Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function. The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome. In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Long COVID: lights and shadows on the clinical characterization of this emerging pathology.

More than 800 million individuals have contracted SARSCOV2 infection worldwide. It was estimated that almost 10-20% of these might suffer from Long COVID. It is a multisystemic syndrome, which negatively affects the quality of life with a significant burden of health loss compared to COVID negative individuals. Moreover, the risk of sequelae still remains high at 2 years in both nonhospitalized and hospitalized individuals. This review summarizes studies regarding long COVID and clarifies the definitions, the risk factors and the management of this syndrome. Finally, it delves into the most frequent long-term outcomes, especially postural orthostatic tachycardia syndrome" (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), brain fog, and their therapeutical possibilities.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis.

BACKGROUND: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients. METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections' contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased). RESULTS: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a "moderate association" by Cohen's d test) compared to both healthy and diseased controls. CONCLUSION: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?

SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.

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

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.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?

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.

Long COVID and chronic fatigue syndrome: A survey of elderly female survivors in Egypt.

OBJECTIVES: This study aimed to investigate post-COVID-19 symptoms amongst elderly females and whether they could be a risk factor for developing chronic fatigue syndrome (CFS) later on. METHODS: This was a retrospective cross-sectional study, in the form of an online survey. A total of 115 responses were finally included. RESULTS: The mean age was 73.18 ± 6.42. Eighty-nine reported symptoms in the post-recovery period; of these 54 had no symptoms of CFS, 60 were possible, and only 1 was probable. Fatigue was reported by 66, musculoskeletal symptoms by 56, and sleep problems by 73. Twenty-nine patients visited a doctor's office as a result. Post-recovery symptoms were significantly related to stress, sadness and sleep disturbances. Also, stress, sadness, sleep disturbances, fatigue, cognitive impairment, and recurrent falls were all significantly associated with CFS-like symptoms. CONCLUSIONS: From our findings, the presence of fatigue, cognitive impairment, stress, sadness, sleep disturbances and recurrent falls in the post-recovery period were all significantly associated with CFS-like symptoms. To conclude it would be reasonable to screen for long COVID and consider the potential for developing CFS later on. Whether it can be a risk factor for developing CFS-like other viral infections will need more larger scale studies to confirm this.

Our Evolving Understanding of ME/CFS.

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the 'hallmark' symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes. We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

BACKGROUND AND MAIN TEXT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies. CONCLUSIONS: This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.

Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island.

Prolonged fatigue is increasingly reported among chikungunya virus (CHIKV)-infected populations. We investigated the relationships between CHIKV exposure, long-lasting rheumatic musculoskeletal pain (LRMSP) and chronic fatigue. 1094 participants (512 CHIKV seropositive and 582 seronegative) of the TELECHIK population-based cohort were analysed considering the duration of the manifestations throughout an average 2-year follow-up. Weighted prevalence rates and prevalence ratios for LRMSP, idiopathic chronic fatigue (ICF), and chronic fatigue syndrome (CFS)-like illness, both latter syndromes adapted from Centers for Disease Control (CDC)-1994/Fukuda criteria, were compared. Population attributable fractions (PAF) were estimated to assess the contribution of CHIKV infection to each of the three phenotypes. Among 362 adult subjects who had reported either rheumatic pain or fatigue at the onset of the infection, weighted prevalence rates of LRMSP, ICF and CFS-like illness were respectively of 32.9%, 38.7% and 23.9%, and of 8.7%, 8.5% and 7.4% among initially asymptomatic peers (P < 0.01, respectively). Each of the three outcomes was highly attributable to chikungunya (PAF of 43.2%, 36.2% and 41.0%, respectively). In the sub-cohort of CHIKV-infected subjects, LRMSP, ICF and CFS-like illness, which overlapped in 70%, accounted for 53% of the chronic manifestations. In addition to rheumatic disease, chronic fatigue could be considered in caring for patients with chronic chikungunya disease.

Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue.

Fatigue reduces productivity and is a risk factor for lifestyle diseases and mental disorders. Everyone experiences physiological fatigue and recovers with rest. Pathological fatigue, however, greatly reduces quality of life and requires therapeutic interventions. It is therefore necessary to distinguish between the two but there has been no biomarker for this. We report on the measurement of salivary human herpesvirus (HHV-) 6 and HHV-7 as biomarkers for quantifying physiological fatigue. They increased with military training and work and rapidly decreased with rest. Our results suggested that macrophage activation and differentiation were necessary for virus reactivation. However, HHV-6 and HHV-7 did not increase in obstructive sleep apnea syndrome (OSAS), chronic fatigue syndrome (CFS) and major depressive disorder (MDD), which are thought to cause pathological fatigue. Thus, HHV-6 and HHV-7 would be useful biomarkers for distinguishing between physiological and pathological fatigue. Our findings suggest a fundamentally new approach to evaluating fatigue and preventing fatigue-related diseases.

Investigation of suspected chronic fatigue syndrome/myalgic encephalopathy.

