12 July 2002

Author's Note: I called the SAS today to congratulate Shawn, Sheldon, Nancy, and the rest on an impressive and successful conference at Penn. Sheldon suggested that I write something for the e-bulletin this week. I decided to give an approximate, abbreviated written text of my presentation for those SAS members who were unable to attend the conference. (In this written summary I have not cited references because it is not audience appropriate. I have, however, done so in my hypothesis paper and the abstract I submitted to the American Autonomic Society. DML)

Before I give an overview of the presentation I gave at the conference, I would just like to thank the Society for Amateur Scientists, its officers, and conferees for both the opportunity to speak and the moving response I received from them regarding my speech. The warm reception I received meant a great deal to me. Indeed, aside from attending a Presidential speech earlier this year, attending the SAS conference was one of the only non-healthcare related outings I've had in the last three years.

I would also like to thank Mr. Guy for supplying me with my dress attire today, and the SAS for creating the Benjamin Franklin Citizen Scientist Award for which I was nominated. It is an honor made greater by the accomplishments of my fellow nominees. Thank you.

Dysautonomia, Chronic Fatigue and the Development of a Proposed Treatment

An approximate and abbreviated written text

By D. M. Lindsay

Background on the Class of Disorders, and the Field

Dysautonomias (pronounced Dis-auto-gnome-ee-uhs) are disorders of the autonomic nervous system (ANS). The ANS assists in controlling your body's heart rate, body temperature, blood pressure, and many other physiological functions. Autonomic nervous system dysfunction is one of many potential causes for the Chronic Fatigue Syndrome (CFS). The brief definition for the chronic fatigue syndrome is a greater than 50 percent reduction in a person's ability to do for a period of greater than six months.

One million Americans are believed to suffer from some type of dysautonomia. Orthostatic intolerance, a symptom commonly associated with dysautonomia, is believed to affect as many as 500,000 Americans. Sufferers with OI develop symptoms that limit their ability to maintain upright posture. Just a few of the symptoms of OI are lightheadedness, palpitations, tachycardia (rapid heartbeat), fatigue, and nausea. For the most part, these symptoms eventually subside when an OI sufferer lies down.

As one of the investigators in the field put it, "The importance of [OI] goes beyond the number of patients it affects, because it is the cause of substantial disability in young, otherwise healthy subjects." Such was the case with me; I myself suffer from orthostatic intolerance and chronic fatigue. These disabling conditions are believed to be caused by a dysautonomia. This condition has left me virtually homebound and forced me and forced me to withdraw from school prior to completing my undergraduate studies.

So, what is my life like, and just what does "substantial disability" mean? Another investigator in the field wrote, "These patients predictably develop symptoms of disabling fatigue, dizziness, diminished concentration, tremulousness, and nausea while standing. Simple activities such as eating, showering, or low intensity exercise may profoundly exacerbate these symptoms and may significantly impair even the most basic activities of daily living." This description is an adequate representation of my own condition, and of that of other dysautonomia sufferers with chronic fatigue and OI.

However, despite the large dysautonomia patient population, and the often severe impact that dysautonomia has on its patient population (and their families), the medical community is largely unaware of these disorders. Presently there are too few practicing physicians aware of dysautonomias. Moreover, there are also too few clinical investigators researching dysautonomias. To make matters worse, the lack of practicing physicians familiar with treating dysautonomias has forced many clinical dysautonomia investigators to play a dual role: that of clinical investigator and, oftentimes, primary caregiver as well. This unfortunate situation has placed an additional workload on the backs of the competent, yet small and already overworked, community of clinical dysautonomia investigators.

But, while the number of clinical dysautonomia investigators is small, their dedication is notable, commendable, and easily observable. Two instances demonstrate these investigators’ dedication to their work. In the first instance, I sent an e-mail to an investigator in the field at 2 AM. I received a response to that e-mail by 3 AM.

