Hello All, I am Sharon Meglathery MD (aka Dr. Sharon, stripey14), a physician (see About Section) who developed mast cell activation (MCAS), postural orthostatic tachycardia syndrome (POTS), raised intracranial pressure, chronic fatigue syndrome (CFS) and a host of other potentially disabling syndromes in the setting of Ehlers-Danlos Syndrome (EDS-HT) in 2009. I was shocked to learn that somehow medical education has completely missed an epidemic affecting so many gifted young people (mostly women), leaving the patients to fend for themselves. I have spent 7 years obsessed with a long list of seemingly connected, overlapping syndromes, gathering patient observations in my clinic and in the forums, scouring the scientific literature, dealing with my own illness and often having to experiment on myself. Early on, my broad medical background revealed that several commonly held assumptions about these conditions must be false. By letting those assumptions go, I was able to find a marker which predicts a higher risk of chronic illness regardless of hypermobility status which has stood the test of several years. From there, a lucky break revealed a set of candidate genes which pulled all of my observations together. The knowledge of these genes changed the course of my illness by presenting novel treatment options, and I expect will pave the way for new pharmaceuticals which will help us.
The first part of the RCCX Theory was born in July 2015. I tried desperately to share it, but I was not successful using traditional methods. I released the first version of this website in February 2016. The website was designed so that the theory would be accessible to everyone, patients and researchers alike. I also included downloadable versions of a Summary for Scientists, Journal Article (now outdated) with references and my pathophysiology diagrams for easy transport. I hoped it would go viral and the information would get to scientists who may be interested in pursuing this.
Developments Since Initial Release of the Website in February 2016: In the first couple days of release, I was approached by the perfect scientist to help me prove it, Karen Herbst MD PhD, Endocrinology. She and I have started a non profit corporation to fund studies exploring the role of the RCCX Module in Chronic Illness. Unfortunately, we have realized that studying the genetic portion of this could be too complex for even a university genetics lab, given the complexity of the RCCX module. We also came to see that endocrine testing is also fraught with difficulty, given the way that the clinical response to stress is very dependent on the overall stress load and length of time a person is stressed (CFS studies show normal stress response followed by high fatiguability on rechallenge) and the fact that no testing has been able to reliably distinguish CYP21A2 carriers from normals. We decided to proceed with a questionnaire demonstrating that the RCCX comorbidities run in individuals and families as a way to get researchers interested. This is in the final stages. See the RCCX Project Below.
In June 2016, a pilot study conducted by Robert Naviaux MD PhD and Ron Davis PhD revealed that mitochondrial shutdown triggered by stress is the likely final pathway in CFS/ME. With this news, I updated the website in July of 2016. I added RCCX Theory Part II to demonstrate how the RCCX Theory provides several highly likely paths to mitochondrial shutdown, including a psychiatric path which I explained fully in the new CAPS section. I edited the rest of the website to show that "CAPS" now stands for CYP21A2 Mutation Associated Neuropsychiatric Spectrum which is a more accurate name than the previous one. The website also now reflects that there are probably many afflicted with chronic illness who are actually homozygotes for mild CYP21A2 mutations, in addition to the heterozygotes I had discussed previously. I believe this is true because people with CAPS are attracted preferentially to other people with CAPS.
By March 2017, there were many developments, all heading in the direction of RCCX Theory, so I decided to add a quick New Developments Section until I could sit down and really write the next chapter. I am increasingly confident that Ron Davis PhD et al. will arrive at the RCCX Theory probably sooner than later as he has said that there seems to be a genetic predisposition to "pushing through" which leads to chronic illness by repeatedly telling the body to shut down the Kreb's cycle. I strongly believe that carriers of CYP21A2 mutations with CAPS are predisposed to pushing through stress because of higher than normal arousal when stressed and then fighting against low basal cortisol to continue to be productive. We also know that many of those with EDS (those with CAPS, I believe) have high adrenaline/sympathetic nervous system tone which can also allow this to happen. Further, it is becoming clear that some folks respond amazingly well (in terms of energy and cortisol production) to bioactive chelated copper supplementation (this is special copper not the usual supplement), myself included. I think those with mutations for defective (as opposed to low amounts) of 21 hydroxylase may be at risk for bioactive copper deficiency which adds a layer of heme-containing enzyme failure and inappropriate heme deposition in places like the brain (heme has recently been found to be inappropriately deposited in brains of people with MS, which I believe is very much an RCCX comorbidity) and maybe in the urine (?pyroluria). More about that can be found in the New Developments section.
How you Can Help:
Pleasecontinue to distribute this theory widely to other patients so that they can know that help may soon be on the way.
Talk about it.
Write about it on your websites.
Please like the Facebook page: RCCX and Chronic Illness for updates.
Our email address is email@example.com for questions and suggestions.
Join our FB discussion group: RCCX and Chronic Illness Discussion to expand and refine the theory.
Consider donating to the cause. Our donations thus far have been modest and cover the cost of putting together the questionnaire and collaborations. The plan is to donate any moneys over what we need to Ron Davis PhD and colleagues at the Open Medicine Foundation.
Disclaimer: The purpose of this website is NOT to recruit patients, give treatment recommendations, sell supplements, get attention, be controversial or become famous. I live a quiet, reclusive life with a small, local and full medical practice. This illness and this discovery has made my life very complicated.
_____________________________________________________________________________________________________________________ Writing this website has been a very difficult task for me. I expect that my audience will diverse.
For Those With Illness: I imagine that you are trying to get answers, comparing your knowledge with what I am saying and your symptoms with what I describe. Many of you are angry and frustrated and wary of doctors trying to profit from your illness. As I mentioned before, I have nothing to sell, I don't want more patients, and I would never have chosen to have a website like this. For you, I need to avoid doctor-speak and show that quite a lot of the common knowledge passed on by doctors and patients alike is not rooted in fact and no longer stands with what is observed in patients with these conditions. Some of you will already know this, but as many will still be holding on to these assumptions, I need to address them. Further, the fact that I show that a psychological profile (not necessarily pathological and often gifted) is currently the footprint for these disorders won't sit well with those of you who are tired of being called crazy or told that your illness is all in your head. Please try to put aside your anger about this if you can. Rest assured that I agree that you and I are indeed very physically sick. Shockingly sick-in fact, I am saying that an enzyme disorder causes an endocrine disorder which then causes inflammation in the brain and/or body at times of stress which wreaks absolute havoc and is desperately serious. I believe that the hormonal issues caused by the enzyme disorder during gestation and in infancy, result in the production of an aberrant (and wonderful in many ways) brain . I have this psychological profile and I'm quite proud of it. This brain makes us smart enough to know we are sick and what may be wrong, but we are discounted and discredited at every turn because our symptoms are so fantastic. There is a lot of tragic irony in how this has played out.
