PHOENIX RISING

A Guide To Chronic Fatigue Syndrome (ME/CFS)

RESEARCH

TREATMENT– This is a laymen’s guide to POTS treatment. Please discuss any potential treatments with your physician.

Pharmaceuticals: The best review on the internet of the efficacy of pharmaceutical drugs in treating orthostatic intolerance can be found at http://www.pediatricnetwork.org/medical/OI/johnshopkins.htm.  Many drugs are used to treat OI; only a few are mentioned on CFS Phoenix. The Johns Hopkins paper, done by Peter Rowe, presents the best general overview of OI I have been able to find on the internet.

While CFS patients experience many OI-like symptoms a study indicated they do did not respond positively to the most common treatment for OI, fluidrocortisone. Rowe notes, however, fluidrocortisone may be helpful for OI in CFS if a high salt and fluid intake accompanies it. Fluidocortisone increases salt retention. Naschitz, however, found excellent results with the use of Midrodrine (an alpha adrenoreceptor agonist) in one patient. In a NIH grant description Stewart states Midodrine will relieve the symptoms of hi-flow POTS patients. Since because midodrine is unable to cross the blood brain barrier and therefore effects only the peripheral nerves it’s apparent effectiveness in some patients buttresses Stewart’s and other’s belief that peripheral nerve dysfunction is a central factor for some POT and CFS patiens.

Calder, a POTS patient, reports that while Midrodrine is helpful for many patients he warns possible hypersensitivity reactions dictate that one should start at low doses.  While some people have had good experiences with beta blockers Calder reports they have been responsible for more bad reactions in POTS and CFS patients than any other drugs. Beta blockers increased symptoms n a small study of adolescent POTS patients done by Stewart. A new drug Celexa has been used with some success.

Other Treatments: Streeten got good results with the use of military suits designed to block the blood pooling occurring during rapid ascents in fighter jets. Waist high support hose and knee high support socks may serve a similar function. Rowe (2002) points out that the management of co-morbid conditions that may exacerbate OI (allergies, asthma, dysmenorrheal, migraines, joint hypermobility, anxiety, depression) can be important.

Christopher Calder, a POTS patient with a website notes the pitiably low knowledge of OI among internists and recommends patients get referrals from the National Dysautonomia Research Foundation  (http://www.ndrf.org/) 

While there are no satisfactory treatments for POTS, there are some simple actions that may ameliorate POTS. Increasing salt (with your doctor’s permission) and fluid intake can be helpful. Increasing salt intake will only work if increased fluids accompany it. (A few CFS patients such as Lauren Hillenbrandt cannot tolerate salt.) Rowe suggests drinking fluids every two hours during the day. Because large meals stress the orthostatic system by diverting blood to the digestive tract, small meals are recommended.

Some sort of exercise, especially involving the legs, is needed to keep the muscle pump as functional as possible. Because water compresses the limbs water jogging or walking may be particularly helpful. Cheney reports hydrotherapy involving standing in water may assist lymphatic activity as well. Since quiet standing reduces muscle pump activity one should periodically tense ones legs muscles or move. Because loss of muscle mass results in deconditioning tensing/relaxation muscles are recommended for bed bound POTS patients. Recliners are preferable to remaining in bed. Elevating the head slightly when sleeping may be helpful.

Rowe reports various postures can enhance muscle pump activity (squatting, standing with ones legs crossed). Sitting with the knees as high as possible by using a low stool etc. or bringing one or both knees to the chest may reduce blood pooling. Because postural ‘asymnetries’ (bad posture) can exacerbate the effects of low blood volume by restricting blood flow, yoga and/or other stretching exercises can be helpful.

Hot weather can exacerbate POTS by increasing blood flow to the skin. Because garlic and nitrates (i.e. sodium nitrate, sodium nitrite) lower blood pressure Calder recommends that POTS patients with low blood pressure NMH avoid them. He also recommends meditation for stress relief and relaxation. I might add that meditation increases the flow of oxygenated blood to the tissues.

Dr. Pocinki (2004) reports the administration of intravenous fluids greatly reduces fatigue, lightheadedness, brain fog, muscle and joint pain temporarily in CFS patients with joint hypermobility. He suggests trying support hose, increasing salt and fluid intake and avoiding dehydrating substances such as caffeine and alcohol. Some pharmacological measures such as fludrocortisone and nondeglycerized licorice that increase salt and fluid retention may be helpful as well. A recent study found fludrocortisone did not significantly benefit CFS patients.

A poster at the 8th IACFS Conference in Fort Lauderdale in January, 2007 indicated that saline IV's markedly helped one CFS patient. Dr. Bell seconded this with a finding from his practice. This treatment approach is still in the early stage.

