hypothesis – Page 5 – American ME and CFS Society

Kynurenine pathway Hypothesis: The nature of the chronic Fatigue syndrome (cFs) Revisited

Moderate physicians consider CFS to be missed diagnoses of uncommon illnesses with atypical features. Hartnup (heterozygotes), Lyme and Whipples—like diseases are examples of conditions which fit these clinical ambiguities. The detractors claim it is non-existent. The protractors complain CFS is excluded from standard medical texts. A broad overview of medical literature and support group newsletters, render these opposing views substantially incorrect.

The patient presents with a confounding array of neurological, mental, gastrointestinal, musculoskeletal and perhaps dermatological and visual signs and symptoms. Episodic night sweats can also be reported. Lack of energy, concentration and mobility, limit lifestyle. These symptom constellations evolve and fluctuate in a seemingly random order and can become entrenched. Alcohol intake, protracted steroid therapy and overt or latent infections usually aggravate the course of CFS.

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195222/

Source: Blankfield A. Kynurenine pathway Hypothesis: The nature of the Chronic Fatigue Syndrome (CFS) Revisited. Int J Tryptophan Res. 2011;4:47-8. doi: 10.4137/IJTR.S7898. Epub 2011 Jul 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195222/ (Full article)

Chronic fatigue syndrome–a neuroimmunological model

Abstract:

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS.

We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults.

The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS.

This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

Source: Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA. Chronic fatigue syndrome–a neuroimmunological model. Med Hypotheses. 2011 Jul;77(1):77-83. doi: 10.1016/j.mehy.2011.03.030. Epub 2011 Apr 6. https://www.ncbi.nlm.nih.gov/pubmed/21474251

Heterologous immunity: immunopathology, autoimmunity and protection during viral infections

There is a strong association between infection-related cell-mediated immunity and autoimmune diseases such as diabetes, multiple sclerosis (MS), rheumatoid arthritis (RA) and lupus erythematosis (SLE)1. Infections have also been associated with unusual immunopathologies of unknown origin, such as Wegner granulomatosis, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans and even chronic fatigue syndrome. Despite exhaustive efforts, a definitive link between one particular pathogen and any of one these pathologies has never been found. More often several pathogens have become associated with each of these conditions. For instance multiple sclerosis has been associated with Epstein Barr virus (EBV), measles virus, HHV-6, varicella-zoster virus, and Picornaviruses2-6. Panniculitis in the form of erythema nodosum and bronchiolitis obliterans have both been associated with unusual cell-mediated immune responses that occur following non-specified viral or intracellular bacterial infections 7-9. Erythema nodosum, which has also been associated with Crohn’s disease8, is a very painful condition, where nodules of inflamed subcutaneous fat often on the shins and forearms persist for months. There is no known therapy. Bronchiolitis obliterans is a lethal condition in humans where the bronchioles become occluded with immune cells and fibrinous material, with no known cause or treatment9.

Chronic fatigue syndrome (CFS) is another unusual multisystem disease which is thought to be associated with immune dysregulation. Over the past two decades millions of patients world wide have suffered from a clinical syndrome of disabling fatigue, myalgias, palpitations and cognitive dysfunction that lasts longer than 6 months. In 50% of cases it develops after a mild viral illness. Cases may appear sporadically or in clusters10,11. Many attempts have been made to define the syndrome on the basis of an etiologic agent. These agents have included Epstein-Barr virus10, Brucella12, Candida albicans13, Borrelia burgdorferi, and human herpesvirus-614,15. More recently it has been associated with enteroviruses and xenoretroviruses 16-18. The general conclusion has been that it is unlikely that the syndrome is caused by a single etiologic agent. The mechanisms mediating CFS are poorly understood, and there are few well designed studies examining its cause. The symptoms of CFS are similar to those experienced during viral infections such as infectious mononucleosis or influenza or in the setting of therapy with cytokines such as interferon or interleukin-2. It has been speculated that some or all the symptoms are reflective of an altered immune response to some pathogen with over production of one or more cytokines. An alternative hypothesis suggests that a number of infectious agents are involved and result in a regulatory imbalance of cytokines and the patient with CFS is unable to reestablish the appropriate balance of cytokines. These theories have been supported by reports of immune deficiency seen associated with CFS19.

