Chronic Fatigue Syndrome
- Article Author:
- Amit Sapra
- Article Editor:
- Priyanka Bhandari
- Updated:
- 6/9/2020 1:42:34 AM
- For CME on this topic:
- Chronic Fatigue Syndrome CME
- PubMed Link:
- Chronic Fatigue Syndrome
Introduction
Chronic fatigue syndrome is a chronic disease that potentially affects about two million Americans.[1] The United States Public Health Services initially described it during an epidemiological study of Los Angeles County during the summer of 1934. Chronic fatigue syndrome, also called myalgic encephalomyelitis, is a complex multisystem disease commonly characterized by severe fatigue, cognitive dysfunction, sleep problems, autonomic dysfunction as well as post-exertional malaise, severely impairing activities of daily living. Things get worsened due to the condition remaining undiagnosed for years secondary to inadequate medical teaching on the subject, provider bias, as well as confusion regarding diagnoses and treatment of the disease.[1]
Etiology
The etiology of chronic fatigue syndrome is controversial, complicated, and incompletely understood. Controversy exists about single versus multiple causations. Theories abound regarding the involvement of infections, immune system as well as genetics in this complex interplay.
Genetics
Increasing evidence supports the role of genetic susceptibility in patients with CFS. Family history study of chronic fatigue syndrome, have shown significantly higher rates of family members of the patient reporting CFS or similar fatigue like symptoms.[2] Studies from the twin registry also have shown increased familial and genetic predisposition of the condition.[2][3][4][5] A study has reported variability in the expression of specific genes in patients with CFS, particularly after exercise, which affects the metabolism and immune responses.[5] At the same time, another study has shown a linkage between CFS, specific genetic mutations, as well as viral infections.[6]
Infection
As stated above, various infectious etiologies, including the Epstein-Barr virus (EBV), the human herpesvirus (HHV)-6, and the human parvovirus B19, are hypothesized to trigger the disease.[7][8][9][10]
Speculations are that in a few patients, acquisition of viral infections like infectious mononucleosis triggers the onset of the disease process.[8][11][12][13]
Researchers have detected anti-HHV-6 IgM antibodies and HHV-6 antigen more commonly in peripheral blood of patients with chronic fatigue syndrome as compared to the general population indicating higher prevalence as well as higher reactivation of the virus in this cohort.[14][15][16][17]
Parvovirus B19, both with and without viremia, has been implicated in the development and triggering of chronic fatigue syndrome.[18] These patients have higher levels of tumor necrosis factor and interferon-gamma.[19]
Alterations in the Immune system
Observations have shown alterations of B cell subsets levels, including those of CD 21+ CD19+ and activated CD5+ cells in patients with chronic fatigue syndrome.[20]
There is also a reported decrease in transitional B cells and plasmablasts, and an increase in the population of CD24+ B cells in these patients.[21][22] Researchers have also found elevations in the levels of immunoglobulins IgG in several studies, again pointing to alteration in the immune functioning of these patients.[23][22][24] Several studies have also described the presence of autoantibodies against nuclear and membrane structure as well as against neurotransmitter receptors.[25][26][27][28]
Epidemiology
Studies have given different prevalence rates for chronic fatigue syndrome based on the type of definition used, the type of population surveyed, and the study design used.[29] Studies have given a current prevalence rate ranging from 0.007% to 2.8% in the general adult U.S. population and from 0.006% to 3.0% in the primary care population.[30][31][32][33][34][35] Studies conducted from 1993 through 1999 reported prevalence of 0.004% to 0.56%, whereas more recent studies have reported prevalence rates of 0.24% to 2.6%.[30][31][33][36] As per the study conducted by Bierl and colleagues in 2004, about 2.2 million American adults suffer from CFS like illness.[37] They estimated that about 1,197 people per 100,000 people suffer from CSF and CFS like illnesses.[37]
Studies have found that the prevalence to be significantly higher in the age group of 40 to 70 years of age group.[30][36][37][38] Women are suffering from it more often than men.[30][36][37][38] The prevalence seems to be higher in the white population rather than the non-whites population.[30] Studies have also reported a markedly higher prevalence in the low-income cohort rather than the higher income and higher educated cohort, suggesting the role of social risk factors such as stress in the causation of CFS.[30][37][38] No regional differences were noticed in the country as far as the prevalence of CFS is concerned.[37]
