Video lecture by Dr Lucinda Bateman: Upright activity & exercise intolerance: critical concepts in the evaluation of chronic fatigue

Upright activity and exercise intolerance: critical concepts in the evaluation of chronic fatigue, by Dr Lucinda Bateman

 

Dr Bateman talks to doctors.  Duration 56 minutes.

Topics covered:

  • how she assesses and diagnoses patients with ME/CFS
  • the questionnaires she gets them to fill in before they see her include the whole of the SF-36 (Rand-36) questionnaire, not just physical function, the fibromyalgia impact questionnaire, questions about hours of upright activity (feet on floor) on good and bad days
  • Post exertional malaise – what it is, and some research relating to it
  • the importance of staying within the energy envelope and some research that showed that those patients who successfully managed their activity to stay within their envelope stabilised and gradually improved over time, and those who didn’t got worse.
  • orthostatic intolerance including 10 minute stand test and pulse, blood pressure and pulse pressure changes.
  • cognitive problems

Dr Lucinda Bateman has run a clinic for patients with ME/CFS and Fibromyalgia in Utah, USA since 2000: Bateman Horne Center

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Rethinking the standard of care for ME/CFS

Rethinking the standard of care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Fred Friedberg, Madison Sunnquist, Luis Nacul in Journal of General Internal Medicine, Published online: 21 October 2019 [doi.org/10.1007/s11606-019-05375-y ]

 

Article abstract:

For over two decades, the standard of care for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been cognitive behavior therapy (CBT) and graded exercise therapy (GET). Both interventions had been recommended by the US Centers for Disease Control and the UK NICE guidelines.1

Behavioral intervention as the clinical standard was given a considerable boost by the 5 million–pound PACE trial, a large multi-arm randomized trial of CBT and GET launched in 2007.2 This British government–funded trial was intended to definitively answer whether such interventions were beneficial in ME/CFS. In their 2011 and 2013 publications, the PACE trial authors announced with widespread publicity that 22% of their patients had “recovered” and 59–61% had clinically improved across the CBT and GET interventions.2, 3

More generally, multiple literature reviews have reported that these therapies are not only effective at improving fatigue and, to a lesser extent, physical function in ME/CFS but also safe.4, 5, 6 It would seem obvious then that good clinical care of these patients would include these behavioral interventions. But, a closer look at these trials has generated many concerns about their applicability to these patients. This perspective critically examines their findings and more generally discusses the behavioral intervention literature in ME/CFS. Finally, we briefly describe a pragmatic clinical approach for these often-marginalized patients.

CARING FOR ME/CFS PATIENTS

In clinical practice, many individuals presenting with the common symptom of persistent fatigue may benefit from activity-based behavioral interventions, e.g., Friedberg et al.26 However, persistent fatigue is not equivalent to the multi-symptom debilitating illness of ME/CFS. Despite the lack of approved treatments or a fully articulated standard of medical care, there are still many actions physicians can take to help these underserved patients. First, practitioners can acknowledge the biomedical reality of the illness and their belief that the patient is genuinely ill. Next, clinicians can help patients to better manage a major illness challenge: how to minimize debilitating post-exertional malaise by learning to stay within their energy envelope.36

The energy envelope delineates the amount of energy that a ME/CFS patient has available to perform all activities.37 The size of this energy envelope can vary from day to day and between patients with some patients lacking energy for basic activities of daily living. When patients exceed their limited energy levels, they experience post-exertional worsening of symptoms and functioning. Medical providers can teach patients how to recognize their own personal energy limits and use pacing (dividing symptom-producing activities into smaller parts with interspersed rest intervals) to stay within those limits.34, 37 Once pacing is effectively used, some patients may be able to use an individualized exercise plan to increase available energy and functioning while avoiding post-exertional worsening.34, 36

Practitioners can also help patients with appropriate pharmacological and non-pharmacological treatments.38, 39 This includes treatments for unrefreshing sleep, e.g., trazodone and low-dose tricyclic antidepressants, and sleep hygiene measures.

In addition, pain can be addressed with low-dose naltrexone40 and anti-epileptics, e.g., gabapentin, and orthostatic intolerance can be treated with fludrocortisone and salt loading. Comorbidities can be managed using standard of care. Drugs should usually be started at low doses because patients can be sensitive to medications. If needed, patients can be referred to counseling to improve coping with the severe impacts of ME/CFS on quality of life.

For optimal patient care, we recommend a ME/CFS specialist or a specialist center supported by a multi-disciplinary team. Unfortunately, few of these practitioners or centers are available, which highlights the need for provider education and training regarding this illness. Realistically, when specialists are not available, care is best provided by the generalist (internal medicine or family doctor) working as part of a multidisciplinary team including expertise (as available) in immunology, infectious disease, cardiology or neurology, psychology, occupational therapy, and social work. With this interprofessional approach, practitioners can lessen harms while helping patients improve their health, function, and quality of life to the extent possible.

