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Ruhoy and Kaufman

Ruhoy and Kaufman take on one of Dr. Ruhoy’s favorite topics – the connective tissues

This is the fifth in our series covering two experts as they explore different facets of complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), postural orthostatic tachycardia syndrome (POTS), and long COVID in their “Unraveled” Patreon podcast series. This blog covers episode 13 on connective tissues.

Join Patreon and watch the episodes, and the dozens of others, by joining Patreon for about $9/month. It’s the best deal in town.

The blog also takes from Dr. Ruhoy’s talk on connective tissues and ME/CFS in her NIH Roadmap presentation in the Lesser Studies Pathologies section.

The Connective Tissues and Chronic, Complex Illnesses

It is a mysterious and wondrous organ in its own right and holds so many important functions in the body”…Ruhoy

 

I think more about connective tissues than anything else these days“…Ruhoy

Check out Geoff’s Narration

The Gist

The Blog

 

We don’t realize how important connective tissues are. Besides lining the highways of our bodies (blood vessels, lymph system, lungs, and the GI tract), connective tissues surround, protect, and keep in place our nerves, eyes, and other organs. They are also major components of our muscles, ligaments, tendons, cartilage, and bones, as well as the meninges and dura mater covering the brain.

THE GIST

  • We are back with our fifth overview of the Unraveled podcasts led by two chronic, complex illness experts: Dr. Ruhoy and Dr. Kaufman. (Check out the list at the top of the blog). This blog also covers Dr. Ruhoy’s connective tissue talk at the “Less Studies Pathologies” part of the NIH’s Roadmap series on ME/CFS (see the video featured in the blog) and check out Geoff’s narration of The GIST.
  • Connective tissues are everywhere. They line the blood vessels, lymph system, lungs, and the GI tract. They surround, protect, and keep in place our nerves, eyes, and other organs. They’re also major components of our muscles, ligaments, tendons, cartilage, and bones, as well as the meninges and dura mater covering the brain (see blog for video).
  • Because connective tissue is everywhere, connective tissue problems can potentially affect almost everything. Blood and lymph flows, gut functioning, neuroinflammation in the brain, muscle issues, inflammation, and spinal problems; the list goes on and on.
  • Kaufman and Ruhoy believe the connective tissue problems they see in most of their patients are “acquired”; i.e. they result from an infection or some other environmental (e.g. outside) insult that kicks off an inflammatory process that damages specific connective tissues. While joint hypermobility increases the risk of connective tissue disorders, most people with joint hypermobility are healthy.  Many of Kaufman and Ruhoy’s connective tissue disease patients exhibit joint hypermobility only in one tissue.
  • Connective tissue problems in the brain and spine can cause high or low intracranial cerebral spinal fluid pressure, cerebral spinal fluid leaks, craniocervical instability, Tarlov cysts, spinal stenosis, and more. These problems can ripple throughout the body affecting the autonomic nervous, immune, and endocrine systems.
  • Connective tissues have shown up intermittently over time ME/CFS. Peter Rowe uncovered the presence of hypermobility and neuromuscular strain and showed that proper physical therapy can be helpful. Jeff Woods and Jen Brea’s successful craniocervical instability surgery highlighted how devastating connective tissue damage (to the ligaments that hold up the skull) can be.
  • A large Swedish study found high rates of intracranial hypertension (high cerebral spinal fluid blood pressure) and craniocervical abnormalities in ME/CFS/FM.  Several studies recently have also found evidence of connective tissue problems.
  • Through a series of papers over the past ten years, Hulens and Higgins have been alerting researchers and doctors of the possible complications of connective tissue damage such as intracranial hyper/hypotension, cerebral spinal fluid leaks, Tarlov cysts, and empty sella syndrome.
  • How big a role might connective tissue problems play in these diseases? Dr. Ruhoy said she thinks about connective tissue issues more than any other.  While she has a handle on treating other common issues (POTS, gut issues, mast cells, etc.) treating connective tissue problems is another matter.
  • Physical therapy – keeping the body in alignment with a physical therapist competent in the kinds of issues found (joint hypermobility) is a mainstay to reduce inflammation.  If craniocervical instability (CCI) is present using invasive traction to assess where a patient will benefit is a necessity. (Not everyone with ME/CFS who has CCI will be helped by surgery).
  • Both Ruhoy and Kaufman are big fans of GHK, a peptide that enhances collagen deposition (connective tissue) and is used for wound healing. Dr. Ruhoy warned, though, that for peptides to be effective, they must be freshly compounded – and that means a prescription.
  • Ayurvedic medicine protocols can strengthen connective tissue by tamping down inflammation. On the nutrition front, there’s the Cusak Protocol which uses supplements to strengthen the connective tissue.
  • Improving mitochondrial health comes into play as well. Both doctors believe mitochondrial problems may be causing a lot of mischief. Not only do strong mitochondria help to tame inflammation, but damaged mitochondria can vastly increase it.
  • Plenty of options to improve mitochondrial health exist (Zone 2 exercise, red light therapy, H5, intermittent fasting, oxaloacetate, and others). Ruhoy uses a mitochondrial cocktail to increase energy levels. (Unfortunately, we didn’t get the ingredients.) I didn’t get the impression that the results are spectacular, but the treatments can help. (A review of the Unraveled episode on the mitochondria is coming up.)
  • Low-dose Rapamycin is an intriguing possibility! Kaufman said that a great deal of evidence suggests that Rapamycin reduces inflammation and aging, and helps to vacuum clean up damaged cells and he thought it might “be an amazing drug for our patients”. The evidence is limited but it suggests that Rapamycin may even be able to reverse connective tissue damage – the holy grail of connective tissue treatment. Check out Health Rising’s blog on Simmaron’s Rapamycin trial and a doctor who recovered from ME/CFS using Rapamycin in the blog (see highlighted blogs).
  • Dr. Ruhoy believes, that ultimately, stem cells may be the answer to repairing connective tissues. Calling stem cells the future of medicine Dr. Ruhoy noted that a stem cell Mt. Sinai study is getting underway.
  • Connective tissues are a relatively new arena of study in these diseases but interest in them is rising rapidly. These two doctors are clearly at the tip of the spear when it comes to understanding and figuring out what to do with the connective tissues issues present. When better connective tissue treatments occur, they’ll surely be the first to give them a try.
  • After saying “I think more about connective tissue than anything else”, Dr. Ruhoy ended the Patreon session by saying “We’re on it”!
Because connective tissue is everywhere, connective tissue problems can potentially affect almost everything. Blood and lymph flows, gut functioning, neuroinflammation in the brain, muscle issues, inflammation, spinal problems; it goes on and on, and can all result from connective tissue damage.