Pathophysiology
Alterations in the Immune System
The pathophysiological changes which lead to chronic fatigue syndrome are not entirely understood.[39]
The hypothesis state that there is an alteration in the nervous system is occurring secondary to the body’s unintended responses to commonly encountered antigens leading to changes in the cell-mediated immunity, activation of oxidative pathways, and alteration in the neuroendocrinal and autoimmune responses against neurons.[40]
Multiple studies have shown alterations in the functioning of the natural killer (NK) cells, interleukins profile, as well as the decreased response of T cells to certain specific antigens.[39]
There is evidence of ongoing inflammation, as indicated by increased production of various proinflammatory interleukins, which also explains some of the malaise and flu-like symptoms that the patients often complain.[39]
Increased Oxidative Stress
Proposals are that chronic fatigue syndrome patients have a significant increase in oxidative stress, which plays a vital role in the etiopathogenesis of the disease. There is an increase in oxidative stress biomarkers like oxidized LDL and certain prostaglandins and, at the same time, a decrease in the amounts of the antioxidants like glutathione.[41][42]
The oxidative damage transforms the fatty acids and proteins into immunogenic targets.[43]
The free radicals also damage the electron transport chain as well as energy productions and finally cause mitochondrial damage.[44][41]
The proposed mechanism of mitochondrial dysregulation is currently actively researched.[45][46][47]
Oligoadenylate Synthetase/RNase L Pathway
The association between the onset of CFS with a viral infection has always been speculated. One of the interferon-activated antiviral pathways involves the activation of the 2’-5’-oligoadenylate (2-5A) synthetase/RNase L system.[48] Severe deregulation of this antiviral pathway occurs in CFS, which leads to a decrease in the apoptotic activity in the cells.
Alteration of Natural Killer (NK) Cells
Studies have shown a lower number of CD3-CD57 white cells lymphocytes, which are a type of NK cell, whereas the levels of the cytotoxic T cells were not changed.[49][50][51]
B Cell Impairment
The profile of B cell subpopulations may be different in CFS compared with controls. CFS is associated with increased production of the CD20+ CD5+ B cell phenotypes correlating with increased autoantibody production, as well as overexpression of CD21 markers acting as receptors for some viruses.[21][22]
Immunoglobulins
There is also an alteration in the immunoglobulin number and distribution in patients with chronic fatigue syndrome. The total level of immunoglobulin G (IgG), particularly subclasses IgG1 and IgG3, is substantially lower. In contrast, there is an increase in the serum levels of IgA and IgM against the lipopolysaccharides of the normal gram-negative bacteria due to alterations in gut permeability.[52][53] These can also serve as corroborative evidence for the provider about the patient suffering from CFS.
Autoimmunity
Studies have also detected autoantibodies against certain neurotransmitters and neurons, leading to alterations in neurotransmitter response, sleep patterns, and neurocognition.[27][54]
Researchers have found antinuclear antibodies (ANA), anti-dsDNA antibodies, as well as antibodies against neuronal and endothelial cells in these patients.[55] Antibodies against the muscarinic M1 acetylcholine beta-adrenergic receptors have been detected in these patients.[27][10] Disturbance in these receptors could explain symptoms of autonomic dysregulation in these patients.[56]
Alterations in the Central Nervous System
Neuroinflammation and Role of Glial Cells
The presence of proinflammatory changes causes speculation about the involvement of neuroinflammation in the pathogenesis and clinical presentation of the disease process.[57] Multiple studies show that the constant proinflammatory state that occurs in CFS causes activation of glial cells, specifically microglia and astrocytes. These activated glial cells produce the expression of a translator protein, which appears to lead to the activation of inflammation in the central nervous system.[58] The increase in glial activation leads to an increase in neuronal excitation as well as neuronal inflammation, which is supposed to be the leading cause of symptoms of chronic pain in these patients.[59] Studies are currently also evaluating the role of “glial toxins” produced by multiple viruses and bacteria, leading to direct damage to these glial cells.[60]
Neuronal Sensitization
The hypothesis state that there is an exaggerated response to painful stimuli in patients with CFS due to the chemical and structural changes taking place at the level of the central nervous system.[59]
This exaggerated response leads to the formation of sensitized neurons that keep the stimulus going due to the process of “kindling.”