Further information on clinical management may be found in the following sources: a free practitioner’s guide to ME/CFS,34 a clinically focused review, 41 and a pragmatic clinical paper.36

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Is a diagnostic blood test for CFS on the horizon?

Is a diagnostic blood test for chronic fatigue syndrome on the horizon?, by
Michael Maes, Laura Andres & Gerwyn Morris in Expert Review of Molecular Diagnostics, Published online: 18 Oct 2019 [https://doi.org/10.1080/14737159.2020.1681976]

 

Expert opinion

Most if not all biomarkers of ME/CFS are pathway biomarkers although a few etiologic or predisposing biomarkers were delineated. These biomarkers indicate the multiple immune, oxidative, and metabolic pathways that underpin the pathophysiology of ME/CFS.

However, until now, no diagnostic, treatment or staging biomarkers could be developed and, therefore, future research should develop those types of biomarkers employing data mining models with biomarkers of the pathways described herein as input variables. Moreover, pathway-phenotype algorithms should be modeled which may be used to diagnose biomarker-validated symptom dimensions including disabling fatigue, cognitive impairments, post-exertional malaise, fibromyalgia-like symptoms, and irritable bowel syndrome.

All in all, a new ME/CFS diagnostic blood test useful to make the diagnosis of ME/CFS is not yet on the horizon. The way forward is to develop adequate diagnostic criteria based on machine learning and to combine biomarkers and clinical phenotypes into pathway-phenotypes using machine learning techniques.

Read the authors’ review of the research into biomarkers so far.

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Investigations of B cell phenotype & metabolic function in patients with ME/CFS

Investigations of B cell phenotype and metabolic function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Fane Kojo Fosu Mensah. PhD thesis University College London, Division of Medicine, Sep 2019

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition characterized by multiple systemic symptoms including fatigue, postexertional malaise and cognitive impairment, lasting for at least 6 months.

Immune system dysfunction triggered by infection or other insult is generally assumed to be a major causal factor that contributes to changes in energy metabolism leading to the pathophysiology of ME/CFS.

B cells became of interest after reported clinical improvement following B cell depletion-therapy with rituximab (anti-CD20). A possible but undefined role for B cells was, therefore, proposed.

The initial aim of this thesis was to explore subtle alterations in B cell sBlausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. ubsets in ME/CFS patients which could be used as a diagnostic and prognostic marker for the disease. Further, the dynamic nature of B cells was utilised as a model to observe changes in energy demand and for performing comprehensive metabolomic profiling of activated and maturating B cells under culture conditions.

Results for HC and ME/CFS patients could, therefore, be compared under similar conditions of stress. Flow-cytometric analysis of CD19+B cells revealed increased frequencies and expression of the heat-stable antigen CD24 in ME/CFS patients, as well as an increased memory B cell subset (CD21+CD38-). Retention of CD24 was linked to unresponsiveness to proliferative and pro-apoptotic signals and phosphorylation of AMPK (pAMPK). PAMPK was found to be largely confined to IgD+IgM+ memory B cells.

Metabolic analysis of cell culture supernatant using 1H-NMR spectroscopy revealed significant correlations between CD24+B cell frequencies and the usage of glucose and the production of lactate.

Novel findings described in this thesis, therefore, established a link between CD24 positivity of B cells and energy metabolism. Immunophenotype and metabolite profiles of cultured B cells from HC and ME/CFS patients were also revealed to respond with different dynamics to interventions, thereby providing a potential platform for more focused research and diagnosis.

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Evidence of altered cardiac autonomic regulation in ME/CFS

Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis, by Maximillian J Nelson, Jasvir S Bahl, Jonathan D Buckley, Rebecca L Thomson, Kade Davison in Medicine October 2019 , Vol 98, Issue 43 [doi: 10.1097/MD.0000000000017600]

 

Review abstract:

Background:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.

Methods:

A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.

Results: 

Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = –13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = –0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (–0.34 ± 0.22, P = .002) were lower in ME/CFS patients.

Conclusions: 

The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.

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The DePaul Symptom Questionnaire-2: a validation study

The DePaul Symptom Questionnaire-2: a validation study, by Helen Bedree, Madison Sunnquist & Leonard A Jason in Journal Fatigue: Biomedicine, Health & Behavior Vol 7, 2019 – Issue 3, pp 166-179 [https://doi.org/10.1080/21641846.2019.1653471]

 

Research abstract:

Background:

The DePaul Symptom Questionnaire (DSQ) was developed to assess the symptomatology and case definition fulfillment of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). The questionnaire was recently revised to improve its psychometric properties, increase its diagnostic reliability, and assess symptoms required by case definitions. The resulting instrument was named the DSQ-2.

