FEATURES

• Dr. Roy Freeman Describes Autonommic Nervous System Dysfunction by Joan S. Livingston

IN THEIR OWN WORDS

• Orthostatic Intolerance and CFS - New Light on an Old Problem by Dr. Peter Rowe, Johns Hopkins Medical School
• New England Premiere of I Remember Me by Rita Sanderson
• Orthostatic Problems in CFIDS/FM and Post Polio Syndrome by Dr. Richard L. Bruno

FEATURES

Dr. Roy Freeman Describes Autonommic Nervous System Dysfunction

by Joan S. Livingston

In a recent presentation to Mass. CFIDS/FM Association, neurologist Dr. Roy Freeman described his CFIDS study findings and those of a wide array of other researchers working on the same basic questions. Dr. Freeman said he hoped his own work would lead to potential treatments “within a year, perhaps two.”

Dr. Freeman is internationally known for his work on the autonomic nervous system (see Primer on ANS) and for the past five-plus years he has concentrated on the relationship between the ANS and CFIDS. Outgoing president of the American Autonomic Association, as well as an associate professor at Harvard Medical School, Freeman directs the Center for Autonomic and Peripheral Nerve Disorders at Beth Israel Deaconess Medical Center in Boston.

His work on CFIDS began in the mid-’90s, after talking with Dr. Anthony Komaroff about a new, “provocative,” research article documenting autonomic problems in CFIDS.The two teamed up to test for possible CFIDS-ANS links, using patients from Komaroff’s study group and the advanced lab technology available at Freeman’s neurology center. Their study spawned further collaboration, and ultimately Freeman launched his own series of ANS/CFIDS studies at BI-Deaconess.

While he is indeed a serious scientist who holds research studies to high, rigorous standards, Dr. Freeman has an engaging, non-serious sense of humor as well. His was a lively, fast-paced lecture, full of give-and-take with listeners, while he tossed around specialized medical jargon as well as catchy slang and jokes with equal ease. His talk interspersed findings from studies he’s conducted with those of other current researchers and earlier work.

Stressing that scientists’ understanding of ANS phenomena in CFIDS/FM is still preliminary, he prefaced many of his remarks with such asides as “Science is funny...” or “Here things get a little murky, kind of messy,” allowing listeners to take a breath before trying to comprehend the difficult, complex issues at hand. And difficult they are, even for those who have read or heard much about the ANS before, as the research continually enters more sophisticated, arcane levels.

IN THEIR OWN WORDS

Orthostatic Intolerance and CFS - New Light on an Old Problem

by Dr. Peter Rowe, Johns Hopkins Medical School

"Chronic fatigue is a prominent symptom in a variety of overlapping syndromes of circulatory dysfunction, the most notable examples of which are neurally mediated hypotension (NMH) and postural tachycardia syndrome (POTS). An early suggestion that such abnormalities were treatable causes of symptoms in what we now call chronic fatigue syndrome (CFS) was made in 1940 by Alexander MacLean and Edgar Allen. They described a group of patients who experienced excessive acceleration of the heart and hypotension after moving from the recumbent to the erect posture, usually associated with symptoms of orthostatic exhaustion, blurring of vision, weakness on exercise, and syncopal episodes. McLean and Allen attributed the tachycardia to a reduced venous return to the heart, in part because symptoms and hemodynamic changes could be provoked within 10 seconds by Flack's test, which involved forced expiration into a tube to maintain a mercury column at 40 mm, thereby reducing blood flow into the thorax. They concluded that this orthostatic tachycardia syndrome seemed similar to “effort syndrome, irritable heart, or neurocirculatory asthenia” the synonyms of the day for what we now call CFS. McLean and Allen reported that patients improved by increasing their intake of fluids and sodium, and by sleeping with the head of the bed elevated. The head-up bed may have helped to conserve intravascular volume by reducing blood flow to the kidney at night. It is a medical curiosity that these detailed observations were largely ignored for several decades.

