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Spring 2003

Research Q&A
Tilt-Test Formula: A Diagnostic Marker for CFS?

Article: Naschitz JE et al. “The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome.” Q J Med. 2003; 96:133-142.

Synopsis: Researchers in Israel have tested the haemodynamic instability score (HIS), a formula that uses measurements taken during a head-up tilt test, to see if it can accurately distinguish patients with chronic fatigue syndrome (CFS) from controls.

The HIS reflects blood pressure and heart rate changes during the tilt test, which is used to determine the functioning of a patient’s autonomic nervous system. A majority of people with CFS display some degree of autonomic dysfunction.

In this prospective controlled study, the researchers examined 40 patients with CFS and compared their HIS scores to those of 278 non-CFS subjects with conditions that included fibromyalgia, syncope, generalized anxiety disorder, essential hypertension, non-CFS chronic fatigue and Familial Mediterranean Fever (FMF). Fifty-nine healthy subjects also were compared.

The results showed that the HIS was an effective tool in differentiating CFS patients from the other study participants. Specifically, 90.3 percent of the CFS patients who completed the tilt test scored above the threshold of HIS >-0.98. This compared to 21.4 percent of the non-CFS chronic fatigue group; 17.9 percent of the syncope group; 13.2 percent of the fibromyalgia group; 11.9 percent of the healthy controls; 8.0 percent of the FMF group; and 3.6 percent of the hypertension group (p<0.0001 in all comparisons). Only the anxiety group (45 percent) scored at a non-significant level.

The authors write that their results suggest a definable, CFS-characteristic autonomic dysfunction may exist. They further contend that “the presence of this distinctive dysautonomia in CFS, which is not usually observed in other fatigue syndromes, lends support to the concept that CFS is a separate entity among illnesses characterized by fatigue.”

Below is a brief question-and-answer session with the study’s lead author, Jochanan E. Naschitz, M.D., associate professor in medicine, Department of Internal Medicine,Bnai Zion Medical Center, Haifa, Israel.

Q: What are the potential benefits of your findings to both researchers and health care providers?

Dr. Naschitz: On the head-up tilt test (HUTT), a particular dysautonomia is revealed in CFS patients that differs from dysautonomia in several other disorders. This distinct abnormality can be identified by HIS >-0.98¹. To further support the prospect of defining a characteristic dysautonomia in CFS patients, an additional methodology was proposed to assess the cardiovascular reactivity during the HUTT.

Beat-to-beat measurements of the heart rate (HR) and the pulse transit time (PTT) were rendered. Ten-minute recording with the patient supine was followed by recording 600 cardiac cycles on tilt, i.e., five to 10 minutes. Data were processed by recurrence plot and fractal analysis. Fifty-two variables were calculated in each subject. On multivariate analysis, the best predictors of CFS were determined, and, based on these predictors, the ‘Fractal & Recurrence Analysis-based Score’ (FRAS) was calculated². The best cut-off differentiating CFS from a mixed control population was FRAS = +0.22. FRAS >+0.22 was associated with CFS (sensitivity 70% and specificity 88%).

The possibility of distinguishing the cardiovascular reactivity of patients with CFS, with the aid of the HIS and FRAS, from reactivity in patients with other functional somatic syndromes, such as fibromyalgia³ and neurally mediated syncope, as described above, tends to support that a CFS-characteristic dysautonomia may be operative. In summary, four cross-sectional studies^1,3-5 converge to support the existence of a distinctive disease-specific dysautonomia in CFS patients.

Therefore, we submit that the HIS and FRAS may be used, in the appropriate clinical context, to support the diagnosis of CFS, which until now, could only be subjectively inferred. A pilot study suggested that midodrine treatment, directed at the autonomic nervous system in CFS, results first in correction of dysautonomia followed by improvement of fatigue. This finding implies that dysautonomia is pivotal in the pathophysiology of CFS, at least in a large part of the patients, and that manipulating the autonomic nervous system may be effective in the treatment of CFS.

Q: How did you develop the HIS concept?

Dr. Naschitz: This question brings about nostalgia. In the late 1990s we added to the standard head-up tilt test a capnography channel to enable diagnosis of hyperven-tilation and called this method “capnography head-up tilt test” (CHUTT)^6,7. (Capnogra-phy involves measuring carbon dioxide levels in the expired breath.) The CHUTT was subsequently applied to the study of CFS patients, since dysautonomia and hyperventilation were the mechanisms supposed to be involved in the pathogenesis of CFS⁸.