For Clinicians, Scientists: Thank you for taking the time to read this because it shows a commitment to helping patients and finding answers. This section is written simply for universal understanding. I bold the key points for quick reading. Please don't underestimate my acumen because of the language.
To Whom Does this Theory Apply? I assume that most of my audience consists of chronically ill patients who suffer from one and probably many of the chronic syndromes/symptoms/diseases which I will list shortly. Please understand that I am NOT saying that everyone with these diagnoses fits in this group; rather I am saying that in many families, a cluster of these diagnoses will be found and I believe that those families are likely to contain the gene mutations I discuss. For example-you may see a family with a member, often female, diagnosed with or suspected to have Ehlers-Danlos Syndome, Hypermobility Type (EDS-HT), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS). Then in the extended family, you may find autoimmune diseases, i.e. multiple sclerosis, cutting and eating disorders, "possible bipolar disorder", gender fluidity, a highly successful and innovative genius, someone with chronic fatigue syndrome (CFS) or fibromylagia (FM), someone with severe post traumatic stress disorder (PTSD) and someone else with bouts of psychosis. The children who are more scrutinized in this day and age, may be diagnosed with attention deficit disorder (ADD), sensory processing issues plus or minus Asperger's Disorder (I know, I know, not in the DSMV:>)). And the kicker, these issues may be found on both sides of the family because I believe that we are attracted to each-other. There is a characteristic psychological profile which goes with this: sensitive, emotional, often gifted and we tend to surround ourselves with others who share these traits.) The degree of hypermobility ranges from none to severe in this family and correlates with the degree of musculoskeletal involvement (joint pain/dislocations/surgeries required to stabilize joints) and orthostasis/"dysautonomia" but not with the other "sick" symptoms which tend to develop later in life only in some, mostly women. Many will react strongly to stress. If this sounds like your family (albeit a dramatic version), I am writing this for you.
Of note: These conditions can occur due to other genes, thus occurring without these clusters. Many people with MCAS and POTS, together or alone have these for a different reason. What I am writing is NOT relevant to them. (However, if you have bendy joints and MCAS and POTS, I am talking to you!)
False Assumptions Block Progress and Can Actually Obscure the Truth At first, I tried to stream-line this section, but then I came to realize that my theory defies too many false assumptions held by many patients and scientists alike that this section needed to be more inclusive. As you know, many breakthrough ideas are held back by prevailing false assumptions, so I must commit adequate time and space to examine them here. Sadly, these false assumptions were held by the editors of the progressive journal where I submitted the paper outlining my hypothesis, leading to rejection.
Look at the picture above and suppose that the truth is right there for all to see in the blue sky, suggested by the color of the shafts of light shining into the forest. If you open your eyes and observe objectively, you will see it, but if you have been told that the most important thing to do is to find and gather tiny salamanders, you won't even see the light. In fact, you will be more concerned with the darkness and fog impeding the ability to find the non-existent salamanders. My point is that the truth is there, exposed for all to see as long as people are seeing all there is to see clearly and objectively. The fastest way to get to the truth is to step back, drop assumptions and judgments and truly assess what you see. When you do this, you will see that while these assumptions seemed correct earlier, over time with more observations/evidence gathered, they don't work any more. At some point, and I would argue it's already started, observations start to be denied or altered to fit the assumptions. When that happens, you are actually obscuring the truth.
Doctors must rely on what is in the medical literature for guidance especially for "rare" diseases. (First false assumption is that these conditions are rare.). This literature is riddled with these assumptions, especially when we talk about EDS-HT. The zebra assumption: "when you hear hoof-beats, think horses, not zebras." is a classic assumption which along with the assumption that EDS is rare, blocks our access to diagnosis and competent care. Our non-specialist doctors look at us, see all of our issues and think "you can't possibly have EDS because it is rare and when you hear hoof-beats..." They doubt what is right in front of them and move onto common ailments and algorithms inculcated by medical training and insurance companies. The next big assumption is that the most common cause of our symptoms is anxiety and hypochondriasis. I was taught this over and over in medical school and residency. As much teaching is pedantic, this is still taught by senior doctors on rounds and unfortunately, this is also in the medical literature here and there, often in case reports. For example, a few years ago, I read a case study in a prominent psychiatry journal describing a young girl with a host of familiar symptoms, the mother had fibromyalgia and the father wanted testing for a genetic disease in his daughter. This teaching case taught that the diagnosis was "delusional disorder" and the right thing to do was to separate the young person from her family. Yikes! We know this is happening ("medical kidnapping" as it is called in the forums). These assumptions can be dangerous and harmful to patients and their family members.
Assumptions block research. Because researchers don't usually see patients, they start with goals based on the assumptions given them by the clinicians and textbooks, i.e. "Find those damn salamanders!" They are not in the forest (not with the patients and often they have little clinical training to recognize what they see anyway). Research based on these assumptions is inefficient at best, completely off-base at worst. It's often the needle in a haystack approach (i.e. using computers to analyze gene variations in a large group of patients versus what is felt to be controls), rather than really looking at the sick people and seeing what they have in common. It is known that my candidate mutation is present in at least 10% of the population (probably much higher than that) and I hypothesize (and the evidence suggests) that it requires a trigger (chronic stress, infection) to reveal itself. Because the gene is hidden without the trigger and is highly prevalent, the current research studies comparing the genes of sick versus normal people probably contain many people with the perpetrating mutation in the group of "normal " people, confounding the conclusions. Further, the other studies which have computers analyzing what genes are active as the disease progresses will only find out what happens "downstream" from the inciting problem. It is not an easy task to swim upstream and understand what upset the apple cart in the first place. My guess is that false assumptions and ignoring the power of direct observation will block the progress towards a cure for possibly decades. Instead of moving forward with false assumptions, we must open our eyes, observe patients, observe each-other and if we see that the presence of salamanders makes no difference as the answer is revealed in the blue sky. I hope that makes sense.
