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Neuroendocrine  Immune  Dysfunction

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The New Era

Every new piece of scientific evidence on ME/CFS, and FM, points in the direction of these syndromes involving a number of organ systems, specifically the nervous, the endocrine, and the immune system. Accordingly, an umbrella term has been proposed for CFS:  Neuro-endocrine-immune Dysfunction Syndrome,  FAQ, NDS, 2002.  Abstracts from American Psychosomatic Society (2007) underlines the interaction between these fields of research, APS.symposium07.txt. Even more so the 2008 CFIDS research grants, grants.CFIDS08.txt.


However, not only ME/CFS have involvement from many organ systems, ‘Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer’, miller.etal08.txt


Two reviews on FM conclude the existence of a neuroendocrine syndrome,  Adler et al., 2002,  and  Wigers, 2002.  The Gulf War Syndrome: From environmental toxins to psychoneuroimmunology and neurodegeneration,  Ferguson & Cassaday, 2002.

A 2001-symposium, sponsored by the CDC and the CAA, resulted in a consensus paper, papanicolaou.etal04.pdf, and a conclusion that ‘it has become clear that CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular, or autonomic nervous system dysfunction. This panel encourages a new emphasis on multidisciplinary research into CFS’, gerrity.etal04.txt, gerrity.etal04.pdf.  However, previously not much hard evidence on the neuroendocrinology of CFS had been obtained,  Cleare, 2003 Cleare, 2003 (pdf).

Exploration of neuroendocrine and immune gene expression in peripheral blood mononuclear cells, nicholson.etal04.txt.

Neuroendocrine and immune network re-modeling in CFS: An exploratory analysis, fuite.etal08.txt.


Neuroinflammation – studies on proteomics

New techniques, analysis of minute amounts of proteins, proteomics, in cerebrospinal fluids seems promising, news.proteomics04.txt, proteomics05.txt.

Very interestingly, this approach has generated a 2008-2009 study at Georgetown university.Analysis of the fluid flowing from the brain will identify factors that may indicate the pathology of CFS to direct the creation of new treatments, and serve as diagnostic biomarkers for future testing’, baraniuk.CFSAC08.txt. ‘Proteomics of Cerebrospinal Fluid in CFS’. This study is currently recruiting participants. Verified by Georgetown University, Nov 2008 proteomics.clinical.trial08.txt.

Cerebrospinal fluid is interesting with respect to CRH-content relating to fatigue and pain, mc.lean.etal06.txt


Cytokines are Neurotransmitters

It is well established that fatigue and sleep disturbances can be caused by dysfunction of inflammatory transmitters, cytokines,  Mullington et al., 2001.  Also cognitive skills depend on immunologic factors,  Brimacombe et al., 2002.  An interesting paper studies brain blood flow and cytokines in FM,  Gur et al., 2002.

Link between Trauma & Neuroendocrine Dysfunction

Childhood trauma and risk for CFS: Association with Neuroendocrine Dysfunction,  heim.etal08.txt, heim.etal.08.txt, heim.etal08.pdf.



Link between Toxins & Immunity

A lengthy paper on the influence of toxins on immunity,  Richardson, 2002,   Richardson, 2002 (pdf).

Neurologic Dysfunction

A study on neurotologic manifestations,  Bayazit et al., 2002.  A paper asks directly "Is FM a neurological disease ?"  Bradley et al., 2002. 


Altered central nervous system signal during motor performance in CFS, siemionow.etal04.txt,  sieminonow.etal04.pdf.  Studies on nasal secretion provided documentation for a neurogenic factor in CFS, baraniuk.etal04.txt, baraniuk.etal04.pdf  and baraniuk.etal05.txt.  Definition of non-allergic rhinitis approaching, staevska.baraniuk05.txt.

The 5-HT3 Receptor

Physiology and pathophysiology of the 5-HT3 receptor. The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; and on a variety of other cells. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, CFS, alcohol abuse, and in pain syndromes such as FM and migraine, farber.etal04.txt. 5-HT3 receptor antagonists was found clinically effective in diarrhoea-predominant irritable bowel syndrome, in fibromyalgia and related pain disorders, haus.etal04.txt. Central pain processing is altered in patients with FMS. The serotonin metabolism, especially the 5-HT3 receptor, seems to play an important role, koeppe.etal04.txt. ‘The assessment of vegetative and functional symptoms in FM patients: the tropisetron experience’, kohnen.etal04.txt. ‘5-HT3 receptor blockade transiently affects monocyte tissue infiltration, modulates T-H1 cytokines in clinical responders as well as MIP-1beta in moderate responders, and transiently affects the ex vivo response to exogenous TNF-alpha’, schneider.etal04.txt. ‘Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron’, muller.stratz04.txt. ‘Treatment of fibromyalgia with tropisetron--dose and efficacy correlations’, spath.etal04.txt. ‘Influence of tropisetron on the serum substance P levels in FM patients’, stratz.etal04.txt. ‘Intravenous treatment of fibromyalgia with the 5-HT3 receptor antagonist tropisetron in a rheumatological practice’, tolk.etal04.txt.

More information on the serotonin receptor type 2 (5HT(2)), smith05.txt.


Brain Transmitters

FM is a pain syndrome involving norepinephrine, martinez-lavin.etal02.txt.  Disturbed uptake of acetylcarnitine in CFS,  Kuratsune et al., 2002.

Latest on the role of Th1/Th2 balance in stressed chronic pain patients, eisner.etal07.txt


The HPA - Immune System - Nervous System

‘CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication’,  Kaavelars et al., 2000.  ‘CFS appears to be associated with a disturbed HPA-axis. Moreover, CFS patients show several immunological

changes suggestive of decreased cellular immunity. It is postulated herein that in CFS patients a decreased Th1/Th2 balance may be the result of selective effects of GC on the IL-10/IL-12 regulatory circuit’,  Visser et al., 2000. 


A solid review of FM and neuroimmune dysfunction,  Buskila & Press, 2001 (pdf).  The role of stress on the HPA axis is studied,  Heim et al., 2000.  The interaction between HPA and the sympathetic nervous system (SNS) is the basis for this interesting review,  Elenkov et al., 2000  and  Elenkov et al., 2000 (pdf). Clonidin studies concluded, that CFS patients may display supersensitive central post-synaptic alpha-2 adrenoceptor function associated with the release of cortisol and growth hormone and initial thinking time in planning tasks,  Morriss et al., 2002.

Greek endocrinologists (diabetes researchers) published a comprehensive review of the complex interaction of various hormone systems and stress, suggesting CRH-potentiators as future treatment options in FM/CFS,  Tsigos & Chrousos, 2002,   Tsigos & Chrousos, 2002 (pdf).


Neurotransmitter Dysfunction

Serotonergic agents reduce the pain in FM,  Miller & Kubes, 2002.  No effect of galantamine hydrobromide (acetyl cholesterone inhibitor) treatment in CFS, a randomized controlled trial, blacker.etal04.txt,  blacker.etal04.pdf. An editorial relating to this work, straus04.txt, and a ‘letter to the editor’, letter.blacker04.txt.


The Muscles

The muscle pain symptoms felt by FM patients for the most part can be explained by neuroendocrine disturbances,  editorial, Bengtsson, 2002.  The fatigue felt as coming from muscles, is also best explained in terms of neural efferent mechanisms,  Gibson et al., 2001.  Many other studies on nociceptive nerve endings have pointed in the same direction, mense03.txt,  mense03.pdf.  Using EMG researchers found diminished central activation during maximal voluntary contraction in CFS patients, schillings.etal04.txt, schillings.etal04.pdf. 


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Mette Marie Andersen, MD