The Importance of Orthostatic Intolerance in the Chronic Fatigue Syndrome
by Ronald Schondorf phD, MD and Roy Freeman MD

ABSTRACT: Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis is a clinically defined syndrome
characterized by persistent or relapsing debilitating fatigue for longer than 6 months in the absence of any definable medical diagnosis. The cause of this syndrome is unknown. Symptoms of orthostatic intolerance, such as disabling fatigue, dizziness, diminished concentration, tremulousness, and nausea, are often found in patients with CFS. In this review, we critically evaluate the relationship between orthostatic intolerance and CFS. Particular emphasis is placed on clinical diagnosis, laboratory testing, pathophysiology, and therapeutic management. It is hoped that this review can provide a stimulus for further study of this complex and disabling condition.

KEY INDEXING TERMS: Chronic fatigue syndrome; Orthostatic intolerance; Syncope; Tachycardia; Dysautonomia. [Am J Med Sci 1999;817(2):117-23.]

The symptom of fatigue is one of the most common symptoms in clinical medicine, accounting for approximately 10 million once visits per year in the United States. Fatigue can often be attributed to underlying systemic illness (diabetes, cardiopulmonary disease, rheumatoid arthritis) Fatigue also accompanies such psychiatric conditions as depression, panic disorder, or somatization. Between 10 and 20% of patients visiting their primary practitioners will have symptoms of fatigue of 6 months duration. The etiology of this isolated fatigue or fatigue associated with other minor illness symptoms remains undiagnosed and poorly treated. The term fatigue can have several meanings, including exhaustion, a perceived decrease in ability to perform mental or physical activity, a delay in recovery after demanding physical activity, or the weariness of unrefreshing sleep.

Chronic Fatigue Syndrome: A Definition of the Problem

Chronic fatigue syndrome (CFS), or myalgic encephalomyelitis, is a clinically defined syndrome characterized by persistent or relapsing debilitating fatigue for longer than 6 months in the absence of any definable medical diagnosis. Not all agree on the specific criteria for the diagnosis of this syndrome. All require the presence of substantial fatigue (50% decrease in activity) for more than 6 months. There is less agreement as to whether mental fatigue or cognitive impairment is an absolute requirement for CFS and whether somatic complaints, such as muscle pain, multijoint pain, headaches, postex-ertional malaise, unrefreshing sleep, adenopathy, and sore throat, must accompany the condition. The most recent consensus statement requires the presence of four of the eight complaints mentioned for more than 6 months in addition to fatigue. The possibility of concomitant psychiatric disorders, such as somatization or masked depression, is often a confounding factor in the diagnosis of CFS.

In one study, the point prevalence of CFS was estimated to range between 0.3 and 1%&rsquo and in another study, between 0.8 and 1.8%, according to the criteria applied for diagnosis. Whether these data reflect community prevalence of CFS is unclear. In our experience and the experience of others, women also seem to be affected by CFS three to four times more frequently than men.In these people, the onset of illness is often subacute. When assessed by the SF-36 health survey questionnaire, patients with CFS exhibited diminished physical and mental health status, even when compared with patients with heart disease, diabetes mellitus, multiple sclerosis, and major depression. Moreover, the prognosis for complete recovery of adults with CFS remains poor. Ultimately, although some dis pute the existence of CFS as a valid diagnosis, we are left with the indisputable fact that many young and previously productive people are disabled by a condition that causes them to be absent from the work force

Orthostatic Intolerance: A Definition of the Problem

Assuming an upright posture causes translocation of approximately 800 ml of blood from the intrathoracic venous compartment to veins of the buttocks, pelvis and legs. The normal compensatory cardiovascular response to this orthostatic stress is a neurogenically mediated increase in heart rate and in systemic vascular resistance. Not all vascular beds contribute equally to the reflex increase in vascular resistance." Splanchnic vasoconstriction accounts for one third of the increased vascular resistance during normal levels of orthostatic stress. Skin and muscle vasoconstriction accounts for approximately 40% of the increased vascular resistance during normal levels of orthostatic stress and for an even higher percentage of the total during very high levels of orthostatic stress. The fact that syncope occurs if these compensatory reflexes are overwhelmed is well known. Most also know that symptoms of orthostatic intolerance develop as these reflexes approach the limit of compensation. Fewer appreciate the existence of a significant patient cohort that chronically or frequently have these symptoms to stressors that have minimal or no effect on asymptomatic subjects. 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