Source: Selin LK, Wlodarczyk MF, Kraft AR, Nie S, Kenney LL, Puzone R, Celada F. Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity. 2011 Jun;44(4):328-47. doi: 10.3109/08916934.2011.523277. Epub 2011 Jan 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633594/ (Full article)

Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue?

Abstract:

Chronic NF-κB activation has been supposed as a key event in chronic fatigue syndrome (CFS) and many other better-defined pro-inflammatory diseases. Knowledge about the impact of deficiency vitamin D on chronic NF-κB activation could open a new disease approach. Whereas NF-κB activation leads at first to a pro-inflammatory immune response, later on a vitamin D-dependent anti-inflammatory response ensues. Binding of the active vitamin D metabolite 1,25(OH)(2)D(3) to vitamin D receptor (VDR) yields a transcription factor which represses NF-κB activation, and additionally modulates and down-regulates adaptive, but enhances innate immune responses, and improves redox balance, thus counterbalancing inflammation on multiple levels. However, this built-in late counterbalance against inflammation works only when stores of calcium and 25(OH)D(3) are abundant. Therefore a connection between lowered vitamin D-metabolism and persistent NF-κB activation, augmented nitrosative-oxidative stress, redox imbalance, chronic inflammation, and concomitant fatigue can be postulated. In order to confirm this hypothesis, randomized controlled clinical studies about the clinical effects of supplementation of calcium and vitamin D(3) would be necessary in diseases characterized by persistent NF-κB activation and chronic inflammation and fatigue.

Source: Hoeck AD, Pall ML. Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue? Med Hypotheses. 2011 Feb;76(2):208-13. doi: 10.1016/j.mehy.2010.09.032. Epub 2010 Oct 25. https://www.ncbi.nlm.nih.gov/pubmed/20980105

A new hypothesis of chronic fatigue syndrome: co-conditioning theory

Abstract:

Chronic fatigue syndrome is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms.

Many potential causes of chronic fatigue syndrome have been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic backgrounds, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found.

It is essential to establish a conceptual theory of chronic fatigue syndrome that can explain its pathophysiology in order to identify the clinical entity and to develop effective treatment methods. In this article, a new conceptual hypothesis about the pathophysiology of chronic fatigue syndrome, the co-conditioning theory, is presented: after repetitive overwork and/or stress, alarm signal to rest and fatigue sensation may cause in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus (overwork and/or stress).

In the future, a new treatment strategy for patients with chronic fatigue syndrome, re-co-conditioning therapy, may be developed on the basis of the co-conditioning theory. In addition, this theory will likely contribute to a better understanding of the pathophysiology of chronic fatigue syndrome.

Source: Tanaka M, Watanabe Y. A new hypothesis of chronic fatigue syndrome: co-conditioning theory. Med Hypotheses. 2010 Aug;75(2):244-9. doi: 10.1016/j.mehy.2010.02.032. Epub 2010 Mar 24. https://www.ncbi.nlm.nih.gov/pubmed/20338693

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?

Abstract:

Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided.

Special emphasis is given to the relationship between immune dysfunctions and fatigue. Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-kappaB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients.

The dysregulation of the RNase L pathway, hyperactive NF-kappaB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied. Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-kappaB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases.

These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.

Source: Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov;29(11):4717-26. http://ar.iiarjournals.org/content/29/11/4717.long (Full article)

Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?

Abstract:

This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS.

Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS.

A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia.

The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.

Source: Shapiro JS. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med Hypotheses. 2009 Nov;73(5):728-34. doi: 10.1016/j.mehy.2009.04.043. Epub 2009 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/19520522

On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics

Abstract:

Close similarities in the courses of multiple sclerosis and schizophrenia laid the theoretical ground for attempting to find a common infectious aetiology for the two diseases. Chlamydia pneumoniae, which belongs to the rickettsial family of microorganisms has been linked to both diseases. It is postulated that since rickettsial microorganisms are ubiquitous in human populations they and the human species normally live in peaceful coexistence. In rare cases, for unknown reasons, varieties of them may become aggressive and pathogenic.

The kynurenic acid hypothesis of schizophrenia has attracted much attention. It also seems to have initiated a paradigmatic shift from the hitherto prevailing serological research approach to one which focuses on immunological factors.

