Category: Biomarker

Gait abnormalities in chronic fatigue syndrome

Abstract:

To evaluate our clinical impression that patients with the chronic fatigue syndrome (CFS) did not walk normally, we assessed gait kinematics at slow walking speeds (i.e., 0.45, 0.89 and 1.34 m/sec) and 30 m run time speeds on CFS patients and on a comparison group of sedentary controls.

Run time was significantly slower for CFS than control subjects (p < 0.001). There was a significant interaction (p < 0.01) between group and speed for maximum hip angle during stance and swing phase with hip angle being significantly larger at 1.34 m/sec for CFS than controls subjects for both cases (p < 0.05). Knee flexion during stance and swing phases was significantly larger for controls than CFS subjects at 0.45 m/sec (p < 0.01). Ratio of stride length divided by leg length was significantly larger for the control subjects than for the CFS subjects with differences occurring at 0.45 and 0.89 m/sec (p < 0.01) but not 1.34 m/sec.

The data indicate that CFS patients have gait abnormalities when compared to sedentary controls. These could be due to balance problems, muscle weakness, or central nervous system dysfunction; deciding which will require further research. Evaluation of gait may be a useful tool to measure outcome following therapeutic interventions.

 

Source: Boda WL, Natelson BH, Sisto SA, Tapp WN. Gait abnormalities in chronic fatigue syndrome. J Neurol Sci. 1995 Aug;131(2):156-61. http://www.ncbi.nlm.nih.gov/pubmed/7595641

 

Sympathetic overactivity in subjects complaining of unexplained fatigue

Abstract:

Theoretical and practical considerations suggest that in subjects complaining of fatigue, in the absence of evident organ dysfunction, an alteration in the autonomic nervous system might be present as a functional correlate.

Autoregressive spectral analysis of R-R interval variability from a surface ECG, was used in healthy control subjects (n = 24, age 45 +/- 4 years) and in subjects complaining of unexplained fatigue (n = 53, age 46 +/- 9 years) to obtain quantitative indices of the state of the sympathovagal balance, both at rest and during a mental stimulus (mental arithmetic), capable of enhancing sympathetic drive. Sympathetic and vagal modulations were inferred from the normalized powers of the low frequency and high frequency spectral components respectively.

We observed in patients, at rest, a prevailing low frequency component of R-R variability (patients low frequency = 73 +/- 11, control subjects 51 +/- 10 normalized units, P < 0.05). The responsiveness to mental arithmetic was reduced in patients as compared with controls. Systolic blood pressure variability did not differ. This suggested a selective imbalance in autonomic control of the sinoatrial node, characterized by sympathetic predominance as well as by vagal withdrawal, at rest.

The possibility of discriminating patients from control subjects on the basis of simple non-invasive functional markers might provide a better understanding of the mechanisms, clinical evolution and outcome of conditions such as the chronic fatigue syndrome, which lack ordinary evidence of disease, but comprise, as physiopathological correlate, a quantitative alteration of autonomic control.

 

Source: Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A. Sympathetic overactivity in subjects complaining of unexplained fatigue. Clin Sci (Lond). 1994 Dec;87(6):655-61. http://www.ncbi.nlm.nih.gov/pubmed/7874856

 

Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome

Abstract:

Levels of 2′,5′-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls.

Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6).

Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

 

Source: Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Müller WE, Schröder HC, Carter WA, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S96-104. http://www.ncbi.nlm.nih.gov/pubmed/8148461

 

Validation of biologic markers for use in research on chronic fatigue syndrome

Abstract:

Unresolved aspects of chronic fatigue syndrome can be addressed by research involving biologic markers. These may be any molecular, biochemical, physiological, or other biologic parameter obtainable from biologic specimens. The use of biologic markers in research requires their validation as dependent or independent variables. Additionally, other characteristics of markers such as reliability of assays, background level, confounding factors, interpretations, and legal and ethical implications should be considered before the use of markers in research. A checklist is provided for evaluating a biologic marker before its inclusion in research.

 

Source: Schulte PA. Validation of biologic markers for use in research on chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S87-9. http://www.ncbi.nlm.nih.gov/pubmed/2020808

 

Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen

Abstract:

Antibody to Epstein-Barr virus (EBV) early antigen has been said to be the most specific indicator of symptomatic chronic EBV infection. We studied the clinical utility of this serologic test in the evaluation of patients with chronic fatigue.

Thirty patients with chronic fatigue and highly elevated titers of antibody to early antigen (greater than or equal to 1:160) were compared with 30 age- and sex-matched controls with no antibody to early antigen.

There were no significant differences noted between patients and controls at the initial evaluation (symptoms, physical examination, laboratory data). Follow-up information, available for 15 matched pairs, showed no differences in outcome between patients and controls. We conclude that the antibody to EBV early antigen is not helpful in the clinical evaluation of patients with chronic fatigue.

 

Source: Hellinger WC1, Smith TF, Van Scoy RE, Spitzer PG, Forgacs P, Edson RS. Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen. JAMA. 1988 Aug 19;260(7):971-3. http://www.ncbi.nlm.nih.gov/pubmed/2840523

 

Immune Markers in Cerebrospinal Fluid Provide Insights Into the Basis for Symptoms Like “Brain Fog”

Press Release: Mailman School of Public Health, March 30, 2015. Scientists at Columbia University’s Mailman School of Public Health have identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction—frequently described by patients as “brain fog”—as well as new hope for improvements in diagnosis and treatment.

In the study published in Molecular Psychiatry, Mady Hornig, MD, and colleagues used immunoassay testing methods to measure levels of 51 immune biomarkers called cytokines in the cerebrospinal fluid of 32 people with ME/CFS for an average of seven years, 40 with multiple sclerosis, and 19 non-diseased controls. The researchers found that levels of most cytokines, including the inflammatory immune molecule interleukin 1, were depressed in individuals with ME/CFS compared with the other two groups, matching what was seen in a blood study in patients who had the disease for more than three years. One cytokine—eotaxin—was elevated in the ME/CFS and MS groups, but not in the control group.

“We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system,” says Dr. Hornig, professor of Epidemiology and director of translational research at the Center for Infection and Immunity at the Mailman School. “These immune differences may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.”

Implications for Diagnosis and Treatment

“Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease,” adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity.

There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.

The study was supported by a grant from the Chronic Fatigue Initiative of the Hutchins Family Foundation and the Edward P. Evans Foundation.

Additional authors include Andrew F. Schultz, Meredith L. Eddy and Xiaoyu Che at the Mailman School; C. Gunnar Gottschalk and Daniel L. Peterson at Sierra Internal Medicine in Incline Village, NV; and Konstance K. Knox at Coppe Health Care Solutions in Waukesha, WI, and Simmaron Research in Incline Village, NV.

Journal Reference: M Hornig, G Gottschalk, D L Peterson, K K Knox, A F Schultz, M L Eddy, X Che, W I Lipkin. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Molecular Psychiatry, 2015; DOI: 10.1038/mp.2015.29