For anyone who steps back and takes a good look, the blue sky is right there and can be found by following the paths of light in the forest. I'm all for science moving at its pace, but we who have this condition are desperately sick and are being told that we need to find salamanders (false assumption) by patient literature, doctors and national organizations set up for patient support. The clinicians who are treating us are being taught this, too. To carry this analogy further, when the doctors see you, they *know* that the salamanders are there based on their training and literature. Your symptoms and presentation suggest that the salamanders are irrelevant and the shafts of light may be important, but our health care system with its ever shorter appointments, does not allow clinicians time to step back and question why what they are seeing doesn't jibe with what they are told. Further, they are punished if they step outside the insurance company-suggested algorithms based on these assumptions and saving money (by doing nothing). Heck, many doctors are so stressed and overworked, some of them barely see their kids or spouse either; it's not just us.
I will return to this idea of false assumptions several more times when they are relevant. There are many more where EDS-HT is concerned.
Everywhere, So Sick Yet Ironically, Invisible To Whom Does this Theory Apply? I assume that most of my audience consists of chronically ill patients who suffer from one and probably many of the chronic syndromes/symptoms/diseases which I will list shortly. Please understand that I am NOT saying that everyone with these diagnoses fits in this group; rather I am saying that in many families, a cluster of these diagnoses will be found and I believe that those families are likely to contain the gene mutations I discuss. For example-you may see a family with a member, often female, diagnosed with or suspected to have Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS). Then in the extended family, you may find autoimmune diseases, i.e. multiple sclerosis, cutting and eating disorders, "possible bipolar disorder," gender fluidity, a highly successful and innovative genius, someone with chronic fatigue syndrome (CFS) or fibromyalgia (FM), someone with severe post-traumatic stress disorder (PTSD) and someone else with bouts of psychosis. The children who are more scrutinized in this day and age, may be diagnosed with attention deficit disorder (ADD), sensory processing issues plus or minus Asperger's Disorder (I know, I know, not in the DSMV:>)). And the kicker, these issues may be found on both sides of the family because I believe that we are attracted to each-other. There is a characteristic psychological profile which goes with this: sensitive, emotional, often gifted and we tend to surround ourselves with others who share these traits.) The degree of hypermobility ranges from none to severe in this family and correlates with the degree of musculoskeletal involvement (joint pain/dislocations/surgeries required to stabilize joints) and orthostasis/"dysautonomia," but not with the other "sick" symptoms which tend to develop later in life only in some, mostly women but not always. Many will react strongly to stress. If this sounds like your family (albeit a dramatic version), I am writing this for you.
Of note: These conditions can occur due to other genes, thus occurring without these clusters. Many people with MCAS and POTS, together or alone have these for a different reason. What I am writing is NOT relevant to them. (However, if you have bendy joints and MCAS and POTS, I am talking to you!)
Over time, it has become clear to anyone who frequents the chronic illness forums, sees patients with an open mind or keeps up with the literature in this field that there seems to be a frequently disabling epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting mainly young, vibrant, talented people (predominantly women) and if you look, many, but not all, have joint hypermobility (double jointedness, ligament laxity). These are (to name a few and I'm probably leaving some out inadvertently):
Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT)
Misc.: Extreme Temperature Dysregulation (Dysautonomia or not), Multiple Chemical Sensitivity, High Adrenaline/Noradrenaline (also called norepinephrine) States, Erythromyalalgia, Raynaud's, Livedo Reticularis, Evidence of Poor connective tissue integrity (dislocations, bruising, bleeding, petechaie, calcific aortic valves, Mitral Valve Prolapse, etc),Dry eyes, Tinnitis, Subcutaneous Adipose Disorders (Lipidema, Dercum's Disease), Left Handedness, Gender Fluidity (LGTB, lack of traditional gender roles)
Perhaps: Medullary Sponge Kidney, Pyroluria, disorders of copper and zinc regulation, Early Onset Parkinson's Disease
I will refer to all of these under the rubric of "Chronic Illness" going forward.
For those of you with EDS, it is important that I clarify a few points. My theory pertains to those who have not been found to have a specific disease-causing collagen mutation, i.e. those who fall into the hypermobile and classical types. I will show you that I believe that we have life-long issues due to poor collagen and inflammation from TGF beta resulting from a TNXB mutation PLUS a propensity for other stress-triggered systemic issues similar to those with other chronic illnesses from an adjacent gene, CYP21A2. I will show you why the current assumption that TNXB mutations are a rare cause of EDS-HT is incorrect, and I will show you why, today, it is impossible to test for even a fraction of the TNXB mutations associated with clinical illness. I know that this goes against the EDS teaching/knowledge base, but keep reading and you will see why I have come to these conclusions.
This section would be hundreds of pages long if I defined or carefully described each of these syndromes/symptoms. As you can see, this is another problem with trying to publish anything about this. I encourage you to Google any of these conditions to see what they are. If you have chronic illness as a result of my proposed genes, my guess is that several of these labels apply to you and family members. These nomenclature issues, along with the above biases and false assumptions have kept all of these medical mysteries shrouded for decades, but the internet/social media/forums have in many ways filled the forest with light. Unfortunately, the medical establishment has responded by blasting "Dr. Google" and becoming almost hostile toward patients who have made an effort to get to the bottom of their health problems. When I started developing these syndromes in 2009, I knew what my doctor would think if I told her, so I, too, turned to "Dr. Google" where I found the connection with EDS-HT and was thrilled to see that I had what I thought would be a legitimate reason for my suffering and one I could share with my doctor. The naivete! Fortunately, over the past year or so, the connections between these conditions have been suggested as small clinical studies linking the various parts together have been published (Ppolycystic ovarian syndrome and autism; EDS, MCAS and POTS; EDS and various psychiatric disorders; POTS and systemic symptoms/pain disorders, MS in EDS, MS in schizophrenia, etc). Large review articles like the mast cell activation article about to be released by Dr. Laurence Afrin specifically tie most of it together. This is a huge step in the right direction. To be fair, the CFS/ME organizations have been writing about the interconnections between these for some time, but for the above reasons and then some, the medical establishment has not been taking notice of those publications (The Forgotten Plague by Ryan Prior addresses why this is). When I tried to publish my theory August 2015, it was an arduous task to try to show the connection between all of these, but even in this short period of time, the literature has become more supportive of this assertion, although the average doctor remains unaware. People with these conditions feel often feel HORRIBLE (with the occasional surprising "good day" interspersed), tolerate very little stress, (ordinary tasks feel insurmountable), and new symptom clusters tend to appear nearly daily. Patients rely on the medical establishment to diagnose and treat them and if they are disabled, to complete disability paperwork so they don't fall into a very desperate financial situation. Due to the assumptions discussed above, patients often leave the non-specialist's office feeling invalidated/angry as they are told to lose weight, engage in graded exercise and start cognitive behavioral therapy (CBT) to address underlying dysfunctional beliefs about their health. I will show that these negative emotions and their subsequent stress response actually may make the person even more sick! It's not a good situation when going to the doctor for help can make you worse!
