Pathology: Part II (Could PEM be a symptom of neural strain?)

How I think brainstem compression and tension on my spinal cord caused my symptoms of post-exertional malaise

In 2016, Dr. Peter Rowe at the Johns Hopkins Pediatric Chronic Fatigue Center published a study in PLOS One that went mostly unnoticed. In it, he took sixty patients with chronic fatigue syndrome diagnoses and twenty healthy controls, laid them flat, then raised one of their legs for fifteen minutes to see what would happen.

If I had read this piece in 2016, before any of the things I’ve experienced in the last year, I would have found the study bizarre. What could this possibly have to do with my metabolic, inflammatory disease? Now, I understand it to be one of the most relevant pieces of research to have been published in the last decade, at least where my case is concerned.

It’s important to remember that the entire nervous system is a single piece. Imagine you are laying flat in bed. Imagine then flexing your feet so that they bend at the ankle, your toes pointing upward toward your head. You have now pulled down on the nerves in the back of your foot, exerting a tensile force that travels all the way up your legs and spine and into your brain. We do this all of the time as we walk, move, engage in any kind of physical activity. For example, if we were to stand up and transition from a full forward bend to a full back bend, everything inside our spinal canals (nerves, dura, blood vessels) would need adjust as much as 5–9 cm in order to accommodate the change!

For most people, most of the time, this is easy to do — our nervous systems are meant to stretch, bend, and be compressed. But sometimes, for many reasons, we might not be able to tolerate this strain.

This is the idea behind a straight leg raise, the test Dr. Rowe used in his study. It helps to measure how well the nerves in one part of your body “glide” or move with muscular strain, as well as how sensitive they are to that strain. If you have a mechanical issue in another part of the body that is impinging the nerves and preventing the nerves from “gliding” normally, such as a herniated disk (or, plausibly, Chiari Malformation, cervical stenosis, or the two conditions I had — craniocervical instability, and tethered cord syndrome), a maneuver like a straight leg raise might cause you to become more symptomatic.

This is precisely what Dr. Rowe found in his study. Performing a straight leg raise on patients with CFS caused them to become more symptomatic (as defined by a composite score of fatigue, body pain, lightheadness, concentration difficulties, and headaches) as compared to patients undergoing a sham leg raise and healthy controls. The intensity of the effect increased 24 hours following the intervention.

While he could not say why patients with CFS had a harder time with the straight leg raise or if any of them had the mechanical diagnoses mentioned above, he did speculate that patients’ sensitivity to neural strain might explain why so many of us have problems with physical activity:

“Our findings have practical implications for the understanding of why exercise and the activities of daily life might be capable of provoking CFS symptoms. If a simple and relatively brief passive SLR strain can provoke symptoms, then prolonged or excessive strain beyond the usual range of motion in daily life might be followed by a similar exacerbation.”

In other words, that post-exertional malaise (PEM) might be what happens to us when movement strains nerves that, for whatever reason, cannot tolerate being strained.

I’ve thought a lot over the last nine months about why my craniocervical fusion and tethered cord release surgeries resolved my PEM. I’ve been thinking about it ever since I reached 30 pounds of invasive cranial traction, long before the fusion itself. I was in an OR with this giant pincer screwed into my head when suddenly, I felt like I was sitting on a 1500 horsepower engine. There was this deep reservoir of energy and power. Is this what it used to feel like? It was there for a few brief minutes and then, with the release of traction, instantly gone.

Many months later, I started reading about tethered cord syndrome, which led me to this whole literature on the biology of what happens when you compress, stretch or kink a nerve beyond its normal physical limits. If my fusion resolved focal brainstem compression symptoms like dizziness, sound sensitivity and immune dysfunction, might decompressing my brainstem and releasing the tension on my spinal cord also have resolved my PEM?

There are roughly three ways neural tissue, whether a nerve, the spinal cord or the brain, can be mechanically stressed: compression, tension (stretching), and deformation (shear stress). Often times, it’s a combination of the three.

Physical stress has two major implications. First, it changes the shape of the cell membrane. Second, it significantly increases edema (swelling from excess fluid) and reduces blood flow. Reduced blood flow means less oxygen (hypoxia). Together, these factors result in following profound metabolic changes:

  1. Cells shift to anaerobic metabolism
  2. Glucose metabolism is impaired and ATP production decreases
  3. Lactate dehydrogenase increases
  4. Intracellular electrolyte concentrations change; in particular, there are increases in intracellular calcium
  5. Prolonged stress increases inflammation and activation of neural fibroblasts, mast cells and macrophages
  6. Tensile stress causes mast cells, located throughout the nervous system including the dura, to degranulate

(See references on this page.)

Some of these findings parallel what we know happens in ME patients, others what we suspect could be happening. First, in ME patients, there is ample evidence of cerebral hypoperfusion, that is, low blood flow to the brain. This is apparently true even of ME patients who do not have POTS or orthostatic hypotension. (Recall in my last piece that I wondered whether my POTS/OI and low cerebral blood might be symptoms caused by different mechanisms.) Moreover, one of the areas of low blood flow found in at least two studies was the brainstem.

Poor blood flow means less oxygen. Normal energy metabolism requires oxygen. In conditions of hypoxia, cells switch to anaerobic metabolism (glycolysis) at lower thresholds. Glycolysis does not require oxygen but it is a less efficient means of producing energy (ATP), so overall energy production decreases. There is some evidence that ME patients have poor delivery of oxygen to muscles, which would correspond to diminished blood flow, if the effects were systemic. (They may well have been true in my case: not only did I have brainstem compression caused by CCI but my tethered spinal cord caused tension across the entire length of my spine and all of the nerves that branch from it.) Lactate dehydrogenase, found at higher levels in the Royal Free outbreak patients, is a key enzyme in glycolysis. Finally, neuroinflammation and mast cell activation, which can both result from neural compression or tension, are both areas of increased interest among researchers and clinicians.