Alterations in the Neuroendocrine System
Changes in Serotonin Transmission
The central fatigue, which is a key symptom in patients with chronic fatigue syndrome, is hypothesized to be due to excess levels of serotonin as well as its metabolites in the central nervous system of these patients.[61] The excess serotonin leads to inhibition of the action potential generation and thus reduced motor activity and appears to be a leading contributor to the fatigue symptoms of these patients.[62][63]
Hypocortisolism
It is also theorized that there are low levels of circulating cortisol in patients with chronic fatigue syndrome secondary to dysfunction in the hypothalamic-pituitary axis {HPA}. Cortisol is the principal hormone of the HPA and leads to the cortisol awakening response (CAR). This response is deficient in patients with CFS leading exhibition of post-exertional malaise.[64]
Genetic Predisposition
Studies have shown that there is an interaction between changes in the genes secondary to changes in the environment, leading to epigenetic modification. DNA methylation appears to be the most studied of these epigenetic modifications that can alter the expression of the gene concerning the environmental stimuli and lead to the development of the disease process.[65]
History and Physical
The hallmark symptom is the post-exertional fatigue associated with numerous neurological, cardiovascular, respiratory, as well as gastrointestinal complaints.[65] The fatigue described by patients is not exertional, worsened by low upright posture, not relieved by rest, and no medical reason can be found for it.[66] Patients often state that they have had high fitness levels before the onset of fatigue.[67] Patients describe the beginning of the fatigue rather abruptly, typically associated with a flu-like illness.[68] They also describe post-exertional malaise where the regular activity is followed by symptoms of worsening of discomfort and fatigue, with delayed recovery, usually taking more than one day.[69] Patients also complain of new-onset chronic headaches with varied weekly fluctuations.[69] Muscle pain is seen more commonly more in pediatric patients and also could be a feature of comorbid fibromyalgia.[70] Patients can also report joint pains, and there could be an associated autoimmune rheumatological condition.[70] Patients state that sleep is disturbed and not refreshing, as well as there is day time hypersomnolence and nighttime insomnia.[69] There are also complaints of cognitive decline with slowed mental processing speed, poor learning abilities, impaired processing of new information, memory decline and decreased attention span, and multitasking ability.[71] Besides, these patients can also manifest autonomic manifestations, including nausea, vomiting, drenching night sweats, dizziness, intolerance to alcohol, and other medications.[72][73] Patients can also exhibit symptoms of uncontrolled anxiety, panic attacks, and impaired social functioning.[72][74][75] Most of these patients have decreased ability to work.[76]
Evaluation
Chronic fatigue syndrome is a diagnosis made on clinical examination and after exclusion of other possible etiologies.
Initially, when the etiological considerations were was considered to be mainly viral in origin, the Center for Disease Control and Prevention (CDC) U.S.A. in the year 1988 came up with the criterion for the same with the primary focus on the physical symptoms. The Oxford criterion was developed in the year 1991 and defined a case of chronic fatigue syndrome if mild to severe symptoms of fatigue, myalgias, and tiredness were present.[74] The Oxford criterion considered fatigue to be the primary symptom and should have a definite beginning and should be severe, disabling, and affecting mental and physical functions. These symptoms should have been present for a minimum of six months and should be affecting the patient more than fifty percent of the time. There was a need for other symptoms like myalgias, mood, and sleep disturbances to be present as well. Exclusion criteria included those with a known medical condition known to cause fatigue as well as those with the diagnosis of mental health disorders like schizophrenia, mania, depression, eating disorders, substance abuse, or known organic brain pathology.[74]
Subsequent conclusions stated that the Oxford criterion was over-inclusive as well as had a low threshold that recruited patients with milder symptoms, leading to the generalization of treatments for all patients. Hence, the treatment guidelines could not be generalized to those with severe symptoms, patients with chronic pain, post-exertional malaise, and other conditions that mimicked chronic fatigue syndrome.[77][78][79]
Considering the need for revision of the diagnostic criterion, the CDC, in the year 1994, came up with a broader definition for chronic fatigue syndrome developed by Fakuda and colleagues.[80] As per these criteria, the patient should have severe fatigue for more than six months as well as at least four of the following symptoms- a new type of headache or a change in the pattern or severity of the headache, myalgias, pain in multiple joints, post-exertional malaise lasting more than one day, sore throat, tender lymph nodes, unrefreshing sleep and lastly a significant impairment in short term memory or concentration.
