Category: Pathophysiology

The Chronic Fatigue Twin Registry: method of construction, composition, and zygosity assignment

Abstract:

Chronic fatigue syndrome (CFS) and the symptom of chronic fatigue are conditions of unknown etiology. The Centers for Disease Control and Prevention (CDC) define CFS as an illness characterized by > or = 6 months of disabling fatigue associated with muscle pain, pharyngitis, and alterations in mood, sleep and neurocognition. We constructed a registry of twins with chronic fatigue to facilitate research on the impact of illness, the associated medical and psychosocial factors, and the heterogeneous proposed mechanisms for these conditions.

We have recruited 204 twin pairs in which one or both members reported persistent fatigue through patient support group newsletters (60%), clinicians/researchers familiar with CFS (12%), notices placed on electronic bulletin boards for CFS (11%), twin organizations and researchers (6%), relatives and friends (3%) and other sources (8%). Complete data are available for 177 pairs (87%). Twins completed an extensive questionnaire booklet that included measures of physical and mental health, functional status, and psychosocial factors; a structured psychiatric interview was also conducted by telephone.

Twins were classified using three increasingly more stringent diagnostic criteria for chronic fatigue: 1) > or = 6 months of fatigue (115 discordant and 61 concordant pairs); 2) chronic fatigue with additional symptoms and application of the medial exclusions of the CDC CFS case definition as obtained by self-report (92 discordant and 41 concordant pairs) and; 3) chronic fatigue with additional symptoms unexplained by self-reported medical conditions and psychiatric diagnoses as determined by the structured interview (69 discordant pairs and 25 concordant pairs).

Despite the limitations of a volunteer registry, the Chronic Fatigue Twin Registry promises to be an important resource for research on CFS and chronic fatigue.

 

Source: Buchwald D, Herrell R, Ashton S, Belcourt M, Schmaling K, Goldberg J. The Chronic Fatigue Twin Registry: method of construction, composition, and zygosity assignment. Twin Res. 1999 Sep;2(3):203-11. http://www.ncbi.nlm.nih.gov/pubmed/10555131

 

Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study

Abstract:

No inclusive or satisfactory biomedical explanation for chronic fatigue syndrome (CFS) has as yet been forwarded. Recent research suggests that a dysregulated hypothalamic-pituitary-adrenal axis (HPA) may be contributory, and in particular that there may be diminished forward drive and adrenal under-stimulation.

In this preliminary study we wished to examine a cohort of CFS patients in whom evidence for such hypofunctioning was found. Our aim was to establish whether these patients had altered adrenal gland size.

Patients were recruited from a fatigue clinic. Those who fulfilled the Centre for Disease Control and Prevention (CDC) criteria underwent a 1 microgram adrenocorticotropin (ACTH) stimulation test, a test of adrenal gland functioning.

Eight subjects (five females, three males) with a subnormal response to this test underwent a computer tomography (CT) adrenal gland assessment. Measurements were compared with those from a group of 55 healthy subjects.

The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects indicative of significant adrenal atrophy in a group of CFS patients with abnormal endocrine parameters.

This is the first study to use imaging methods to measure adrenal gland size in CFS. It is a limitation of this study that a selected CFS sample was employed. A future larger study would optimally employ an unselected cohort of CFS patients. This study has implications not only for the elucidation of CFS pathophysiology, but also for possible therapeutic strategies.

 

Source: Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology. 1999 Oct;24(7):759-68. http://www.ncbi.nlm.nih.gov/pubmed/10451910

 

Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue

Abstract:

OBJECTIVES: To describe the orthostatic tachycardia syndrome (OTS) in adolescents, similarities to and differences from chronic fatigue syndrome (CFS), and patterns of orthostatic intolerance during head-up tilt (HUT).

STUDY DESIGN: Using electrocardiography and arterial tonometry, we investigated the heart rate and blood pressure responses during HUT in 20 adolescents with OTS compared with 25 adolescents with CFS, 13 healthy control subjects, and 20 patients with simple faint.

RESULTS: Of the control subjects, 4 of 13 experienced typical vasovagal faints with an abrupt fall in blood pressure and heart rate, and 14 of 20 patients with simple faint experienced similar HUT responses. All patients with CFS (25/25) experienced severe orthostatic symptoms with syncope in 2 of 25, early orthostatic tachycardia during HUT in 16 of 23 (13/16 hypotensive), and delayed orthostatic tachycardia in 7 of 23 (6/7 hypotensive). Acrocyanosis and edema occurred in 18 of 25. Early orthostatic tachycardia occurred in 10 of 20 patients with OTS. Of these, 9 of 10 were hypotensive, but hypotension was delayed in 4 of 9. Delayed tachycardia occurred in 10 of 20 (all hypotensive). Acrocyanosis and edema occurred in most patients with CFS, fewer patients with OTS, and in one patient with simple faint. Orthostatic symptoms were similar but more severe in patients with CFS compared with patients with OTS.

