Onset: Part III (Connections)

Continued from: Onset: Part II (Mold damage)

Collagen fibils

I’ve previously written about how a bad mold exposure and my acute, viral onset of myalgic encephalomyelitis (ME) could have directly and indirectly damaged my connective tissue, including the ligaments in my neck, causing craniocervical instability (CCI). A key mediator of that damage might have been mast cell activation and collagen-degrading enzymes.

The coup de grâce (and it really was, oddly, a “stroke of grace”) was the thyroid surgery that took a “mild,” purely biochemical case of CCI and turned it into a symptom complex clear and severe enough to be diagnosed.

I printed out the Hunter-Hopkins advice sheet for people with ME/CFS and showed it to the anesthesiologist. I was at UCLA to have a complete removal of my thyroid due to Stage I papillary thyroid cancer. The sheet got a lot right, with advice applicable to patients with POTS and with mast cell activation syndrome (two syndromes I also had), although it did not explicitly name either. My anesthesiologist was wonderful: very happy to find a protocol that he was both comfortable administering and that adhered to this advice. He skipped several drugs, keeping it “clean” and giving me primarily (possibly solely) propofol.

The one thing Hunter-Hopkins did not say, but I believe should have said was this piece of advice, from the 1990s:

“the most important component of anesthesia is a neutral neck position and avoidance of hypotension. The former may increase cord compression and the latter may decrease blood flow to the spinal cord. Together, the effect may be severe.”

If the Hunter-Hopkins sheet had said this, I likely would never have developed central apnea, would never have fallen over, immobile, every time I turned my head, would never have had a horrific flare of leg pain and numbness, would never have had to live through the worst year of my life. (The story of why this advice was discarded or forgotten is an interesting story of its own, for another time.) However, I also would never have gotten diagnosed with CCI and tethered cord syndrome, would never have had surgery, and may have remained ill with the symptoms of ME for years, perhaps decades, possibly the rest of my life. I would never be writing this series and you would never be reading it.

Stroke of grace, indeed.

General anesthesia was initiated with a first dose of propofol. I fell unconscious. The drugs administered during anesthesia paralyze the muscles of the body, including the diaphragm, making it impossible to breathe on one’s own. So, as per usual, a tube would have been inserted through my mouth and into my airway, allowing me to breathe with the aid of a respirator. This is called intubation.

This process of inserting a breathing tube can be done without extending the neck but generally isn’t, unless the patient has some preexisting medical condition that mandates a more time-consuming process, such as video-assisted intubation (i.e., fiberoptic intubation/GlideScope). There are reams of articles written in anesthesiology journals about the importance of a neutral neck position in patients with Rheumatoid Arthritis, Down’s Syndrome, and other groups at risk of having craniocervical or atlantoaxial instability. This risk has never been quantified in patients with diagnoses of ME.

When I woke up after surgery, my jaw hurt. It hurt so much that I cried as I was waking. Every time I would try to get up from bed and transfer to the wheelchair I had arrived in, I would collapse, unable to move or speak. I finally left the hospital the next day, supine in an orthopedic wheelchair. Something had gone terribly wrong.

If connective tissue damage or structural neurological problems play a role in some patients with ME, why has that knowledge never been properly studied, consolidated or applied? One way to think of this is the “Streetlight Effect.”

A policeman sees a drunk man searching for something under a streetlight and asks what the drunk has lost. He says he lost his keys and they both look under the streetlight together. After a few minutes the policeman asks if he is sure he lost them here, and the drunk replies, no, and that he lost them in the park. The policeman asks why he is searching here, and the drunk replies, “this is where the light is.”

The streetlight effect describes a kind of observational bias that occurs when we look only where it is easiest to look. So much of our research has focused on studying products in the blood, a problem if what we are looking for is actually in the brain or tissues.

The other is the parable of the Blind Men and an Elephant.”

A group of blind men heard that a strange animal, called an elephant, had been brought to the town, but none of them were aware of its shape and form. Out of curiosity, they said: “We must inspect and know it by touch, of which we are capable”. So, they sought it out, and when they found it they groped about it. In the case of the first person, whose hand landed on the trunk, said “This being is like a thick snake”. For another one whose hand reached its ear, it seemed like a kind of fan. As for another person, whose hand was upon its leg, said, the elephant is a pillar like a tree-trunk. The blind man who placed his hand upon its side said the elephant, “is a wall”. Another who felt its tail, described it as a rope. The last felt its tusk, stating the elephant is that which is hard, smooth and like a spear.

To mix parables, we’ve been looking where the light is when the problem isn’t a tail or an ear, but an elephant. And we patients have also been fighting, sometimes viciously with one another, about what is the “real ME” and what causes it when we might just be playing tug of war over various elephantine body parts. What if in the aggregate, many things are true? What if in any individual case, causality is combination of a few different factors taken from the a common universe of possibilities? And what if what connects all those factors is connective tissue?

There have been a number of risk factors long associated with ME (some well established in the scientific literature, some unpublished clinical or patient observation). Some of these factors are associated with onset, others with a worsening of symptoms. What might connect all of these factors? One possibility is collagen and other components of connective tissue. (For citations, please see the “Collagen” page on MEpedia.)