Take something as simple as a blood draw. If you have trouble with blood draws, the connective tissues surrounding your blood vessels may have become hardened or the connective tissue holding the blood vessels in place may have become too loose. It may not be surprising that three of the first five Unraveled podcasts Health Rising has covered in one way or another involved the connective tissues.

A lot can go wrong with such a comprehensive and diverse group of tissues. Over 400 different heritable connective tissue disorders have been identified, and in Ehlers-Danlos Syndrome (EDS), 14 different clinical EDS subtypes are recognized – and that doesn’t take into account acquired connective tissue conditions that have shown up in post-viral diseases.

Acquired Connective Tissue Diseases

While most of the connective tissue diseases have genetic origins, both Kaufman and Ruhoy believe the connective tissue problems they see in many of their patients are “acquired”; i.e. they’re the result of an infection or some other environmental (e.g. outside) insult that kicks off an inflammatory process that damages specific connective tissues.

Indeed, while the ligaments in the necks of the ME/CFS/FM/long-COVID patients with craniocervical instability are hypermobile, that’s often the only part of their body that is. While hypermobile people are more prone to connective tissue problems like craniocervical instability, people with no connective tissue problems can – and do – come down with them frequently.

Indeed, autoimmune disorders like sarcoid, Sjögren’s, scleroderma, and systemic lupus erythematosus, as well as tethered cord syndrome, cranial cervical instability, intracranial hypertension, intracranial hypotension, and median arcuate ligament syndrome can all result from “acquired” connective tissue problems.

The point is that you don’t have to have a “connective tissue disorder” to have connective tissue problems.

The Brain

Dura mater

Check out the dura mater – a protective connective tissue that protects the brain.

Take the brain. Connective tissue problems can act like a tourniquet on the veins in the brain, causing congestion and intracranial hypertension (high spinal fluid pressure). They can also weaken the dura mater – the thick membrane surrounding the brain and spinal cord – causing cerebral spinal fluid leaks, and the opposite problem – intracranial hypotension (low cerebral spinal fluid pressure).

