Tag: 2021

Off label use of shows promise as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a retrospective study of 101 patients treated with a low dose of Aripiprazole

In a retrospective study, we reviewed the medical records of 101 patients who met the criteria for a ME/CFS diagnosis according to three separate case definitions (Fukuda, CCC, and IOM) and who received off-label aripiprazole (Table ​(Table1).1). Medical records were included for individuals evaluated in the clinic at least twice, representing periods before and after the use of the medication. The age range was from 18 to 84 years old (mean 50 years), with a gender distribution of 67% female and 33% male, and the duration of illness was from 1 to 54 years (median 13 years).

The daily oral dose of aripiprazole ranged from 0.2 to 2.0 mg/day (mean 1.1 mg/day). Dosage started at 0.25 mg/day and titrated up or down based on each patient’s observations and feedback. The duration of aripiprazole therapy ranged from less than one month to 17 months (mean 7.8 months). Patient records were also evaluated for concurrent use of various classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), serotonin modulators, norepinephrine–dopamine reuptake inhibitors (NDRIs), and tri-cyclic antidepressants. The difference in antidepressant use between responders vs. non-responders was not statistically significant (p = 0.145) using the test for proportions, suggesting that antidepressant use does not predict or preclude a clinical response to aripiprazole.

Source: Crosby LD, Kalanidhi S, Bonilla A, Subramanian A, Ballon JS, Bonilla H. Off label use of Aripiprazole shows promise as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a retrospective study of 101 patients treated with a low dose of Aripiprazole. J Transl Med. 2021 Feb 3;19(1):50. doi: 10.1186/s12967-021-02721-9. PMID: 33536023; PMCID: PMC7860172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860172/ (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where Will the Drugs Come From?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5% and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability.

While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.

Source: Toogood PL, Clau DJ, Phadke S, Hoffman D. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where Will the Drugs Come From? Pharmacol Res. 2021 Jan 30:105465. doi: 10.1016/j.phrs.2021.105465. Epub ahead of print. PMID: 33529750. https://pubmed.ncbi.nlm.nih.gov/33529750/

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis

Abstract:

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved.

This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases.

The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Source: Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. 2021 Feb 4;12(4):573–80. doi: 10.1021/acschemneuro.0c00793. Epub ahead of print. PMID: 33538586; PMCID: PMC7874499. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874499/ (Full text)

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients.

Research Question

Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design and Methods

We analyzed 1516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls. Rest-to-peak changes in cardiac output (Qc) were compared to oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.

Results

During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Interpretation

These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Abbreviation:

Ca-vO2/[Hb] ( Arterial–mixed venous oxygen content difference/hemoglobin concentration), iCPET ( Invasive cardiopulmonary exercise test), NAM ( National Academy of Medicine, formerly the Institute of Medicine), ME/CFS ( Myalgic encephalomyelitis/chronic fatigue syndrome), MM ( Mitochondrial myopathy), mPAP ( Mean pulmonary artery pressure), PAWP ( Pulmonary arterial wedge pressure), PLF ( Preload failure), POTS ( Postural orthostatic tachycardia syndrome), PVR ( Pulmonary vascular resistance), RAP ( Right atrial pressure), Qc ( Cardiac output), SFN ( Small fiber neuropathy), VO2 ( Oxygen uptake), vPO2 ( Venous oxygen tension)

Source: Phillip Joseph, MD, Carlo Arevalo, MD, Rudolf K.F. Oliveira, MD, PhD, Donna Felsenstein, MD, Anne Louise Oaklander, MD, PhD, David M. Systrom, MD. Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. February 09, 2021. DOI:https://doi.org/10.1016/j.chest.2021.01.082 https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses

Abstract:

The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a “long hauler” version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3].

Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.

Source: Comella PH, Gonzalez-Kozlova E, Kosoy R, Charney AW, Peradejordi IF, Chandrasekar S, Tyler SR, Wang W, Losic B, Zhu J, Hoffman GE, Kim-Schulze S, Qi J, Patel M, Kasarskis A, Suarez-Farinas M, Gümüş ZH, Argmann C, Merad M, Becker C, Beckmann ND, Schadt EE. A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses. medRxiv [Preprint]. 2021 Feb 2:2021.01.29.21250755. doi: 10.1101/2021.01.29.21250755. PMID: 33564792; PMCID: PMC7872387.  https://pubmed.ncbi.nlm.nih.gov/33564792/

Experiences of Living with Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness. Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered.

This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely. Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.

Source: Strassheim V, Newton JL, Collins T. Experiences of Living with Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Healthcare (Basel). 2021 Feb 5;9(2):168. doi: 10.3390/healthcare9020168. PMID: 33562474. https://pubmed.ncbi.nlm.nih.gov/33562474/

Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales.