The true prevalence of orthostatic intolerance is unknown; even rudimentary estimates are hard to obtain. These patients complaints are often dismissed because of the nonspecific nature of the symptoms reported. Other patients with orthostatic intolerance are incorrectly diagnosed as having panic disorder or chronic anxiety. Moreover, the clinical examination alone is often unrevealing because patients with orthostatic intolerance do not have florid autonomic failure or orthostatic hypotension. The recognition of the problem is further complicated by the fact that mild and transient orthostatic intolerance may be observed in normally asymptomatic subjects during mild hypovolemia, after prolonged bedrest, and in some women during certain phases of the menstrual cycle.
Orthostatic Intolerance in CFS

In 1987, Streeten noted symptoms of weakness and fatigue in about one third of patients with or-thostatic intolerance. Moreover, severe fatigue was the most prominent symptom observed in seven patients who exhibited a delayed (after 10-30 minutes) fall in blood pressure while standing. The pivotal report of Rowe et al has brought to the fore the question of the relationship between orthostatic intolerance and CFS. In this initial report, all seven adolescent patients tested with a protocol of head-up tilt during intravenous infusion of the adrenergic agonist isoproteronol developed clinically important hypotension and presyncope or syncope. Four of these patients had apparent improvement of symptoms when treated with atenolol or disopyramide. This reported therapeutic success has attracted the attention of the many patients with CFS who, to date, have not had effective medical treatment of their condition.

Delineation of the relationship between CFS and orthostatic intolerance is important for several reasons. First, many of the primary symptoms of ortho-static intolerance are often seen in patients with disabling CFS. It is conceivable that patients with primary disorders of orthostatic tolerance may be mislabeled as having CFS. Alternatively, those with orthostatic intolerance may constitute one well-defined subgroup of CFS. Second, insights derived from the pathogenesis of orthostatic intolerance may provide valuable insights into CFS. Third, strategies that are effective in the treatment of orthostatic intolerance may prove effective in the treatment of CFS. Lastly, objective documentation of orthostatic intolerance may aid patients with CFS who are attempting to prove that they are aflicted with a valid medical illness. This review will attempt to address critically the following questions: Is there a relationship between orthostatic intolerance andg CFS? If so, can it be recognized clinically? What type of laboratory evaluation should be carried out? Who should be evaluated? And, finally, is the condition amenable to therapy? Are Patients with Orthostatic Intolerance Clinically Recognizable( They are recognizable if appropriate attention is paid to history and physical examination. Certain features of CFS bear strong resemblance to those of the postural tachycardia syndrome (POTS). More often than not, there is a history of subacute onset of symptoms, often preceded by a viral prodrome. Women seem to be disproportionately affected (almost 4:1). The age of presentation of POTS is similar to CFS (between 15 and 50 years). Most patients have had symptoms for about 1 year when first evaluated; these symptoms may persist for several years. The symptoms that are most helpful include exacerbation of primary symptoms (fatigue, lightheadedness, or diminished during upright posture, heat stress, or after exercise. Some may also complain of urinary frequency, diarrhea or constipation, or early satiety. We consider the abrupt onset of symptoms to be an important clinical feature. We have occasionally seen patients with a history of mild orthostatic intolerance&ldquo that clearly preceded the onset of CFS. This mild orthostatic intolerance may be found in many normal healthy individuals. Interestingly, these patients may report that tilt-table testing mimicked their symptoms of occasional lightheadedness but not the primary symptoms of CFS. The signs that are most helpful include the presence of livedo reticularis or acral vasoconstriction, collapse of pulse pressure during rapid standing, and exaggerated postural tachycardia or large swings in heart rate or pulse pressure during stand. It is important to realize that patients often have good or bad periods of several days duration; hence, clinical signs may fluctuate. If an appropriate history is obtained but signs are lacking, we suggest that the patient be reevaluated clinically.