Because mast cells permeate the dura mater (as well as other connective tissues) and live close to the pain-sensing neurons, mast cell activation can both degrade connective tissues and result in more pain, etc.

Activated mast cells next to the blood-brain barrier could wreak havoc on it, allowing all sorts of foreign materials (to the brain) into the brain, resulting in neuroinflammation – which Jarred Younger believes is pretty much a done deal in ME/CFS.

The Spine

Because the spine is a series of joints held together by connective tissues, it’s uniquely vulnerable to connective tissue issues. A weakening of the spinal connective tissues can result in problems like Chiari malformation Type I, atlantoaxial instability, and craniocervical instability.

Just as with the dura mater, connective tissues protect the nerves. If that protective layer fails, nerves are vulnerable to becoming compressed and irritated.

The foramen magnum – the hole at the base of the skull through which several ligaments, several arteries, and nerves pass –  and which tonsils, the cerebellum, the lower end of the brainstem abut – is an exceptionally complex and important piece of real estate. It’s also potentially a weak point structurally. Mess up the ligaments that keep the foramen magnum centered properly, and all sorts of problems can ensue.

Heading south, we come to the craniocervical junction (CCJ) at the top and most mobile part of the spine. The CCJ contains arteries, nerve roots, cerebral spinal fluid, and the bottom of the brainstem. Connective tissue damage to the ligaments that keep this junction centered and working can result in craniocervical instability (CCI).

CCI can result in reduced blood flow into and out of the brain, compressed nerves, reduced cerebral spinal fluid flows, and affect the heartbeat, breathing and blood pressure, sleep, breathing and swallowing, sensory stimuli and touch. Because this area of the brain speaks to the HPA axis and autonomic nervous system, problems there can wreak havoc with those systems which, in turn, affect the immune, gut, cardiovascular, etc. systems.

Continuing to track downwards, an instability of the spine caused by weakened connective tissue can produce scoliosis (horizontal curvature of the spine), kyphosis (upper back curve), listhesis, (slippage of vertebral bodies over one another), spinal stenosis (compressed spinal cord), and further cervical myelopathy (spinal cord damage).

That’s just the brain and the spine! It turns out that connective tissues are also full of innate immune cells, including mast cells. Simply the presence of “loosey-goosey” and overstretched connective tissues can produce inflammation. In lipidema, for instance, which often shows up during hormonal changes in women, the loss of “elastic recoil” allows fat to settle in the interstitial spaces rather than be cleared by the lymphatic system.

Surprised face.

Kaufman said that after 30 years as an infectious disease specialist that the fact that infections could result in connective tissue damage was a rude awakening.

The Awakening

My guess is that ten years ago, almost no one thought of connective tissues about ME/CFS and only a few did for fibromyalgia. Even though we now believe that infections can trigger connective tissue breakdowns and may play a major role in post-infectious illnesses, Dr. Kaufman noted that in his 30 years in infectious disease work, he’d never encountered connective tissue disorders. Recognizing that connective tissue does matter was a rude awakening for him.

While connective tissue problems have historically never played a central role in ME/CFS or fibromyalgia research, they have popped up from time to time.

Chronic Fatigue Syndrome (ME/CFS)

Not surprisingly, it was that supreme diagnostician Peter Rowe back in 1999 who first alerted the ME/CFS/FM world to the joint hypermobility/ME/CFS connection. In 2013 and 2014, Rowe uncovered another possible indication of connective tissue problems when he documented the presence of “neuromuscular strain” in adolescents with ME/CFS which resulted in reduced range of motion.

In 2016, Rowe showed that simple leg raises could trigger body pain, problems with concentration, lightheadedness, and overall symptoms. He attributed those symptoms to movement restrictions in the tissues that strain the muscles, fascia, spinal cord, peripheral nerves, and soft tissues (!) and contribute to the central sensitization present.

In 2018, Rowe reported on the use of “manual physical techniques”, which by improving the range of motion, improved physical functioning. Rowe also demonstrated that resolving spinal stenosis – a possible result of connective tissue dysfunction – can, in some cases, greatly improve ME/CFS/FM symptoms and orthostatic intolerance.

Van Putte, a Dutch researcher, asked whether connective tissue laxity was present in ME/CFS in a small 2005 study. British researchers found that joint hypermobility was common in both fibromyalgia and ME/CFS in 2021. A 2023 study did not find increased joint hypermobility after infectious mononucleosis, but a 2024 Solve M.E. study found that ME/CFS patients with joint hypermobility, particularly those with Ehlers-Danlos Syndrome, had more severe symptoms and reduced quality of life.