In this issue of The Journal of Pediatrics, 3 articles address related aspects of orthostatic control of blood pressure and heart rate, two of which take advantage of newer methodologic tools to better understand microvascular flow and cerebral oxygenation. In 23 healthy adolescents, Stewart noted that 44% had reductions in blood pressure of >20 mm Hg systolic in the first minute of upright tilt to 70 degrees, associated with transient symptoms of lightheadedness. At a formal level, these patients met the adult criteria for orthostatic hypotension, but in contrast to the usual course in adults, the hemodynamic changes resolved during one minute and did not require treatment. The reduction in blood pressure correlated with increased calf blood flow measured by strain gauge plethysmography. These valuable observations provide a physiologic explanation for common and self-limited episodes of lightheadedness in adolescents, and they support a conservative approach to treatment, provided resolution of symptoms is rapid. Stewart suggests a need for better pediatric norms for the response to orthostatic stress, and as we generate these, we will be wise to make them age-specific. There is now good evidence that pubertal children have a greater susceptibility to orthostatic stress than prepubertal children. Although the mechanisms for this change in susceptibility during adolescence are as yet unclear, the observation is in agreement with epidemiologic and clinical impressions that orthostatic intolerance syndromes and CFS are much less prevalent in prepubertal children.

The paper by Tanaka et al brings further insight to the pathophysiologic features of symptoms during upright posture in patients with CFS. In orthostatic intolerance syndromes, it has been widely assumed that lightheadedness and other symptoms are caused by a reduction in cerebral blood flow. Our own studies using transcranial Doppler ultrasonography do not identify a distinctive pattern of cerebral blood flow velocity during upright tilt in adolescents and adults with CFS and orthostatic intolerance compared with controls. The much earlier onset of symptoms during head-up tilt in patients with CFS suggests that other factors not measured by transcranial Doppler may play an important role.

Near infrared spectroscopy (NIRS) offers a different insight into cerebral changes during upright posture. This noninvasive technique measures changes in the absorption of near infra-red light by oxygenated or deoxygenated hemoglobin and can be used to assess changes in cerebral tissue oxygenation rather than the changes in blood flow velocity that are available through transcranial Doppler studies. NIRS has been used to study cerebral oxygenation in a variety of settings, including upright tilt in patients with syncope, during lower body negative pressure (a simulated orthostatic stress), and in neonates. Tanaka et al used NIRS to compare cerebral oxygenation between 20 healthy controls and 28 patients with either CFS or idiopathic chronic fatigue. Sixteen patients with chronic fatigue had hemodynamic evidence of orthostatic intolerance during a brief 7-minute period of active standing, compared with 2 of 20 controls of a similar age. After an initial drop in cerebral oxyhemoglobin at the onset of standing in most controls, 18 of 20 experienced a rapid recovery. In contrast, only 7 of 28 patients with chronic fatigue had a rapid recovery, and reductions below the basal level were more common in patients with CFS than in controls. Of interest, 6 of 12 patients with chronic fatigue and abnormal cerebral oxygenation had no evidence of orthostatic intolerance during the 7 minutes of standing, although it is impossible to know whether these patients would have gone on to develop hypotension after a longer period of orthostatic stress.

The results of this study are intriguing but will need to be corroborated by others. Further support for the relevance of reduced cerebral oxygenation to the development of CFS symptoms will depend on showing whether cerebral oxygenation normalizes in patients whose CFS symptoms improve either spontaneously or with treatment of the orthostatic intolerance. It will be important in future studies to ensure that the orthostatic stress is sufficiently long to identify clinically important NMH, which in most cases would be missed by a 7-minute test. Another noninvasive technique that would add to such studies would be the incorporation of end-tidal carbon dioxide measures, to assess the effect of changes in carbon dioxide tensions on cerebral blood flow and oxygenation.