On CHUTT, vasodepressor reaction, cardioinhibitory reaction, orthostatic hypotension, postural tachycardia syndrome, or hyperventilation occurred in only half of CFS patients. Increased lability of blood pressure (BP) and heart rate (HR) was perceived in all subjects on HUTT. However, there was no appropriate measure to express these findings. The following study was undertaken in order to define objective and precise parameters of hemodynamic instability on postural challenge. Our proposed method involves computation of BP and HR changes during HUTT, followed by processing of the data by novel image analysis methods. An equation was deduced to calculate the hemodynamic instability score (HIS) in the individual patient: HIS = 64.3303 + (SYST-FD.abs  x -68.0135) + (SYST-SD.cur x 111.3726) + (HR-SD.cur  x  60.4164). The best cut-off differentiating CFS from healthy was –0.98. HIS values >-0.98 were associated with CFS (sensitivity 97% specificity 96.6%). The drawback of the HIS is the prerequisite that 30 minutes of HUTT is completed. If the tilt is prematurely terminated because of a symptomatic event, as it occurs in almost one third of CFS patients, the HIS cannot be computed.

Subsequent studies validated the HIS^3,4, improved the technique⁵, shortened the duration of the tilt phase, thus practically eliminating tilt drop-outs².

Q: What comes next for you and your research team?

Dr. Naschitz: First, treatment of CFS by manipulating the autonomic nervous system. We hypothesized that midodrine treatment could benefit patients with the CFS. Ten patients with CFS and five control patients with non-CFS fatigue were studied. The patients were off medications for at least two weeks before entering the study. A dysautonomic reaction on HUTT (i.e., HIS >-0.98) was present in all CFS but not in the non-CFS control patients. With midodrine treatment, six of 10 CFS patients showed subjective and objective improvement, which was maintained during 12 months of treatment. On last HUTT the average HIS was -1.51 (range from -0.87 to -1.98). Non-CFS fatigue patients, with normal HIS at baseline, had no improvement in HIS and fatigue scores while taking midodrine⁹. Results of this pilot study spurs larger prospective studies on the principle of manipulating the autonomic nervous system to improve both dysautonomic phenomena and fatigue in CFS.

Second, separating fibromyalgia from CFS. Distinction between fibromyalgia and CFS could be possible based on their cardiovascular reactivities.

Third, developing an objective test in support of the diagnosis of FMF based on its specific cardiovascular reactivity. Finally, examination of additional groups of patients with “somatic functional syndromes” in searching for disease-specific cardiovascular reactivity patterns.

Editor’s note: The authors acknowledge limits to their present study. Fifty-six HUTT examinations were terminated because of syncope or presyncope, including nine in the CFS group.

Notes

1)         Naschitz JE et al. Hemodynamic instability in chronic fatigue syndrome: indices and diagnostic significance. Semin Arthritis Rheum. 2001;31:199-208.

2)         Naschitz JE, Sabo E, Naschitz S, Rozenbaum M, Rosner I, Musafia-Priselac R, Shaviv N, Ahdoot A, Ahdoot M, Gaitini L, Eldar S, Yeshurun D. Fractal Analysis and Recurrence Quantification Analysis of Heart Rate and Pulse Transit Time for Diagnosing Chronic Fatigue Syndrome. Clin Autonomic Res. 2002;12:264-272.

3)         Naschitz JE, et al. Cardiovascular response to upright tilt in fibromyalgia differs from that in chronic fatigue syndrome. J Rheumatol. 2001;28:1356-1360.

4)         Naschitz JE, Sabo E, Naschitz S, Rosner I, Rozenbaum M, Fields M, Isseroff H, Musafia Priselac R, Gaitini L, Eldar S, Zukerman E, Yeshurun D. Hemodynamic Instability Score in Chronic Fatigue Syndrome (CFS) and non-CFS Chronic Fatigue. Semin Arthritis Rheum. 2002;32:141-148.

5)         Naschitz JE, Rosner I, Rozenbaum M, Naschitz S, Shaviv N, Fields M, Isseroff H, Zuckerman E, Yeshurun D, Sabo E. The head-up tilt test with hemodynamic instability score in diagnosing chronic fatigue syndrome. Q J Med. 2003;96:133-142.

6)         Naschitz JE, Gaitini L, Eridzhanyan L, Keren D, Sabo E, Yeshurun D, Hardoff D, Yaffe M. The capnography tilt test for the diagnosis of hyperventilation syncope. Q J Med. 1997;90:139-145.

7)         Naschitz JE, Hardoff D, Bystritzki I, Yeshurun D, Gaitini L, Tamir A, Yaffe M. The role of the capnography head-up tilt test in the diagnosis of syncope in children and adolescents. Pediatrics. 1998:101:1-6.

8)         Naschitz JE, Rosner I, Rosenbaum M, Gaitini L, Bistritzki I, Zuckerman E, Sabo E, Yeshurun D. The capnography head-up tilt test for evaluation of chronic fatigue syndrome. Semin Arthritis Rheum. 2000;30:79-86.

9)         Naschitz JE, Rosner J, Rozenbaum M, Musafia Priselac R, Sabo E, Gaitini L, Eldar S, Zukerman E, Yeshurun D. Successful Treatment of Chronic Fatigue Syndrome with Midodrine: a Pilot Study. Clin Exp Rheumato. In press.