From Doctor to Patient to Sleuth Back to Doctor I wasn't going to include my story here as I had been told, even by fellow EDSers and my spouse (an internal medicine doctor) that telling my story decreased my credibility among medical professionals and researchers. I was told that presenting myself as the illustrative case in my paper submitted for publication had been the fatal mistake. Thinking about that made me angry. How much more evidence do we need that having a chronic illness causes you to lose everything, including your voice? My scientific observations and reasoning are discredited despite the fact that I have four years of college, two years of graduate school, four years of medical school, six years of residency, double boarding in Internal Medicine and Psychiatry, and 20 years' experience treating patients by admitting that I am sick with EDS-HT, MCAS, POTS, and CFS. Those false assumptions are mighty and they are even held by our nearest and dearests. So here it is, an excerpt from the journal article modified for a more general audience.
My Story: In childhood, I had painful ankle sprains, easy bruising, bloody noses, stretch marks, and I was cold and constipated. I pursued my interests with perfectionism and fervor. My social rhythm was off, but I was very sensitive to others’ feelings. I worried a lot, often associated with physical symptoms, but despite this, I was independent with some adrenaline-fueled hobbies. Puberty was late and arrived with dizziness when going from sitting to standing, palpitations, insomnia, painful periods and ovarian cysts. The demands of an Ivy League university, resulted in worsening insomnia, worrying and fatigue. My obsessive mind latched on to the mysteries of psychiatry and determination led me to the Biological Psychiatry Branch of the NIH where, rather than socializing, I attended every medical lecture offered. Tenacity and a lack of concern for social convention led to a solo backpacking trip around Asia and Africa, during which several episodes of dehydration required medical intervention. At medical school, my almost photographic memory and ability to turn on the “turbo” (reading a thick textbook in 2 days), along with my ability to process and analyze large amounts of information quickly helped me immeasurably. However, the “turbo” faltered. Episodes of exhaustion, mental dullness and concentration challenges increased. I developed rituals to access the “turbo” involving caffeine, salt and music to drown out distractions.
In a combined internal medicine/psychiatry residency program at a very demanding institution, I had no control over my sleep patterns, time standing in place or meal timing, and I was having palpitations, jaw pain, migraines, insomnia, muscle cramps and feeling faint with standing still associated with overwhelming bursts of physical anxiety. The high standards I set for myself made the situation worse. Instead of being sharp or focused, I was over-stimulated. I transferred to another program where I was able to have more control of my self-care, adopted a low-carb/high-protein diet, lost 30 pounds and excelled again, receiving awards for my performance and attention to detail. I finished both residencies, becoming board-certified in both psychiatry and internal medicine and headed to a warm climate. I became very interested in therapy, and I learned a repertoire of techniques for lowering stress response which were of great benefit to both me and my patients.
In 2008 at 43 years old, I was hit with a multitude of stressors. Over several months, I developed facial flushing, burning eyes, migraines, a feeling of imbalance when I was standing or turning my head, head pressure and over-stimulation again. Coincidentally, I realized that I scored a 9 out of 9 on the Beighton scale, the 9 point scale used to assess hypermobility in EDS-HT and I found that I had many of the known comorbidities associated with this syndrome: loose joints, migraines, asthma, bleeding/bruising, TMJ, orthostatic intolerance (feeling faint when standing due to low blood pressure), etc.. The diagnosis was confirmed and I started supplementation with magnesium as I knew that EDS-HT is often associated with malabsorption and resulting vitamin and mineral deficiencies. Very quickly, most of the symptoms resolved, but fatigue lingered.
In 2013, I was again under stress and the magnesium deficiency symptoms returned, along with a few new symptoms. I was very distractible as sensory stimulation was overwhelming; I was exhausted, yet wired and felt faint when standing. I could only drive short distances as blood pooling in my legs gave me bursts of panic from sympathetic nervous system (SNS) activation (excessive adrenaline). Beta blockers were necessary for a racing heart when I was upright, so that I could sleep and work. My handwriting was large, sloppy and there were often extra loops in the letters; I had dysphagia for liquids, hives, dermatographism, asthma, nasal/sinus congestion, burning eyes, flushing, throbbing migraines and explosive diarrhea and brain fog within minutes after eating. Also, a sense of dread/disgust would jolt through my body after an alarming thought or when falling asleep, followed by the need to run with a restless, akathisia-like feeling in my legs. “Disgust/jolt/run” I called it. The pressure in my head and vertigo (spinning sensation) worsened. I developed nystagmus (eye jerking) and lost the ability to track with my left eye. Aware of the EDS-HT association with Chiari malformation (brainstem sinking into the spine sometimes due to high intracranial pressure, sometimes due to hypermobile spine, sometimes present at birth), I scheduled an appointment with a neurosurgeon well-versed in this condition. I wondered if I was developing CFS or FM as I knew that hypermobility was highly associated with both.