In the third article, Stewart provides a concise summary of the growing literature on the pathophysiology and current treatment of common syndromes of orthostatic intolerance. Treatment of these disorders begins, as it did in 1940, with education, reassurance, dietary measures, postural maneuvers to prevent blood from pooling in the limbs, the use of compression garments, and avoidance of situations that provoke symptoms. An underappreciated aspect of management is the need for effective control of other comorbid conditions that may independently contribute to orthostatic intolerance, including allergies, asthma, dysmenorrhea, migraine headaches, movement dysfunctions (especially those associated with joint hypermobility), and anxiety and depression. Failure to bring these problems under adequate control in the setting of clinical trials will lead to underestimates of the effect size of any intervention. Of the medications that have been proposed, stimulant medications may have received less attention than they may deserve in the treatment of pediatric orthostatic intolerance, despite being used as therapy for hypotension long before their discovery for the treatment of attention deficit disorder and hyperactivity.

As Stewart notes, clinicians have few randomized controlled trials available to guide their decisions about treating orthostatic intolerance, and even fewer when it comes to medications targeted to adolescents. Further progress is likely to come as we gain an improved understanding of the pathophysiologic heterogeneity of these syndromes, but in the interim, a much greater effort needs to be devoted to treatment trials. One methodologic challenge posed by the heterogeneity of these disorders is that randomized trials of single agents will need large sample sizes, thereby making them rather unwieldy to conduct and expensive for funding agencies. A more economic design for the determination of efficacy of medications may be to study treated patients at a stable point in their illness. Persons who have improved by using a medication assumed, but not proven, to be efficacious could be randomized to either active medication or placebo. This randomized withdrawal design would have the advantage of being relatively brief in duration, less costly, and low in new adverse events. If cerebral oxygenation is consistently abnormal in patients with orthostatic intolerance and CFS, its measurement may prove useful as a more objective marker of the response to treatment than self-report of symptoms."

(Source: This is an editorial from The Journal of Pediatrics 2002 Apr;140(4):387-9)

New England Premiere of I Remember Me

by Rita Sanderson

On April 9, 2002 I had the good fortune of attending the New England Theatrical Premiere of the highly-acclaimed film about CFIDS/FM, "I Remember Me." This program was organized by Mass. CFIDS/FM Association and included a guest appearance and presentation by the film's Director, Kim Snyder. The Premiere took place at the Brattle Theatre, a relatively small but cozy movie revival house in Cambridge, where many documentaries, independent and foreign films are the mainstay. The 250-seat theater is often referred to as Boston's unofficial film school. The theatre was filled to capacity for the first showing.

This was a very compelling and informative account of “life with CFIDS/FM.” This 74-minute documentary film was directed by Kim Snyder, an experienced filmmaker from New York, and a person with CFIDS/FM. This film marks Kim's directorial debut. Her film credits include documentaries i.e. Oscar-winning film Trevor, and feature films i.e. Home for the Holidays. The film focuses on Kim's personal struggles with CFIDS/FM and her pursuit of answers over a 5+ year period. Snyder’s reflections and revelations about her own experience took on the form of an interview that was intertwined with stories of other people with CFIDS/FM, observations by a variety of clinicians and researchers, and visits to key locations. In between the dialogue and these clips, a mixture of scenes were interposed, such as the storminess of the sea, seclusion by the riverside, the fury of a strong wind tearing across the fields, and buildings crumbling to the ground – visual images that conveyed to me what I believe were Snyder’s innermost feelings and suffering.

Snyder’s quest for information took her to Lake Tahoe, Nevada, site of one of the first known clusters of this mysterious illness during the mid-1980s, where an extensive conversation with Dr. Dan Peterson was recorded and presented in segments. Dr. Peterson showed genuine concern about people who had been well, suddenly became ill, many still remain ill, and those who had taken their lives over the years. He also expressed disgust with the sloppy investigation conducted by CDC and NIH officials who left skeptical that anything unusual had taken place. A clip was also shown of Dr. David Bell who spoke about a similar occurrence in upstate New York.