Materials and methods: In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks.

Results: Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.

Conclusions: (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.

Source: Haghighi S, Forsmark S, Zachrisson O, Carlsson A, Nilsson MKL, Carlsson ML, Schuit RC, Gottfries CG. Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome. Brain Behav. 2021 Feb 2:e02040. doi: 10.1002/brb3.2040. Epub ahead of print. PMID: 33528911. https://onlinelibrary.wiley.com/doi/10.1002/brb3.2040 (Full text)

Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19

Abstract:

As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months.

All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration.

The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.

Source: Simani L, Ramezani M, Darazam IA, Sagharichi M, Aalipour MA, Ghorbani F, Pakdaman H. Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19. J Neurovirol. 2021 Feb 2:1–6. doi: 10.1007/s13365-021-00949-1. Epub ahead of print. PMID: 33528827; PMCID: PMC7852482.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852482/ (Full text)

Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design

Abstract:

Objective: To explore the relationship between symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM). The hypothesis predicated that there would be no significant differences between the group’s symptom experience.

Design: A quasiexperimental design. Structural equation modelling (SEM) and invariance testing.

Participants: Males (M) and females (F) >16 with a confirmed diagnosis of CFS/ME or FM by a general practitioner or specialist. CFS/ME (n=101, F: n=86, M: n=15, mean (M) age M=45.5 years). FM (n=107, F: n=95, M: n=12, M=47.2 years).

Outcome measures: Diagnostic criteria: the American Centers for Disease Control and Prevention (CDC) for CFS/ME and the American College of Rheumatology (ACR) criteria for FM. Additional symptom questionnaires measuring: pain, sleep quality, fatigue, quality of life, anxiety and depression, locus of control and self-esteem.

Results: Invariance was confirmed with the exception of the American CDC Symptom Inventory, Fibromyalgia Impact Questionnaire and Hospital Anxiety and Depression Scale (p<0.05) based on five questions. Consequently, it was erroneous to conclude differences. Therefore, the Syndrome Model was created. SEM could not have tested the ACR previously, as it comprised a single data point. Thus, it was combined with these three questionnaires, increasing the data points, to create this new measurable model. Results confirmed no significant differences between groups (p=0.07 (p<0.05)).

Conclusion: Participants responded in a similar manner to the questionnaire, confirming the same symptom experience. It is important to consider this in context with differing criteria and management guidelines, as this may influence diagnosis and the trajectory of patient’s management. With the biomedical cause currently unclear, it is the symptom experience and the impact on quality of life that is important. These findings are meaningful for patients, clinicians and policy development and support the requirement for future research.

Source: Mckay PG, Walker H, Martin CR, Fleming M. Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design. BMJ Open. 2021 Feb 1;11(2):e041947. doi: 10.1136/bmjopen-2020-041947. PMID: 33526500. https://bmjopen.bmj.com/content/11/2/e041947.long (Full text)

Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers

Abstract:

Background: Chronic fatigue syndrome (CFS) is defined according to subjective symptoms only, and several conflicting case definition exist. Previous research has discovered certain biological alterations. The aim of the present study was to explore possible subgroups based on biological markers within a widely defined cohort of adolescent CFS patients and investigate to what extent eventual subgroups are associated with other variables.

Methods: The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) has previously performed detailed investigation of immunological, autonomic, neuroendocrine, cognitive and sensory processing functions in an adolescent group of CFS patients recruited according to wide diagnostic criteria. In the present study, hierarchical cluster analyses (Ward’s method) were performed using representative variables from all these domains. Associations between clusters and constitutional factors (including candidate genetic markers), diagnostic criteria, subjective symptoms and prognosis were explored by standard statistical methods.

Results: A total of 116 patients (26.7% males, mean age 15.4 years) were included. The final cluster analyses revealed six clusters labelled pain tolerant & good cognitions, restored HPA dynamics, orthostatic intolerance, low-grade inflammation, pain intolerant & poor cognitions, and high vagal (parasympathetic) activity, respectively. There was substantial overlap between clusters. The pain intolerant & poor cognitions-cluster was associated with low functional abilities and quality of life, and adherence to the Canada 2003 diagnostic criteria for CFS. No other statistically significant cluster associations were discovered.

Conclusion: Within a widely defined cohort of adolescent CFS patients, clusters could be delineated, but no distinct subgroups could be identified. Associations between clusters and constitutional factors, subjective symptoms and prognosis were scarce. These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most “narrow” CFS diagnostic criteria.

Source: Asprusten TT, Sletner L, Wyller VBB. Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers. J Transl Med. 2021 Jan 30;19(1):48. doi: 10.1186/s12967-021-02713-9. PMID: 33516248; PMCID: PMC7847574. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847574/ (Full text)