I joined the Ehlers-Danlos National Foundation (EDNF) patient forum where, I learned about the association of EDS with POTS and MCAS, years prior to its appearance in the medical literature. POTS refers to clinical symptoms of orthostatic intolerance in upright posture with heart rate greater than 120 bpm or heart rate 30 bpm higher than a resting heart rate after standing for 10 minutes. Its etiology is multifactorial. It is frequently comorbid with EDS plus/CFS/FM/MCAS and infectious conditions. MCAS is due to pathological activation of mast cells leading to inappropriate degranulation and symptoms due to liberated mediators; Lab testing is usually inconclusive. I had all of the symptoms of both conditions: postural orthostatic tachycardia, hives, dermatographism, nasal/sinus congestion, burning eyes, flushing, migraines, asthma, food sensitivities and diarrhea. I started anti-histamines and mast cell stabilizers as recommended on a website started by a fellow EDS patient, Diana Driscoll OD. Within several weeks, all that remained was fatigue and a small amount of malaise. I cancelled my neurosurgery appointment and twice tried to taper my medication unsuccessfully. I could ride my bike for an hour, work two days in a row, with salt and fluid loading between patients, but would require a recovery day afterwards and did not tolerate shopping trips or standing in line.
Several months later, I developed 1+ pitting edema (swelling due to fluid retention) in my feet and ankles; puffy hands; my breasts became tender and swollen; adipose tissue started to appear; my period stopped; and, instead of being cold all of the time, I was overheated and sweaty. My joints started subluxing. Again, I had severe orthostasis (feeling faint with standing) but without the pronounced tachycardia (high heart rate)/anxiety I had experienced with POTS/MCAS. I couldn’t raise my arms above my head without dizziness, and I was short of breath, weak, struggling to ride my bicycle. I cut out all non-essential routines. The disgust/jolt/run episodes returned and a deep, crampy pain in my leg muscles became more prominent. I only slept for about an hour between episodes, each ending in a night sweat followed by intense shivering. I would wake up retching, and in the morning, I was sore and irritable. My hair was thinning. I was now active in multiple forums (EDS, CFS, POTS, MCAS and chronic Lyme) and these same symptoms were described in much younger women, so I knew this was not menopause. Additionally, in the forums I saw multiple sclerosis (MS) and other classic autoimmune diseases, hormone abnormalities and neuropathic pain syndromes. I asked myself, what was it about EDS-HT that put people at risk for all of this and why were women more susceptible?
I tried berberine, an alkaloid used in Chinese medicine to favorably alter gut flora. All of the symptoms disappeared within 12 hours and over the next couple of weeks, my LDL dropped 60 points, I lost 15 pounds, my periods restarted and my elevated blood sugar normalized. From this point onward, I started cycles of berberine whenever my orthostasis, subluxations, pain and fatigue crept back. I avoided anything that was exciting, good or bad, because activation triggered MCAS symptoms and hyperadrenergic states, despite my mast cells being in pharmacological lock-down. My personality morphed from being bold and extroverted to inhibited and isolated. I was found to have hepatic steatosis on MRI and bilateral adrenal hyperplasia was noted on CT scan after a horse accident in October 2015. In January 2016, I developed my first cold since 2009 and I rejoiced! My immune system may be recovering...
I came to understand that EDS-HT had somehow predisposed me to this mess and I became determined to find out why. In addition to joining all of the forums mentioned above and religiously reading all of the patients' posts, I read new articles almost as soon as they were released. I started doing Beighton scores (for hypermobility) on all of my psychiatric patients as a matter of course. Also, my assessments started to include more extensive health questions and observations about the syndromes/symptoms and diseases listed above. For the past 10 years, I have worked in settings where I have been able to spend an inordinate amount of time getting to know my patients during their assessments. I routinely assess ways of thinking, levels of emotional intensity and presence or absence of certain skills, in addition to the traditional psychiatric evaluation questions. I know my patients for weeks to years. What I discovered was shocking for me, as I was a doctor with many of the biases prevalent in the general medical community. Yet, my observations had me falling into an alternative universe, a rabbit hole.
Early on, it was clear that all of these conditions must be stemming from a common predisposition which has something to do with hypermobility. The story I heard again and again: a talented and active person (often female and often hypermobile or with hypermobility in the family, if asked) with a tendency to get some physical symptoms and anxiety under stressful conditions (often mild MCAS symptoms), is exposed to a severe short-term stressor (usually infectious) or a major prolonged stressor (physical/emotional trauma, pregnancy, menopause, infection (Epstein Barr, Lyme Disease, etc...), loss, work stress, etc...) and develops, in a reasonably short period of time (sometimes over night, but usually over months), severe and disabling illness, involving the above syndromes/symptoms/diseases/etc... That was my story too. The people have healthy family members who are often very driven and successful (and, therefore, sometimes especially invalidating).
To me, it made sense to conceptualize this as: A person, usually female with a genetic vulnerability (familial) is exposed to chronic stress or a strong stressor which results in a cascade of physiological events causing characteristic chronic illness involving multiple overlapping, co-morbid syndromes/symptoms/diseases. Now, this is the same reasoning that the CFS/ME researchers have begun to use and that Dr. Diana Driscoll, OD from the www.prettyill.com website also was using when I "met" her in 2011 online. (The EDS community still attributes all of this to a collagen issue which I will address below). Most have held that the stressor is infectious or interpreted to be infectious by the body, resulting in the immune system turning on inappropriately due to an immune system genetic abnormality, showering the body with cytokines (signaling molecules produced by immune cells to mount immune response), triggering this mess. It took a long time for science to get to this point because for years the researchers jumped from one pathogen to the next, trying to determine how each pathogen caused a separate type of disease. This thinking is still held in the Lyme Disease and Toxic Mold communities. Behind this is the argument that there have been documented epidemics of chronic illness in unrelated people triggered by an infectious agent. While this would normally strongly suggest a non-genetic cause, it is important to understand that the genetic mutations which I believe predispose to chronic illness are extremely common (at least 10% of the population and probably higher than that) and there are many pathogenic variants. So, there is a high likelihood that if there is a group exposure to a highly stressful pathogen, many members of the group could develop chronic illness. Additionally, treatment for these pathogens has resulted in less than stellar response for the patients due to a triggered autoimmune response which proceeds independent of the pathogen. The mold folks sometimes get better living in mold-free communities, but these are also stress-free communities. More about the effect of lowering stress on the expression of chronic illness later.
Because abnormal cytokine profiles have been found in CFS/FM and some of the other conditions, and cytokine manipulation can result in improvement clinically, I was sure that the immune system was certainly involved and a predisposing genetic abnormality of the immune system made sense. Mitochondrial disease could follow from immune system disease/inflammation. But how could sick people with EDS-HT fit with this? They were assumed to have all of their problems due to an underlying genetic defect of collagen and not an immune system problem. While a good proportion of the people with the above syndromes/symptoms/diseases are found to be hypermobile, many have no evidence of hypermobility or collagen disorder (although often had family members who did) but all of the same symptoms.