A number of other doctors were interviewed including Drs. Nancy Klimas, Peter Rowe, D.A. Anderson, and Alexis Shelekov, and several others, all of whom strongly supported the serious, complex nature of this illness. They reported on their clinical or research experiences. Commentary by Dr. William Reeves, former branch chief of the CDC, was also included regarding the diversion of funds from CFIDS studies and acknowledgment that CFIDS has become a major health problem. Contrary to these opinions, Dr. Peter Manu, an ill-informed doctor, was filmed at one of the CFIDS conferences saying that he believed CFIDS was nothing more than a form of hypochondriasis, where patients and advocating doctors have been trying to "create" or turn it into a "real" illness.

Another comparable, but earlier outbreak of a CFIDS-like illness occurred over 40 years ago in Punta Gorda, Florida. Snyder was able to identify and meet with several of the women who had become ill but they had no idea, until recently, what had happened to them. Apparently, a medical article had been published about their cases but no one had ever gotten back to them. There were three other significant interviews. One was with Michelle Akers, Olympic gold medallist and world’s top soccer player, who spoke with a lot of emotion and frustration about her experience (she has since had to retire from soccer due to CFIDS.) Another one was a rare discussion with Blake Edwards, a famous Hollywood film director (Breakfast at Tiffany's, Days of Wine and Roses, Pink Panther) and husband of singer Julie Andrews. Edwards was very candid but cynical about his struggles with this illness.

The most touching of all the interviews was the story of Stephen Paganetti, a young high school student from Conn. At the age of sixteen, this boy had a very abrupt change in his health and quickly became bedridden for over 2 years. He had to be home-schooled and have all his daily needs taken care of by his parents, including being fed through a tube. The film recorded the exhausting preparation for his graduation where he was brought by ambulance while receiving IVs and oxygen. He was wheeled on a gurney to receive his diploma. Later on, he was surrounded by many of his former classmates, some of whom made thoughtless remarks. None of them had ever paid him a visit at home during that time.

The film moved reflectively from past to present through numerous scenes, people and places capturing certain experiences that I feel effectively portrayed the kind of roller coaster ride Kim Snyder and most of us have been on. All the tests, brush-offs by local doctors, ridicule by other people, and the overall frustration, isolation, and pain are situations that I, and my peers, could readily identify with (with the exception of the severity of Stephen's case). A segment was included regarding suicide. Each of the leading CFIDS/FM doctors admitted to having lost several patients over the years, mainly due to pain, and in one case, driven by the total disbelief and disregard by local doctors making this individual’s life unbearable.

At the end of the film, the audience enthusiastically applauded Kim Snyder and expressed great appreciation for all the seven years of hard work that she put into making and marketing this film. It was a true labor of love! It was also a critically-acclaimed success garnering the following awards: Winner Best Documentary, People's Choice Award, Denver Film Festival; First Runner Up, Sarasota Film Festival; and Honorable Mention, Hamptons Film Festival.

Patients could say that they are already intimately familiar with this illness, so why go and pay to see a movie about it? All I can say is that people went to show their support for an incredible accomplishment by someone who has walked in our shoes. This film also provides a great opportunity to educate family and friends who still don't understand what CFIDS/FM is and how it impacts our life. Most importantly, our patient community now has a great new tool to educate medical professionals and others who don't quite get it. We thank Kim Snyder for her enduring legacy! For most of us, it took us one day (and perhaps another day or two of recovery) to see the results of Snyder’s investment of 5+ years in the making of this film. She has been traveling to film festivals and screenings over the past year or more, making it a seven-year journey.