I want to be clear: this is a far cry from saying that every ME patient has either spinal cord compression or tension. The above dynamics can happen in many different situations where there is damage to the brain or spinal cord. For example, traumatic brain injury causes the same “ischemia-like pattern” of low blood flow, edema, and the resulting switch to glycolysis. However, I do think that brainstem compression (due to craniocervical instability) and spinal cord tension (due to tethered cord syndrome) were the specific causes of poor blood flow, low oxygen, hypometabolism and increased anaerobic metabolism described above, in my case. In other words, that this could have caused my PEM. It happened throughout my entire central nervous system. And it happened every time I would exert myself, subtly straining my stretched spinal cord and compressed brainstem, which at baseline were already at their limits.

Combined with the direct effects of brainstem compression on autonomic function and sensory processing, as well as one more pathology I’ll talk about in my next article, I believe this could explain all of my symptoms. I also believe it might explain why I had such a profound recovery following my craniocervical fusion and tethered cord release surgeries.

I remember the moment my neurologist diagnosed me with conversion disorder. He told me an emotional trauma — one I might not even be able to remember — was causing all of my symptoms. On a gut level, I knew this was not true, but I had just spent three years in a Ph.D program studying a lot of formal modeling and statistics. I still believed then in the wisdom of doctors and in the value of expertise. (Both are important but no human can know all things, so humility trumps all.) “Test the hypothesis,” I told myself. So I did. As I said in my TED Talk:

That day, I ran a small experiment. I walked back the two miles from my neurologist’s office to my house, my legs wrapped in this strange, almost electric kind of pain. I meditated on that pain, contemplating how my mind could have possibly generated all this. As soon as I walked through the door, I collapsed. My brain and my spinal cord were burning. My neck was so stiff I couldn’t touch my chin to my chest, and the slightest sound — the rustling of the sheets, my husband walking barefoot in the next room — could cause excruciating pain. I would spend most of the next two years in bed.

Little did I know then that in walking home, I was stretching a spinal cord that was tethered to the middle of my lumbar spine. With every step, my cord tugged up on the nerves in my legs from above and pulled down on my brain from below, ringing it like a church bell.

This is a more extreme version of what an actual medical study found in young people with tethered spinal cords:

A study of adolescents with tethered cord syndrome found that they required more energy (as measured by the volume of oxygen, VO2) to perform the same activities as healthy controls. This might be due to the reduced blood flow to the spinal cord and hypoxia associated with tethered cord. In sum, that the “energy cost per metre during walking at preferred speed and physical strain were higher than in peers without disability.”

Thankfully, if you untether the cord, blood flow is restored (and, presumably, normal metabolism along with it):

A study of five children undergoing surgery for tethered cord syndrome measured a mean spinal cord blood flow prior to untethering of 12.6 ml/min per 100 g of tissue. It increased in all cases after release to a mean of 29.4 ml/min per 100 g of tissue.

In other words, perhaps some version of this is why immediately after fusion surgery, I woke up with such healthfully rosy cheeks (even as my POTS would come and go for the next several months, before finally resolving).

Wait, does this mean all people with ME have craniocervical junction issues or tethered spinal cords?

No, not at all! Again, the same symptoms can have many different causes. Hell, the same pathologies can have many different causes. It is likely that a number of conditions that cause brain or spinal cord compression, tension, deformation or damage can result in the pathophysiology above. And they would each require different treatments. This is why biomarkers and diagnostics for this disease are so key.

In my view, there is suggestive evidence that craniocervical junction abnormalities, in particular those associated with Ehlers-Danlos Syndrome (e.g., Chiari malformation, craniocervical instability, atlanto-axial instability, cervical stenosis, and possibly tethered cord syndrome), are among those diagnoses that could cause PEM and many of the other symptoms of ME. This hypothesis should be formally tested, because these conditions do have “biomarkers,” methods of diagnosis, clear(ish) pathologies, and treatments. Those treatments are less than ideal, but they are still treatments; and perhaps, with work, someday there will be better ones.

People with ME diagnoses are almost never adequately tested for these conditions, if at all. Even when they are, as is the case of a dozen people with ME I’ve encountered these last few months who have old Chiari malformation diagnoses, they are told their pathology couldn’t possibly be causing their symptoms. In my mind, the work isn’t done until every ME etiology is identified, is diagnosable, and all people living with ME, regardless of etiology, have access to safe and effective treatments.

OK, *maybe* this makes sense but what about cognitive PEM or cognitive dysfunction?

I’ll cover all things cognitive in my next piece! And also go deeper into cerebral blood flow.


Here’s a random fun fact, courtesy of Phoenix Rising. We know that low natural killer cell function has been found in patients with ME. Where else is low natural killer cell function found? In patients with chronic spinal cord injury.

Thank you to all the PwME on Facebook who contributed to and helped improve the clarity of this article. My special thanks to Nora Helfand, who sent me Peter Rowe’s neuromuscular strain article and down a multi-day Google Scholar rabbit hole.

Consider this a 1.0 version. If you see any important errors or omissions, please drop me a line!

Up next: Pathology: Part III (Fluid dynamics)

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.

Maker of @unrestfilm. Plotter of revolution @MEActNet. Wife of @owasow.