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Chronic fatigue syndrome, also called myalgic encephalomyelitis, represents a complex disorder marked by profound fatigue, postexertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and, in many cases, orthostatic intolerance. Diagnosis remains clinical and requires exclusion of alternative conditions, with contemporary frameworks emphasizing activity reduction, PEM, and sleep disturbance, plus either cognitive impairment or orthostatic intolerance. Research results suggest immune dysregulation, autonomic imbalance, and mitochondrial dysfunction, although no validated biomarker is available for routine practice. The illness often follows a relapsing course and substantially impairs daily functioning. Management relies on nonpharmacological strategies such as pacing, activity modification, sleep optimization, and targeted rehabilitation, while pharmacologic therapy focuses on comorbid pain, sleep disorders, mood symptoms, and dysautonomia. Clear communication about prognosis, energy conservation, and functional goals supports shared decision-making and reduces stigma. The participant learns a practical, stepwise diagnostic approach that incorporates structured history-taking, focused examination, use of validated symptom inventories, and selective testing to exclude mimicking conditions. Instruction highlights individualized pacing, workplace or school accommodations, sleep and autonomic management, and treatment of comorbid psychiatric or pain conditions. Evidence-based appraisal of behavioral and rehabilitative interventions further strengthens clinical decision-making. Collaboration among an interprofessional team—such as clinicians, mental health specialists, physical or occupational therapists, and social workers—enhances coordination, supports patient-centered care, and contributes to improved functional outcomes. Objectives: Identify comorbidities such as mood disorders, chronic pain, mast cell activation features, or orthostatic intolerance that influence prognosis. Select supportive resources, rehabilitation modalities, and workplace or school accommodations tailored to functional capacity. Evaluate the effectiveness of nonpharmacological and pharmacological interventions to optimize overall functioning.

Identify comorbidities such as mood disorders, chronic pain, mast cell activation features, or orthostatic intolerance that influence prognosis. Select supportive resources, rehabilitation modalities, and workplace or school accommodations tailored to functional capacity. Evaluate the effectiveness of nonpharmacological and pharmacological interventions to optimize overall functioning. Implement interprofessional team strategies to enhance care coordination and communication, ensuring optimal outcomes for patients with chronic fatigue syndrome. Access free multiple choice questions on this topic.

Chronic fatigue syndrome (CFS) is a complex disease that affects approximately 2 million people in the United States.[1] The United States Public Health Services initially described CFS during an epidemiological study in Los Angeles County during the summer of 1934. Chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME), is a complex, multisystem disease commonly characterized by severe fatigue, cognitive dysfunction, sleep disturbances, autonomic dysfunction, and postexertional malaise, which severely impair activities of daily living. Outcomes are often poor due to delayed or misdiagnosis, inadequate clinician education, clinician bias, and misinformation regarding the diagnosis and treatment of the disease.[1] ME/CFS has been identified as 1 of the 10 chronic overlapping pain conditions by the National Institutes of Health.[2] Patients with chronic overlapping pain conditions often experience nociplastic pain, which arises from altered nociceptive processing in the absence of a clear lesion or disease affecting the somatosensory nervous system, or without actual or threatened tissue damage that would typically activate peripheral nociceptors. Compared to nociceptive or neuropathic pain, nociplastic pain is more frequently associated with central nervous system–related symptoms, including fatigue, cognitive and memory disturbances, depression, and anxiety.[2][3] CFS presents with fatigue, cognitive dysfunction, and impairment of routine functioning that persists for at least 6 months. CFS is a biological condition, not a psychological disorder, and the exact pathogenesis is not fully understood. Various mechanisms and biochemical changes have been implicated, including immune dysregulation (natural killer cell and T-cell dysfunction, elevated cytokine levels, and autoantibodies), hormonal dysregulation, and response to oxidative stress.[4] Although infectious causes have been proposed, no causal relationship has been identified.[5] Furthermore, patients with CFS can sometimes present to the emergency department with several complex symptoms, such as orthostatic intolerance, postexertional malaise, fatigue, and diarrhea.[6]