A lengthy Q & A session with Kim took place after the first showing of the film. She responded to dozens of questions from the audience who praised this award-winning film. She recounted her now seven-year experience working on this film. A couple of questions were raised concerning a few aspects that may have been overlooked in this film. One is the "poverty" that is often brought on by this illness, and the other is the need for a more accurate representation of the "ethnic" groups afflicted by this illness. Viewers felt these aspects ought to have been included. Other questions included: why Fibromyalgia had not been mentioned to which Snyder answered that her research used the terms/definitions coined during these early outbreaks that she had investigated. She recognizes that FM and CFIDS are intertwined, and she acknowledged having both. In response to one of the last questions, she announced that after 7 years, she found herself doing considerably better – for no explainable reason other than “luck.”

This film was aired several times during April on the Sundance Cable Channel. I am not sure if it will be broadcast later this spring or summer. You can check their schedule at: www.sundancechannel.com. Last but not least, please note this film has now been released as a video tape and made available for purchase at: www.irememberme.com and copies are available at the Mass. CFIDS/FM Association’s lending library.

Rita Sanderson is on the Board of Mass. CFIDS/FM Association and is our very committed Support Group Coordinator. Special Thanks to both Rita and Tamara, as well as our heart-felt thanks to Kim for this great film.

Speaker Preview: Dr. Bruno will be our next speaker in the Mass. CFIDS/FM Association's continuing Medical Lecture Series.  His lecture topic will be "Common Ground: the Connection Between CFIDS/FM and Post Polio Syndrome."

Orthostatic Problems in CFIDS/FM and Post Polio Syndrome

by Dr. Richard L. Bruno

While watching a football game President Bush swallowed a pretzel and fainted. They said it irritated his throat and made his blood pressure fall. I feel faint when food seems to get stuck behind my breastbone. I also get lightheaded and very tired after a big meal. Other people with CFIDS/FM tell me they do, too. Are these CFIDS/FM symptoms?

President Bush swallows a pretzel that irritates his esophagus. The irritation causes his blood pressure to plummet and he faints. An unheard of experience? Not for some of the world's 20 million polio survivors and the estimated 10 million people with CFIDS/FM.

The President's problem likely had to do with the pretzel overstimulating the vagus nerve, the main highway for nerve traffic to your esophagus, your swallowing tube, and to your stomach. The vagus nerve carries commands from brain stem neurons to activate the muscles in your throat, esophagus and stomach that make swallowing possible. The vagus nerve also sends commands that tell your heart muscle to slow down and your blood vessels to open up. Vagus nerve stimulation, causing a drop in blood pressure due to blood vessels opening up, is responsible for the common faint, called vaso-vagal syncope.

But the vagus nerve is a two-way street: it both sends commands to your heart and gut and listens to the results of those commands. The vagus carries information about how much food is inside your throat, esophagus and stomach back to those same brain stem neurons. Anything that irritates the esophagus-- like a pretzel getting stuck or even a full stomach -- can stimulate the vagus nerve enough to drop blood pressure and cause a faint, which seems to be what happened to the President.

For Mr. Bush this is likely a one-time thing. But for polio survivors and people with CFIDS/FM, low blood pressure, lightheadedness and even fainting can be frequent occurrences. We know that the poliovirus damaged brain stem neurons that control the vagus nerve and possibly damaged the nerve itself. We have been following a growing number of post-polio patients who feel exhausted after eating meal. Food sticking in the esophagus or a full stomach apparently overstimulate the vagus nerve, trigger a drop in blood pressure and cause feelings of severe fatigue, even though these polio survivors don't usually faint.

In 1995, pediatrician Peter Rowe found that some patients with CFIDS also have fatigue that is associated with a drop in blood pressure when they stand up, take a hot shower or are in a hot room. Rowe's observations parallel the finding from our 1985 Post-Polio Survey that fatigue increased in more than one third of polio survivors when they were exposed to heat. Another parallel with polio survivors was Rowe's observation that a CFIDS patient had "a purple discoloration" of her feet and hands after standing. This discoloration was reported in patients with CFIDS back in 1959 and is remarkably similar to polio survivors' cold and purple "polio feet." These findings indicate that both polio survivors and some CFIDS/FM patients have lost the ability to regulate the size of their veins, which allows blood to pool, blood pressure to drop and causes feelings of fatigue.