CONCLUSIONS: Symptoms and patterns of orthostatic heart rate and blood pressure change in OTS overlap strongly with those of CFS. Orthostatic intolerance in OTS may represent an attenuated form of chronic fatigue pathophysiology.

 

Source: Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatr. 1999 Aug;135(2 Pt 1):218-25. http://www.ncbi.nlm.nih.gov/pubmed/10431117

 

Hypotension: a forgotten illness?

Abstract:

Low blood pressure is a frequently encountered phenomenon in clinical practice. Few practitioners in the Western world however regard chronic low blood pressure as a genuinely pathological disease state. Evidence is emerging that chronic hypotension is associated with considerable morbidity in the community. It has recently been implicated as the causative mechanism in patients with the chronic fatigue syndrome.

Identification of low blood pressure can prove problematic, so ambulatory blood pressure monitoring may prove a more reliable method both for determining mean blood pressure levels and for identifying episodes of marked hypotension. Low blood pressure is broadly divided into two categories, chronic constitutional hypotension and hypotension associated with abnormal postural control. The causes are examined and the clinical presentations are discussed. An approach to investigation and diagnosis is outlined, and current options regarding treatment and management are described. The clinical spectrum of low blood pressure is wide. From young patients with vagally mediated syncope or patients with iatrogenic hypotension to elderly patients with autonomic degenerative conditions, there exists a substantial body of patients with potentially avoidable or treatable morbidity. Such a group requires more rigorous scientific investigation and a more sympathetic clinical approach.

 

Source: Owens PE, O’Brien ET. Hypotension: a forgotten illness? Blood Press Monit. 1997 Dec;2(1):3-14. http://www.ncbi.nlm.nih.gov/pubmed/10234084

 

Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome

Abstract:

Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is a disorder characterized by debilitating fatigue associated with immunological abnormalities and cognitive impairments. The recently cloned RNase L Inhibitor (RLI) gene encodes a specific protein which is believed to regulate 2-5A synthetase and RNase L activity via the formation of a latent heterodimeric protein complex.

In the present study, we investigated the levels of 2-5A synthetase, RNase L and RLI in patients with CFIDS as compared to healthy controls. Quantitative Competitive PCR (Q/C PCR) analysis showed a statistically significant decrease in RLI mRNA present in the peripheral blood lymphocytes (PBL) of patients with CFIDS (n = 25, mean = 569, S.E = 154) as compared to RLI mRNA level present in peripheral blood lymphocytes (PBL) of healthy controls (n = 15, mean = 2296, S.E = 506; p < 0.0001).

The decrease in RLI mRNA in CFIDS individuals correlated directly with RLI and RLI: RNase L protein ratio while showing an inverse relationship to the 2-5A synthetase and RNase L activity. This RLI mRNA and protein deficiency in CFIDS patients may explain the increase in activity of RNase L found in CFIDS patients.

The unidirectional decrease in RLI message and protein levels in CFIDS individuals may contribute to the destabilization of the latent RLI:RNase L heterodimeric protein complex, resulting in the excessive activation of RNase L shown in this study.

The increased activation of RNase L may result in an increased cellular RNA turnover and subsequent inhibition of protein synthesis; thus resulting in general fatigue, myalgia muscle weakness and other symptomatologies shown in CFIDS patients.

Furthermore, this data supports the hypothesis that the antiviral 2-5 oligoadenylate synthetase (2-5OAS) overexpression in individuals with CFIDS correlates with an increase in RNase L activity and with a decrease in RNase L inhibitor.

 

Source: Vojdani A, Choppa PC, Lapp CW. Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome. J Clin Lab Immunol. 1998;50(1):1-16. http://www.ncbi.nlm.nih.gov/pubmed/10189612

 

Orthostatic intolerance in the chronic fatigue syndrome

Abstract:

This study aims to investigate the prevalence and pathophysiology of orthostatic intolerance (OI) and its potential contribution to symptoms of a group of unselected patients with chronic fatigue syndrome (CFS).

Seventy five patients (65 women, 10 men) with CFS were evaluated. During an initial visit, a clinical suspicion as to the likelihood of observing laboratory evidence of OI was assigned. Laboratory investigation consisted of beat-to-beat recordings of heart rate, blood pressure (Finapres), and stroke volume (impedance cardiograph) while supine and during 80 degrees head-up tilt (HUT), during rhythmic deep breathing (6 breaths/min) and during the Valsalva maneuver. The responses of 48 age-matched healthy controls who had no history of OI were used to define the range of normal responses to these three maneuvers.

Forty percent of patients with CFS had OI during head-up tilt. Sixteen exhibited neurally-mediated syncope alone, seven tachycardia (> 35 bpm averaged over the whole of the head-up tilt) and six a mixture of tachycardia and syncope. Eight of 48 controls exhibited neurally-mediated syncope. The responses to the Valsalva maneuver and to deep breathing were similar in controls and patients. On average, the duration of disease and patient age were significantly less and the onset of symptoms was more often subacute in patients with OI than in those without OI.

We conclude that there exists a clinically identifiable subgroup of patients with CFS and OI that differs from control subjects and from those with CFS without OI for whom treatment specifically aimed at improving orthostatic tolerance may be indicated.

