Demitrack – American ME and CFS Society

Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study

Abstract:

A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders.

Blood plasma was assayed for cortisol and ACTH every 10 min for 24h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was “personalized” by estimating an individualized set of parameters from each participant’s data. Day and nighttime parameters were assessed separately.

Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups (“fatigue-predominant” patients with CFS only versus “pain-predominant” patients with FM and comorbid chronic fatigue) from controls (all p’s<.05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p’s<.05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p<.05).

Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol’s anti-inflammatory and sleep-modulatory effects. Patients’ HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping “behavioral phenotypes” of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.

Comment in: A moving target: taking aim at the regulatory dynamics of illness. [Brain Behav Immun. 2012]

Source: Aschbacher K, Adam EK, Crofford LJ, Kemeny ME, Demitrack MA, Ben-Zvi A. Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study. Brain Behav Immun. 2012 Oct;26(7):1047-56. doi: 10.1016/j.bbi.2012.06.002. Epub 2012 Jun 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725324/ (Full article)

Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary

Abstract:

Chronic fatigue syndrome (CFS) is a complex, multisymptom illness of unknown etiology. A variety of operational case definitions based on symptom report have been developed that share some common clinical features. Patients often come to clinical presentation after months or, more typically, years of symptomatic distress. Comorbid presentation with psychiatric illnesses has been noted.

Due to these fundamental issues, the impact of patient selection and the specification of the methods of outcome assessment loom large in therapeutic studies of CFS. While a substantial body of research has focused on increasing our understanding of the basic pathobiology of CFS, there have been comparatively fewer studies that have addressed the problems of patient characterization and outcome assessment. The role of clinical methodology in the study of the therapeutics of CFS is not trivial, and may confound our understanding of pragmatic recommendations for treatment.

Source: Demitrack MA. Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary. Pharmacogenomics. 2006 Apr;7(3):521-8. https://www.ncbi.nlm.nih.gov/pubmed/16610962

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome

Abstract:

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups.

Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs.

There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups.

We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Source: Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004 Jul;18(4):314-25. http://www.ncbi.nlm.nih.gov/pubmed/15157948

What is chronic fatigue syndrome? Heterogeneity within an international multicentre study

Abstract:

OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data.

METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA).

RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%).

CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

Source: Wilson A, Hickie I, Hadzi-Pavlovic D, Wakefield D, Parker G, Straus SE, Dale J, McCluskey D, Hinds G, Brickman A, Goldenberg D, Demitrack M, Blakely T,Wessely S, Sharpe M, Lloyd A. What is chronic fatigue syndrome? Heterogeneity within an international multicentre study. Aust N Z J Psychiatry. 2001 Aug;35(4):520-7. http://www.ncbi.nlm.nih.gov/pubmed/11531735

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome

Abstract:

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress associated disorders mainly affecting women. FM is characterized primarily by widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but there is considerable overlap of clinical symptoms between these 2 syndromes. Neuroendocrine abnormalities have been noted in both FM and CFS and desynchronization of circadian systems has been postulated in their etiology. The pineal hormone melatonin is involved in synchronizing circadian systems and the use of exogenous melatonin has become widespread in patients with FM and CFS.

METHODS: We examined the characteristics and relationship of melatonin and cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared to age and menstrual cycle phase matched controls. Blood was collected from an indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and cortisol were determined by radioimmunoassay at 60 and 10 min intervals, respectively.

RESULTS: Night time (23:00-06:50) plasma melatonin levels were significantly higher in FM patients compared to controls (p<0.05), but there was no significant difference in melatonin levels between CFS patients and controls. No differences in the timing of cortisol and melatonin secretory patterns and no internal desynchronization of the 2 rhythms were found in either patient group, compared to controls.

CONCLUSION: Raised plasma melatonin concentrations have been documented in several other conditions that are associated with dysregulation of neuroendocrine axes. Increased melatonin levels may represent a marker of increased susceptibility to stress induced hypothalamic disruptions. These data indicate that there is no rationale for melatonin replacement therapy in patients with FM and CFS.

Source: Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C, Masterson L, Engelberg NC, Haus E, Demitrack MA, Crofford L. Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. J Rheumatol. 1999 Dec;26(12):2675-80. http://www.ncbi.nlm.nih.gov/pubmed/10606381

The relationship between temporomandibular disorders and stress-associated syndromes

Abstract:

OBJECTIVES: The purpose of this study was to determine the comorbidity of temporomandibular disorders and other stress-associated conditions in patients with chronic fatigue syndrome and fibromyalgia.