The etiology of CFS is controversial, complicated, and incompletely understood. There is controversy over whether it has a single or multiple etiologies. Several theories exist regarding the interplay between infections, the immune system, and genetics in this complex process. Genetics Increasing evidence supports the role of genetic susceptibility in patients with CFS. Many studies' results have reported the role of family history in the development of CFS or similar fatigue-like symptoms.[7] Study results from the twin registry have also shown increased familial and genetic predisposition to the condition.[8][9] A study observed variability in the expression of specific genes in patients with CFS, particularly after exercise, affecting metabolism and immune responses.[10] In another study, the results showed an association between CFS and specific genetic mutations and viral infections.[11] Infection Various infectious etiologies, including Epstein-Barr virus, human herpesvirus 6 (HHV-6), and human parvovirus B19, are hypothesized to trigger the disease.[12][13][14][15] In some patients, viral infections such as infectious mononucleosis trigger the onset of the disease.[16][17][18] Researchers have detected anti–HHV–6 immunoglobulin M antibodies and HHV-6 antigens more frequently in the peripheral blood of patients with CFS than in the general population, indicating a higher prevalence and increased viral reactivation in this cohort.[19][20][21][22] Parvovirus B19, both with and without viremia, has been implicated in triggering CFS.[23] Patients with infectious causes also have higher levels of tumor necrosis factor and interferon-γ.[24] Alterations in the Immune System Alterations in the levels of CD21+, CD19+, and activated CD5+ cells have also been observed in patients with CFS.[25] Decreases in transitional B cells and plasmablasts, along with an increase in CD24+ B cells, have also been observed in these patients.[26][27] Researchers have also found elevated immunoglobulin levels in several studies, indicating immune dysfunction.[28][29] Results from several studies have also reported the presence of autoantibodies against nuclear and membrane antigens, as well as neurotransmitter receptors.[30][31][32][33]

Study results report varying prevalence estimates for CFS, depending on the definition used, the type of population surveyed, and the study design.[34] Current prevalence estimates range from 0.007% to 2.8% in the general adult population in the United States and from 0.006% to 3.0% in primary care populations.[35][36][37][38][39] Results from studies conducted between 1993 and 1999 reported prevalence rates of 0.004% to 0.56%, whereas more recent studies' results have reported rates ranging from 0.24% to 2.6%.[40] According to a 2004 study conducted by Bierl et al, approximately 2.2 million adults in the United States had CFS-like illnesses.[41] They estimated that about 1197 people per 100,000 population had CSF and CFS-like illnesses.[41] Further, results from some studies report that the prevalence is significantly higher among individuals aged 40 to 70.[42] Furthermore, women are diagnosed more often than men.[43] The prevalence appears to be higher in White individuals than in other racial or ethnic populations.[43] Study results also demonstrate a markedly higher prevalence in lower socioeconomic groups, suggesting that possible social determinants of health, such as stress, may play a role.[41][42] No significant regional differences were observed.[41]

Alterations in the Immune System The pathophysiological mechanisms leading to CFS are not entirely understood.[44] Altered nervous system functioning occurs secondary to an immune response to common antigens, leading to changes in cell-mediated immunity, activation of oxidative pathways, and alterations in neuroendocrine and autoimmune responses against neurons.[45] Results from multiple studies have shown alterations in the function of natural killer cells, interleukins, and the T-cell response to specific antigens.[44] Increased production of various proinflammatory interleukins contributes to malaise and flu-like symptoms.[44] Increased Oxidative Stress Some study results suggest that CFS is associated with a significant increase in oxidative stress. Increases in biomarkers such as oxidized low-density lipoprotein and certain prostaglandins, along with decreases in antioxidants such as glutathione, contribute to inflammation.[46][47] Oxidative damage transforms the fatty acids and proteins into immunogenic targets.[48] Free radicals also damage the electron transport chain (impairing energy production) and mitochondria.[49] The mechanism underlying mitochondrial dysregulation is not entirely known.[50][51][52] Oligoadenylate Synthetase/RNase L Pathway Results from several studies have supported the association between the onset of CFS and viral infection. One of the interferon-activated antiviral pathways involves the activation of the 2',5’-oligoadenylate synthetase/RNase L system.[53] Severe dysregulation of this antiviral pathway occurs in CFS, resulting in decreased apoptotic activity in cells. Alteration of Natural Killer Cells Results of a study found lower numbers of CD3+ and CD57+ lymphocytes (a type of natural killer cell), whereas cytotoxic T cell levels remained unchanged.[54][55][56] B-Cell Impairment The profile of B-cell subpopulations may differ in CFS compared with controls. CFS is associated with an increased proportion of CD20+ and CD5+ B-cell phenotypes, correlating with increased autoantibody production and overexpression of CD21, a receptor for certain viruses.[26][27] Immunoglobulins