An open clinical pilot study in which, during 2006, eight female and five male patients with psychotic symptoms were treated with a combination of antibiotics is presented, to which, in the beginning of 2007 two female patients suffering from severe and long standing chronic fatigue syndrome were added. On one year follow-up, six out of the eight female patients showed stable excellent treatment results, whereas two were rated as showing significant treatment results. Four of the five men who entered the study were suffering from chronic schizophrenia, whereas the fifth, was a case of severe acute catatonic schizophrenia.

Two of the male patients showed significant treatment results, whereas three of them were rated as having had a slight to moderate improvement. No less than three of the women had suffered their first episode of psychosis after giving birth to their first (and only) child. This finding, as these women all responded excellently to treatment with antibiotics, indicates that post partum psychosis could be regarded as an infectious complication of childbirth of, as to the causative agent, unknown aetiology. High priority ought therefore be given to initiate controlled clinical trials with antibiotic treatment of this serious condition. The otherwise promising results of the pilot study seem to warrant further and controlled clinical trials with treatment with antibiotics of patients with psychotic symptoms.

As the second patient with psychotic symptoms to enter the study, had a long standing history of chronic fatigue, where an initial treatment with the antidepressant fluoxetine had only worsened her condition, whereas ninety days of treatment with antibiotics, combined with vitamin B injections, effected a complete recovery, the author decided, when two patients with long standing and incapacitating chronic fatigue syndromes sought the clinic in February and March 2007, to include them in the study. The first of them, after sixty days of treatment with antibiotics showed excellent treatment results on follow-up one year later, whereas the second, who also took the combination of antibiotics for sixty days, was rated as having shown a significant improvement.

Comment in: Hypotheses concerning rickettsial microorganisms, autoimmune diseases and new treatment strategies. [Med Hypotheses. 2010]

Source: Frykholm BO. On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics. Med Hypotheses. 2009 Jun;72(6):736-9. doi: 10.1016/j.mehy.2008.11.045. Epub 2009 Mar 6. https://www.ncbi.nlm.nih.gov/pubmed/19269110

Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system?

Abstract:

The etiopathogenesis of chronic fatigue syndrome (CFS) remains poorly understood. Although neuroendocrine disturbances – and hypothalamic-pituitary-adrenal (HPA) axis hypofunction in particular – have been found in a large proportion of CFS patients, it is not clear whether these disturbances are cause or consequence of the illness.

After a review of the available evidence we hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. As a result, a disturbed balance between glucocorticoid and inflammatory signaling pathways may give rise to a pathological cytokine-induced sickness response that may be the final common pathway underlying central CFS symptoms, i.e. effort/stress intolerance and pain hypersensitivity.

This comprehensive hypothesis on HPA axis hypofunction in CFS may stimulate diagnostic refinement of the illness, inform treatment approaches and suggest directions for future research, particularly focusing on the neuroendocrine-immune interface and possible links between CFS, early and recent life stress, and depression.

Source: Van Houdenhove B, Van Den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system? Med Hypotheses. 2009 Jun;72(6):701-5. doi: 10.1016/j.mehy.2008.11.044. Epub 2009 Feb 23. https://www.ncbi.nlm.nih.gov/pubmed/19237251

Can sustained arousal explain the Chronic Fatigue Syndrome?

Abstract:

We present an integrative model of disease mechanisms in the Chronic Fatigue Syndrome (CFS), unifying empirical findings from different research traditions. Based upon the Cognitive activation theory of stress (CATS), we argue that new data on cardiovascular and thermoregulatory regulation indicate a state of permanent arousal responses – sustained arousal – in this condition.

We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning).

Furthermore, sustained arousal may explain documented alterations by establishing vicious circles within immunology (Th2 (humoral) vs Th1 (cellular) predominance), endocrinology (attenuated HPA axis), skeletal muscle function (attenuated cortical activation, increased oxidative stress) and cognition (impaired memory and information processing). Finally, we propose a causal link between sustained arousal and the experience of fatigue.

The model of sustained arousal embraces all main findings concerning CFS disease mechanisms within one theoretical framework.

Source: Wyller VB, Eriksen HR, Malterud K. Can sustained arousal explain the Chronic Fatigue Syndrome? Behav Brain Funct. 2009 Feb 23;5:10. doi: 10.1186/1744-9081-5-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654901/ (Full article)