What Is the Prevalence of Orthostatic Intolerance in CFS? There are few data concerning the prevalence of orthostatic intolerance in CFS; all data obtained suffer from the limitation of referral bias of academic centers. Data from the group at Johns Hopkins suggest that virtually all subjects (22 of 23) with CFS have many of their primary symptoms reproduced during head-up tilt. In contrast, others who attempted to specifically recruit subjects with CFS who reported symptoms of orthostatic intolerance found that only 25% (4 of 16) of patients had syncope or presyncope during head-up tilt. In another study, 40% (30 of 75) of unselected patients with CFS had clinical and laboratory evidence of orthostatic intolerance. Another study suggested that 28% (22/78) of patients had abnormal responses to head-up
Laboratory Evaluation of Orthostatic Intolerance in CFS The Controversy. The methodology of the laboratory evaluation of patients with CFS goes to the heart of the definition of orthostatic intolerance. In its strictest definition, orthostatic intolerance reflects the inability to maintain consciousness in the upright position. Those who define orthostatic intolerance as the inability to maintain postural normo-tension in the face of a normal gravitational stress test patients with 40-60 minutes of head-up tilt alone. If syncope does not result and an appropriate hemodynamic response is observed, then the patient cannot be deemed to be orthostatically intolerant. This physiological approach is the one that we advocate. All of the studies that report abnormal response in the range of 25-40% have used this approach.The Johns Hopkins group suggest that head-up tilt be combined with isoproteronol. This necessitates a quasi-fasting state and insertion of an intravenous catheter during testing. A standard head-up tilt is performed; if negative, it is repeated during isoproteronol infusion. The use of isoproteronol as a provocative agent for inducing syncope is well-established. The rationale for its use stems from the view that neurally mediated syncope is triggered reflexively by input from unmyelinated vagal cardiac ventricular afferents and is activated by maneuvers that impair cardiac filling or that increase cardiac contractility.This hypothesis has been seriously questioned by many investigators. Moreover, isoproteronol and invasive instrumentation have the added disadvantage of provoking syncope in many healthy young subjects and in provoking panic attacks in those prone to anxiety. The limitations of isoproteronol may perhaps be overlooked, given the need to diagnose the cause(s) of unexplained syncope.&ldquo In our opinion, the use of isoproteronol is less defensible if it is required to demonstrate orthostatic intolerance. Lastly, although we assume that the chronic symptoms of orthostatic intolerance are the equivalent of those of impending syncope (fatigue, malaise), there is no evidence that mechanisms that trigger syncope are continuously operant in the production of the symptoms of orthostatic intolerance.

Laboratory Evaluation of Orthostatic Intolerance in CFS?

What Is an Abnormal Response? Widespread severe autonomic failure has not been observed in CFS. Although neurally mediated syncope may be observed in normal subjects during head-up tilt," in our experience, many normal subjects do not experience the prolonged prodrome of malaise and lightheadedness that patients with orthostatic intolerance do. Moreover, the syncopal response to head-up tilt in those with true orthostatic intolerance is highly reproducible over time. The criteria used to diagnose postural tachycardia is a sustained heart rate increase of greater than 30 beats/minute if a short duration (5-10 minutes) head-up tilt is used. A rise of 30 beats/minute during prolonged head-up tilt has been defined as abnormal in some studies, but this value is often noted in young subjects near the end of the tilt duration. To discriminate between milder forms of orthostatic intolerance and POTS, some have suggested the criterion of a rise in heart rate to greater than 120 beats/minute in addition to an increase of 30 According to this definition, approximately 25-40% ofthe patients with CFS and orthostatic intolerance that we have tested would have POTS. Lastly, it is important to realize that many patients with CFS may be taking medications (eg, antidepressants) that treat symptoms empirically but may interfere with autonomic testing. We advocate discontinuing all such medications for at least five half-lives and, if possible, for a minimum of 1 month before testing to be able to unequivocally document orthostatic intolerance if it exists.

Pathophysiology of Orthostatic Intolerance in CFS.

The different patterns of postural tachycardia and neurally mediated syncope suggest that there is no unique abnormality underlying orthostatic intolerance and CFS. A detailed discussion of the current theories concerning the pathogenesis of POTS and neurally mediated syncope is beyond the scope of this review and the reader is referred elsewhere for discussion of these issues. As a general principle, it can be said that the exaggerated tachycardia and vasoconstriction of POTS compensates for chronic conditions that promote central hypovolemia (depleted intravascular volume, exaggerated venous pooling), whereas impaired vasoconstrictor function is often seen in neurally mediated syncope. Minor abnormalities of cardiovascular autonomic function tests have been noted in some studies but there is no evidence of widespread pandysautonomia in these patients. As noted above, the acuity of onset of symptoms in many patients is reminiscent of POTS and may suggest that CFS is in some cases an attenuated form of pandysautonomia. We are unaware of any studies that systematically test other autonomic effectors in patients with orthostatic intolerance and CFS, but data of this kind would be very useful in determining whether some of these patients have an attenuated form of generalized dysautonomia.

