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Response to Guidelines for the Treatment of CFS Revised Draft 2001
Peter C. Rowe, MD

Re: Revised Chronic Fatigue Syndrome Guidelines

To Whom It May Concern:

I have had an opportunity to review the revised Australian CFS guidelines. I am disappointed by the complete failure to integrate the scientific evidence regarding circulatory abnormalities in CFS. In a detailed letter on the draft guidelines written to Dr. Loblay in April of 1998, I discussed ways in which the guidelines might better acknowledge the association between CFS and syndromes of orthostatic intolerance. Despite the fact that many more scientific studies have emerged on this topic in the past three years, the current revision of the guidelines contains even less on orthostatic intolerance. As Wessely and colleagues emphasized in a JAMA article in 1998, the failure to integrate literature from many sources perpetuates pre-existing disciplinary biases in reviews on CFS, and an analogous failure to discuss a large literature on orthostatic intolerance in CFS affects the revised guidelines.

A variety of disorders of orthostatic intolerance, most notably postural tachycardia syndrome and neurally mediated hypotension, are characterized by symptoms similar to those seen in CFS. The symptoms in common include chronic fatigue, difficulty thinking and concentrating, headaches, myalgias and chest wall pain, nausea, palpitations, and anxiety. In Jacobžs recent study of postural tachycardia syndrome, chronic fatigue was reported by 67%. Even if one is not enthusiastic about the overall contribution of orthostatic tachycardia and hypotension to the pathophysiology of symptoms in CFS, some mention of these disorders surely belongs in any section describing the differential diagnosis of chronic fatigue.

The evidence for an association between CFS and orthostatic intolerance is strongest in adolescents (constituting Level 1 evidence), but there is no mention of this association in the draft guidelines. In the 9 controlled studies published thus far, 7 have identified a higher prevalence of orthostatic intolerance in CFS patients than in healthy controls. In our recently published randomized trial of fludrocortisone, fully 66% of 171 study subjects with CFS who were screened with a 2-stage upright tilt table test developed neurally mediated hypotension, postural tachycardia syndrome, or both. Even if one accounts for some bias in patient decisions to enroll in this study, orthostatic intolerance is recognized frequently in those with CFS, and I believe it warrants at least some mention in the guidelines.

For patients with recurrent syncope due to neurally mediated hypotension, at least four randomized controlled trials have demonstrated efficacy of medications for reducing symptoms and improving quality of life (midodrine, paroxetine, atenolol, and enalapril). For those with postural tachycardia syndrome, a number of physiological studies and case series have suggested avenues of treatment that might prove beneficial, although I am aware of no randomized trials on this disorder.

The revised draft has recommended "active approaches to the control of key symptoms," focussing primarily on analgesics and antidepressants, as a means of improving daily function. It would be consistent with this approach to expand this list of symptomatic treatments to include methods of treating orthostatic symptoms, provided the latter are sufficiently distressing. Treatments for orthostatic symptoms might include non-pharmacologic methods like pressure garments, postural maneuvers, and an increased intake of water and sodium, as well as carefully selected pharmacologic therapies.

Although the optimal treatment of recurrent neurally mediated syncope or postural tachycardia is the subject of debate, few physicians would withhold therapy from those with serious orthostatic symptoms, even if that therapy only involved adding sodium to the diet and recommending support hose. I donžt think the guidelines should ignore treatment of persistent orthostatic symptoms in those with CFS any more than they should ignore the treatment of sleep disorders or panic attacks. There may, in fact, be better evidence for the treatment of orthostatic dysfunction in CFS than there is for treatment of the sleep disorders.

The following suggestions for inclusion in the draft guidelines (modified slightly from my April 1998 letter to Dr. Loblay) may be useful for the revised draft as part of a general approach to the evaluation and treatment of CFS:

Fatigue is a cardinal feature of a number of overlapping syndromes of orthostatic intolerance, including orthostatic hypotension, postural tachycardia syndrome, idiopathic hypovolemia, and neurally mediated hypotension. Other symptoms of orthostatic intolerance include chronic or severe lightheadedness with upright posture, exercise intolerance, recurrent syncope, and palpitations or excessive tachycardia with standing.

In those with substantial worsening of symptoms during quiet upright posture, orthostatic hypotension can be excluded with a 3 minute standing test. Prolonged orthostatic testing to exclude postural tachycardia syndrome or neurally mediated (vaso-vagal) hypotension may be appropriate in those whose symptoms are aggravated by several minutes of quiet upright posture.

In those with postural tachycardia syndrome or neurally mediated hypotension, use of pressure garments, postural maneuvers, increased fluid and sodium intake, and specific medications may provide benefit.