Results of a study found lower numbers of CD3+ and CD57+ lymphocytes (a type of natural killer cell), whereas cytotoxic T cell levels remained unchanged.[54][55][56] B-Cell Impairment The profile of B-cell subpopulations may differ in CFS compared with controls. CFS is associated with an increased proportion of CD20+ and CD5+ B-cell phenotypes, correlating with increased autoantibody production and overexpression of CD21, a receptor for certain viruses.[26][27] Immunoglobulins Alterations in the number and distribution of immunoglobulins occur in CFS. The total immunoglobulin (Ig) G level, particularly subclasses IgG1 and IgG3, is substantially lower. In contrast, IgA and IgM serum levels against gram-negative bacterial lipopolysaccharides increase due to alterations in gut permeability.[57][58] Autoimmunity Autoantibodies directed against specific neurotransmitters and neurons alter neurotransmitter responses, sleep patterns, and neurocognition.[32][59] Moreover, antinuclear antibodies, anti-double-stranded DNA antibodies, and antibodies targeting neuronal and endothelial cells have been identified in these patients.[60] Antibodies against the muscarinic M1 acetylcholine β-adrenergic receptors have also been detected.[15][32] Disturbance in these receptors could explain symptoms of autonomic dysregulation.[61] Alterations in the Central Nervous System Neuroinflammation and the role of glial cells The presence of proinflammatory changes in the central nervous system has led to hypotheses of neuroinflammation in the disease's pathogenesis.[62] For example, the persistent proinflammatory state in CFS activates glial cells, specifically microglia and astrocytes. These activated glial cells express a protein that propagates inflammation in the central nervous system.[63] Increased glial activation leads to increased neuronal excitation and inflammation, which is believed to be the primary contributor to chronic pain symptoms in these patients.[64] Studies are also evaluating the role of glial toxins produced by multiple viruses and bacteria, which can directly damage these glial cells.[65] Neuronal sensitization

The presence of proinflammatory changes in the central nervous system has led to hypotheses of neuroinflammation in the disease's pathogenesis.[62] For example, the persistent proinflammatory state in CFS activates glial cells, specifically microglia and astrocytes. These activated glial cells express a protein that propagates inflammation in the central nervous system.[63] Increased glial activation leads to increased neuronal excitation and inflammation, which is believed to be the primary contributor to chronic pain symptoms in these patients.[64] Studies are also evaluating the role of glial toxins produced by multiple viruses and bacteria, which can directly damage these glial cells.[65] Neuronal sensitization The hypothesis of neuronal sensitization posits that patients with CFS exhibit an exaggerated response to painful stimuli, driven by chemical and structural changes in the central nervous system.[64] This heightened immune response leads to the formation of sensitized neurons that perpetuate the stimulus through a process known as kindling. Alterations in the Neuroendocrine System Changes in serotonin transmission Central fatigue, a key symptom in patients with CFS, is hypothesized to result from elevated levels of serotonin and its metabolites in the central nervous system.[66] Excess serotonin inhibits action potential generation, thereby reducing motor activity and contributing to fatigue-related symptoms.[67][68] Hypocortisolism Low circulating cortisol levels have been reported in patients with CFS, secondary to dysfunction of the hypothalamic-pituitary axis. Cortisol is the principal hormone of the hypothalamic-pituitary axis and mediates the cortisol awakening response. This response is deficient in patients with CFS, which may contribute to postexertional malaise.[69] Genetic Predisposition An interaction between genes, secondary to environmental changes, leads to epigenetic modification. DNA methylation is the most extensively studied of these epigenetic modifications, altering gene expression in response to environmental stimuli and contributing to the development of disease processes.[70]

The hallmark symptom of chronic fatigue syndrome is postexertional malaise, which is often accompanied by numerous neurological, cardiovascular, respiratory, and gastrointestinal tract symptoms.[70] The fatigue described by patients is worsened by exertion and upright posture, is not relieved by rest, and has no alternative medical explanation.[71] Patients often report high fitness levels before fatigue onset.[72] Patients typically describe fatigue as usually associated with a flu-like illness.[73] They also describe postexertional malaise, which occurs when regular activity is followed by worsening discomfort and fatigue, with delayed recovery (typically more than 24 hours).[74] Patients also describe recent-onset, recurring headaches with varied weekly fluctuations.[74] Muscle pain is more common in children and could also reflect comorbid fibromyalgia.[75] Patients may also report joint pain, and some have an associated autoimmune rheumatological disease.[75] Sleep disturbance and morning fatigue lead to daytime hypersomnolence and nighttime insomnia.[74] Additionally, patients may experience cognitive decline, characterized by slowed mental processing speed, impaired learning abilities, difficulty processing new information, memory loss, decreased attention span, and reduced multitasking ability.[76] Autonomic manifestations include nausea, vomiting, drenching night sweats, dizziness, and intolerance to alcohol and other medications.[77][78] Patients can also exhibit symptoms of uncontrolled anxiety, panic attacks, and impaired social functioning.[79][80] Most patients have decreased occupational functioning.[81]

