Pathogenesis – Page 9 – American ME and CFS Society

Neuromuscular strain as a contributor to cognitive and other symptoms in chronic fatigue syndrome: hypothesis and conceptual model

Abstract:

Individuals with chronic fatigue syndrome (CFS) have heightened sensitivity and increased symptoms following various physiologic challenges, such as orthostatic stress, physical exercise, and cognitive challenges. Similar heightened sensitivity to the same stressors in fibromyalgia (FM) has led investigators to propose that these findings reflect a state of central sensitivity.

A large body of evidence supports the concept of central sensitivity in FM. A more modest literature provides partial support for this model in CFS, particularly with regard to pain. Nonetheless, fatigue and cognitive dysfunction have not been explained by the central sensitivity data thus far.

Peripheral factors have attracted attention recently as contributors to central sensitivity. Work by Brieg, Sunderland, and others has emphasized the ability of the nervous system to undergo accommodative changes in length in response to the range of limb and trunk movements carried out during daily activity. If that ability to elongate is impaired-due to movement restrictions in tissues adjacent to nerves, or due to swelling or adhesions within the nerve itself-the result is an increase in mechanical tension within the nerve. This adverse neural tension, also termed neurodynamic dysfunction, is thought to contribute to pain and other symptoms through a variety of mechanisms. These include mechanical sensitization and altered nociceptive signaling, altered proprioception, adverse patterns of muscle recruitment and force of muscle contraction, reduced intra-neural blood flow, and release of inflammatory neuropeptides. Because it is not possible to differentiate completely between adverse neural tension and strain in muscles, fascia, and other soft tissues, we use the more general term “neuromuscular strain.”

In our clinical work, we have found that neuromuscular restrictions are common in CFS, and that many symptoms of CFS can be reproduced by selectively adding neuromuscular strain during the examination. In this paper we submit that neuromuscular strain is a previously unappreciated peripheral source of sensitizing input to the nervous system, and that it contributes to the pathogenesis of CFS symptoms, including cognitive dysfunction.

Source: Rowe PC, Fontaine KR, Violand RL. Neuromuscular strain as a contributor to cognitive and other symptoms in chronic fatigue syndrome: hypothesis and conceptual model. Front Physiol. 2013 May 16;4:115. doi: 10.3389/fphys.2013.00115. eCollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655286/ (Full article)

Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course

Abstract:

BACKGROUND: A high prevalence of chronic fatigue has previously been reported following giardiasis after a large waterborne outbreak in Bergen, Norway in 2004. The aim of this study was to describe and evaluate differential diagnoses and natural course of fatigue five years after giardiasis among patients who reported chronic fatigue three years after the infection.

METHODS: Patients who three years after Giardia infection met Chalder’s criteria for chronic fatigue (n=347) in a questionnaire study among all patients who had laboratory confirmed giardiasis during the Bergen outbreak (n=1252) were invited to participate in this study five years after the infection (n=253). Structured interviews and clinical examination were performed by specialists in psychiatry, neurology and internal medicine/infectious diseases. Fukuda et al’s 1994 criteria were used to diagnose chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). Self-reported fatigue recorded with Chalder Fatigue Questionnaire three and five years after infection were compared.

RESULTS: 53 patients were included. CFS was diagnosed in 41.5% (22/53) and ICF in 13.2% (7/53). Chronic fatigue caused by other aetiology was diagnosed in 24.5% (13/53); five of these patients had sleep apnoea/hypopnoea syndrome, six had depression and five anxiety disorder, and among these two had more than one diagnosis. Fatigue had resolved in 20.8% (11/53). Self-reported fatigue score in the cohort was significantly reduced at five years compared to three years (p<0.001).

CONCLUSION: The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study. Improvement of chronic fatigue in the period from three to five years after giardiasis was found.

Source: Mørch K, Hanevik K, Rivenes AC, Bødtker JE, Næss H, Stubhaug B, Wensaas KA, Rortveit G, Eide GE, Hausken T, Langeland N. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterol. 2013 Feb 12;13:28. doi: 10.1186/1471-230X-13-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598369/ (Full article)

A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Abstract:

Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

Source: Blankfield A. A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Int J Tryptophan Res. 2012;5:27-32. doi: 10.4137/IJTR.S10085. Epub 2012 Sep 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460668/ (Full article)

Loss of stress response as a consequence of viral infection: implications for disease and therapy

Abstract:

Herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. Having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. Host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. In the case of Newcastle disease virus, the effects of viral infection on heat shock proteins may be leveraged as a therapy for cancer. Finally, the search for a specific virus being responsible for a condition like chronic fatigue syndrome may not be worthwhile if the disease is simply a nonspecific response to viral infection.

Source: Hooper PL, Hightower LE, Hooper PL. Loss of stress response as a consequence of viral infection: implications for disease and therapy. Cell Stress Chaperones. 2012 Nov;17(6):647-55. doi: 10.1007/s12192-012-0352-4. Epub 2012 Jul 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468676/ (Full article)

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS.

Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients.

In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients.

If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients’ symptom profiles.

Source: Pacini S, Fiore MG, Magherini S, Morucci G, Branca JJ, Gulisano M, Ruggiero M. Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Med Hypotheses. 2012 Sep;79(3):403-7. doi: 10.1016/j.mehy.2012.06.007. Epub 2012 Jul 12. https://www.ncbi.nlm.nih.gov/pubmed/22795611

Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence

Abstract:

BACKGROUND: A waterborne outbreak of Giardia lamblia gastroenteritis led to a high prevalence of long-lasting fatigue and abdominal symptoms. The aim was to describe the clinical characteristics, disability and employmentloss in a case series of patients with Chronic Fatigue Syndrome (CFS) after the infection.