My clinical experience (obtaining Beighton scores, symptom checklists and searching for physical evidence of the above syndromes on all psychiatric patients) was very revealing. Again, please understand that my evaluations are in preparation for intensive therapy, are several hours long and involve assessing how the person sees the world and thinks, in addition to evaluating for psychiatric diagnoses. Then I really see my patients over time, providing therapy as they negotiate with the world. You can say that this is anecdotal and not scientific, but I will share with you what I found:
There is a classic, recognizable psychological profile (ways of thinking, not specific psychiatric diagnoses) present in ALL patients/people I have seen with:
Hypermobility (sick and well) with physical signs/symptoms (e.g. livedo reticularis, dilated pupils, Raynaud's, fidgeting, dysautonomia, etc)
No Hypermobility (well), but hypermobility/CFS/FM/autism/chronic illness in the family
No Hypermobility in someone who is initially well but develops CFS/FM/MCAS/chronic illness in front of me as stress increases
FM/CFS/Chronic Illness +/- hypermobility, often with hypermobility/CFS/FM/autism/chronic illness in family members.
I could NEARLY ALWAYS predict what medical characteristics I would find in the patient and family members based on whether this profile was present or not. This profile could be found in NEARLY ALL of my patients, with about 80% of them showing some degree of hypermobility. It is present in some of my friends, acquaintances and loved ones, again mostly with some degree of hypermobility. I DO NOT see this profile as pathological (remember, I have it myself), as it can be associated many gifts/bonuses, but the sensitive nature makes the person vulnerable to anxiety, negative thinking, obsessionalism and post traumatic stress disorder. (More below). I DO NOT believe that the sensitivity is THE CAUSE of the chronic illness. This psychological profile has been described nearly exactly by someone else, Elaine N. Aron, PhD, the author of the Highly Sensitive Person series of books. A self-described HSP herself, she has done considerable research to show that HSP's make up 15-20% of the population and her description of them is widely accepted in the psychology literature, starting with an article on "sensory processing sensitivity" in 1997. I will write more about this at a later time, but I share her books with many of my patients because she has so many useful tips for maximizing life with this profile. Of note, I have found that men and women are equally represented in people with this profile, although women tend to have more of the adrenaline-associated features due to their increased orthostasis with rising progesterone as a result of their menstrual cycles. Despite this, there is a known predominance of women with chronic illness, medical and psychiatric, which I believe results from the tendency of people with this profile to have very high 17 hydroxyprogesterone during times of stress, women more than men, further increasing the acute stress response (more about that later) which flips the switch into chronic illness.
(Deep breath...I know many of you reading this are triggered by this information as you are all tired of being labelled crazy and being told all of this is in your head. That is absolutely NOT where I am going. Remember that I believe that our physical symptoms are actually due to a very serious enzyme deficiency involved in the acute stress response and causing the brain to develop a certain way resulting in this profile.)
Because this profile is in hypermobiles, sick and well, and in those who develop chronic illness before they become sick, this psychological profile is closer to the underlying vulnerability to all of this chronic and psychiatric illness than the hypermobility is. It is a marker for vulnerability to a very wide array of syndromes/symptoms/diseases.This profile is NOT the cause of the illness, but is often (I'm going to say in my experience, always) present in those at risk. (Before medicine knew what HIV was or how to test for it, we tested for hepatitis C which was often present in people with HIV. This allowed us to tell which patients needed closer watching. This is the same idea.
I need to digress back to EDS for a minute as my findings initially stood in contrast to the EDS literature available at the time and may be confusing for some of you who hold some of the common assumptions about EDS which are slowly being proven to be false. Again, these assumptions are huge roadblocks to progress:
That "EDS" is rare; that hypermobility with symptoms is common and that they are not the same thing.
That the degree of hypermobility correlates with severity of EDS symptoms/disability in ways other than pain or dislocation.
That CFS/FM in hypermobile patients is fundamentally different than CFS/FM in others.
That EDS is not associated with inflammation.
That psychological issues in EDS are all explained by dysautonomia or "pseudopsychiatric."
That EDS must be diagnosed by a geneticist.
These assumptions have all made it nearly impossible to publish any research in this area which goes outside of the box. They also make it very difficult to diagnose, treat or publish about patients unless you are an "expert". The end result is that knowledge doesn't progress, patients don't get diagnosed or treated and studies don't get published. As long as EDS remains "rare", medical educators don't care about it, so it is not covered in textbooks or lectures.
If you hold any of these assumptions, I ask you to read what I say below and do some digging on the internet. You may have to watch video lectures because a lot of this is not making it into print. You will see what I mean. The evidence is mounting against them.
Hypermobiles who feel sickare everywhere and they are terribly sick. The experts are now saying 1/50 for EDS-HT prevalence.
Hypermobility does NOT correlate with degree of illness.Sick hypermobiles have well hypermobile family members and were previously well hypermobiles themselves! The forums are packed full of (and I have seen many) non-hypermobiles with all of the physical and psychological characteristics who have family members with hypermobility, CFS, autism, bipolar disorder etc.... Yes, this doesn't make sense if EDS with sickness is ONLY a problem with collagen. Clearly, there must be some sort of trigger outside of collagen. Also, it is starting to seem ludicrous to tell some of these sick people they have EDS and others that they don't when the only diagnostic test involves degree of hypermobility. Doctors are reported by patients in the forums to say a child has EDS, but a mother with CFS who was once hypermobile does not, even though they are both sick. Some doctors have been reported to "take away" the diagnosis as hypermobility decreases with age. It is time to look at this with common sense. We need to stop comparing scores; they are meaningless. We need to look deeper.
Look at the symptoms for CFS/FM/chronic illness versus what is experienced by EDS patients who are sick-the symptoms are many, bizarre and the SAME. It seems improbable that it is bad collagen ALONE causing all of these symptoms in the sick person with EDS-HT and sparing other hypermobile family members, while non-hypermobile people have all of the same symptoms for a completely different reason. Why would my psychological profile be present in all hypermobiles (sick and well) and people with chronic illness (or who later developed chronic illness) presenting in my psychiatric clinic? Why would these two groups have the same brain/thinking if all of their issues caused by a collagen disorder in EDS-HT and the other doesn't have anything wrong with their collagen, according to the assumption?