CFS is a complex clinical diagnosis of exclusion made after ruling out other medical and psychiatric conditions. The National Institutes of Health recognizes ME/CFS as one of the 10 chronic overlapping pain conditions, which is commonly associated with nociplastic pain, a centrally mediated pain type characterized by fatigue, cognitive issues, and mood disturbances. This condition manifests with persistent, unexplained fatigue that impairs activities of daily living.[82] Historical Evolution of Diagnostic Criteria At the time of its initial recognition, CFS was frequently attributed to viral causes, which played a key role in shaping the first diagnostic guidelines. In 1988, the US Centers for Disease Control and Prevention proposed the first formal diagnostic criteria, primarily focused on physical manifestations. However, this initial approach was considered narrow and lacked specificity. In 1991, the Oxford criteria were introduced, broadening the diagnostic lens. These criteria emphasized persistent or relapsing fatigue as the core symptom. According to the Oxford framework, fatigue had to be severe, have a defined onset, and be present for at least 6 months, affecting physical and mental performance more than half the time. While secondary symptoms such as myalgia, mood disturbances, and sleep dysfunction were considered, the criteria also explicitly excluded active psychiatric conditions, substance use disorders, or known organic brain diseases.[79] Despite its wide adoption, the Oxford criteria drew criticism for being overly inclusive, often leading to the diagnosis of individuals with nonspecific or mild fatigue. This diluted the homogeneity of CFS populations in clinical trials and research, thus limiting the generalizability of findings, particularly for those with classic postexertional malaise and more disabling forms of the condition.[83][84][85] To address these limitations, Fukuda et al introduced a revision under the CDC in 1994. This updated criterion required persistent fatigue for at least 6 months, not resulting from ongoing exertion or relieved by rest. Additionally, patients needed to report at least 4 out of 8 specific symptoms: Unrefreshing sleep Postexertional malaise Myalgia Arthralgia Headaches of a new type or intensity Sore throat Tender lymphadenopathy Impaired memory or concentration [86]

Despite its wide adoption, the Oxford criteria drew criticism for being overly inclusive, often leading to the diagnosis of individuals with nonspecific or mild fatigue. This diluted the homogeneity of CFS populations in clinical trials and research, thus limiting the generalizability of findings, particularly for those with classic postexertional malaise and more disabling forms of the condition.[83][84][85] To address these limitations, Fukuda et al introduced a revision under the CDC in 1994. This updated criterion required persistent fatigue for at least 6 months, not resulting from ongoing exertion or relieved by rest. Additionally, patients needed to report at least 4 out of 8 specific symptoms: Unrefreshing sleep Postexertional malaise Myalgia Arthralgia Headaches of a new type or intensity Sore throat Tender lymphadenopathy Impaired memory or concentration [86] The Fukuda criteria represented a significant advance, incorporating both physical and neurocognitive aspects. However, critics argued that it still lacked precision, especially in research classification, as it allowed patients to meet diagnostic thresholds without including hallmark symptoms, such as postexertional malaise.[87] The 2015 Institute of Medicine Redefinition In 2015, the Institute of Medicine, now the National Academy of Medicine, conducted a comprehensive review of existing criteria to develop a more unified, evidence-based definition of the term. The resulting framework emphasized core, measurable symptoms and proposed the name systemic exertion intolerance disease, although the traditional term CFS/ME is widely used. The Institute of Medicine criteria require the following 3 core symptoms, present for more than 6 months and of at least moderate to severe intensity, at least 50% of the time: Substantial reduction in preillness activity levels: Fatigue that is not improved with rest and is not the result of ongoing exertion. Postexertional malaise: Worsening of symptoms following physical, mental, or emotional effort. Unrefreshing sleep: Waking feeling unrefreshed or exhausted. In addition to the core features, at least one of the following must also be present: Cognitive impairment: Often described by patients as brain fog, characterized by slowed thinking, memory lapses, or impaired attention.

