDA-approved for this indication, so we really need reliable data on their activity, or lack thereof. It doesn’t make sense to have done a mixed analysis with primary progressive MS, which we already know doesn’t respond to the current treatments apart from possibly Ocrevus.

In the study abstract, the authors didn’t include the failure of these treatments in their grouping of progressive MS. This is of concern because 63% of the time, physicians only read the abstracts of medical journal articles and not the rest of the article. And I think it’s fair to predict that most busy physicians don’t critically appraise an article if they do read the whole thing. Wouldn’t it be human nature to be less inclined to scrutinize an article written by 59 eminent authors and published by a prominent journal like Neurology?

And was it responsible reporting by Physician’s Weekly to leave out the study findings that treatment failed to improve patients in the combined progressive MS group over 15 years of use? Isn’t that important information that should have been included in their headline? According to Harvard Health Publishing, “health news headlines can be deceiving” due to overstating study findings and overlooking important outcomes.

And it appears that the authors eliminated benign MS from their analyses—Keep in mind that these were MS patients followed for 15 years.

“In order to eliminate the scenario when treated and untreated cohorts are not comparable (due to strong indication bias that would lead to the allocation of patients with benign MS to the untreated cohort) and to fulfil the assumption of positivity, we have restricted inclusion to only those patients who qualified for at least one immunotherapy during the course of their disease.”

Benign MS lacks progression of disease without treatment over 15 years, and according to Johns Hopkins, “cannot be predicted at the time of diagnosis or even after a few years with MS.” So, this is a diagnosis that can only be made retrospectively after many years of observation. So if the authors couldn’t have predicted who would have benign MS at the beginning of their disease course, did they omit these patients after having looked back 15 years? If so, I wonder how the reduction of disability accrual in relapsing-remitting MS may have been different if these patients had not been omitted, as the outcome likely barely meets statistical significance as the study currently stands.

And here we have complicated and questionable math used in the study:

Do they expect their readers to perform complex math?—I’ll admit right now that I didn’t even try to figure this one out. Without this being readily digestible by the average consumer, how can we be sure that the weighting of this data is accurate?

Typically, weaknesses of a study are reviewed in the Discussion section. The authors, I feel, appropriately addressed many of their study’s weaknesses, but not all, and not in the neutral manner I would have preferred. For example, they mentioned excluding those with benign MS, but didn’t comment on the possibility that this was an incorrect decision, and if it was, how it may have affected study results. Would it have changed the relapsing-remitting MS outcome so that reduction in disability accrual was no longer statistically significant?

In regard to the labyrinthine math used in the study, the authors admitted that “further mathematical justification of such an approach is required.” But this statement was lost amidst several paragraphs of text so verbally complex that, comparable to the confusing math, also lent itself impervious to analysis.

The authors mentioned the lack of benefits in their grouped progressive MS, but did not discuss what appears to have been an enormous omission—Failing to separately analyze outcomes for primary and secondary progressive MS. And then they didn’t include in the abstract the finding of no benefits in their grouping of progressive MS, which, as previously pointed out, may be all that physicians are reading most of the time.

And lastly, there’s no mention in the Discussion section that the prevention of disability accrual, explicitly described by the authors as the main goal of MS treatment, likely bordered on statistical insignificance.

Study Funding

It’s very important to point out that this study was enormously funded by, and its authors have received payments from, many pharmaceutical companies, (bold type provided by me for clarity) which may pose financial conflicts of interests.

Please note at the end where it says, “Go to Neurology.org/N for full disclosures.” Does that mean that the following is only a partial list?

“This study was financially supported by National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) and Biogen (research grant 2016003-MS). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors.