Purpose:

The current study sought to evaluate the utility and reliability of the new and revised items in the DSQ-2.

Method:

A cross-sectional sample of 399 adults with ME or CFS was recruited to complete the DSQ-2.

Results:

Descriptive analyses of the DSQ-2 suggest that the new and revised items enhance the instrument’s ability to assess certain symptom domains and evaluate recent case definitions. Additionally, an exploratory factor analysis resulted in an eight-factor solution: post-exertional malaise, cognitive impairment, fever and flu, pain, sleep disruption, orthostatic intolerance, genitourinary issues, and temperature intolerance. The items within each factor demonstrated strong internal consistency reliability (Cronbach’s alphas = .73 – .91).

Conclusion:

These analyses indicate that the DSQ-2 offers a more thorough and precise understanding ME and CFS symptomology and case definition fulfillment.

Read full paper

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Naltrexone restores impaired Transient Receptor Potential Melastatin 3 ion channel function in Natural Killer Cells from ME/CFS

Naltrexone restores impaired Transient Receptor Potential Melastatin 3 ion channel function in Natural Killer Cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients, by Helene Cabanas,  Katsuhiko Muraki,  Donald Staines and Sonya Marshall-Gradisnik in Front. Immunol., 31 October 2019 [https://doi.org/10.3389/fimmu.2019.02545]

 

Research abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation.

ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions.

Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role.

Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS.

Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin.

We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.

The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

More information about the safety and use of naltrexone in medicine

Low-dose Naltrexone Explored as Option for Chronic Pain (in FM & ME/CFS)

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The effect of comorbid medical & psychiatric diagnoses on CFS

The effect of comorbid medical and psychiatric diagnoses on Chronic Fatigue Syndrome, by Benjamin H Natelson, Jin-Mann S Lin, Gudrun Lange, Sarah Khan, Aaron Stegner & Elizabeth R Unger in Annals of Medicine, published online: 23 Oct 2019 [https://doi.org/10.1080/07853890.2019.1683601]

 

Research abstract:

Objective:

To determine if presence of co-existing medically unexplained syndromes or psychiatric diagnoses affect symptom frequency, severity or activity impairment in Chronic Fatigue Syndrome.

Patients:

Sequential Chronic Fatigue Syndrome patients presenting in one clinical practice.

Design:

Participants underwent a psychiatric diagnostic interview and were evaluated for fibromyalgia, irritable bowel syndrome and/or multiple chemical sensitivity.

Results:

Current and lifetime psychiatric diagnosis was common (68%) increasing mental fatigue/health but not other illness variables and not with diagnosis of other medically unexplained syndromes. 81% of patients had at least one of these conditions with about a third having all three co-existing syndromes. Psychiatric diagnosis was not associated with their diagnosis. Increasing the number of these unexplained conditions was associated with increasing impairment in physical function, pain and rates of being unable to work.

Conclusions:

Patients with Chronic Fatigue Syndrome should be evaluated for current psychiatric conditions because of their impact on patient quality of life, but they do not act as a symptom multiplier for the illness. Other co-existing medically unexplained syndromes are more common than psychiatric co-morbidities in patients presenting for evaluation of medically unexplained fatigue and are also more associated with increased disability and the number and severity of symptoms.

Key Messages

  • When physicians see patients with medically unexplained fatigue, they often infer that this illness is due to an underlying psychiatric problem.
  • This paper shows that the presence of co-existing psychiatric diagnoses does not impact on any aspect of the phenomenology of medically unexplained fatigue also known as chronic fatigue syndrome. Therefore, psychiatric status is not an important causal contributor to CFS.
  • In contrast, the presence of other medically unexplained syndromes [irritable bowel syndrome; fibromyalgia and/or multiple chemical sensitivity] do impact on the illness such that the more of these that co-exist the more health-related burdens the patient has.

Read full paper

 

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Intra brainstem connectivity is impaired in CFS

Intra brainstem connectivity is impaired in chronic fatigue syndrome, by Leighton R Barnden, Zack Y Shan, Donald R Staines, Sonya Marshall-Gradisnik, Kevin Finegan, Timothy Ireland, Sandeep Bhuta, in NeuroImage: Clinical Vol 24, 2019, [https://doi.org/10.1016/j.nicl.2019.102045]

 

Research highlights:

  • RAS connectivity was detected in HC and CFS groups both during rest and task.
  • Strong connections were active for CFS from hippocampus to midbrain and medulla.
  • RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
  • RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
  • Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.

Research abstract:

Brain stem highlighted

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem.

Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC).

We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections.

When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. Strong hippocampal connections with midbrain and medulla nuclei were detected for ME/CFS. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task.