The modified CDC criterion was in extensive usage until the year 2015 when the Institute of Medicine ( IOM) came up with the criterion to diagnose chronic fatigue syndrome.[81] The current IOM criterion developed after reviewing the 1994 CDC guidelines by Fakuda and colleagues, the 2003 Canadian clinical case definition for CFS, the 2007 Clinical Guidelines for CFS from the British National Institute for Health and Clinical Excellence (NICE) along with the 2010 revised Canadian Consensus Criteria for CFS (Revised CCC).[81]
2015 IOM Diagnostic Criteria for CFS
Diagnosis requires the presence of the following three symptoms for more than six months as well as the intensity of the symptoms should be moderate or severe for at least 50% of the time.
The three main symptoms include:
- Fatigue - A noticeable decrease or impairment in patient's ability to engage in activities which they would enjoy before the onset of the illness, and this impairment continues for more than six months and is associated with new-onset severe fatigue, unrelated to exertion, and not relieved by rest.
- Post-exertional malaise - Patients experience worsening symptoms and function after exposure to physical or cognitive stressors, which they previously well tolerated.
- Unrefreshing sleep-patients feel that tired after a night's sleep.
Criterion fulfillment for diagnosis requires the three above stated symptoms, plus one of the additional below mentioned symptom.
- Cognitive impairment - Problems with the thought or executive function worsened by exertion, effort, or stress or time pressure
- Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining an upright posture. Symptoms are improved, although not necessarily abolished, by lying back down or elevating the feet.[81]
The typical approach to a patient with chronic fatigue should begin with a history and physical examination, focusing on identifying the underlying symptoms and ruling out any underlying serious illnesses. The providers should use a validated clinical questionnaire like the DePaul symptom questionnaire or the Center for Disease Control Symptom Inventory.[82][83]
There are no pathognomonic or diagnostic tests or single biomarkers of CFS. Tests to rule out other etiologies and undertaken in the context of the particular patient. The standard laboratory tests include urinalysis, complete blood count with differential, blood chemistries, thyroid function tests, muscle enzymes like creatine kinases, and C- reactive protein.[80] The National Institute for Clinical Excellence (NICE) also conducting tests for gluten sensitivity recommends using immunoglobulin A endomysial antibodies, urine drug screening, and rheumatological antibodies as indicated and recommend against using viral titers unless required by the patient's clinical examination.[84]
Treatment / Management
Non-Pharmacologic Management
The primary treatment modalities are cognitive behavior therapy (CBT) and graded exercise therapy (GET).
A randomized control trial conducted in 2011 in the United Kingdom compared the effectiveness and safety CBT, GET, adaptive pacing therapy (APT), and specialist medical care in the management of chronic fatigue syndrome. Overcoming fatigue and improvement of physical function were taken as measures of effectiveness while safety assessment comprised of recording all adverse effects. The results showed that both CBT and the GET improved outcomes when added to, whereas APT was not a useful addition.[77]
Treatment for any comorbid condition should be undertaken to minimize symptom burden.[80][85]
Cognitive Behavior Therapy (CBT)
During the CBT sessions, the therapist emphasizes the role of thought process and its impact on the patient’s actions and feelings as well as recognize behaviors which cause them to feel more tired and hence minimize them. Multiple trials, as well as Cochrane reviews, have shown the positive benefits of CBT on improving the fatigue, mood, and post-exertional malaise in both the adolescent and adult patients.[77][85][86][87][88] Studies have also shown lower school absences when CBT is provided to the adolescent population.[89]
Graded Exercise Therapy (GET)
GET involves a supervised, gradual increase of physical activity intensity and duration. This therapy got much publicity after the PACE trial, which showed effectiveness for fatigue and functional impairment with the GET.[77] The trial encouraged the participants to gradually increase the timing of their physical activity to a final goal of 30 minutes, spread over 52 weeks to a final goal of 30 minutes of light exercise five days per week while trying to avoid overexertion. Other studies have also supported its efficacy.[90][91][92]
Pharmacologic Management
Pain Medications
Nonsteroidal, including COX-2 inhibitors, are used due to their action in relieving pain and associated inflammation.[93][94] Opioid medications are addictive and hence only used for very severe cases for the shortest possible duration.[95]
Tricyclic Antidepressants
Multiple tricyclic antidepressants have shown varying degrees of success in improving sleep, pain levels, as well as the severity of fatigue.[93] Doses used here are typically lower than the doses used for use in the treatment of depression.[96]
Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Many SSRIs like fluoxetine, sertraline, paroxetine have been used for treating depression and anxiety, which either accompany the disease process or occur as a consequence of it.