Is the reduced orthostatic tolerance of some patients with CFS simply the result of cardiovascular deconditioning? The two models of cardiovascular deconditioning for which data are available are prolonged bedrest or the zero-gravity conditions of prolonged space flight. Both are associated with significant reductions in orthostatic tolerance, postural tachycardia, or syncope. The postulated patho-geneses include compensatory hypovolemia caused by the initial central translocation of intravascular volume, decreased baroreflex responsveness, and increased leg and venous compliance. None of these mechanisms is universally agreed upon; some researchers have been unable to document changes in venous compliance or capillary filtration, baroreflex responsiveness, or autonomic function seen by others. A recent report has raised the intriguing suggestion that prolonged bedrest leads to a smaller, less distensible left ventricle that operates on a more compliant portion of the Starling curve, ultimately causing a reduction in upright stroke volume and in orthostatic tolerance. Ultimately, although bedrest might provide insights into the underlying pathophysiology of decondition-ing, it is important to realize that the effect of diminished physical activity on orthostatic tolerance has not been shown to be equivalent to the effect of prolonged bedrest.Although deconditioning undoubtedly contributes to the orthostatic intolerance in CFS, in our opinion, it cannot fully account for the magnitude of the problem. Freeman et al found that deconditioning accounted for some but not all of the laboratory abnormalities commonly associated with orthostatic intolerance. Schondorf et al found that the duration of symptoms of patients with CFS and orthostatic intolerance was significantly less than that of patients with CFS without orthostatic intolerance.If chronic deconditioning is the primary contributor to orthostatic intolerance, then those with longer symptom duration would be more affected. The possibility that there is a spectrum of susceptibility to the cardiovascular effects of deconditioning can also not be ruled out at the present time. Although some have suggested that this may depend on physical factors, such as body habitus, there does not seem to be a significant difference in body habitus between those who are orthostatically intolerant and those who are not.

Treatment of Orthostatic Intolerance in CFS.

Because many patients with orthostatic intolerance are severely limited in their activities of daily life, it is obviously important to identify and test strategies that might improve orthostatic tolerance. It is reasonable to suppose that maneuvers that supplement arterial and venous adrenergic activity or that increase plasma volume would significantly improve orthostatic tolerance. Some of these modifications may occur after a program of moderate exercise.&rdquo Although patients with CFS are limited by the discomfort of an increased perception of exertion, there are some data to support the notion that an appropriately designed exercise program is beneficial.This benefit may not be related to improved orthostatic tolerance; supine exercise normalized aerobic fitness and blood volume but had no effect on orthostatic tolerance.Volume repletion by increasing sodium intake or by treatment with fludrocortisone may theoretically improve orthostatic tolerance by replenishing intra-vascular volume. The efficacy of treatment may be limited by the aldosterone escape and by a diminution in baseline sympathetic activity that is also observed even when no increase in plasma volume is observed. Those who elect to try fludrocortisone must be aware that many of the symptoms of sympathetic overactivity are enhanced by fludrocortisone and many have severe headaches as a result of treatment. The therapeutic effect of chronic administration of adrenergic analogs may also be limited by compensatory reductions in sympathetic activity and plasma volume. We suggest that any pharmacological treatment be tailored to the physiological abnormalities observed and be implemented only in conjunction with a program of gradual reconditioning. We stress patient education concerning avoidance of stressors that may exacerbate orthostatic intolerance. Physical counter-maneuvers are also employed to improve orthostatic tolerance. In our opinion, any therapeutic options should be the subject of blinded, placebocontrolled trials involving several centers with an interest in treatment of CFS and orthostatic intolerance.

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From the *Autonomic ReflexLaboratory, Dept. of Neurology, McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada and the autonomic
and Peripheral Nerve Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
This work supported by CFIDS Association of America (RS) and National Institutes
of Health Grant R01-HL5g459.
Correspondence: Ronald Schondorf Ph.D., M.D., Dept. of Neurology, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote St. Catherine,
Montreal Quebec, Canada H3T lE2 (E-mail: cxrs@musica.mcgilLca).