Onset: Part I (Viral onset)
It started with a high fever. Of that much I am sure. Like 80% of people with Myalgic Encephalomyelitis (ME), I can remember an infection, and a very clear before and after. Everything else is a mystery. Even though I can point to the trigger that seemingly started this all, I will never, can never, know exactly why or how I got sick.
What I do know with a high degree of certainty is that the mechanism underlying most of my ME symptoms was craniocervical instability. For more than seven years, my head was sinking on my spinal column due to a weakness in the ligaments that connect my skull to my neck. This caused brainstem compression and with it, autonomic dysfunction. It also caused intracranial hypertension and abnormal blood and cerebrospinal fluid flow to my brain. The surgery which fixed this cranial settling, a craniocervical fusion, resolved all of my ME symptoms instantly, save those caused by tethered cord syndrome, for which I also had surgery, and my mast cell activation syndrome (MCAS), which is now gradually improving.
Knowing the mechanism behind my symptoms is not the same thing as knowing the cause. Why did my skull suddenly drop after 28 years of good health? How did the ligaments (connective tissue) in my neck become compromised?
In this next series of articles, I will attempt to reinterpret my illness history through the lens of the connective tissue damage that led to craniocervical instability. Then, I will explain how craniocervical instability could cause many of the symptoms of ME, especially in combination with intracranial hypertension, spinal fluid leaks, MCAS and, in some cases, tethered cord syndrome.
Everything I’ve written up until now about my individual medical case has been fact, as best as my doctors know it and I can relate it. What follows is speculation. I want to make clear that what I am about to tell you is a story. I hope it is an interesting story. I think it is plausible one. It is, nonetheless, a story of which I am uncertain, that has some significant gaps, and that I will never be able to prove in my specific case, even if the scientific literature one day validates aspects of it in general. However, if you are a patient reading this, maybe you’ll find echoes of your story in mine. Perhaps it will help you on your journey in some way. Or, if you are a clinician or researcher, maybe it will lead to some interesting, testable hypotheses. So, that is why I tell it, but do take it with a grain of salt.
It also merits repeating that not all cases of ME will have as their central mechanism craniocervical instability. However, I do think there are a group of mechanisms, all of which may relate to connective tissue, all of which can co-occur in the same patients, that could, in a subset of patients, cause many of the symptoms associated with ME. These include spinal fluid leaks, jugular or transverse sinus stenosis (often found in intracranial hypertension), cervical stenosis and CCI. What’s more, I believe these mechanisms are not inconsistent with the acute, viral onset many of us had, as well as more gradual onsets involving environmental injuries or physical trauma.
I’ve been asked a lot since writing about my CCI diagnosis, how could a structural issue cause systemic, biochemical problems? How could a biochemical problem (e.g., a massive infection, an environmental exposure) cause structural changes? I think collagen could be what “connects” them. Non-traumatic CCI could be a collagen problem. Spinal fluid leaks could be a collagen problem. Incompetent blood vessels could be a collagen problem. Collagen, along with other proteins like gelatin and elastin, are the building blocks of our connective tissues. Its biochemistry and metabolism helps create our structure — — bones, ligaments, blood vessels — and that structure can in turn have profound effects on our biochemistry.
And so it’s through that lens of collagen and connective tissue that I have tried to reconstruct my story.
It did “start” — in a sense — with a virus. I describe this onset in my TED Talk. In brief: in early 2011, I had a fever for ten days, after which I became very dizzy. I developed what I later learned was post-exertional malaise (PEM), a severe worsening of symptoms after physical or mental exertion. Over the course of the year, I became progressively more ill. I had infection after infection. My energy envelope shrank. I crashed after less and less effort. I developed postural orthostatic tachycardia (POTS). My neurological symptoms accumulated until I became bedridden.
Blood tests days after my fever showed an elevated white blood cell count. My doctor said I had had an infection, presumably viral. He did not test for any antibodies or viral proteins via PCR, so I can never know which infection I had.
John Chia thinks it was Coxsackie B4. He told me my onset and symptoms were consistent with an enterovirus. Repeated testing over the years showed very high titers of antibodies (1:320 to 1:640) to that virus, and only that virus. I think it matters that it was likely an enterovirus because enteroviruses may trigger the onset of ME at higher rates than other infections. There is some suggestive direct evidence to this effect, including muscle, gut and brain biopsy studies. And there is some strongly suggestive indirect evidence, namely the history of epidemic Myalgic Encephalomyelitis, at least pre-1984. After reading every published case of every outbreak documented in the literature, I believe that owing to the incubation period, method of transmission and symptoms, these outbreaks could only have been caused by an enterovirus or (much less likely) by a family of viruses yet to be categorized or discovered.
