Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS.

Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta).

We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection.

The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.

 

Source: Maes M, Mihaylova I, Kubera M, Bosmans E. Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase inchronic fatigue syndrome. Neuro Endocrinol Lett. 2007 Aug;28(4):463-9. https://www.ncbi.nlm.nih.gov/pubmed/17693978

 

Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells

Abstract:

There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation.

We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol.

The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls.

Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.

 

Source: Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett. 2007 Aug;28(4):477-83. https://www.ncbi.nlm.nih.gov/pubmed/17693977

 

Chronic fatigue syndrome in a 15-year-old girl

Abstract:

Fatigue and lack of energy are frequent symptoms in children and adolescents. A diagnosis of chronic fatigue syndrome should be considered in children and adolescents who complain of chronic fatigue associated with other symptoms without a demonstrable physical cause. Lack of knowledge about this syndrome and late diagnosis may have a negative impact on the normal development of affected children and adolescents. Treatment should be based on a rehabilitation program with cognitive behavioral therapy and a gradual increase in activities.

 

Source: Díaz-Caneja Greciano A, Rodríguez Sosa JT, Aguilera Albesa S, Sánchez-Carpintero R, Soutullo Esperón C. Chronic fatigue syndrome in a 15-year-old girl. An Pediatr (Barc). 2007 Jul;67(1):74-7.[Article in Spanish] https://www.ncbi.nlm.nih.gov/pubmed/17663911 (Full article available in Spanish)

 

The relationship between chronic fatigue and somatization syndrome: a general population survey

Abstract:

OBJECTIVE: The objective of this study was to assess the prevalence of chronic fatigue (CF) and its association with somatization syndrome [Somatization Syndrome Index (SSI) 4/6: >/=4 somatoform symptoms in men, 6 in women] in the general population.

METHODS: A representative sample of the German population (N=2412) completed a fatigue questionnaire and a screening instrument for current somatoform symptoms (Screening for Somatoform Symptoms 7).

RESULTS: The prevalence rate of CF was 6.1% (n=147). Females were affected significantly more often as compared with males (7% vs. 5.1%). The mean number of somatoform symptoms was higher in CF cases than in control subjects without CF (11 vs. 2; P<.001). Seventy-two percent of the subjects with CF fulfilled the SSI4/6 criterion for somatization syndrome. Quality of life (EUROHIS-QOL and 8-item Short-Form Health Survey) and well-being (5-item WHO Well-Being Index) were markedly decreased in CF and SSI4/6. The results of regression analyses suggest that fatigue and somatization severity had a similar impact on quality of life.

CONCLUSIONS: The results suggest that CF is relevant in the general population. Its substantial overlap with somatization syndrome supports the hypothesis that the two syndromes are only partially different manifestations of the same underlying processes.

 

Source: Martin A, Chalder T, Rief W, Braehler E. The relationship between chronic fatigue and somatization syndrome: a general population survey. J Psychosom Res. 2007 Aug;63(2):147-56. https://www.ncbi.nlm.nih.gov/pubmed/17662751

 

Publication trends in chronic fatigue syndrome: comparisons with fibromyalgia and fatigue: 1995-2004

Abstract:

OBJECTIVE: In order to identify publishing patterns in chronic fatigue syndrome (CFS), we compared the annual number of peer review articles for CFS, fibromyalgia (FM), and non-CFS fatigue over a recent decade (1995-2004).

METHOD: Citations were drawn from Ovid/Medline, PsychInfo, and the Journal of Chronic Fatigue Syndrome for peer review articles focusing on CFS, FM, and fatigue for each year of the decade ending in 2004. Statistics included chi-square, tests for differences in proportions, and regression-based curve estimation.

RESULTS: The frequency of CFS peer review articles did not significantly change from the first half to the second half of the decade (1995-2004). By comparison, the output of both FM and fatigue articles significantly increased (P<.0001). A quadratic model (inverted U shape; P<.02) best fit the data for CFS annual publication frequency. By comparison, exponential models best fit the data for both FM (P<.0001) and fatigue (P<.0001) citations. The highest percentage of citations (15-16%) for both CFS and FM fell within the domains of diagnosis, physiopathology, and psychology. For fatigue, almost one third (31.4%) of the citations were focused on etiology, while psychology (11.5%) and physiopathology (10.4%) articles were the next most cited. Based on first-author affiliation, CFS articles were most likely to originate in the United States (37.7%), England (31.4%), and the Netherlands (4.9%).

CONCLUSION: The output of CFS peer review articles has not increased over the past decade, while the number of FM and fatigue articles has increased substantially.

 

Source: Friedberg F, Sohl S, Schmeizer B. Publication trends in chronic fatigue syndrome: comparisons with fibromyalgia and fatigue: 1995-2004. J Psychosom Res. 2007 Aug;63(2):143-6. https://www.ncbi.nlm.nih.gov/pubmed/17662750

 

A real-time assessment of the effect of exercise in chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) report substantial symptom worsening after exercise. However, the time course over which this develops has not been explored. Therefore, the objective of this study was to investigate the influence of exercise on subjective symptoms and on cognitive function in CFS patients in natural settings using a computerized ecological momentary assessment method, which allowed us to track the effects of exercise within and across days.

Subjects were 9 female patients with CFS and 9 healthy women. A watch-type computer was used to collect real-time data on physical and psychological symptoms and cognitive function for 1 week before and 2 weeks after a maximal exercise test. For each variable, we investigated temporal changes after exercise using multilevel modeling.

