105 Morris Avenue, Suite 200,Springfield, NJ  07081 Tel:  973-218-9191

FIBROMYALGIA DISABILITY MEDICAL EVIDENCE—January 5, 2005

by Richard N. Podell, M.D., M.P.H

105 Morris Avenue

Springfield, NJ 070781

973 218-9191; www.DrPodell.org

As of 1994, an expert panel report convened by the Center for Disease Control provided these opinions (1):

The chronic fatigue syndrome is a clinically defined condition characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairments in concentration and short-term memory, sleep disturbances, and musculoskeletal pain

Diagnosis of the chronic fatigue syndrome can be made only after alternate medical and psychiatric causes of chronic fatiguing illness have been excluded. No pathognomonic signs or diagnostic tests for this condition have been validated in scientific studies; moreover, no definitive treatments exist for the chronic fatigue syndrome.

Recent longitudinal studies suggest that some persons affected by the chronic fatigue syndrome improve with time but that most remain functionally impaired for several years

…The central issue in chronic fatigue syndrome research is whether the chronic fatigue syndrome or any subset of it is a pathologically discrete entity, as opposed to a debilitating but nonspecific condition shared by many different entities. Resolution of this issue depends on whether clinical, epidemiologic, and pathophysiologic features convincingly distinguish the chronic fatigue syndrome from other illnesses. 

Now, fast forward to early 2005. Fair progress has been made, and Chronic Fatigue Syndrome’s Existence as an Important Physical Ailment Is No Longer In Reeal Dispute.

 Physicians who specialize in chronic fatigue syndrome, are now generally in agreement on these as scientific facts:

1. CFS is a real and a primarily physical illness. In principle, CFS is distinguishable from psychological and other physical illnesses. 

2. Misclassification can occur i.e. where fatigue caused by psychological problems is incorrectly attributed to CFS ; where fatigue due to CFS is incorrectly attributed to psychological illness. A sophisticated medical judgment may be required to judge the relative importance of  physical versus psychological factors. 

Non-specialist physicians typically accept the above conclusions. However, some remain skeptical about the validity of  CFS.  

As of early 2005 recent scientific evidence has strengthened the case for CFS’ being a valid, physical illness. This is also true for fibromyalgia (FMS), a condition that overlaps CFS in many respects. Examples of this evidence for CFS:

Immune Dysfunction: Many studies demonstrate a higher incidence of immunological dysfunction in CFS patients. These include increased activity of 

T lymphocytes and circulating cytokines; poor cellular immune response as shown by low natural killer (NK) cell cytotoxicity and impaired T lymphocyte responses to various mitogens; and abnormalities in the 2-5A synthetase/RNAse L pathway, which is part of the cell’s  antiviral defenses. (2)

Endocrine Dysfunction: CFS patients differ from controls in several hormonal       parameters. (3,4)

However, with regard to immune, hormonal and other laboratory tests there is substantial overlap between CFS and controls. Therefore, for any individual patient, no laboratory test, by itself, provides a firm basis for establishing the diagnosis of CFS or for excluding CFS as the diagnosis.

Reliability of patient’s self-reports: Several research studies support the reliability and long term consistency of CFS patients’ subjective reports of feeling tired, maintaining reduced activity and not being able to work. (5-6). The degree of symptoms and functional limitation reported are of the same order as those reported by persons with multiple sclerosis or with rheumatoid arthritis.

Thus, Hill found that only 4% of a subset of severely ill CFS recovered from their illness over a four year follow-up period.  Some patients showed modest improvement, but the majority did not improve at all. (7,8)

Hill wrote: Overall, the prognosis for CFS appears to be poor, as the majority of participants remained functionally impaired over time and were unemployed at follow-up…(8)

Delayed Post-exertional Flare-up: Of special importance with regard to disability is the frequent report by CFS patients that they worsen after exertion. Such flare-ups typically occurs with a delay of hours to days. The increase in symptoms and reduced activity may last for hours or for days.  Recent studies tend to substantiate these claims. (9,10)

Current methods for assessing disability, such as the FCE, typically fail to address the “delayed flare-up” phenomenon. Improved methods are needed.

Objective Confirmation of Fibromyalgia-type Pain:  Many, perhaps most persons with severe CFS also suffer from diffuse chronic pain that usually qualifies for the diagnosis of fibromyalgia. 

 Controlled studies using functional MRI, cerebral evoked potentials and other objective markers document fibromyaglia as a disorder of the central nervous system’s pain signaling pathways. There is increased sensitivity to and augmentation of the painful aspects of stimuli.   Put simply, the volume knob for the neural pain system is turned up to “very high”, amplifying and distorting the patient’s perception of pain. This is called “neural sensitization”.