 

Source: Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst. 1999 Feb 15;75(2-3):192-201. http://www.ncbi.nlm.nih.gov/pubmed/10189122

 

The importance of orthostatic intolerance in the chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis is a clinically defined syndrome characterized by persistent or relapsing debilitating fatigue for longer than 6 months in the absence of any definable medical diagnosis. The cause of this syndrome is unknown. Symptoms of orthostatic intolerance, such as disabling fatigue, dizziness, diminished concentration, tremulousness, and nausea, are often found in patients with CFS. In this review, we critically evaluate the relationship between orthostatic intolerance and CFS. Particular emphasis is placed on clinical diagnosis, laboratory testing, pathophysiology, and therapeutic management. It is hoped that this review will provide a stimulus for further study of this complex and disabling condition.

 

Source: Schondorf R, Freeman R. The importance of orthostatic intolerance in the chronic fatigue syndrome. Am J Med Sci. 1999 Feb;317(2):117-23. http://www.ncbi.nlm.nih.gov/pubmed/10037115

 

Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome

Abstract:

Mycoplasma fermentans and other Mycoplasma species are colonizers of human mucosal surfaces and may be associated with human immunodeficiency virus infection. While many infectious agents have been described in different percentages of patients with Chronic Fatigue Syndrome (CFS), little is known about the prevalence of mycoplasmas and especially M. fermentans in CFS patients.

A polymerase chain reaction (PCR)-based assay was used to detect Mycoplasma genus and M. fermentans genomes in peripheral blood mononuclear cells (PBMC) of CFS patients. Blood was collected from 100 patients with CFS and 50 control subjects. The amplified products of 717 bp of Mycoplasma genus, and 206 bp of M. fermentans were detected in DNA purified from blood samples in 52% and 34% of CFS samples, respectively. In contrast, these genomes were found in only 14% and 8% of healthy control subjects respectively (P < 0.0001).

All samples were confirmed by Southern blot with a specific probe based on internal sequences of the expected amplification product. Several samples, which were positive for Mycoplasma genus, were negative for M. fermentans indicating that other Mycoplasma species are involved. A quantitative PCR was developed to determine the number of M. fermentans genome copies present in 1 microg of DNA for controls and CFS patients.

Mycoplasma copy numbers ranging from 130 to 880 and from 264 to 2400 were detected in controls and CFS positive subjects, respectively. An enzyme immunoassay was applied for the detection of antibodies against p29 surface lipoprotein of M. fermentans to determine the relationship between M. fermentans genome copy numbers and antibody levels. Individuals with high genome copy numbers exhibited higher IgG and IgM antibodies against M. fermentans specific peptides. Isolation of this organism by culture from clinical specimens is needed in order to demonstrate specificity of signal detected by PCR in this study.

 

Source: Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome. FEMS Immunol Med Microbiol. 1998 Dec;22(4):355-65. http://femsim.oxfordjournals.org/content/22/4/355.long (Full article)

 

Parallels between post-polio fatigue and chronic fatigue syndrome: a common pathophysiology?

Abstract:

Fatigue is the most commonly reported and most debilitating of post-polio sequelae affecting the >1.8 million North American polio survivors. Post-polio fatigue is characterized by subjective reports of difficulty with attention, cognition, and maintaining wakefulness. These symptoms resemble those reported in nearly 2 dozen outbreaks of post-viral fatigue syndromes (PVFS) that have recurred during this century and that are related clinically, historically, anatomically, or physiologically to poliovirus infections.

This article reviews recent studies that relate the symptoms of post-polio fatigue and chronic fatigue syndrome (CFS) to clinically significant deficits on neuropsychologic tests of attention, histopathologic and neuroradiologic evidence of brain lesions, impaired activation of the hypothalamic-pituitary-adrenal axis, increased prolactin secretion, and electroencephalogram (EEG) slow-wave activity.

A possible common pathophysiology for post-polio fatigue and CFS, based on the Brain Fatigue Generator Model of PVFS, and a possible pharmacotherapy for PVFS based on replacement of depleted brain dopamine, will be described.

 

Source: Bruno RL, Creange SJ, Frick NM. Parallels between post-polio fatigue and chronic fatigue syndrome: a common pathophysiology? Am J Med. 1998 Sep 28;105(3A):66S-73S. http://www.ncbi.nlm.nih.gov/pubmed/9790485

 

Chronic fatigue disorders: an inappropriate response to arginine vasopressin?

Abstract:

Chronic fatigue disorders are characterized by a subjectively defined group of symptoms such as chronic fatigue, mental confusion, exertional malaise, weight changes, and/or diffuse multi-joint pains.

Significant clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both chronic fatigue disorders and SIADH are characterized by lethargy and mental confusion. Both disorders can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids.

Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders.

 

Source: Peroutka SJ. Chronic fatigue disorders: an inappropriate response to arginine vasopressin? Med Hypotheses. 1998 Jun;50(6):521-3. http://www.ncbi.nlm.nih.gov/pubmed/9710328