Following exercise, physical symptoms did get worse but not until a five-day delay in CFS patients. Despite this, there was no difference in the temporal pattern of changes in psychological symptoms or in cognitive function after exercise between CFS patients and controls. In conclusion, physical symptoms worsened after several days delay in patients with CFS following exercise while psychological symptoms or cognitive function did not change after exercise.

 

Source: Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH. A real-time assessment of the effect of exercise in chronic fatigue syndrome. Physiol Behav. 2007 Dec 5;92(5):963-8. Epub 2007 Jul 25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170105/ (Full article)

 

Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse

Abstract:

The cranial rhythmic impulse is a palpable, rhythmic fluctuation believed to be synchronous with the primary respiratory mechanism. The precise physiologic mechanism of the cranial rhythmic impulse is not fully understood. Based on traditional and current views of the cranial rhythmic impulse, animal studies, and clinical findings in patients with chronic fatigue syndrome, the author argues that the cranial rhythmic impulse is the rhythm produced by a combination of cerebrospinal fluid drainage from the neuraxis (brain and spinal cord) and pulsations of central lymphatic drainage induced by the sympathetic nervous system. In addition, evidence is provided to demonstrate that a disturbed, palpable, and visible neurolymphatic process leads to chronic fatigue syndrome. This process may also explain the pathophysiologic mechanisms leading to other disease states. Finally, the author’s proposed manual treatment protocol for patients with chronic fatigue syndrome is described.

 

Source: Perrin RN. Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse. J Am Osteopath Assoc. 2007 Jun;107(6):218-24. https://www.ncbi.nlm.nih.gov/pubmed/17635902

 

Symptoms of autonomic dysfunction in chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is common and its cause is unknown.

AIM: To study the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria.

DESIGN: Cross-sectional study with independent derivation and validation phases.

METHODS: Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis.

RESULTS: Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86-0.99) and a negative predictive value of 0.84 (0.70-0.93) for the diagnosis of CFS.

DISCUSSION: Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a ‘cross-cutting’ aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.

 

Source: Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM. 2007 Aug;100(8):519-26. Epub 2007 Jul 7. http://qjmed.oxfordjournals.org/content/100/8/519.long (Full article)

 

Abnormal thermoregulatory responses in adolescents with chronic fatigue syndrome: relation to clinical symptoms

Abstract:

OBJECTIVES: Chronic fatigue syndrome is a common and disabling disease of unknown etiology. Accumulating evidence indicates dysfunction of the autonomic nervous system. To further explore the pathophysiology of chronic fatigue syndrome, we investigated thermoregulatory responses dependent on catecholaminergic effector systems in adolescent patients with chronic fatigue syndrome.

PATIENTS AND METHODS: A consecutive sample of 15 patients with chronic fatigue syndrome aged 12 to 18 years and a volunteer sample of 57 healthy control subjects of equal gender and age distribution were included. Plasma catecholamines and metanephrines were measured before and after strong cooling of 1 hand. Acral skin blood flow, tympanic temperature, heart rate, and mean blood pressure were measured during moderate cooling of 1 hand. In addition, clinical symptoms indicative of thermoregulatory disturbances were recorded.

RESULTS: Patients with chronic fatigue syndrome reported significantly more shivering, sweating, sudden change of skin color, and feeling unusually warm. At baseline, patients with chronic fatigue syndrome had higher levels of norepinephrine, heart rate, epinephrine, and tympanic temperature than control subjects. During cooling of 1 hand, acral skin blood flow was less reduced, vasoconstrictor events occurred at lower temperatures, and tympanic temperature decreased more in patients with chronic fatigue syndrome compared with control subjects. Catecholamines increased and metanephrines decreased similarly in the 2 groups.

CONCLUSIONS: Adolescent patients with chronic fatigue syndrome have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling, supporting a hypothesis of sympathetic dysfunction and possibly explaining important clinical symptoms.

 

Source: Wyller VB, Godang K, Mørkrid L, Saul JP, Thaulow E, Walløe L. Abnormal thermoregulatory responses in adolescents with chronic fatigue syndrome: relation to clinical symptoms. Pediatrics. 2007 Jul;120(1):e129-37. https://www.ncbi.nlm.nih.gov/pubmed/17606539

 

A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset

Abstract:

Variable reports of neuropsychological deficits in individuals with chronic fatigue syndrome (CFS) may, in part, be attributable to methodological limitations. In this study, these limitations were addressed by controlling for genetic and environmental influences and by assessing the effects of comorbid depression and mode of illness onset. Specifically, the researchers conducted a co-twin control study of 22 pairs of monozygotic twins, in which 1 twin met strict criteria for CFS and the co-twin was healthy.

Twins underwent a structured psychiatric interview and comprehensive neuropsychological assessment evaluating 6 cognitive domains. Results indicated that twin groups had similar intellectual and visual memory functioning, but fatigued twins exhibited decreases in motor functions (p = .05), speed of information processing (p = .02), verbal memory (p = .02), and executive functioning (p = .01). Major depression did not affect neuropsychological functioning among fatigued twins, although twins with sudden illness onset demonstrated slowed information processing compared with those with gradual onset (p = .01).

Sudden onset CFS was associated with reduced speed of information processing. If confirmed, these findings suggest the need to distinguish illness onset in future CFS studies and may have implications for treatment, cognitive rehabilitation, and disability determination.

 

Source: Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset. Neuropsychology. 2007 Jul;21(4):507-13. https://www.ncbi.nlm.nih.gov/pubmed/17605583