However, “it’s an enterovirus” is not a very satisfying explanation. First, we know that other infections can trigger ME including Epstein-Barr virus, Ross River virus and Q fever, a bacterial infection. (I wonder if tickborne infections can as well.) Also, while 80% of people who develop the symptoms of ME recall an acute infection, 20% do not. Moreover, the same enterovirus that can trigger ME can also trigger Type 1 Diabetes or myocarditis. (I know of one couple who contracted an enterovirus at the same time. One developed ME, the other, Type 1 diabetes.) Most people who contract an enterovirus will experience absolutely no symptoms at all and never know they were ever infected.
What matters, and what we still don’t understand, is first, who is vulnerable and why? What genetic or other individual factors predispose some people to develop ME after any of the above infections when most will not? What is the mechanism or ongoing damage that prevents the vast majority of us with ME from ever recovering? (An estimated 95% will not recover once they have been ill more than five years.) How does that mechanism cause the cluster of symptoms we call ME?
I know that in my case, the ongoing, post-viral damage was damage to the ligaments in my neck since that is what caused my craniocervical instability and because treating that instability resolved my post-viral symptoms. What do many of the above infections have in common? As part of our normal inflammatory process, they all increase the body’s production of matrix metalloproteinaises (MMPs), enzymes that degrade elastin and collagen, proteins critical to the structural integrity of connective tissue. In other words, infections can weaken connective tissue, directly and via the body’s own inflammatory response.
Of course, the weakening of connective tissue is not a major concern for most people who have viral infections. However, a viral infection and the resulting inflammation might be the “straw that breaks the camel’s back” in people who are already vulnerable. This vulnerability may arise from preexisting structural damage to the neck (e.g., a previous concussion or accident) or result from a systemic connective tissue problem, perhaps due to a genetic disorder, an environmental injury, or both. Maybe this is why Dr. Byron Hyde, a noted ME clinician in Canada, writes, “Patients with pre-existing or newly-discovered (a) Ehlers-Danlos Hypermobility Syndrome, (b) Collagen diseases… are among the most disabled patients we have seen”; why Dr. David Kaufman has noted that roughly half of his ME/CFS patients also have EDS; why the vascular neurosurgeon who first reached out to me after he saw my empty sella in an MRI in Unrest said, “You know, a lot of my EDS patients, after an acute viral infection, develop exactly your symptoms, Jen”; and why when I went to see that same neurosurgeon for invasive testing, his nurse described to me their severe EDS patients with their earplugs and their eye masks and their sensitivity to the slightest light, sound or exertion…
I do not meet the diagnostic criteria for any type of EDS or any known genetic connective tissue disorder by a mile, but as my best doctors have often said, “medicine is a spectrum.” While I am not hypermobile, perhaps there are still some variants in my collagen or elastin genes, or in the genes that encode for the inflammatory mechanisms that regulate MMP production, and that those variants somehow predisposed me to damage my own collagen in response to the virus I contracted at onset. After all, one of the risk factors for developing ME after an infection is the severity of that infection, in other words, of the intensity of the inflammatory response to the pathogen. Perhaps the more extreme the inflammatory event, the more severe the connective tissue damage. A 104.7 degree fever is pretty extreme.
I take the fact that I started developing symptoms of CCI right after my viral onset as evidence that my inflammatory response to the virus damaged my connective tissue. However, I have another reason to think this. Soon after becoming bedridden, I noticed some very obvious physical changes. First, the lunulae (the half moons at the base of my nails) disappeared. My nails, once strong and healthy, became ridged. (Many other patients have reported similar experiences.) When I was well, I never had any problems getting blood samples drawn. Nurses even commented on what an easy stick I was. After my ME onset, my veins all but vanished and it became much more difficult to draw blood or insert IVs. This has not changed. Although my fusion surgically corrected my craniocervical instability and resolved my ME symptoms, I still have horrible nails. My veins are still so small, I had to come back a second time to get blood drawn for the Stanford study. Whatever process damaged my connective tissue in the first place, whether environmental, infectious or epigenetic, I believe it is still ongoing and that worries me.
The virus mattered. I suspect my genetics mattered, too. However, neither were destiny. I’ve been getting sick — and recovering — all of my life. Why did I develop ME at age 28 and not 17 or 36? Why did I not recover from this specific infection? I think in my case, there had to be an important environmental component at play as well.
Continued in Onset: Part II (Mold)
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.