 Recent research objectively confirms that fibromyalgia patients actually feel the increased pain they report, and that abnormal neural sensitization plays a central role. Thus, the “end organ damage” of  fibromyalgia affects and occurs within  the nervous system, particularly in the central nervous system’s  spinal and brain pain signaling pathways. (See appendix on fibromyalgia, below.)

Fewer functional brain imaging studies have been done for CFS than for fibromyalgia. However, preliminary evidence suggests there may be analogous damage in the nervous system’s fatigue signaling pathways. 

Thus, Siemionow and colleagues had CFS patients and healthy controls perform isometric hand grip contractions at 50% of maximal force while recording 58 channels of brain EEG through the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related cortical potential (MRCP) was calculated by averaging the EEG signals associated with the muscle contractions.

Sieminonow found that  (i) Motor performance of the CFS patients was poorer than for controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performance was significantly greater in the CFS than control group (P < 0.05), (iii) The amplitude of MRCP  potential  for the task was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the MRCP was greater in the CFS patients when performing a more difficult task (hands contracting every 5 seconds) compared to the MRCP during a less difficult task (contracting every 10 seconds). In contrast, showed no difference in MRCP between the more and less difficult task.

The authors’ conclusion:  These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. (11)

Schillings, asked 14 women with CFS and 14 healthy controls to maximally contract their biceps brachii muscle for two minutes. He also stimulated the muscle electrically to determine the degree to which additional contraction force could be generated beyond that of the subjects’ “maximum voluntary contraction”. After 45 seconds of contracting, the difference between the voluntary contraction force and the electrically stimulated maximum force was much greater for the 14  CFS patients compared to the 14 control patients.  For CFS patients the electrical stimulus increased contraction force by an average of 36.5% greater. For controls the average increase force induced by the electrical stimulation was only 12.9%.

            The authors believe  that the CFS patients studied were not malingering or voluntarily decreasing effort. They suggest, but have not definitively proved, that neuro-physiological factors account for the difference, potentially changed corticospinal excitability, or changed concentrations of CNS neurotransmitters. (13)

            Cardiovascular/Autonomic Abnormalities: A substantial subset of CFS patients have cardiovascular autonomic dysregulation mainifesting as low blood pressure on standing. This is called. Neurogenic, orthostatic or neurally mediated hypotension  (NMH). CFS patient may also have increased heart rate on standing i.e. postural orthostatic tachycardia (POTS). Abnormalities on tilt-table testing are fairly common. (14)

 Neuropsychological Testing: Testing confirms that neurologically-based cognitive dysfunction plays a prominent role in a subset of patients. The following quotations are from the abstracts of recent publications:

Servatius: CFS patients displayed impaired acquisition of the eyeblink response using a delayed-type conditioning paradigm…In the absence of sensory/motor abnormalities, impaired acquisition of the classically conditioned eyeblink response indicates an associative deficit. These data suggest organic brain dysfunction within a defined neural substrate in CFS patients. (15)

Lange: Patients with CFS but no psychological illness “Showed (on MRI) a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych (i.e. those with CFS plus psychological illness) and (also compared to) the Healthy Control groups…Cerebral changes in the CFS-NO Psych group consisted mostly of small, punctuate, subcortical white matter hyperintensities, found predominantly in the frontal lobes… This frontal lobe pathology could explain the more severe cognitive impairment previously reported in this subset of CFS patients.(16)

            An anatomical basis for frontal lobe dysfunction has been suggested in a preliminary study of MRI by Okada, who found  a reduced volume of grey matter in CFS patients’ prefrontal cortex compared to controls. (17)

 Cook, using MRI  studies showed an increased volume of the ventricular section of the brain of CFS patients compared to controls. Cook wrote:

“The results of this study provide further evidence of subtle pathophysiological changes in the brains of participants with CFS.”(18)

            Cook concluded:

These results demonstrate that the presence of brain abnormalities in CFS are significantly related to subjective reports of physical function and that CFS subjects with brain abnormalities report being more physically impaired than those patients without brain abnormalities.