Disclosure

The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support, or conference travel support from Acthelion (E.K.H., R. Ampapa), Almirall (M. Trojano, F. Grand'Maison, R.B., C.R.-T., J.L.S.-M.), Bayer (M. Trojano, A.L., P.S., R. Alroughani, M. Terzi, C.B., J.L.-S., E.P., V.V.P., R.B., D.S., R. Ampapa, J.O., J.L.S.-M., S. Hodgkinson, C.R., A.G.K., T.C., N.S., B.T., M. Simo, C.-A.S.), BioCSL (T.K., A.G.K., B.T.), Biogen (T.K., T.S., D.H., E.K.H., M.T., G.I., A.L., M.G., P.D., P.G., V.J., A.v.d.W., Grand'Maison, F. Granella, P.S., D.F., R. Alroughani, R.H., C.B., J.L.-S., E.P., V.V.P., F. Grand'Maison, R.B., R. Ampapa, C.R.-T., J.P., J.O., M.B., J.L.S.-M., S. Hodgkinson, C.R., C. Shaw, O.G., A.G.K., T.C., B.S., N.S., B.T., M. Simo, H.B.), Biologix (R. Alroughani), Celgene (E.K.H.), Genpharm (R. Alroughani), Genzyme-Sanofi (T.K., E.K.H., M. Terzi, G.I., A.L., M.G., P.D., P.G., A.v.d.W., Grand'Maison, F. Granella, P.S., D.F., R. Alroughani, R.H., M. Trojano, C.B., J.L.-S., E.P., E.P., V.V.P., F. Grand'Maison, R.B., R.B., D.S., C.R.-T., J.P., J.O., M.B., J.L.S.-M., S. Hodgkinson, O.G., A.G.K., H.B.), GSK (R. Alroughani), Innate Immunotherapeutics (A.G.K.), Lundbeck (E.P.), Merck/EMD (T.K., D.H., E.K.H., M.Te., G.I., A.L., M.G., P.D., P.G., V.J., A.v.d.W., P.S., D.F., R. Alroughani, R.H., M. Trojano, C.B., J.L.-S., E.P., V.V.P., F.G., R.B., D.S., R. Ampapa, J.O., M.B., J.L.S.-M., C.R., F.M., O.G., A.G.K., T.C., B.S., M. Simo, H.B.), Mitsubishi (F. Grand'Maison), Novartis (T.K., T.S., D.H., E.K.H., M. Terzi, G.I., A.L., M.G., P.D., P.G., V.J., A.v.d.W., F.G., P.S., D.F., R. Alroughani, R.H., M. Trojano, C.B., J.L.-S., E.P., V.V.P., F. Grand'Maison, R.B., D.S., R. Ampapa, C.R.-T., J.P., J.O., M.B., J.L.S.-M., S. Hodgkinson, C.R., F.M., C. Shaw, O.G., A.G.K., T.C., N.S., B.T., M. Simo, H.B.), ONO Pharmaceuticals (F. Grand'Maison), Roche (T.K., E.K.H., A.L., M. Terzi, C.B., V.V.P., B.T.), Teva (T.K., D.H., E.K.H., M. Terzi, G.I., A.L., M.G., P.D., P.G., V.J., F. Grand'Maison, P.S., D.F., R.H., M. Trojano, C.B., J.L.-S., V.V.P., R.B., D.S., R. Ampapa, J.P., J.O., J.L.S.-M., C.R., A.G.K., T.C., M. Simo, C.-A.S.), WebMD (T.K.), and UCB (E.P.). Go to Neurology.org/N for full disclosures.”

The public puts a great deal of trust in smart people, as if they can somehow transcend the biases that are inherent to our species, but this isn’t so. To think of research scientists as neutral beacons of truth, unaffected by the insidious siren song of financial conflicts of interest is a beautiful thought, but it’s been demonstrated to be patently false. In fact, an extensive review article from the prestigious Annals of Internal Medicine compiled the results from 36 published medical studies and found that financial relationships between physicians and pharmaceutical companies altered physician decision making. Doctors who received pharma industry payments more frequently prescribed expensive drugs with uncertain medical benefits. Physicians from Memorial Sloan Kettering Cancer Center, wrote a compelling article about this:

“The arguments in favor of industry payments no longer have traction in light of current evidence. Accepting industry money can no longer be rationalized as beneficial, or even permissible. Doctors take an oath to work in their patients’ best interests, a commitment they take seriously. The problem we must now confront is that all of the evidence suggests that industry payments run counter to what is best for our patients.”

In sum, I find all of this to be of great concern, especially in light of the reasonable assumption that the MS study I analyzed represents the best of the best for the field of MS. I truly didn’t expect to find so many significant issues in a study with 59 authors. Maybe the old adage about too many cooks in the kitchen is true. Could groupthink have caused errors in judgement? I don’t know, but however we got here, it doesn’t appear optimum. I have to think that there might be a better way through this—That there could be a more efficient road back to good health for MS patients by taking a closer look at cause, rather than focusing only on symptom suppression.

“Once You Label Me, You Negate me.”

Søren Kierkegaard

Of all the mysteries to MS, chief among them is its cause. So physicians have done what they’ve always done when they don’t know the origin of an illness. They label it by description. And then they further describe it. And then they describe it some more. And over time, after a multitude of medical journal articles have been published on the descriptive diagnostic criteria for MS, we get further and further away from the simple, but ultimately crucial, question—“Why?”

As we’ve barreled ahead full steam on this descriptive highway, there have been many diagnostic criteria for MS over the years, with the most recent one, the revised McDonald Criteria, making it simpler and quicker to diagnose MS at the time of its first neurologic attack.

From the British medical journal, The Lancet Neurology:

“Recognise that the McDonald criteria were not developed to differentiate multiple sclerosis from other conditions but to identify multiple sclerosis or a high likelihood of the disease in patients with a typical clinically isolated syndrome once other diagnoses have been deemed unlikely.”

The McDonald criteria is designed to diagnose MS quickly. It doesn’t speak to cause and explicitly disclaims its use as a means to rule out other conditions. So the good news is, MS patients are being diagnosed sooner. The bad news is, MS patients are being diagnosed sooner.

Huh? What do I mean by that?