STUDY DESIGN: Of 92 patients who fulfilled the criteria for chronic fatigue syndrome or fibromyalgia (or both), 39 (42%) reported a prior diagnosis of temporomandibular disorder. Further questionnaires were sent to the members of this group, and 30 patients responded.

RESULTS: Of the original 92 patients, of whom 42% reported temporomandibular disorders, 46% had histories of irritable bowel syndrome, 42% of premenstrual syndrome, and 19% of interstitial cystitis. Of the patients with temporomandibular disorders, the great majority reported an onset of generalized symptoms before the onset of facial pain. Despite this, 75% had been treated exclusively for temporomandibular disorders, usually with bite splints.

CONCLUSIONS: Patients appearing for treatment with chronic facial pain show a high comorbidity with other stress-associated syndromes. The clinical overlap between these conditions may reflect a shared underlying pathophysiologic basis involving dysregulation of the hypothalamic-pituitary-adrenal stress hormone axis in predisposed individuals. A multidisciplinary clinical approach to temporomandibular disorders would improve diagnosis and treatment outcomes for this group of patients.

Source: Korszun A, Papadopoulos E, Demitrack M, Engleberg C, Crofford L. The relationship between temporomandibular disorders and stress-associated syndromes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998 Oct;86(4):416-20. http://www.ncbi.nlm.nih.gov/pubmed/9798224

Chronic fatigue syndrome and fibromyalgia. Dilemmas in diagnosis and clinical management

Abstract:

There has been a resurgence of interest in recent years in both chronic fatigue syndrome and fibromyalgia. These perplexing and common clinical conditions are a source of significant patient morbidity and frame one of the more enduring dilemmas of contemporary Western medical thought, namely the ambiguous interface between mind and body. In this article, the current definitions are reviewed, and a framework for an emerging psychobiological model of these syndromes is presented. These issues are synthesized into a pragmatic approach to clinical management.

Source: Demitrack MA. Chronic fatigue syndrome and fibromyalgia. Dilemmas in diagnosis and clinical management. Psychiatr Clin North Am. 1998 Sep;21(3):671-92, viii. http://www.ncbi.nlm.nih.gov/pubmed/9774804

Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic-pituitary adrenal axis and hypocortisolemia.

OBJECTIVE: To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS.

DESIGN: A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996.

SETTING: A single-center study in a tertiary care research institution.

PATIENTS: A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications.

INTERVENTION: Oral hydrocortisone, 13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks.

MAIN OUTCOME MEASURES: A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist.

RESULTS: The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P =.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001).

CONCLUSIONS: Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.

Source: McKenzie R, O’Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia-Borreguero D, Blackwelder W, Straus SE. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998 Sep 23-30;280(12):1061-6. http://www.ncbi.nlm.nih.gov/pubmed/9757853

Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms.

Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia).

How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function.

In order to provide a more refined view of the nature of the HPA disturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.

Source: Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci. 1998 May 1;840:684-97. http://www.ncbi.nlm.nih.gov/pubmed/9629295

Neuroendocrine correlates of chronic fatigue syndrome: a brief review

Abstract:

Chronic fatigue syndrome remains one of the more perplexing syndromes in contemporary clinical medicine. One approach to understanding this condition has been to acknowledge its similarities to other disorders of clearer pathophysiology.

In this review, a rationale for the study of neuroendocrine correlates of chronic fatigue syndrome is presented, based in part on the clinical observation that asthenic or fatigue states share many of the somatic symptom characteristics seen in recognized endocrine disorders. Of additional interest is the observation that psychological symptoms, particularly disturbances in mood and anxiety, are equally prominent in this condition.

At this time, several reports have provided replicated evidence of disruptions in the integrity of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. It is notable that the pattern of the alteration in the stress response apparatus is not reminiscent of the well-understood hypercortisolism of melancholic depression but, rather, suggests a sustained inactivation of central nervous system components of this system.

Recent work also implicates alterations in central serotonergic tone in the overall pathophysiology of this finding. The implications of these observations are far from clear, but they highlight the fact that, though chronic fatigue syndrome overlaps with the well-described illness category of major depression, these are not identical clinical conditions.

Source: Demitrack MA. Neuroendocrine correlates of chronic fatigue syndrome: a brief review. J Psychiatr Res. 1997 Jan-Feb;31(1):69-82. http://www.ncbi.nlm.nih.gov/pubmed/9201649