Postexertional malaise: Worsening of symptoms following physical, mental, or emotional effort. Unrefreshing sleep: Waking feeling unrefreshed or exhausted. In addition to the core features, at least one of the following must also be present: Cognitive impairment: Often described by patients as brain fog, characterized by slowed thinking, memory lapses, or impaired attention. Orthostatic intolerance: Upright posture can worsen fatigue, dizziness, or cognitive symptoms in some patients, a phenomenon that typically improves when lying down. This redefinition helped clinicians recognize CFS as a multisystem disorder with profound effects on energy metabolism, neurocognition, and autonomic function.[87] Diagnosing CFS requires a methodical and comprehensive clinical evaluation. The cornerstone of assessment includes: Detailed medical history and physical examination Exclusion of other medical or psychiatric causes of fatigue, including anemia, thyroid dysfunction, chronic infections, autoimmune diseases, sleep disorders, and depression Use of validated tools (eg, DePaul Symptom Questionnaire, Centers for Disease Control Symptom Inventory) for symptom quantification and longitudinal monitoring CFS lacks a pathognomonic biomarker, so initial evaluation generally includes laboratory examinations aimed at excluding other illnesses: Complete blood count Metabolic profile and liver/renal function examinations Thyroid function tests (thyroid-stimulating hormone, free thyroxine) Inflammatory markers such as C-reactive protein or erythrocyte sedimentation rate Creatine kinase for muscle involvement Additional tests may be tailored based on specific presentations. The National Institute for Health and Care Excellence suggests excluding celiac disease with IgA antiendomysial antibodies when gastrointestinal symptoms are prominent. Urine toxicology and rheumatologic panels (eg, antinuclear antibody) may be indicated in certain cases. Importantly, routine viral titers are discouraged unless guided by clinical suspicion, as they often do not alter management.[88][89]

Additional tests may be tailored based on specific presentations. The National Institute for Health and Care Excellence suggests excluding celiac disease with IgA antiendomysial antibodies when gastrointestinal symptoms are prominent. Urine toxicology and rheumatologic panels (eg, antinuclear antibody) may be indicated in certain cases. Importantly, routine viral titers are discouraged unless guided by clinical suspicion, as they often do not alter management.[88][89] Results from recent studies suggest potential immune dysregulation, mitochondrial dysfunction, and autonomic nervous system imbalance may play central roles in pathophysiology. Ongoing research is investigating metabolomic, proteomic, and neuroimaging biomarkers, although none are currently validated for clinical use. Notably, the COVID-19 pandemic has renewed interest in CFS, as a significant subset of individuals with long COVID exhibit symptoms overlapping with ME/CFS, particularly fatigue, cognitive fog, and postexertional malaise. This intersection may help accelerate the discovery of biomarkers and the development of therapeutic trials.[90]

Nonpharmacologic Management There is debate over the most effective treatment for chronic fatigue syndrome. A randomized controlled trial conducted in 2011 in the United Kingdom compared the effectiveness and safety of cognitive-behavioral therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT), and specialist medical care in the management of chronic fatigue syndrome. Improvement in fatigue and physical functioning were measures of effectiveness, while safety was assessed by recording all adverse events. The results showed that CBT and GET improved outcomes when combined, whereas APT did not.[83] Further analysis of the available data has raised questions about the statistical significance of the benefits of CBT and GET.[91] The CDC recommends treating associated depression, stress, and anxiety, but states that these interventions are not cures for CFS. Techniques such as deep breathing and muscle relaxation, massage, yoga, and tai chi may be beneficial. Moreover, treatment for any comorbid condition should be undertaken to minimize symptom burden.[86][92] During CBT sessions, the therapist emphasizes the role of thought patterns and their impact on the patient's actions and feelings, focusing on behaviors that exacerbate fatigue. Results from multiple trials and Cochrane reviews have demonstrated the positive benefits of CBT in improving fatigue, mood, and postexertional malaise in both adolescent and adult patients.[92][93][94][95] Study findings have also shown lower school absences among adolescents when CBT is provided.[96]