SNRIs have the added benefit of providing neuropathic pain relief besides the antidepressant effect. However, neither SSRIs nor SSNRIs has any direct action on the underlying pathophysiology of the disease process.[77]
Antiviral Therapy
The hypothesis regarding viral etiologies, including Epstein Barr virus, for chronic fatigue syndrome, several antiviral medications have been tried in these patients, but most of these studies have been inconclusive.[97][98]
Randomized control trials comparing the effect of nucleotide analog inhibitors like acyclovir, valacyclovir, and ganciclovir, versus placebo, have shown no difference in symptom control.[99]
Studies with the use of interferons versus placebo on chronic fatigue syndrome also did not show evidence of clear benefit.[100]
Immunoglobulin
A systemic review conducted by Whiting et al. in 2001 evaluated the effect of the five RCT’s on the use of immunoglobulins in patients of chronic fatigue syndrome, and four RCTs showed positive results.[77] Unfortunately, other studies did not report any benefit and, in fact, concluded the potential dangers of the immunoglobulins.
Corticosteroids
Multiple RCTs and systemic reviews performed with steroids in 2005 showed varying responses. One systemic review conducted in 2015 showed a weak benefit from low dose hydrocortisone, but the effect was only short-lived and was associated with adverse effects.[101]
Complementary and Alternative Medicines
Systemic reviews of the studies using essential fatty acids, magnesium, acetyl -l-carnitine, vitamin B12, and antioxidants have shown only partial response and require further studies to decipher a definitive relation.[102]
Newer Treatments and Trials
Rintatolimod
Rintatolimod is a newly approved immunomodulator, and an antiviral drug for the treatment of chronic fatigue syndrome, in Canada and Europe.[103] An RCT published in the Journal of American Medical Association (JAMA) in 2001, showed the medication to be of some benefit in these patients.[104] The U.S. FDA rejected the drug to be marketed in the U.S. for the treatment of CFS, citing insufficient safety and efficacy data.
Rituximab
Rituximab is an anti-CD20 monoclonal antibody causing the depletion of B cells. 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 might have a significant role in the pathogenesis of some of the patients of chronic fatigue syndrome.[105] A more extensive study, however, showed no fatigue difference between patients who received rituximab versus who did not receive it.[106] Also, patients receiving rituximab showed more adverse effects, including neutropenia and infections.[106]
Fecal Microbiota Transplantation
Alteration in gastrointestinal (GIT) microbiota in patients of CFS has been hypothesized as one of the etiologies as well. Trials of fecal microbiota transplantation is an exciting, relatively safe, and rapidly growing treatment modality that is currently undergoing experimentation for the management of multiple medical conditions, including CFS. The process involves the transfer of feces from a healthy donor into the gut of a patient. Numerous studies in recent years have shown significant symptom relief in these patients after the fecal microbiota transfer providing some promising therapeutic insights.[107][108][109][110][111][112][113]
Even though currently there has been some success with the fecal microbiota, it is still too early to conclude but opens doors for future research in this direction.
Differential Diagnosis
Chronic fatigue syndrome can potentially affect the instrumental activities of daily living (IADLs), which comprise activities like cleaning, laundry, driving, and managing finances.[114] Hence, the clinicians must be able to diagnose this condition but, at the same time, also be able to differentiate it from other commonly encountered disorders in clinical practice, which can have overlapping presentations.
Chronic Fatigue
Even though chronic fatigue syndrome has fatigue as one of the three mandatory symptoms, it is a complex multisystem neurological disease with evidence of inflammation at the brain and hence the term myalgic encephalomyelitis.[115] Chronic fatigue, on the other hand, lacks the associated post-exertional malaise, unrefreshing sleep, as well as cognitive impairment.[115] To minimize the confusion with the terminology, the Institute of Medicine (IOM) has even suggested switching the terminology from chronic fatigue syndrome to systemic exertion intolerance disease (SEID)" instead of CFS.[1]
Rheumatological Disorders
Fibromyalgia, polymyalgia rheumatica, polymyositis, as well as autoimmune disorders like systemic lupus erythematosus [116], rheumatoid arthritis [117], Sjogren syndrome [118] can present a significant diagnostic dilemma for the provider. It requires proper history, clinical examination, laboratory testing for autoantibodies before arriving at the correct diagnosis.