One of the top EDS specialists stood up at the 2012 EDS Conference and said that "there is no inflammation in EDS," despite the fact that millions of EDS patients were having terrible mast cell symptoms and complications of inflammation. I was already being treated for mast cell activation with high doses of ketotifen and would have been disabled if I hadn't read about this on Diana Driscoll, OD's website. We now know MCAS is rampant in EDS and so probably is high TGFbeta. ( I actually take losartan due to my concerns about this.) My guess is that the EDS patients with FM/CFS have the same cytokine storm seen in the non hypermobiles with these conditions. Just because an expert says it, doesn't mean it is necessarily true. My guess is that he didn't see how a collagen disorder would link with inflammation, so he said it doesn't happen, rather than question that sick people with EDS might have more than a collagen disorder.
Evidence is mounting that people with joint laxity/EDS have very different brain structures from other people and a high rate of a spectrum psychiatric disorders, including anxiety, autism, mood disorders (bipolar), ADD, psychosis/schizophrenia and have two spectrum disorders named after them, ALPIM (anxiety, ligament laxity, pain, immunological issues, mood), neurovisceral disorder. It is also true that high sympathetic states/dysautonomia causes psychiatric symptoms, notably anxiety and panic. The evidence suggests that people with EDS have BOTH wiring /structural brain differences and adrenaline-induced psychiatric issues. My psychological profile suggests that hypermobiles and people at risk for chronic illness are both vulnerable to psychiatric issues due to the sensitivity of people with this profile.
By insisting that an EDS diagnosis requires a geneticist when any medical professional can do a Beighton scale and a symptom checklist , the number of people diagnosed stays low, the importance in medical education stays low and the number of people qualified to treat, run studies, publish and discuss EDS stays low. If you still believe these myths, please don't stop reading because when you see what my candidate genetic mutations can do, you may want to go back and check these assumptions. .
Back to My Findings:My Psychological Profile (CAPS) is the Marker for Vulnerability to Chronic Medical and Psychiatric illness Involving Inflammatory Pathways, Regardless of Hypermobility A more in-depth description of this psychological profile (which I called CAPS-Congenital Adrenal Hyperplasia Heterozygosity-Associated Psychiatric Spectrum) can be found in the Journal Article. Briefly, most people have more than a few of these characteristics: anxiety/over-arousal during times of stress (evidence of high adrenaline) with resulting insomnia and sometimes manic-like characteristics, under-arousal during times of low stress (often leading diagnosis of ADD, and to compulsive behaviors-eating, smoking, etc... and sometimes thrill-seeking behaviors to increase arousal), high emotionality/sensitivity/reactivity to environmental stimuli, sensory processing disorders (usually over-stimulation in places with a lot of noise or chaos), a strong ability to read emotions in others but a social awkwardness in response, easily traumatized by "small" events (horror movie or off-hand comment by another person for example), a tendency toward nonconformity, special abilities (the type varies-but often includes very gifted musicians, scientists, etc...), hyper-focus and obsession with certain areas of interest to them leading to often remarkable accomplishments, in concert with the special abilities. A high degree of tenacity and determination are often present if the person doesn't become hobbled by bad experiences or overstimulation. The strong emotions can be positive or negative, depending on outlook and life experience. These characteristics then manifest in a variety of ways: Obsessional worrying, harm avoidance, OCD (strong thoughts followed by compulsive-need to be performed- behaviors), OCPD (perfectionism, high standards for self and other) can manifest if there have been traumatic events in an attempt to prevent more bad events. People with this profile can be highly successful due to their abilities and tenacity, but some are not able to function because of high adrenaline, overstimulation, trauma reaction to past failures, excessive perfectionism, sensitivity and obsessionalism without a goal. It is no coincidence that if you dig, you will see that hypermobility and chronic illness surrounds people with amazing accomplishments and abilities-genuises, celebrities, mavericks. The Facebook pages regarding "Famous people with EDS" makes me smile because we are seeing the same thing. I have spent quite a bit of time on YouTube looking for hypermobility and finding it in exceptional people. This brain comes with great gifts but there is a cost in terms of physical and as it turns out, psychiatric illness.
Unfortunately, this psychological profile seems to predispose to more severe mental illness, too. I was very resistant to this idea and spent much time on the EDS forums explaining to fellow EDSers that I believed that the CAPS profile was what we had and not bipolar disorder, psychosis or schizophrenia. I must eat crow... Most of my patients don't have severe mental illness so I was not sure about the prevalence of this profile in the seriously mental ill. I could imagine how the heightened acute stress response could be mistaken for mania and I assumed that the ALPIM group had done this. However, over time, more and more of my patients "crossed over" from heightened acute stress to hypomania and some to mania which responded well to lamotrigine. Interestingly, almost all had MCAS symptoms appearing and worsening as they "crossed over" and these symptoms were more pronounced in those who went on to become psychotic.Again, the link between this psychological profile (CAPS), stress and physical and now psychiatric illness was apparent: As Aristotle said, "there was never a genius without a tincture of madness" and I looked for and found hypermobility in the videos posted of some famous geniuses with severe mental illnesses. My theory expanded to include the idea that stress triggered inflammation in this population and that inflammation could be in the body, triggering chronic illness or in the brain, triggering mental illness, or in both, causing a combination of symptoms. As we shall see in the next session, I propose that MCAS occurs as a result of high corticotropin releasing hormone (CRH) during times of stress in this vulnerable population and MCAS has been linked again and again with psychiatric conditions by Dr. Afrin. This begs the question of whether treatment for MCAS could help people who have crossed over into mania or psychosis.