During CBT sessions, the therapist emphasizes the role of thought patterns and their impact on the patient's actions and feelings, focusing on behaviors that exacerbate fatigue. Results from multiple trials and Cochrane reviews have demonstrated the positive benefits of CBT in improving fatigue, mood, and postexertional malaise in both adolescent and adult patients.[92][93][94][95] Study findings have also shown lower school absences among adolescents when CBT is provided.[96] GET involves a supervised, gradual increase in the duration and intensity of physical activity. After the trial Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE), this therapy received substantial publicity, which reported effectiveness for fatigue and functional impairment with GET.[83] The trial encouraged participants to gradually increase the duration of their physical activity over 52 weeks, aiming for a final goal of 30 minutes of light exercise, 5 days per week, while avoiding overexertion. Other studies have also supported its efficacy.[97][98][99] However, CBT and GET are adjunctive management options and are not curative. Activity management is also called pacing. The goal is to learn to balance rest and activity to avoid flare-ups. These exacerbations can be caused by intolerable exertion. Pharmacologic Management Pain medications Nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors, are used due to their analgesic and anti-inflammatory properties.[100][101] However, opioid medications are addictive and should be used only for very severe cases for the shortest possible duration.[102] Tricyclic antidepressants Multiple tricyclic antidepressants have shown varying degrees of success in improving sleep, pain levels, and fatigue severity.[100] The doses used are typically lower than the doses used in the treatment of depression.[103] Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors

Tricyclic antidepressants Multiple tricyclic antidepressants have shown varying degrees of success in improving sleep, pain levels, and fatigue severity.[100] The doses used are typically lower than the doses used in the treatment of depression.[103] Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors Many selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, sertraline, and paroxetine, have been used to treat depression and anxiety, which may accompany the course of chronic fatigue syndrome or occur as a consequence. Serotonin-norepinephrine reuptake inhibitors (SNRIs) have the added benefit of providing neuropathic pain relief besides the antidepressant effect. However, neither SSRIs nor SNRIs directly treat the underlying pathophysiology.[83] Antiviral therapy Several antiviral medications have been studied, but the results have been largely inconclusive.[104][105] Results from randomized controlled trials comparing the effects of nucleoside analog antivirals, such as acyclovir, valacyclovir, and ganciclovir, with placebo have shown no difference in symptom control.[106] Studies using interferons compared with placebo in CFS also did not show evidence of a clear benefit.[107] Immunoglobulin A systematic review conducted by Whiting et al in 2001 evaluated 5 randomized controlled trials of immunoglobulin use in patients with CFS; four were positive.[83] Unfortunately, other study findings did not report benefits and instead reported potential harms associated with immunoglobulins. Corticosteroids Multiple randomized controlled trials and systematic reviews of corticosteroid use in CFS in 2005 reported varying responses. Results from a 2015 systematic review showed a weak benefit from low-dose hydrocortisone, but the effect was short-lived and was associated with adverse events.[108] Complementary and alternative medicines Results from systematic reviews of interventions such as using essential fatty acids, magnesium, acetyl-L-carnitine, vitamin B12, and antioxidants have shown only partial response and require further studies to establish a definitive relationship.[109] Newer Treatments and Trials Rintatolimod

Complementary and alternative medicines Results from systematic reviews of interventions such as using essential fatty acids, magnesium, acetyl-L-carnitine, vitamin B12, and antioxidants have shown only partial response and require further studies to establish a definitive relationship.[109] Newer Treatments and Trials Rintatolimod Rintatolimod is a newly approved immunomodulator and an antiviral drug for the treatment of CFS in Canada and Europe.[110] Results from a randomized clinical trial published in the Journal of the American Medical Association in 2001 reported that the medication was of some benefit.[111] The US Food and Drug Administration rejected the drug for the treatment of CFS, citing insufficient safety and efficacy data. Rituximab Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. Results from an initial small, double-blind, placebo-controlled trial of 30 patients with CFS receiving rituximab showed some benefit, leading the researchers to hypothesize that B cells may have a significant role in the pathogenesis of CFS.[112] However, findings from a larger study showed no difference in fatigue between patients who received rituximab and those who did not. Also, patients receiving rituximab had more adverse events, including neutropenia and infections.[113] Fecal Microbiota Transplantation Alterations in the gastrointestinal tract microbiota have been hypothesized as a possible etiology of CFS.[114][115] Fecal microbiota transplants are an exciting, relatively safe, and rapidly growing treatment modality currently under study for the management of multiple medical conditions, including CFS.[116][117] The process involves transferring feces from a healthy donor into a patient's gut.[118] Results from numerous studies have shown significant symptom improvement in these patients after fecal microbiota transfer, providing promising therapeutic insights.[119][120] Although there has been some success with fecal microbiota transplant, it is still too early to draw definitive conclusions. Cannabis-Based Medicines