Psychiatric Disorders
Roughly 20% of the patients presenting to primary care clinics that have an underlying undiagnosed depressive illness and a targeted mental health history is critical.[119] There could be a range of undiagnosed or underdiagnosed disorders like major depressive disorder, bipolar disorder, eating disorder, schizophrenia somatoform disorders as well as substance abuse. It is the utmost importance to remember that in the elderly symptoms of fatigue, unrefreshing sleep, as well as cognitive changes, can be very much part of the symptom complex of late-onset depression.[120]
Endocrine Disorders
There could be adrenal abnormalities (Addison disease, adrenal insufficiency, Cushing disease), thyroid abnormalities (both hypothyroidism and hyperthyroidism) as well as diabetes mellitus, which can mimic symptoms of chronic fatigue syndrome.
Hematological and Oncologic Disorders
Undiagnosed malignancies can present with symptoms of fatigue and mandates a search for underlying cancer which as well as age-appropriate screening. However, age alone should not be the only determining criterion for ordering these screenings.[121]
Anemia from any cause can present with excessive tiredness and fatigue.[122][123][124][125]
Infectious Diseases
Infectious diseases like Human immunodeficiency virus, tuberculosis, chronic hepatitis can have ongoing fatigue as their initial presentation.
Gastrointestinal Disorders
Inflammatory bowel disease can present with chronic fatigue symptoms.[126] Celiac disease can present with fatigue and without sometimes even without gastrointestinal symptoms.
Neurological Disorders
Fatigue is the main presenting feature of multiple sclerosis.[127] Dementia, which has cognitive impairment as its major presentation, can cause a diagnostic dilemma, as can pseudodementia.
Age-related Orthostatic Hypotension
It is again imperative to recognize that there are age-related changes in blood vessels, causing decreased autonomic responsiveness, which gets worsened with lack of adequate fluid intake as well as polypharmacy.[128]
Respiratory Disorders
Chronic respiratory conditions like chronic obstructive pulmonary disease (COPD) and sarcoidosis can present with chronic fatigue.[129]
Sleep Apnea
Undiagnosed obstructive sleep apnea can present with fatigue as well as unrefreshing sleep, which are two of the main diagnostic criteria for chronic fatigue syndrome. This is diagnosed by polysomnography.[130]
Enhancing Healthcare Team Outcomes
Chronic fatigue syndrome frequently poses a diagnostic dilemma. The hallmark symptom is the post-exertional fatigue associated with numerous neurological, cardiovascular, respiratory, as well as gastrointestinal complaints. Patients can also exhibit symptoms of uncontrolled anxiety, panic attacks, and impaired social functioning. Chronic fatigue syndrome is a diagnosis made on clinical examination and after exclusion of other possible etiologies. Considering the need for revision of the diagnostic criterion, the CDC, in the year 1994, came up with a broader definition for chronic fatigue syndrome developed by Fakuda and colleagues. As per these criteria, the patient should have severe fatigue for more than six months and also have at least four of the following symptoms- a new type of headache or a change in the pattern or severity of the headache, myalgias, pain in multiple joints without any swelling or redness, post-exertional malaise lasting more than one day, sore throat, tender lymph nodes, unrefreshing sleep and lastly a significant impairment in short term memory or concentration.
It is important to consult with an interprofessional team of specialists that include a pain specialist, a psychiatrist, a psychotherapist, and possibly a physical therapist. Even though chronic fatigue syndrome has fatigue as one of the three mandatory symptoms, it is a complex multisystem neurological disease with evidence of inflammation at the brain. Hence, the term myalgic encephalomyelitis, a neurology consultation can be useful when indicated. The main non-pharmacological treatment modalities are cognitive behavior therapy and graded exercise therapy. There is a wide range of medications that can be used for CFS. They range from NSAIDs to antidepressants. A broad range of differential diagnoses should be considered before diagnosing chronic fatigue syndrome. However, to improve outcomes, consultation with an interprofessional group of specialists is recommended.