BACKGROUND: Chronic fatigue is a frequently occurring problem in both the primary and specialist health services. The Department of Neurology at Haukeland University Hospital has established a standard assessment for patients referred with suspected CFS/ME. This study reports diagnoses and findings upon assessment, and considers the benefit of supplementary examinations. MATERIAL AND METHOD: Diagnoses and findings from examinations of 365 patients assessed for suspected CFS/ME are retrospectively reported. RESULTS: A total of 48 patients (13.2%) were diagnosed with CFS/ME, while a further 18 patients (4.9%) were diagnosed with post-infectious fatigue. Mental and behavioural disorders were diagnosed in 169 patients (46.3%), and these represented by far the largest group. Serious, but unrecognised somatic illness was discovered in two patients, while changes of uncertain significance were identified by MRI and lumbar puncture in a few patients. INTERPRETATION: Fatigue is a frequently occurring symptom in the population. Thorough somatic and psychiatric investigation is necessary before referral to the specialist health services. Mental disorders and reactions to life crises are common and important differential diagnoses for CFS/ME. Long waiting times in the specialist health services may result in delayed diagnosis for these patients.

Neurological aspects of human parvovirus B19 infection: a systematic review.

Parvovirus B19 has been linked with various clinical syndromes including neurological manifestations. However, its role in the latter remains not completely understood. Although the last 10 years witnessed a surge of case reports on B19-associated neurological aspects, the literature data remains scattered and heterogeneous, and epidemiological information on the incidence of B19-associated neurological aspects cannot be accurately extrapolated. The aim of this review is to identify the characteristics of cases of B19-associated neurological manifestations. A computerized systematic review of existing literature concerning cases of B19-related neurological aspects revealed 89 articles describing 129 patients; 79 (61.2%) were associated with CNS manifestations, 41 (31.8%) were associated with peripheral nervous system manifestations, and 9 (7.0%) were linked with myalgic encephalomyelitis. The majority of the cases (50/129) had encephalitis. Clinical characteristic features of these cases were analyzed, and possible pathological mechanisms were also described. In conclusion, B19 should be included in differential diagnosis of encephalitic syndromes of unknown etiology in all age groups. Diagnosis should rely on investigation of anti-B19 IgM antibodies and detection of B19 DNA in serum or CSF. Treatment of severe cases might benefit from a combined regime of intravenous immunoglobulins and steroids. To confirm these outcomes, goal-targeted studies are recommended to exactly identify epidemiological scenarios and explore potential pathogenic mechanisms of these complications. Performing retrospective and prospective and multicenter studies concerning B19 and neurological aspects in general, and B19 and encephalitic syndromes in particular, are required.

Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces.

Borna disease virus (BDV) is a non-cytolytic, neurotropic RNA virus that can infect a wide variety of vertebrate species from birds and primates to humans. Several studies have been carried out to investigate whether BDV is associated with neuropsychiatric diseases. However, this association is still inconclusive. Two panels of subjects consisting of 1,679 various neuropsychiatric patients and healthy people from three western China provinces were enrolled in this study. BDV p24 or p40 RNA in peripheral blood mononuclear cells (PBMCs) were detected in the first panel of 1,481 subjects using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and cerebrospinal fluid (CSF) samples from the BDV RNA-positive individuals were subjected to BDV p24 antibodies testing by enzyme-linked immunosorbent assay (ELISA). BDV p24 or p40 RNA in PBMCs and p24 antibodies in plasma were detected in the second panel of 198 subjects by RT-qPCR and Western blot. A higher prevalence for BDV RNA was demonstrated in patients with viral encephalitis (6.70%), Guillain-Barré syndrome (6.70%), schizophrenia (9.90%) and chronic fatigue syndrome (CFS) (12.70%) compared to healthy controls in the first panel. CSF p24 antibodies were demonstrated in three viral encephalitis patients, two schizophrenia patients and two major depressive disorder (MDD) patients. The prevalences of p24 antibodies in plasma from patients with viral encephalitis (13.24%), multiple sclerosis (25.00%) and Parkinson's disease (22.73%) were significantly higher than healthy controls. This study demonstrates that BDV infection also exists in humans from three western China provinces, and suggests the involvement of the contribution of BDV in the aetiology of Chinese patients with some neuropsychiatric disorders, including viral encephalitis, schizophrenia, CFS, multiple sclerosis and Parkinson's disease.

No evidence of XMRV provirus sequences in patients with myalgic encephalomyelitis/chronic fatigue syndrome and individuals with unspecified encephalopathy.

Xenotropic murine leukemia virus-related virus (XMRV) has been considered a possible trigger of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and could also be linked with unspecified encephalopathy. The aim of this study was to analyse the frequency of XMRV proviral sequences in peripheral blood leukocyte (PBL) DNA from 150 patients with ME/CFS and 30 apparently healthy individuals, as well as in PBL and brain tissue DNA from 61 individuals with/without unspecified encephalopathy. Targeting the XMRV proviral gag gene sequence by nested polymerase chain reaction (nPCR) with previously reported primer sets, provirus was not detected either in DNA from patients with ME/CFS and individuals with unspecified encephalopathy, or in apparently healthy individuals. Only the positive control gave the amplimer of 410 base pairs (bp) after the second round that corresponds to the expected XMRV gag gene fragment. In addition, DNA was found to be negative in nPCR assays, targeting XMRV specific env gene sequence, using previously described primer sets. Also only positive control gave the amplimer of 218 bp after the second round, corresponding to the expected XMRV env gene fragment. Using nPCR we found no evidence of XMRV infection either in apparently healthy individuals or in patients with ME/CFS and individuals with unspecified encephalopathy.

Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.