The Water Effect – Interestingly, given the high fluid levels CFS patients typically imbibe, Stewart stated the physiology in POTS is similar to that found in dehydration. The effects of water drinking on blood pressure (BP) and ANS functioning have been vigorously investigated in the last five years. Drinking 500 ml of water was found to increase NE levels in younger adults and NE levels and BP in older adults. Muscle sympathetic nerve activity (MSNA) was increased in one study and but not another. Most intriguingly for CFS patients given their possible lower leg denervation, patients with sympathetic nerve denervation reacted most strongly to water ingestion. Both BP and NE changes reached a peak approximately half an hour after ingestion and decreased over the next 30 to 45 minutes.

The cause of the low blood volume in CFS patients is unclear. Because SNS activity influences the absorption of solutes (such as sodium) by the kidneys, autonomic dysfunction could a source. Thus CFS patients could receive benefits from water drinking either because it boosts their SNS activity or because it increases their blood volume (because it increases both). CFS patients with low blood volume also appear to display reduced plasma renin levels. While water ingestion by healthy controls changed neither plasma renin or vasopressin levels it is notable levels of NE were significantly increased. Interestingly water drinking did not change the plasma volume of healthy individuals

It appears that water drinking increases NE but not plasma renin or blood volume in healthy adults. Increased NE release after water ingestion suggests water drinking either induces the release of locally acting vasoconstrictive or depletes local vasodilating substances. Interestingly, drinking water appears to have the same type of effect that the alpha-2 receptor agonist yohimbine does. Many POTS patients respond favorably to A AR agonists. Increased vasoconstriction means less’ leakage’ of plasma into the surrounding tissues.

We will have to await further tests to find out the effects of water drinking in people with low blood volume.

A BIOMARKER FOR CFS?

Naschitz and colleagues in Israel noticed in 2000 – to their surprise - that CFS patients had a specific pattern of ‘cardiovascular reactivity’ in response to tilt tests. They used statistical analyses of common measures of autonomic function (heart rate, blood pressure) obtained during tilt table testing to create a ‘hemodynamic instability score’. These scores enabled researchers to differentiate CFS patients from a wide variety of control groups. This study was notable in the large number of control groups tested.

The authors posit that the very complex interactions between the heart and the neuro-endocrine systems that are involved in baroreflex activation give rise to specific disease patterns in certain illnesses.

With the notable (and rather surprising?) exception of the patients with generalized anxiety disorder, this test was remarkably effective. Forty-five percent of patients with the anxiety disorder had similar HIS scores. The authors gave no indication why CFS patients had similar scores to anxiety patients. Since anxiety disorder is linked to over activity of the sympathetic nervous system perhaps this is not a surprising finding.

In another study a specific cutoff point for fractal HRV had a high sensitivity (90%) and specificity (72%) when it was used to discriminate CFS patients from controls. It appears that measures of ANS function during tilt may have a high discriminatory value; i.e. may provide a biomarker and possibly – dare one say it? – afford CFS some legitimacy.

One interesting and very promising side notes of this study was its restriction to patients with mild to moderate CFS. Patients with more severe CFS were unable to complete the 30 minute Tilt table test without fainting. Thus this finding is probably quite robust.

Conclusions: The extent and significance of orthostatic intolerance in CFS is still unclear. With some exceptions we find the same heterogeneity in test results that plagues other research efforts into CFS. The rapidly evolving nature of the field of orthostatic intolerance and the heterogeneous nature of the CFS patient population guarantee a degree of opacity will prevail. In particular, tests of BP and the valsalva maneuver have differed between groups. Estimates of orthostatic intolerance (neurally mediated hypotension, POTS, etc.) in CFS patients have ranged from over 90% to less than 20%. The latest research indicates approximately 40% of CFS patients are believed to fulfill the parameters for POTS. Perhaps the most significant finding regarding OI prevalence in CFS, however, was the increased rate of symptoms for all CFS patients undergoing TILT tests regardless of whether they meet the stated definition of OI (Poole et. al. 2000). As in other fields of CFS research, studies have been plagued by small sizes, different methodologies and parameters and poorly defined CFS and control patient sets.

Some consistencies have, however, emerged. CFS typically display ANS abnormalities when challenged, not at rest. CFS patients also consistently display significantly increased heart rates and significantly decreased heart rate variability. These findings suggest sympathetic rather than parasympathetic dysfunction. A subset of CFS patients appear to have reduced blood volumes. When CFS patients have orthostatic intolerance it is generally in the form of POTS.