Our 2001 International Chronic Fatigue Syndrome Survey found that those with CFIDS/FM fainted nearly twice as often as they did before having CFIDS/FM. Our 1995 International Post-Polio Survey found that polio survivors do not faint any more frequently than those who didn't have polio. But the 1995 Survey did find that anyone who had fainted even once in their lifetime reported significantly more severe daily fatigue than those who had never fainted. This suggests that damage to brain stem blood pressure control and vagus nerve neurons may be coupled to damage to brain activating neurons, the neurons that our and others' research suggests are responsible for symptoms of "brain fatigue" in polio survivors and those with CFIDS/FM. So polio survivors and patients with CFIDS/FM share abnormalities of blood vessels and blood pressure that seem to be related to brain stem neurons that are not functioning normally, probably as a result of virus damage to both brain activating and blood pressure control neurons.

What's to be done? Everyone with CFS should have their heart rate and blood pressure taken lying, sitting and standing. If fatigue is associated with a drop in blood pressure, compression stockings are often helpful to stop blood from pooling in the legs. If you need more help, go to a specialist in low blood pressure and ask about medications that increase the amount of fluid in your blood or reduce the size of your veins to stop blood from pooling in the legs. If fatigue is associated with meals, eating small bites and washing them down with liquid, as well as eating frequent, small, higher protein meals, can stop food from sticking in the esophagus and the stomach from getting too full, prevent over stimulating the vagus nerve and prevent fatigue or even a faint.

REFERENCES

• Bou-Holaigah I. Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia. Clinical & Experimental Rheumatology, 1997; 15: 239-46.
• Bruno RL. The Polio Paradox: Uncovering the Hidden History of Polio to Understand and Treat "Post-Polio Syndrome" and Chronic Fatigue. Warner Books, 2002.
• Bruno RL. Paralytic versus non-paralytic polio: A distinction without a difference? American Journal of Physical Medicine and Rehabilitation, 1999; 79: 4-12. (ftp://members.aol.com/harvestctr/Library/npp.html)
• Bruno RL. Fainting and Fatigue: Causation or Coincidence? CFIDS Chronicle, 1996; 9(2): 37-39. (ftp://members.aol.com/harvestctr/Library/faint.html)
• Bruno RL. Chronic fatigue, fainting and autonomic dysfunction: Further similarities between post-polio fatigue and Chronic Fatigue Syndrome? Journal of Chronic Fatigue Syndrome, 1997; 3: 107-117. (ftp://members.aol.com/harvestctr/Library/ffans.html)
• Bruno RL, Frick NM. Stress and "Type A"behavior as precipitants of Post-Polio Sequelae. In Research and Clinical Aspects of the Late Effects of Poliomyelitis. White Plains: March of Dimes Research Foundation, 1987.
• Manyari D. Abnormal reflex venous function in patients with neurally mediated syncope. J Am College Cardiology, 1996; 27: 1730-5.
• Palmer E. The upper gastrointestinal vasovagal reflexes that affect the heart. Am J Gastroenterology, 1976; 66: 513-22.
• Rowe P. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatrics, 1999; 135: 494-9.

Dr. Richard Bruno will be our next speaker in the Mass. CFIDS/FM Association's continuing Medical Lecture Series. Dr. Bruno is the Director of Fatigue Management Programs and The Post-Polio Institute at Englewood (NJ) Hospital and Medical Center. His new book, The Polio Paradox: Uncovering The Hidden History of Polio to Understand and Treat “Post-Polio Syndrome” and Chronic Fatigue, will be published by Warner Books in June. See his website at www.postpolioinfo.com. E-mail any questions to Dr. Bruno at PolioParadox@aol.com