Jeff and Jen’s successful surgeries to fix their craniocervical instability – caused by damage to the ligaments in the brain – produced a wave of shock (heavy-duty spinal surgery!) and awe (complete recoveries!) to spread through the ME/CFS community. A large 2020 Swedish study confirmed that connective tissue issues, or problems related to them, were common when it frequently found hypermobility, signs of idiopathic intracranial hypertension, and craniocervical obstructions.

Craniocervical Instability, Neurosurgery and M.E.: Just the Facts, Please – An Editorial by Jeff Wood

Through a series of papers over the past ten years, Hulens and Higgins have been alerting researchers and doctors of the possible complications of connective tissue damage such as intracranial hyper/hypotension, cerebral spinal fluid leaks, Tarlov cysts, and empty sella syndrome.

Unraveled #3: Ruhoy and Kaufman on Idiopathic Intracranial Hypertension in ME/CFS and Complex Diseases

Fibromyalgia

In fibromyalgia, altered levels of collagen – a major component of connective tissues – showed up in 1998 and have been found several times since. In 2021, Eccles found that 81% of ME/CFS and/or FM patients met the Brighton criteria for hypermobility syndrome and 18% met 2017 hypermobile Ehlers-Danlos syndrome (hEDS) criteria. A 2022 systemic review reported on the strong overlap between FM and hypermobile Ehlers-Danlos Syndrome (hEDS) prevalence and the many similar symptoms including joint pain and swelling, muscle weakness, neurological problems, dysautonomia and quality of life.

Ruhoy pointed out that the trigger points in FM (and presumably myofascial pain syndrome) are all about the connective tissue. They appear to occur in areas where thinned-out “fascial planes” leave the nerves below them twitchy and irritated – possibly leading to small fiber neuropathy – a condition found in many people with fibromyalgia, ME/CFS, and long COVID.

Long COVID

The first link to long COVID came in a paper proposing that joint hypermobility plus a coronavirus infection could lead to fibromyalgia. Beth Pollack’s 2023 paper showed that diseases like long COVID, POTS, ME/CFS, and connective tissue disorders share many gynecological features. A 350,000-person study found that COVID-19 “was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders” and a genetic analysis highlighted the “cognitive-behavioral, neuro-autonomic, and immune-inflammatory alterations of connective tissue in these conditions.”

The Hypermobility Question

Over here in ME/CFS/POTS land, we often think of hypermobility – the ability to move joints in ways they don’t seem intended to go – as a connective tissue problem, but it’s not necessarily so. The connective tissue is changed in hypermobility, but it’s not necessarily a problem. Millions of people with hypermobility are just fine. It takes some extra hit – an infection, an exposure to some toxin, physical or emotional trauma – to turn hypermobility pathogenic.

Indeed, Dr. Kaufman stated that one of his “aha” moments regarding connective tissue was the realization that the connective tissue was not static and that repeated insults that produce inflammation (mast cell activation, coronary artery disease,  atherosclerosis) can affect it. Both Kaufman and Ruhoy are coming to believe that the impact of chronic inflammation on connective tissues plays a large role in aging.

Treatment

“I sit and I meditate on connective tissues” Dr. Ruhoy

CCI, Traction and Surgery

Jeff’s and Jen Brea’s CCI stories put craniocervical instability (CCI) – a rather harrowing diagnosis that can require an extensive surgical procedure to remedy – on the map. Not all cases of CCI, though, require surgery – and not all cases of CCI contribute to ME/CFS symptoms. (Some ME/CFS patients who underwent CCI have not improved substantially.)

Jennifer Brea’s Amazing ME/CFS Recovering Story: the Spinal Series – Pt. II

Dr. Ruhoy noted that she attempts conservative management first, and requires that CCI patients meet several criteria, including invasive cervical traction, which very often requires ICP bolt monitoring, to identify patients likely to improve from surgery.

When asked if non-severe, non-bedbound cases with suspected neck compression or instability, physical therapy should be tried, the answer was a definite ‘yes’. An EDS-literate physical therapist who understands CCI, connective tissue issues, and the spine is “completely warranted”. Many very competent and literate physical therapists are available, but you have to find one.

Treating Other Connective Tissue Problems

Two treatment focuses are present: tamping down the inflammatory insult that’s damaging the connective tissues, and repairing the damage that’s been done. Studies are rare, leaving doctors to venture out on the skinny branches and take educated guesses.