The splintering of the POTS patients into three coherent subsets – all of which occur in CFS - further refines (and complicates) our understanding of the orthostatic dysfunction occurring in CFS patients. It is generally agreed POTS occurs when insufficient venous flows of blood to the heart during standing because of blood pooling in the abdomen or legs triggers a compensatory response consisting of an increased heart beat. The proximate causes of the increased blood pooling are varied; they include inadequate peripheral vasoconstriction in the legs possibly caused by denervation; increased local blood blows in the legs caused by increased levels of a local vasodilating agent such as NO or acetylcholine and inadequate vaso and venoconstriction in the abdomen. Symptoms appear to be exacerbated by reduced blood volume in a subset of CFS patients. The ultimate causes of these dysfunctions are unknown but may include pathogen induced vasodilation of the peripheral blood vessels, endothelial dysfunction, blunted HPA axis activity or others. While deconditioning can cause POTS, no studies indicate deconditioning plays a major role in the orthostatic intolerance seen in CFS.

A most promising development in this field is the possible development of a biomarker created using heart rate and blood pressure changes during a tilt test. This test, which was surprisingly effective in differentiating CFS patients from a variety of control groups, suggested a distinctive pattern of ANS dysfunction occurred in CFS patients.

While orthostatic intolerance does not appear to be primary in CFS, its prevalence in CFS and similar symptoms indicate it is an integral part of it. It is likely the disruptions underlying OI will be found to some extent in most CFS patients whether they meet the standards for OI or not. Uncovering the source of the OI seen in CFS will undoubtedly contribute greatly to our understanding of the pathophysiology of CFS. Thankfully this is one area of ‘CFS’ research that has some funding; several projects are underway that should illuminate this most intriguing aspect of CFS in the near future.

(Produced Fall 2004, brief update - 2007)

WEBSITES

The National Dysautonomia Research Foundation (NDRF) provides patient referrals to doctors and information on OI and other autonomic disorders - http://www.ndrf.org/

Christopher Calder, a POTS patients, has the most engaging paper on POTS I have found It is part of the CFSResearch website - http://www.cfsresearch.org/cfs/research/abnormalities/1nf.htm

Peter Rowe’s paper illuminates the basic aspects of OI and gives valuable info on pharmaceutical drugs and other types of treatments - http://www.pediatricnetwork.org/medical/OI/johnshopkins.htm

Not surprisingly Julian Stewart’s site has much information on the causes of orthostatic intolerance - http://www.nymc.edu/fhp/centers/syncope/index.htm

Besides a great deal of information on orthostatic intolerance in adolescents with CFS, the very large and well designed website put out by The Pediatric Network for Chronic Fatigue Syndrome, Fibromyalgia and Orthostatic Intolerance has much information on CFS itself - http://www.pediatricnetwork.org/index.htm

adrenergic receptors - most effector tissues are innervated by adrenergic postganglionic fibers of the sympathetic nervous system. Such receptors can be activated by norepinephrine and/or epinephrine and by various adrenergic drugs; receptor activation results in a change in effector tissue function, such as contraction of arteriolar muscles or relaxation of bronchial muscles; adrenergic receptors are divided into )-receptors and *-receptors, on the basis of their response to various adrenergic activating and blocking agents. .

artery - A relatively thick-walled, muscular, pulsating blood vessel conveying blood away from the heart. With the exception of the pulmonary and umbilical arteries, the arteries contain red or oxygenated blood.

baroreceptor - 1. In general, any sensor of pressure changes. 2. Sensory nerve ending in the wall of the auricles of the heart, vena cava, aortic arch, and carotid sinus, sensitive to stretching of the wall resulting from increased pressure from within, and functioning as the receptor of central reflex mechanisms that tend to reduce that pressure.

capillary - 1. Resembling a hair; fine; minute. 2. A capillary vessel; e.g., blood capillary, lymph capillary. 3. Relating to a blood or lymphatic capillary vessel.

norepinephrine - is a catecholamine hormone secreted in response to hypotension (low blood pressure) and physical stress; in contrast to epinephrine it has little effect on bronchial smooth muscle, metabolic processes, and cardiac output, but has strong vasoconstrictive effects and is used pharmacologically as a vasopressor, primarily as the bitartrate salt. Syn: noradrenaline.

vasodilation - Widening of the of blood vessels. Syn: vasodilatation.

vasculitits - Inflammation of a blood vessel (arteritis, phlebitis) or lymphatic vessel (lymphangitis). Syn: angitis

vein - A blood vessel carrying blood toward the heart; postnatally, all veins except the pulmonary carry dark unoxygenated blood. Syn: vena [TA].

venous blood - blood which has passed through the capillaries of various tissues, except the lungs, and is found in the veins, the right chambers of the heart, and the pulmonary arteries; it is usually dark red as a result of a lower content of oxygen

Bonyhay, I and R. Freeman. 2004. Sympathetic nerve activity in response to hypotensive str essin the postural tachycardia syndrome. Circulation 110: 3193-3198.