In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations.

Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

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How psychiatric referrals influence stigmatization in patients with ME & CFS

How psychiatric referrals influence stigmatization in patients with myalgic encephalomyelitis and chronic fatigue syndrome: an examination of American and British models, by Julia Terman, Joseph Cotler, Leonard A Jason in Community Psychology in Global Perspective Vol 5, #2, pp 19–29 , Oct 2019 [DOI: 10.1285/i24212113v5i2p19]

 

Research abstract:

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are controversial chronic illnesses with a myriad of debilitating symptoms. This study aimed to explore physician referrals to psychiatrists or psychologists, perceived stigma, and estrangement for patients with ME and CFS.

Findings indicate that patients who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness.  These relationships are moderated by the country of residence, the United States and the United Kingdom. The implications of physician referrals for people with ME and CFS are discussed.

Discussion:

The present findings indicate that patients with ME and CFS who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness. As previous studies have shown a high propensity of patients with ME and CFS to be misdiagnosed with a psychiatric condition (Deale & Wessely, 2000), these referrals are likely a cause of anxiety and stigma for the patient receiving them. The relationship between psychiatric referral and estrangement was mediated by perceived stigma, yet the impact was stronger for the British sample than the American sample.

Despite the different mediation model outcomes due to the moderation effect of country, all three variables correlate with one another for individuals from both countries. These findings corroborate the qualitative accounts that have been reported in previous literature (Åsbring & Närvänen, 2002; Dickson et al., 2007; Jason, Taylor, Plioplys, Stepanek, & Shlaes, 2002), which suggest that physician attitudes related to stigma and estrangement of individuals with ME and CFS.

Findings indicated that patients are at risk for estrangement and high stigma. Stigma can impair help-seeking and predict mental health challenges (Clement et al., 2015; McManimen et al., 2018). Estrangement is also a risk factor for patients because socially isolated individuals may experience loneliness, and loneliness predicts subsequent depression (Cacioppo, Hawkley, & Thisted, 2010; Matthews et al., 2016). Thus, individuals with chronic illness who feel estranged may be at risk for depression (Cacioppo et al., 2010), as well as early mortality (Smith, Jackson, Kobayashi, & Steptoe, 2018).

The differences between the American and British models may, in part, be explained by different illness profiles and cultural differences. British individuals experience more severe symptomology than Americans across several indicators (Zdunek et al., 2015), which may impact their experiences with healthcare providers and peers. It is possible that a patient with more severe symptoms may be treated more negatively by physicians than someone with less severe symptoms, especially if the physician upholds a stigmatizing view of the illness.

Another possibility may be due to differences in diagnostic and treatment guidelines between the two countries. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidelines for ME and CFS stipulate the cognitive behavioural therapy (CBT) and graded exercise treatment (GET) should be part of the treatment program for patients with ME and CFS (https://www.nice.org.uk/guidance/cg53/chapter/1-Guidance#diagnosis)…

While this has positive outcomes for patients with depression, patients report that GET often exacerbate symptoms and leaves them feeling more fatigued and more ill than before (Wilshire et al., 2018; Maes & Twisk, 2010). CBT has had more mixed findings, but it has been demonstrated that CBT’s effectiveness is directly tied to patient comorbid diagnosis of depression (Sunnquist & Jason, 2018).

While these guidelines are in place for U.K. practitioners, the Institute of Medicine in the U.S. does not have specific guidelines for treating ME or CFS. Attitudes toward the illness and treatment likely differ in Britain compared to America due to these nuanced sets of differences, as has been demonstrated with attitudes toward the cause of ME and CFS (Zdunek et al., 2015). These outcomes highlight the importance of co-production in patient healthcare, as stigmatization in patient healthcare can be reduced through the involvement of patients in planning and implementing their treatment and outcome options (Turakhia & Combs, 2017).

Community psychologists can use these findings to identify patients who may be at risk for further social and family estrangement due to false positive referrals, and to help administer proper therapies aimed at reintegration into social settings that negate perceived stigma.

In summation, physician treatment, societal stigma, and the social estrangement of individuals with ME and CFS are interconnected in our two samples of patients. Findings indicate that referral to psychiatric treatment can be damaging when prescribed to someone as a means of dismissing physical complaints. Physicians can utilize a shared decision making treatment model to treat patients with ME and CFS (Bieber et al., 2008). This method involves mutual exchange of information between the doctor and patient, as the doctor holds medical knowledge and the patient holds knowledge about individual health experiences. This model has been effective for those with chronic invisible illnesses and may better allow physicians to aid patients who feel their symptoms are physical and not psychological (Bieber et al., 2008). By remaining sensitive, physicians, friends, and family can aim to improve the lives of those with ME and CFS.

 

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