CNS inflammation – American ME and CFS Society

Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome

CFS a complex disorder characterized by unexplained severe fatigue for over 6 months with a broad range of additional symptoms involving the nervous, endocrine and immune systems, and an estimated prevalence of 1%1. Tricyclic antidepressants (TCAs) are prescribed off label for a number of painful diseases that are often comorbid, such as chronic fatigue syndrome (CFS), fibromyalgia, interstitial cystitis, and irritable bowel syndrome, the symptoms of which are worsened by stress2. However, there is no known mechanism to explain the apparent beneficial action of TCAs3.

Mast cells and their mediators have been implicated in inflammatory diseases4, including CFS5. Mast cells are located perivascularly in close proximity to neurons in the thalamus and hypothalamus, especially the median eminence6, where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive nerve processes7. CRH activates mast cells to release vascular endothelial growth factor (VEGF)8, which could participate in neurogenic inflammation and contribute to the pathogenesis of CFS. Such mediators may be released locally in the brain or may cross the blood-brain-barrier (BBB), which can be disrupted by stress, subsequent to mast cell activation9. Given the above, we hypothesized that TCAs may be helpful through inhibition of mast cell release of pro-inflammatory mediators.

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/

Source: Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. J Clin Psychopharmacol. 2011 Jun;31(3):385-7. doi: 10.1097/JCP.0b013e3182196e50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/ (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

A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection

Abstract:

OBJECTIVE: To conduct neurologic, immunologic, and virologic studies in patients with a chronic debilitating illness of acute onset.

DESIGN: Cohort study with comparison to matched, healthy control subjects.

PATIENTS: We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in.

MAIN OUTCOME MEASURES: Detailed medical history, physical examination, conventional hematologic and chemistry testing, magnetic resonance imaging (MRI) studies, lymphocyte phenotyping studies, and assays for active infection of patients’ lymphocytes with human herpesvirus type 6 (HHV-6).

MAIN RESULTS: Patients had a higher mean (+/- SD) CD4/CD8 T-cell ratio than matched healthy controls (3.16 +/- 1.5 compared with 2.3 +/- 1.0, respectively; P less than 0.003). Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P less than 10(-9)). Primary cell culture of lymphocytes showed active replication of HHV-6 in 79 of 113 patients (70%; CI, 61% to 78%) and in 8 of 40 controls (20%; CI, 9% to 36%) (P less than 10(-8], a finding confirmed by assays using monoclonal antibodies specific for HHV-6 proteins and by polymerase chain reaction assays specific for HHV-6 DNA.

CONCLUSIONS: Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction. Our study did not directly address whether HHV-6, a lymphotropic and gliotropic virus, plays a role in producing the symptoms or the immunologic and neurologic dysfunction seen in this illness. Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.

Comment in:

The chronic fatigue syndrome controversy. [Ann Intern Med. 1992]

Source: Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992 Jan 15;116(2):103-13. http://www.ncbi.nlm.nih.gov/pubmed/1309285