That’s what these curious and empathetic doctors do. Dr. Ruhoy, her heart on her sleeve, simply said, “I can’t stand suffering. I hate when anyone suffers”, and so tries out new things she thinks might work at low doses. A lot of the experimentation she does, she said, is trying to fix the connective tissues.

Tamping Down Inflammation

Tamping down inflammation is much more doable, and that means physical therapy to keep the body in alignment, thereby destressing the connective tissues and keeping the immune system from reacting and the nerves from acting up.

Dr. Ruhoy called a physical therapist who keeps the body in alignment a cornerstone of connective tissue treatment. (Check out an EDS manual written by an EDS-literate physical therapist.)

Both Ruhoy and Kaufman are big fans of GHK, a peptide that enhances collagen deposition (connective tissue) and is used for wound healing. Peptides have become a big deal recently. Dr. Ruhoy warned, though, that for peptides to be effective, they must be freshly compounded.

Dr. Ruhoy noted that Ayurvedic medicine protocols can strengthen connective tissue by tamping down inflammation. On the nutrition front, there’s the Cusak Protocol which uses supplements to try and strengthen the connective tissue.

Improving mitochondrial health comes into play as well. Both doctors believe mitochondrial problems may be causing a lot of mischief. Not only do strong mitochondria help to tame inflammation, but damaged mitochondria can vastly increase it.

Kaufman started off skeptical when it came to enhancing mitochondrial health, but when he found that using oxaloacetate significantly improved 3/4’s of patients’ fatigue, his most difficult-to-treat symptom, he became a believer.

Plenty of options to improve mitochondrial health exist (Zone 2 exercise, red light therapy, H5, intermittent fasting, oxaloacetate, and others). Ruhoy uses a mitochondrial cocktail to increase energy levels. (Unfortunately, we didn’t get the ingredients.) I didn’t get the impression that the results are spectacular, but the treatments can help.

  • More on the mitochondria is coming up when Health Rising covers Unraveled’s mitochondria episode.

Repairing Connective Tissues

Dr. Ruhoy said she had at least an answer for just about everything (SIBO, mast cells, POTS, etc.); i.e. she can put together a plan, and knows where to start, etc. – but repairing connective tissue – that’s a tough one.

Low-dose Rapamycin is an intriguing possibility, though. Kaufman said that a great deal of evidence suggests that Rapamycin reduces inflammation and aging, and helps to vacuum clean up damaged cells.

In this podcast – done 9 months before the Simmaron Research Foundation began their Rapamycin trial – Kaufman said he thought it might “be an amazing drug for our patients” as the scant data thus far available suggests it might be able to reverse connective tissue damage. (Kaufman warned about trying to get and use Rapamycin without your doctor’s permission.)

Simmaron’s ME/CFS Trial of Rapamycin – a Mitochondrial Enhancer – to Begin Soon

Stem cells may ultimately be the answer. Dr. Ruhoy believes stem cells are the future of medicine and noted that a stem cell Mt. Sinai study is getting underway.

Moving Forward

Intersections

The connective tissues are found almost everywhere in the body. Dr. Ruhoy said she thinks about them more than anything else in these diseases.

Connective tissues were a late, surprising, and in some ways disturbing entry into the ME/CFS/FM, post-viral illness, and long–COVID fields. Dr. Ruhoy was surely referring to the craniocervical issues below when she described the field stumbling upon them. That occurred when a very determined patient, Jeff, uncovered them. Ruhoy said, “we cannot un-see a pattern that we have seen over and over again”. We’re just beginning to learn how important connective tissues are.

Toward the end of her Roadmap talk, Dr. Ruhoy laid out where we are:

“So, what we have stumbled upon, what we think we know, what we do not understand, what we have done, and what we are planning to do are important topics that we need to have further discussions on. We cannot see a pattern that lies in a direction towards which we are not looking. And we cannot see a pattern if our sample is too small. And we cannot un-see a pattern that we have seen over and over. And that, I think, is what I often try to explain.”

The insertion of a connective tissue talk into the Roadmap Initiative at the NIH indicates that connective tissues are getting recognized. These two doctors are clearly at the tip of the spear when it comes to understanding and treating them. When better connective tissue treatments show up I have the feeling they will be all over them.

After saying “I think more about connective tissue than anything else”, Dr. Ruhoy ended the Patreon session by saying “We’re on it”!

 

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