Alterations in the gastrointestinal tract microbiota have been hypothesized as a possible etiology of CFS.[114][115] Fecal microbiota transplants are an exciting, relatively safe, and rapidly growing treatment modality currently under study for the management of multiple medical conditions, including CFS.[116][117] The process involves transferring feces from a healthy donor into a patient's gut.[118] Results from numerous studies have shown significant symptom improvement in these patients after fecal microbiota transfer, providing promising therapeutic insights.[119][120] Although there has been some success with fecal microbiota transplant, it is still too early to draw definitive conclusions. Cannabis-Based Medicines A current question is whether cannabis-based medicines (CBMs) can help manage CFS, particularly by improving sleep and reducing pain. Chronic pain and sleep disruption frequently coexist in CFS, and these symptoms have a bidirectional relationship. Poor sleep can exacerbate pain, and pain can interfere with sleep quality. While some observational studies and large case series have reported improvements in sleep quality and reductions in opioid consumption with cannabinoid use, the evidence remains mixed. Short-term improvements in sleep have been noted with cannabinoids, but some studies indicate potential worsening of sleep with long-term use.[82][121][122] A recent high-quality systematic review by the International Association for the Study of Pain Presidential Task Force highlighted significant methodological limitations in the CBM clinical trial literature, including small sample sizes, brief follow-up periods, inconsistent outcome measures, and a lack of studies focusing on CBD-only formulations. For other pain conditions such as fibromyalgia or cancer-related pain (both of which share symptomatic overlap with CFS), the evidence is insufficient due to underpowered and limited trials.[123][124]

Chronic fatigue syndrome can affect instrumental activities of daily living, including tasks such as cleaning, laundry, driving, and managing finances. Please see StatPearls' companion resource, "Instrumental Activity of Daily Living," for further information. Therefore, clinicians must be able to diagnose this condition while also differentiating it from other commonly encountered disorders in clinical practice with overlapping presentations. Chronic Fatigue Even though CFS has fatigue as one of the 3 core symptoms, it is a complex, multisystem neurological disease with evidence supporting neuroinflammation, hence the term myalgic encephalomyelitis.[125] Conversely, chronic fatigue is characterized by the absence of associated postexertional malaise, unrefreshing sleep, and cognitive impairment.[125] To minimize confusion with terminology, the Institute of Medicine has suggested replacing the term chronic fatigue syndrome with systemic exertion intolerance disease.[1] Rheumatologic Disorders Fibromyalgia, polymyalgia rheumatica, polymyositis, and autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren disease present a significant diagnostic dilemma for clinicians.[126][127][128] Accurate diagnosis requires a thorough history, a comprehensive clinical examination, and laboratory testing for autoantibodies to confirm the correct diagnosis. Psychiatric Disorders Roughly 20% of patients presenting to primary care clinics have an underlying undiagnosed depressive illness, and a targeted mental health history is critical.[129] A range of undiagnosed or underdiagnosed disorders, including major depressive disorder, bipolar disorder, eating disorders, schizophrenia, somatoform disorders, and substance use disorders, could have overlapping presentations. In older adults, symptoms of fatigue, unrefreshing sleep, and cognitive decline can be components of the symptom complex of late-onset depression. Please see StatPearls' companion resource, "Late-Life Depression," for further information. Endocrine Disorders Adrenal abnormalities (eg, Addison disease, adrenal insufficiency, Cushing disease), thyroid abnormalities (both hypothyroidism and hyperthyroidism), and diabetes mellitus can mimic symptoms of CFS. Hematologic and Oncologic Disorders

Roughly 20% of patients presenting to primary care clinics have an underlying undiagnosed depressive illness, and a targeted mental health history is critical.[129] A range of undiagnosed or underdiagnosed disorders, including major depressive disorder, bipolar disorder, eating disorders, schizophrenia, somatoform disorders, and substance use disorders, could have overlapping presentations. In older adults, symptoms of fatigue, unrefreshing sleep, and cognitive decline can be components of the symptom complex of late-onset depression. Please see StatPearls' companion resource, "Late-Life Depression," for further information. Endocrine Disorders Adrenal abnormalities (eg, Addison disease, adrenal insufficiency, Cushing disease), thyroid abnormalities (both hypothyroidism and hyperthyroidism), and diabetes mellitus can mimic symptoms of CFS. Hematologic and Oncologic Disorders Undiagnosed malignancies can present with symptoms of fatigue and warrant a search for underlying cancer with age-appropriate screening. However, age alone should not be the only determining criterion for obtaining these screenings. Please see StatPearls' companion resource, "Breast Cancer Screening in the Average-Risk Patient," for further information. For example, anemia from any cause can present with excessive tiredness and fatigue.[130][131][132][133] Infectious Diseases Infectious diseases such as the human immunodeficiency virus, tuberculosis, and chronic hepatitis can have ongoing fatigue as their initial presentation. Gastrointestinal Tract Disorders Inflammatory bowel disease can present with chronic fatigue symptoms.[134] Celiac disease can present with fatigue without gastrointestinal tract symptoms. Neurological Disorders Fatigue is the typical presenting feature of multiple sclerosis.[135] Dementia, which has cognitive impairment as its major presentation, can cause a diagnostic dilemma, as can pseudodementia. Age-Related Orthostatic Hypotension Age-related changes in blood vessels lead to decreased autonomic responsiveness, which worsens with inadequate fluid intake and polypharmacy. Please see StatPearls' companion resource, "Vital Sign Assessment," for further information. Respiratory Disorders Chronic respiratory conditions like chronic obstructive pulmonary disease and sarcoidosis can present with chronic fatigue.[136] Sleep Apnea