DeLuca: Compared to healthy controls (HC) and a group of participants with rheumatoid arthritis (RA) the CFS-noPsych group displayed significantly reduced performance on tests of information processing speed, but not on tests of working memory. (19)

Busichio: On the 18 (neuropsychological) measures administered, CFS patients scored 1 standard deviation below the health mean on nine measures and scored 2 standard deviations below the health mean on four of the measures. Moreover, results indicated that CFS patients were more likely than healthy controls to fail (1.6 SD below the health mean) at least one test in each of the following domains: attention, speed of information processing and motor speed…Finally, CFS patients demonstrated a greater total number of tests failed across domains (20)

Gene Expression in CFS versus Controls: The Center for Disease control and others have reported that CFS patients express abnormal activity of multiple genes compared to controls. A large proportion of these abnormally expressed genes involve immune system defenses and inflammation. (21, 22)

References

 

1. Fukuda, K. Straus, S, Hickie, I. et al.  and the International Chronic Fatigue Syndrome Study Group,  The Chronic Fatigue Syndrome: A Comprehensive Approach to its Definition and Study, Annals of Internal Medicine 1994;121, 953-959.

2. Suhadolnik, R., Peterson D, Reichenbach, N., Clinical and Biochemical Characteristics Differentiating Chronic Fatigue Syndrome from Major Depressiona nd Health Control Populations: Relation to Dysfunction in the Rnase L Pathway,  Journal of Chronic Fatigue Syndrome, 2004;12: 5-33.

3. Papanicolaou, D Amsterdam J Levine S et al. Neuroendocrine Aspects of Chronic Fatigue Syndrome, NeuroImmunoModulation 2004;11:65-74)

4. Komaroff A, Buchwald D Chronic fatigue syndrome: an update.  Annu Rev Med. 1998;49:1-13.  

5. Ohashi K , Bleijenberg G van der Werf S et al. Decreased fractal correlation in diurnal physical activity in chronic fatigue syndrome, Methods Inf Med 2004;43:26-9

6. Cook D, Nagelkrik, P Peckerman A et al. Perceived exertion in fatiguing illness: civilians with chronic fatigue syndrome Med Sci Sports Exerc 2003;35:563-8)

7. Hill N Tiersky L Scavalla V et al. Natural history of severe chronic fatigue syndrome Arch Phys Med Rehabil 1999;80:1090-4

8. Tiersky  L, DELuca J Hill N et al. Longitudinal assessment of neuropsychological functioning, psychiatric status, functional disability and employment status in chronic fatigue syndrome, Apppl Neuropsychol 2001; 8:41-50

9.Sisto S,  Tapp W, LaManca J, Physical activity before and after exercise in women with chronic fatigue syndrome, QJM 1998;91:465-73

 
11. Siemionow V, Fang Y, Calabrese L, et al. Altered central nervous system signal during motor performance in chronic fatigue syndrome. Clin Neurophysiol. 2004 Oct;115(10):2372-81.

12. Kent-Braun J, Sharma K, Weiner M et al. Central basis of muscle fatigue in chronic fatigue syndrome, Neurology 1993;43:125-31

13. Schillings M, Kalkman S, van der Werf et.a l. Diminished central activation during maximal voluntary contration in chronic fatigue syndrome, Clinical Neurophysiology 115;2004:2518-2524.

14. Peckerman, A, LaManca J Bushra Q et al. Baroreceptor Reflex and Integrative Stres Responses in Chronic Fatigue Syndrome, Psychosomatic Medicine 65; 889-895).

15. Servatius R Tapp W Bergen M et al. Impaired associative learning in chronic fatigue syndrome Neuroreport 1998;9:1153-7:

16. Lange G, DeLuca J Maldjian J et al. Brain MRI abnormalities exist in a subset of patient with chronic fatigue syndrome, J Neurol Sci 1999;171:3-7

17. Okada, T, Tanaka, M, Kuratsune, H et al. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome, BMC Neurol 2004;4:14

18. Cook D , Lnge G Deluca J Natelson B , Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndromem Int J Neurosci 2001;107:1-6

19. DeLuca J, Christodoulou C , Diamond B et al. Working memory deficits in chronic fatigue syndrome: differentiating between speed and accuracy of information processing, J Int Neuropsychol Soc 2004;10:101-9

20. Busichio K, Tiersky L, DeLuca J Natelson B, Neuropscyological deficits in patients with chronic fatigue syndrome, J Int Neuropscyol Soc 2004;10:278-85

21. Seinau, M., Unger, E, Vernons, S, et al., Differntial-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med 2004; 82:750-5)

22. Whistler T, Unger E, Neisenbaum, R. et al. Integration of gene expression, clinical and epidemiologic data to characterize Chronic Fatigue Syndrome, J Transl Med 2003; 1:10.

See Chronic Fatigue Disability: How To Be Your Own Medical Expert Witness

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