Pharmacologic and non-pharmacologic treatments (including postural maneuvers) may provide symptomatic relief of orthostatic symptoms in people with CFS (Level IV).

I have included a partial bibliography of the more pertinent studies in this area. In closing, I feel the debate about the optimal treatment for patients with CFS is not advanced by ignoring a substantial body of the current evidence. Guidelines that do not even acknowledge the research findings in this area will risk being dismissed as hopelessly biased.

Sincerely,

Peter C. Rowe, MD

Correspondence:
Peter C. Rowe, MD
Professor of Pediatrics
Brady 212 Johns Hopkins Hospital
600 N. Wolfe St.
Baltimore, MD 21287
e-mail: prowe@jhmi.edu

Postural tachycardia and chronic orthostatic intolerance:

  1. MacLean AR, Allen EV. Orthostatic hypotension and orthostatic tachycardia: treatment with the "head-up" bed. JAMA 1940;115:2162-7.
  2. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia? Neurology 1993;43:132-7.
  3. Grubb BP, Kosinski DJ, Boehm K, Kip K. Postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing. PACE 1997;20:2205-12.
  4. Jacob G, Shannon JR, Black B, Biaggoni I, Mosqueda-Garcia R, Robertson RM, Robertson D. Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. Circulation 1997;96:575-80.
  5. Furlan R, Jacob G, Snell M, Robertson D, Porta A, Harris P, Mosqueda-Garcia R. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation 1998;98:2154-9.
  6. Tanaka H, Yamaguchi H, Matushima R, Tamai H. Instantaneous orthostatic hypotension in children and adolescents: a new entity of orthostatic intolerance. Pediatr Res 1999;46:691-6.
  7. Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural tachycardia syndrome. N Engl J Med 2000;343:1008-14.

Orthostatic intolerance and CFS:

  1. Streeten DHP, Anderson GH. Delayed orthostatic intolerance. Arch Int Med 1992;152:1066-72.
  2. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue? Lancet 1995;345:623-4.
  3. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. Relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-7.
  4. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997;102:357-64.
  5. De Lorenzo F, Hargreaves J, Kakkar VV. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Autonom Res 1997;7:185-90.
  6. Yacato A, Talo H, Rowe P, Kass DAA, Berger RD, Calkins H. Comparison of heart rate variability in patients with chronic fatigue syndrome and controls. Clin Autonom Res1997;7:293-7.
  7. Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome. Clin Autonom Res 1998;8:221-30.
  8. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv System 1999;75:192-201.
  9. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics 1999;103:116-21.
  10. LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, Natelson BH. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol 1999;19:111-20.
  11. Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatr 1999;135:218-25.
  12. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci 2000;320:1-8.

Treatment of orthostatic intolerance:

  1. Rosen SG, Cryer PE. Postural tachycardia syndrome: Reversal of sympathetic hyperresponsiveness and clinical improvement during sodium loading. Am J Med 1982;72:847-50.
  2. Tanaka H, Yamaguchi H, Tamai H. Treatment of orthostatic intolerance with inflatable abdominal band. Lancet 1997;349:175.
  3. Weiling W, van Lieshout JJ, van Leeuwen AM. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clin Autonom Res 1993;3:57-65.
  4. Hickler RB, Thompson GR, Fox LM, Hamlin JT III. Successful treatment of orthostatic hypotension with 9-alpha fluorohydrocortisone. N Engl J Med 1959;1959;261:788-91.
  5. Scott WA, Pongiglione G, Bromberg BI, et al. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol 1995;76:400-2.
  6. Mahanonda N, Bhuripanyo K, Kangakagate C, Wansanit K, Kulchot B, Nademanee K, Chaithiraphan S. Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J 1995;130:1250-3.
  7. Zeng C, Zhu Z, Liu G, Hu W, Wang X, Yang C, et al. Randomized, double-blind, placebo-controlled trial of oral enalapril in patients with neurally mediated syncope. Am Heart J 1998;136:852-8.
  8. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998;79:45-9.
  9. Di Girolamo E, De Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, for refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33:1227-30.
  10. Jankovic J, Gilden J, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Terazi FM. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993;95:38-48.
  11. Low PA, Gilden JL, Freeman R, Sheng K, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study. JAMA 1997;277:1046-51.

Treatment of orthostatic intolerance in CFS

References 7, 8, 9, and 18, above, and:

  1. Peterson PK, Pheley A, Schroeppel J, et al. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Int Med 1998;158:908-14.
  2. Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini BA, Soto N, Hohman P, Snader S, Lucas KE, Wolff M, Straus SE. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome. JAMA 2001;285:52-59

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