As the hypermobiles have this profile and have been the most studied prior to becoming chronically ill, I assumed that the brain findings of a larger than normal amygdala and smaller than normal anterior cingulate Eccles found in the hypermobiles' brains are also probably present in those with the other chronic illnesses before they became sick. My psychological profile fit perfectly with these findings. The amygdala is the fear and emotional center in the brain, its larger size can explain the emotional intensity in people with CAPS. Autistic wiring, present to a degree in all people with this profile as well has been found in hypermobiles both by me and in the literature (Eccles again) which suggests underlying mast cell activation during infancy as cause, per Dr. Theoharides. "Dysautonomia"/high adrenaline certainly contributes to the harm avoidance behaviors (high anxiety/adrenaline associated with mistakes), some of the compulsive behaviors (to calm the nervous system and avoid mistakes), the insomnia and increased arousal/anxiety. I am going to argue that a heightened stress response is driving this sympathetic nervous system predominance. There are a few studies looking at psychiatric characteristics of people with chronic illness who are not hypermobile and they were suggestive of this profile, but there was quite a lot of back-lash regarding these findings as people with chronic illness found them invalidating, so research in this area stopped. This is another example where judgment/assumptions about what may have been objective observations may have blocked the path to the Truth, but this time the perpetrator is not the medical establishment.
Now, again, I am having to figure out why my observations go against two common firmly held assumptions, this time in the field of psychiatry. Assumptions: 1. Psychiatric disorders are distinct and separate in their inheritance and presentation, 2. Psychotic, anxiety and mood disorders are due to neurotransmitter level issues primarily. Before I had to worry about this too much, there was a major discovery published in April 2015; it was found that all five of the major psych disorders (autism, ADD, Mood Disorders, Schizophrenia and Anxiety Disorders) share common genetic origins, meaning that they all develop in similar people and are probably spectrum disorders (the same dish with different spices, just like CAPS!). That took care of assumption number 1. Regarding number 2, in the past year there has been a flurry of studies published revealing that mood disorders and psychosis are strongly associated with brain inflammation (rather than neurotransmitters) and strongly linked with MCAS. Just this week (end of January 2016), schizophrenia was linked to the C4 gene which sits right next to the TNXB gene(what I believe is the gene conferring EDS-HT) on the RCCX module!
Trying to Pull It All Together Anyway, back to my theory and a quick summary of what I knew so far: A person, usually female with a genetic vulnerability (familial) is exposed to chronic stress or a strong stressor which results in a cascade of physiological events causing characteristic chronic illness involving multiple overlapping, co-morbid syndromes/symptoms/diseases, medical and/or psychiatric. This vulnerable person is frequently hypermobile or has hypermobility in the family and has a distinct pre-illness psychiatric profile involving stress over-reaction, high emotionality/sensitivity, autistic features and often special abilities.This psychological profile may be a very powerful tool for getting to the bottom of all of this because if you can locate a vulnerable population, you can start looking for genetic markers. At this point, I believed that the infectious and toxic conditions which led to chronic illness (Chronic Lyme, Gulf War Syndrome, toxic mold) were able to do this because they were examples of a strong stressor capable of flipping the chronic illness switch, causing a characteristic illness with shared features of the other chronic illnesses. This became clear when I realized that one of my best friends from childhood with the CAPS profile has a much younger brother (who I don't personally know) who battled chronic Lyme and symptoms of MCAS for years.
Now I had some specific questions to ponder: what genetic mutation could alter brain formation to cause autistic wiring, a big amygdala, a small anterior cingulate and sometimes cause hypermobility? Dr. Theoharides was putting out his MCAS lectures, calling autism an allergy of the brain and providing evidence that mast cell activation during infancy can result in autism. It was finally in the medical literature that EDS, POTS and MCAS co-occur, years after I had found Diana Driscoll, OD's website and had been getting treated for this. For a minute, I thought this was all mast cell activation syndrome as Afrin claims. Regarding the hypermobility, I thought that maybe some the inflammatory mediators could cause an acquired hypermobility. Downstream inflammatory effects could explain the cytokine abnormalities and maybe even mitochondrial disorders. But, there were some major problems with this theory: I have met people with MCAS and POTS who are not hypermobile, don't have the psychological profile (CAPS) and don't have all of the other comorbidities. (As it turns out MCAS and POTS can have many origins). Also, the brain structural abnormalities aren't easily explained by MCAS alone, and at this point, my own mast cells were in a strait jacket on 8 mg of ketotifen and 2000 mg of quercetin (I had NO mast cell symptoms), and I had lots of other symptoms. Many of these symptoms eventually responded to berberine (at that time, I didn't know why). I kept my eyes peeled for any immune system gene which could alter brain structure, cause hypermobility and cause MCAS.
Then one day in early July 2015, I was on the EDS forum talking about how the field of psychiatry seems to be the closest to revealing the mysteries of chronic illness when a fellow EDSer, Martha Cassell, sent me an article about the RCCX module saying that she didn't completely understand what the article was saying but that she thought it was very important and I should read it. Honestly, I had to dig deep to follow it because, while I did take graduate school immunology and genetics, it was a LONG time ago. I was astounded at the implications. My world turned upside down.
As a result of tremendous positive response to the RCCX Theory:
Karen Herbst MD PhD (Endocrinology) and I have set up a non-profit corporation to fund research investigating the possible role of the RCCX Module in familial chronic illness clusters (Ehlers-Danlos Hypermobility Type, Chronic Fatigue Syndrome, Fibromyalgia, Chronic Lyme, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, Pain Syndromes, Psychiatric Spectrum Disorder (including PTSD, Anxiety Disorders, Autism Spectrum Disorder, Bipolar Disorder, Psychosis, Depression, ADHD), Autoimmune/Immunological Disorders, Endocrine disorders,Subcutaneous Adipose Tissue Disorders and Neurological Conditions (Including raised Intracranial Pressure, Chiari, Chronic Migraine, etc.), etc.).
We will be gathering a large amount of family and clinical data from people with chronic illness (CFS, chronic Lyme, FM, etc), hypermobility, the CAPS profile, CYP21A2 mutations and subcutaneous adipose tissue disorders and will compare with normal controls. We are trying to track down geneticists and other collaborators to assist us with phase 2.
Should we have money left over, we will donate to the Open Medicine Foundation to assist Ron Davis PhD et al. in their pursuit of the cause and treatment of CFS/ME (which we are quite sure will eventually lead to the RCCX module).
Please consider making a donation today. To our knowledge, no one else is looking at this!
We promise to spend your money wisely. We have no salaried employees. We are volunteering our time. We are both completely committed to finding answers. A heart-felt thank you for believing in us and helping us to try to crack this mystery. RCCX Project, Inc. is a non-profit corporation formed April 12, 2016, based in Tucson, Arizona. It is organized exclusively for charitable or educational purposes within the meaning of section 501(c)(3) of the Internal Revenue Code.