METHODS: Patients who reported persistent fatigue, lowered functional capacity and sickness leave or delayed education after a large community outbreak of giardiasis enteritis in the city of Bergen, Norway were evaluated with the established Centers for Disease Control and Prevention criteria for CFS. Fatigue was self-rated by the Fatigue Severity Scale (FSS). Physical and mental health status and functional impairment was measured by the Medical Outcome Severity Scale-short Form-36 (SF-36). The Hospital Anxiety and Depression Scale (HADS) was used to measure co-morbid anxiety and depression. Inability to work or study because of fatigue was determined by sickness absence certified by a doctor.

RESULTS: A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmed giardiasis were diagnosed with CFS. In all, 1262 patients had laboratory confirmed giardiasis. At the time of referral (mean illness duration 2.7 years) 16% reported improvement, 28% reported no change, and 57% reported progressive course with gradual worsening. Mean FSS score was 6.6. A distinctive pattern of impairment was documented with the SF-36. The physical functioning, vitality (energy/fatigue) and social functioning were especially reduced. Long-term sickness absence from studies and work was noted in all patients.

CONCLUSION: After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.

Source: Naess H, Nyland M, Hausken T, Follestad I, Nyland HI. Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. BMC Gastroenterol. 2012 Feb 8;12:13. doi: 10.1186/1471-230X-12-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292445/ (Full article)

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology

Abstract:

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction.

Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction.

We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites.

In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.

Source: Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012 Sep;25(9):1073-87. doi: 10.1002/nbm.2772. Epub 2012 Jan 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896084/ (Full article)

Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome

Abstract:

BACKGROUND/PURPOSE: It has been shown that the abnormality in immune cells in chronic fatigue syndrome (CFS) patients is closely associated with the participation of TGF-β. In order to study the relationship between TGF-β1 and CFS, we investigated the mRNA levels of TGF-β1 in peripheral blood mononuclear cells (PBMCs) in patients with CFS.

METHODS: Fluorescent quantitative real time reverse-transcription polymerase chain reaction (FQ-RT-PCR) was performed to test TGF-β1 mRNA expression in PBMCs in 63 cases of CFS, 50 cases of disease controls, and 50 cases of healthy controls.

RESULTS: The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01). No significant difference was detected between disease and healthy controls (p > 0.05).

CONCLUSION: The expression of TGF-β1 in PBMCs is significantly elevated in patients with CFS. It might be correlated to the pathogenesis of the disease.

Source: Zhang HY, Liu ZD, Hu CJ, Wang DX, Zhang YB, Li YZ. Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. J Formos Med Assoc. 2011 Nov;110(11):701-4. doi: 10.1016/j.jfma.2011.09.006. Epub 2011 Oct 22. http://www.jfma-online.com/article/S0929-6646(11)00070-2/fulltext (Full article)

Fibromyalgia and chronic fatigue syndrome in children

Abstract:

BACKGROUND: Fibromyalgia (FM) is characterized by widespread persistent pain and the presence of multiple discrete tender points. Chronic fatigue syndrome (CFS) is a syndrome characterized by debilitating fatigue associated with a variable number of non-specific complaints. Because neither condition had necessarily been recognized in children until recently, those patients have been treated as having school refusal without being diagnosed as having either syndrome. There is a considerable overlap of clinical symptoms between these two syndromes. It is therefore controversial as to whether these syndromes have the same pathogenesis or not. The aim of the present study was to clarify the relationship between these syndromes in children.

METHODS: Fifteen patients with FM and 21 patients with CFS were investigated both clinically and immunologically. Immunological assessments included thorough analysis of autoantibodies using several techniques.

RESULTS: Anti-nuclear antibody titers were higher and the prevalence of anti-Sa antibody was far more frequent in CFS patients than in FM patients.

CONCLUSION: CFS and FM are different from each other at least in childhood, from an immunological aspect, although some patients could have both conditions.

Source: Itoh Y, Shigemori T, Igarashi T, Fukunaga Y. Fibromyalgia and chronic fatigue syndrome in children. Pediatr Int. 2012 Apr;54(2):266-71. doi: 10.1111/j.1442-200X.2011.03514.x. Epub 2012 Jan 12. https://www.ncbi.nlm.nih.gov/pubmed/22115414

Role of infection and neurologic dysfunction in chronic fatigue syndrome

Abstract:

Chronic fatiguing illnesses following well-documented infections and acute “infectious-like” illnesses of uncertain cause have been reported for many decades. Chronic fatigue syndrome (CFS) was first formally defined in 1988. There is considerable evidence that CFS is associated with abnormalities of the central and autonomic nervous systems. There also is evidence linking several infectious agents with CFS, although no agent has been proven to be a cause of the illness.

Most of the infectious agents that have been linked to CFS are able to produce a persistent, often life-long, infection and thus are a constant incitement to the immune system. Most also have been shown to be neuropathogens. The evidence is consistent with the hypothesis that CFS, in some cases, can be triggered and perpetuated by several chronic infections that directly or indirectly affect the nervous system, and that symptoms are a reflection of the immune response to the infection.

Source: Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011 Jul;31(3):325-37. doi: http://dx.doi.org/10.1055/s-0031-1287654. Epub 2011 Sep 30. https://www.ncbi.nlm.nih.gov/pubmed/21964849