• Viral infection: viral infection can increase the body’s production of metalloproteinases (MMPs), which break down collagen.
• Bacterial infection: bacterial infections can increase host production of MMPs as well as directly secreting collagenases. There is a case of Bartonella infection, for example, causing an Ehlers-Danlos Syndrome-like hypermobility syndrome.
• Mold: some studies have found that black mold also releases collagen-degrading enzymes.
• Antibiotics: doxycycline, which anecdotally some patients have benefited from, inhibits MMPs. Fluroquinolone antiobiotics, which can produce an ME/CFS-like illness, increases MMPs and in December 2018, the FDA issued a warning against its use in patients with Ehlers-Danlos Syndrome and Marfan Syndrome.
• Pregnancy: causes significant changes in collagen and elastin production. Patients with EDS report increased dislocations and some that their pain symptoms began with their first pregnancy. Some ME/CFS patients report feeling better during pregnancy, others worse. Some ME/CFS patients had their onset post-pregnancy while others recovered long-term after pregnancy. There are obviously many things that happen to a woman while pregnant but changes in collagen and elastin metabolism is one of them. It’s complex but worth exploring…
• Surgery, car accident, concussion: these can all cause structural damage to the neck and a stretching or mechanical damage of the neck’s ligaments.
• Ehlers-Danlos Syndrome and other connective tissue disorders: ME expert Byron Hyde wrote, “Patients with pre-existing or newly-discovered (a) Ehlers-Danlos Hypermobility Syndrome, (b) Collagen diseases… are among the most disabled patients we have seen.”
• Sex hormones: Patients with hypermobile EDS (hEDS) are predominantly female. Patients with ME are predominantly female and it has been observed clinically that some boys who develop ME as children “grow out of it” after puberty. Testosterone is a potent anti-inflammatory hormone that, in animal studies, has been associated with increased collagen. Estrogen, by contrast, has been associated with decreased collagen.

Because of the public nature of my work, I have received thousands of emails and met almost as many patients in person. I have heard more first person stories than I will ever be able to count. One pattern I have observed is that many of the most severely ill patients I’ve encountered had not one hit, but several, creating a cumulative effect. Some had “mild” ME following a bacterial infection but became severe after surgery or a concussion. Others seemingly recovered only to be felled, years later, after a severe mold exposure. I’ve even seen cases that go, “concussion, virus, mold exposure, pregnancy, antibiotics” where each hit brought that person further down the spectrum of severity.

This is related to the concept of “equifinality,” the idea that many different “causes” can end up in the same result. Michael VanElzakker has spoken many times about how this concept has influenced his thinking on the disease. The question I raise here is could this same end result occur because all of these “causes” act on the same component: connective tissue.

I must emphasize that this is, again, a story, pulled together from fragments of my one case and fragments of research literature. My hunch is that connective tissue and its components, including collagen, will prove to play an important role in this disease, at least among a subset. When we understand its role, it might help explain why ME and hEDS are not infrequently co-morbid and why among patients, the stories we have be telling for years about viral infections, bacterial infections, antibiotics, mold, pregnancy and traumatic accident are all, in part, true. All, in some way, relevant to our understanding of this disease. My hope is that someone reading this will think this story is interesting or plausible, and use it to go do some science.

I related some version of the preceding story to Ron Davis. He has often said, summoning Charles Darwin, that the “first act of science is to observe.” That’s what he does, without rushing to judgment. New information is neither rashly rejected nor embraced. It just becomes another observation, part of a growing universe of data. Some of his most influential discoveries came from choosing not to discard observations or results that did not immediately make sense but rather pulling and pulling on the thread until something no one unexpected to find led to a new discovery or invention.

After I told him my long, long story he sat for a few moments, quiet and in deep thought until he finally said, “the patients in the Severely Ill Patient Study had elevated levels of hydroxyproline.”

Hydroxyproline is a protein found in collagen. It’s what creates its stability. High levels of it in the blood are indicative of collagen breakdown.

Robert Naviaux’s of UC-San Diego’s study found elevated hydroxyproline in female patients; he has suggested hydroxyproline as one possible biomarker. At this year’s Emerge Australia conference, Neil McGregor of the University of Melbourne discussed increased connective tissue degradation in both burn patients and ME/CFS patients, and that burn patients with joint hypermobility have increased susceptibility to this breakdown. Last year, Wenzhong Xiao of Harvard University presented on the results of the Severely Ill Patient Study and shared that hydroxyproline was one of the three metabolites whose levels were most different in patients: it was significantly elevated. This is the result Dr. Davis was referring to towards the end of our conversation.

So there is at least some evidence that the factors above––viral infection, bacterial infection, mold exposure, fluroquinolone antibiotics, pregnancy, hereditary connective tissue disorders, and sex hormones––all affect collagen synthesis and degradation. There are varying degrees of evidence that these factors all affect susceptibility to developing ME or experiencing worsening symptoms. And again, two studies of ME patients––Robert Naviaux’s metabolomics study and the Severely Ill Patient study––both found elevated hydroxyproline, an indicator of collagen breakdown. My personal experiences bias me, but I think this is a thread worth pulling on.

If more broadly true, it could explain the close connection between a whole cornucopia of chronic illnesses including ME, EDS, postural orthostatic tachycardia (POTS), fibromyalgia, mast cell activation syndrome (MCAS), and even chronic Lyme Disease.

I’ve explored whether the three main factors in the onset or worsening of my symptoms––mold exposure, viral infection and surgery––may have had as their common factor connective tissue, specifically the ligaments in my neck. Next, I’ll dig deeper into just how my CCI (plus a few other things) could have created the symptom cluster described in the International Consensus Criteria for ME, at least in my case.

Read next: Pathlogy: Part I: (A walk around my brainstem)

My gratitude for the thousands of conversations that have informed my thinking on all this, especially with Jeff Wood, Dr. David Kaufman and Dr. Emma Reinhold.

Read all the posts in my CCI + tethered cord series

Read this disclaimer. Crucially, surgery carries risks and it’s important to remember that in medicine, the same exact symptoms can have multiple, different causes. We have no idea how prevalent CCI is in our community and there’s been no research into its relationship with ME. We do know that it is more common among patients with EDS.