When patients are diagnosed with MS, the search into the cause of their illness effectively stops. They’re sent down the path toward disease modifying drugs, most being immunosuppressants, which are often lifelong, expensive, and can carry significant risks. One medication for example, Ocrevus, at the time of this writing, costs $68,121.64 per year and, according to the manufacturer, can increase the risk of life threatening infections and cancers.

There’s little doubt in my mind that some disease modifying treatments can be helpful in slowing down some metrics of disability in relapsing-remitting MS to some degree, but there’s equally little doubt in my mind that they don’t work nearly well enough, especially in progressive MS where a subset of them lack evidence of any efficacy. And the high risks and enormous expense of these drugs speak for themselves. So it’s not surprising to me that many MS patients are dissatisfied with their quality of life and their suicide rates are more than twice that of the general population.

I fear that when MS is diagnosed, patients are not informed of medical information that runs counter to what is currently an immensely profitable pharma narrative—Why not? Isn’t it part of informed consent to fully inform? Yes of course it is. But to be frank, how is it possible? Much of what you’re about to read isn’t taught in medical school. Some were revelations made during the first half of the 20th century, a period widely referred to as “The Golden Age in Medicine” and the most recent findings haven’t yet trickled down to clinical practice. The Golden Age was a time of rapid discovery, which I believe was largely due to the pristine motives of scientists during this era—In search of understanding and truth, it doesn’t get better than that. It was a time before pharma impacted virtually every layer of the medical sciences.

“When a knowledge system importantly loses integrity, ceasing to provide the kinds of trusted knowledge expected of it, we can label this epistemic corruption. Epistemic corruption often occurs because the system has been co-opted for interests at odds with some of the central goals thought to lie behind it. There is now abundant evidence that the involvement of pharmaceutical companies corrupts medical science.”

Lost Wisdom

The following information was difficult to retrieve, taking me many days of research, because Pubmed doesn’t store all medical journal articles before 1947—But that doesn’t mean that they don’t have value, rather, it’s quite the opposite.

"Some contemporary medical questions can only be answered by consulting the older literature."—Dr. Donald Lindberg

In 1913, an article supporting an infectious etiology to MS was published by the esteemed medical journal The Lancet — Researchers described the means by inoculation to transmit the illness from humans to rabbits. A few years later, the floodgates opened. Scientists from around the globe began finding that when lab animals were inoculated with spinal fluid and brain tissue from MS patients, neurologic illness often followed, sometimes resulting in paralysis and death. Kuhn and Steiner famously found spirochetes, a spiral-shaped bacteria, in both guinea pigs and rabbits inoculated with central nervous system tissues from MS patients. In 1925, Adams et al published on the transmission of MS from humans to monkeys, and after the monkeys became ill, finding spirochetes in the monkeys’ brains. The organism found in the brains of MS patients was named Spirochaeta Myelophthora, and from its appearance, it was determined to most likely be a borrelia, a sub-type of the spirochete family.

A spirochete found in the brain of an MS patient https://pubmed.ncbi.nlm.nih.gov/13118387/

A spirochete found in the brain of an MS patient https://pubmed.ncbi.nlm.nih.gov/13118387/

Scientific debate ensued, with many researchers publishing medical journal articles documenting these spirochetes from MS patients and citing them as the etiology for the illness and many detractors decrying their findings.

“A spiral-shaped organism has been noted in multiple sclerosis by so many investigators, over so many decades, in so many countries that it can hardly be ignored.—Dr. Lida Mattman

The most famous, or rather infamous, spirochete, is arguably the one that causes syphilis. It’s called Treponema Pallidum and it literally took over a century to figure out how to maintain its growth in a test tube. Similarly, many other disease causing spirochetes have been notoriously difficult to culture in the lab.

Whereas most researchers found spirochetes from MS patients only when the organisms were killed and stained in tissues, some found them still alive and motile in smears for up to seven hours. In 1957, Ichelson published an article detailing the successful culture of live spirochetes from the spinal fluid of MS patients. By the end of 1958, her results were replicated by multiple independent researchers, ultimately being confirmed by Newman et al, of Stanford University. But it wasn’t enough. Several scientists failed to repeat her findings, in whole or in part, with the study by Kurtzke et al being possibly the most influential. Why did some succeed and others fail in their efforts to replicate Ichelson’s results?

What about EBV, chlamydia, coronaviruses, and other infections implicated in MS? What about the perfect storm that led to the ending of the Golden Age of Medicine, and the dawn of the era of autoimmune diseases?

My analysis, through the lens of the last 60+ years of accumulated medical knowledge, is included in Part 2. It’s such a complex topic, beyond the email word limit for a single post—so please stay tuned, Part 2 will be released soon!

I want to personally thank you for taking the time to consider my thoughts on MS. I so appreciate your subscription to this newsletter (and am extraordinarily appreciative of those generously opting for the paid subscriptions!!). If you like what you’ve read here today and think that it can help someone in need, please share it widely.

Disclaimer: None of my posts contain medical advice. These posts are intended for purely informational purposes only. Please check with your doctor before undertaking any course of treatment.