The second instance that demonstrates their dedication involves the responses I received when I invited two of the investigators in the field to attend this presentation at Penn. On a Friday afternoon, I sent two investigators e-mail invitations to attend my presentation. Monday morning I awoke to a phone call from one of them, an M.D. Ph.D. chronic fatigue/dysautonomia investigator, who called me long distance from New York City to regretfully explain that he would be unable to attend. His colleague at another university, the second investigator I invited to attend my presentation, responded with similar courtesy by e-mail. These investigators work diligently to serve the dysautonomia community, but that community is one million strong, and small number of investigators and knowledgeable practicing physicians add up to a dysautonomia patient population that is undeserved by the medical community overall.

Therefore, I would be honored to add my efforts to those of these investigators in helping to improve the lives of dysautonomia sufferers. It is my hope that my contentions regarding metabolic and combined alpha and beta-adrenergic components (in some dysautonomias) contribute significantly to the understanding of the problem of dysautonomia. These contentions initially arose from my quest to understand seemingly contradictory findings in my own suspected dysautonomia. I also hope that my proposed treatment, which followed logically from consideration of my novel contentions, will improve not only my life, and that my mother and aunt, but the lives of a significant number of those who suffer from similar dysautonomias.

I believe that the best way to determine whether my contentions and proposed treatment will help dysautonomia sufferers will be to implement my proposed treatment. Therefore, over the upcoming months, I will be pursuing two goals: publication of my contentions and proposed treatment in peer review journals, and collaboration with one of the investigators in the field who has the experience and resources I currently lack. Regarding the first of these two goals, I have already submitted an abstract to the American Autonomic Society and hope to present at their annual meeting this October. Regarding the second, I hope to approach several investigators in the field at the National Dysautonomia Research Foundation conference in Washington DC this July in hopes of finding one interested in a collaboration.

Timeline of My Illness, and My Investigation

In June of 1999, while conducting research on calmodulin at the University of Kansas, I came down with mononucleosis. By September 1999 my condition had worsened significantly. I was diagnosed with a thyroid problem and begun of thyroid hormone replacement therapy. However, despite some improvement, by February 2000 I was taking a large dose of Synthroid, yet still suffering from hypothyroid-like symptoms. After reading my endocrinology, physiology, and pharmacology texts, I suggested we run a blood test to determine whether my body was metabolizing T4 correctly. It was not. I was switched to Cytomel, a T3 preparation (a different type of thyroid medication that does not need to be metabolized into its most active form by the body) and showed additional, yet limited improvement.

By April 2000, it had become clear to my endocrinologist and me that something in addition to a thyroid problem was involved. He stated, "the rate of change in the way that you feel is too rapid to be attributed to just a thyroid problem." So, I went back to my endocrinology text and found something remarkable. It stated, "Several clinical manifestations of hyperthyroidism and hypothyroidism resemble the effects of increased and decreased catecholamine actions, respectively." (In this instance, catecholamines referred to the sympathetic nervous system -- and sympathoadrenal – products epinephrine and norepinephrine. The sympathetic nervous system (SNS) is a branch of the autonomic nervous system.) So, because of this similarity between the clinical manifestations of increased and decreased thyroid and adrenaline actions, respectively, and because of the short half-life of catecholamines, I believed that a sympathetic nervous system disorder was a possible explanation for my disabling condition.

I then used the available resources to investigate thyroid/adrenaline interaction and wrote a brief paper detailing my findings. My initial research seemed to support the idea that a sympathetic nervous system disorder could be involved in causing my disability. From April 2000 to January of 2001, I was told by a number of doctors that the type of autonomic disorder I described (and claimed may be responsible for my fatigue and lightheadedness) did not exist. But, because their dismissals did not refute the science that suggested to me such disorders could exist (and be responsible for my symptoms), I persisted. I also turned to several Ph.D.'s for guidance and began to learn about the world of research medicine.

In January 2001, less than a month after gaining a computer with Internet access, I found the National Dysautonomia Research Foundation (NDRF) and proof that disorders such as I described did indeed exist. I also found that the initial treatment I proposed in April of 2000 was referred to as having "paradoxical" benefits. It now seemed that there was evidence from within the field of dysautonomia research that the drug I suggested might help some patients might indeed help them. Furthermore, it also seemed that these paradoxical benefits had not been fully explored.