Age-related changes in blood vessels lead to decreased autonomic responsiveness, which worsens with inadequate fluid intake and polypharmacy. Please see StatPearls' companion resource, "Vital Sign Assessment," for further information. Respiratory Disorders Chronic respiratory conditions like chronic obstructive pulmonary disease and sarcoidosis can present with chronic fatigue.[136] Sleep Apnea Undiagnosed obstructive sleep apnea can present with fatigue and unrefreshing sleep, 2 of the main diagnostic criteria for CFS. Sleep apnea is diagnosed by polysomnography.[137]

CFS has no known cure, and the symptoms can persist for years. The clinical course often fluctuates with remissions and relapses. According to findings from one prospective study, approximately 50% of patients with CFS may return to part-time or full-time employment.[138] Factors associated with poor prognosis include longer duration of illness, comorbid depression, greater fatigue severity, and anxiety.[139] Favorable outcomes are associated with milder fatigue at baseline, a better sense of control over symptoms, and the absence of attributing the disease to a physical cause.[140] Although considerable morbidity is associated with CFS, there is no evidence of increased mortality.

As with any chronic illness, patients with CFS often experience depression, stress, and anxiety. While CFS is not a psychological condition, it is highly debilitating. Symptom severity can be unpredictable and fluctuate over time. Patients often face ongoing challenges in their education, career, and personal life as they strive to balance obligations and personal goals. Many individuals with CFS describe feeling demoralized or hopeless.

Living with CFS can be stressful because symptoms can affect quality of life. Many individuals are generally healthy and active before developing CFS, making it particularly distressing. The most crucial factor in patients' successful coping with CFS is establishing a strong relationship with an experienced healthcare professional. Having a clinician that patients can trust, who listens to them and understands that their symptoms are real, can be validating and helpful. While it is discouraging to know that there is no quick cure for CFS, an experienced clinician can work with the patient to find ways to manage symptoms and maximize their quality of life.

Chronic fatigue syndrome frequently poses a diagnostic dilemma. The hallmark symptom is post-exertional fatigue, accompanied by numerous neurological, cardiovascular, respiratory, and gastrointestinal symptoms. Patients can also exhibit uncontrolled anxiety, panic attacks, and impaired social functioning. CFS is a diagnosis made on clinical evaluation after excluding other possible etiologies. Therefore, consulting with an interprofessional team of specialists, including a pain specialist, psychiatrist, psychotherapist, nursing staff, other clinicians, and possibly a physical therapist or pharmacist, can be helpful. Even though CFS has fatigue as one of the 3 core symptoms, it is a complex, multisystem neurological disease with evidence of neuroinflammation. As the term myalgic encephalomyelitis suggests, a neurology consultation may be beneficial when indicated. All interprofessional team members must monitor the patient, record any changes in their condition, and report progress or deterioration to inform other team members, allowing for adjustments in management approach if necessary. Open communication and diligent documentation are essential to the interprofessional strategy, ensuring that all team members have access to the same patient data. These practices help support better outcomes. The primary nonpharmacological treatment modalities are cognitive behavior therapy and graded exercise therapy. A wide range of medications can be used for CFS, ranging from nonsteroidal anti-inflammatory drugs to antidepressants; therefore, a pharmacist consultation is advisable. The pharmacist can perform medication reconciliation and check medication dosing, reporting any concerns to the other team members as appropriate. A broad differential diagnosis should be considered before making a diagnosis of CFS. However, consultation with an interprofessional healthcare team is recommended to improve outcomes.