Armed with the information that dysautonomias did exist, and that my initial proposed treatment had shown some benefits, I decided to try to further develop my initial metabolic contentions. I scoured MEDLINE for articles that related to my contentions. Throughout the remainder of 2001, I recruited friends from medical schools to copy necessary journal articles and mail, fax, or e-mail them to me. In several instances, I even contacted the authors of the desired articles themselves who, in many instances, were more than happy to comply with my request for copies. I also continued my discussions with investigators in various fields, not only about my contentions, but about the best way to pursue progress, in my situation. We discussed science writing, peer review, the differences between practicing physicians and research physicians, and many other topics. Without the input of these Ph.D. investigators, and without their tremendous kindness, and without the benefit of their experience, I do not believe that I would have progressed as rapidly as I have, if I was able to progress at all.

By March 2002, I completed the rough draft of my hypothesis paper on previously unreported aspects of autonomic nervous system dysfunction. I then sent copies to investigators in related fields for their review. After receiving their input, I had a much-improved second draft completed by the end of this April. Again, I sent that second draft to investigators in relevant disciplines for their input.

And just this June, I submitted an abstract entitled "Acute and chronic aspects of dysautonomia prompt proposed novel pharmacological treatment" to the American Autonomic Society. Moreover, I hope to have my nearly-publication ready third draft completed by the end of this month.

Virtues Helpful to Me in My Quest

There have been a great many things helpful to me over the past few years of investigation. While there is not the time to list all of them, I would like to list a few in hopes that they will be helpful to you in your scientific endeavors.

Curiosity: To be a scientist you must be curious. You must also challenge unacceptable explanations. If an explanation is unacceptable to you, then it is unacceptable. Example: Having just come from KU where I was concerning myself with a solitary, but crucial H-bond between two amino acids necessary for the stability of the protein calmodulin, the broad symptomatic definition of chronic fatigue syndrome was unacceptable to me. Challenging this unacceptable explanation was the beginning of my quest.

Confidence: Confidence in science comes from preparation and adherence to logic and fact. Example: Several doctors dismissed me when I claimed that an autonomic nervous system disorder could be responsible for my fatigue and lightheadedness. But, because I had confidence in my preparation and logic, I was able to see that their dismissal of me did nothing to refute the science involved in my contentions. This allowed me to persist despite what was, at that time, a dismissive practicing medical community.

(It is of special note that I recently found a doctor who has heard of dysautonomia, and who is willing to refer me to one of the dysautonomia research institutions.)

Passion: The more you do something you're passionate about, the more you want to do it. Example: When I took physiology in 1999 I stated, "If my life ever depends on knowing about the renin/angiotensin system, I'll be in big trouble." It was springtime, I had good grades, and I decided I could do without more renal physiology. At that time, to me, the renin/angiotensin system was a bore. But in August of 2001, I saw that renal physiology would be crucial to the thoroughness of my paper, so I devoured all the information on it I could find. Now the function of the renin/angiotensin/aldosterone system in autonomic dysfunction is an important component of my hypothesis paper.

Patience: While patience seems contrary to passion, it is not. When you have passion, you even have passion for the thoroughness and meticulousness of good science. Example: In April of 2000, I developed the novel component of my proposed treatment. Since that time, I have believed that my proposed treatment would improve my health. However, I understand that the time I have spent since April of 2000 has been important and probably necessary. I have added significant aspects to my contentions since April of 2000. The additions I have made to my contentions since April 2000 make my contentions much stronger and, therefore, more likely to be accepted by the medical community.

Boldness: Dr. Henry Huang, the scientist who conceived of the modern DNA sequencer (an invention that has made the genome project, and much of modern genetics possible), said this to me regarding problem solving, "Go for the throat." Look for a solution that would fix the problem rather than tweak the edges a bit was his advice. Example: The science of my rough draft on autonomic dysfunction indeed went for the throat. My science writing, however, did not. I skirted two important issues because I did not want to offend any of the investigators in the field. But, as Dr. Blumer (Washington University Medical School) said to me, "Welcome to the world of science writing." From that statement I came to realize that if you do anything less than "go for the throat" -- if you do anything less than make the best case you can -- you're doing a disservice to yourself, your contentions, your colleagues, and the course of science.

Inquisitiveness: Ask the experts. If you are genuinely curious, confident in your preparation, and you are passionate and patient in your work, it has been my experience that the experts in the field you are in will be more than willing to help.

My Contentions

While a complete discussion of my contentions would be inappropriate here, I do not think it would be inappropriate to give a brief discussion of the overall concepts involved.

First, the goal of my proposed treatment is to mimic as closely as is possible autonomic nervous system function in the non-diseased state. I believe a person with a dysautonomia that has significant metabolic aspects is like a car that is out of tune. Neither will work right, and each has to work a lot harder than they should to do less than they could.

This brings me to my second major concept: dysautonomia is a chronic problem that results in both chronic manifestations and acute manifestations. These acute manifestations develop when a dysautonomia sufferer with OI tries to do something, such as maintaining upright posture. Similarly, an out of tune car is always out of tune, but the fact that it is out of tune only becomes important when you want it to do something and it can't.

The third important concept in my contentions comes from my endocrinology text. It states, "It is fundamental to recognize that the endogenous catecholamines norepinephrine and epinephrine are mixed agonists. They interact with both alpha and beta-adrenergic receptors. Thus, the response of a given tissue is largely a function of the types (and subtypes) of adrenergic receptors that populate that tissue." This statement explains that adrenaline interacts with any type of adrenergic receptor it encounters. In the non-diseased state your autonomic nervous system releases norepinephrine locally which stimulates either alpha or beta-adrenergic receptors. In the non-diseased state alpha and beta-adrenergic stimulation often occur in concert to produce a desired physiological effect.

The final important concept in my contentions is that I believe there is evidence that suggests that there is both insufficient alpha and beta-adrenergic stimulation in some dysautonomias. I believe that the individual manifestations of some dysautonomia patients can be explained by insufficient alpha-adrenergic stimulation, insufficient beta-adrenergic stimulation, or a combination of the two.

Therefore, based on my goal to closely mimic the non-diseased state, my belief that dysautonomia is a chronic problem that has acute and chronic manifestations, my understanding that adrenaline interacts with any type of adrenergic receptor it encounters, and my belief that -- in some dysautonomias -- both alpha and beta-adrenergic stimulation is insufficient, I believe that drugs that stimulate both alpha 1 and all beta- adrenergic receptors would be useful in the treatment of some types of dysautonomias.

I believe it is important point out that while the metabolic contentions of my hypothesis paper are novel -- as is the combination of medications in my proposed treatment -- much of the renal, erythropoietin, renin/angiotensin/aldosterone system, and cardiovascular components of my contentions are built on the backs of the current contentions. My current understanding of dysautonomia comes from my literature investigations into the novel components of my contentions, my observation of my own condition, and the published work of other autonomic investigators.

Thanks and Dedications

I wish to thank Linda Smith, dysautonomia sufferer and founder of the NDRF; Dr. Robertson, Dr. Stewart, Dr. Freeman, Prof. Mathias, and all the other dysautonomia investigators for their work and dedication; Dr. Blumer, Doc Wilson, Dr. Stephen Thomas (of Penn), and all the other investigators (of which there are more than a dozen) who have helped me in the course of my research; and I would like to thank Donny Carver, Capital Zach Jones, and Jon Scheibel for helping me around on this trip.

I also wish to thank Dr. Kendall Blumer, Dr. Henry Huang, and Dr. Kelly Carpenter (all from the Washington University School of Medicine) for allowing me to interview them in preparation for this presentation.

And lastly, I would like to dedicate this presentation to my late aunt Adelaide, who left me the money to make the trip to Penn; my mother, who is a constant inspiration to me; and to the late WHO bassist John Entwhistle, for his contributions to music, my life, and my writing.