Empathetic and supportive care is needed when treating patients with this chronic inflammatory disease.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, systemic condition characterized by fatigue lasting six months or longer, and signs and symptoms that negatively impact daily life that are not relieved by rest.1–5 Chronic muscle pain, sleep disturbances, and influenza-like symptoms, such as tender lymph nodes and sore throat, are common. The cognitive impact of ME/CFS, described as “brain fog,” increases sensitivity to light and sound, and hinders concentration, reading, communication and memory. The severity of symptoms varies, but a marked decrease in activity due to post-exertional malaise (PEM) and fatigue is consistent.1–4 This condition can cause significant disability, thereby reducing the level of participation in family, social and work activities.4,6
Widely underdiagnosed and misdiagnosed, ME/CFS affects an estimated 1% to 3% of the population worldwide, including 2.5 million Americans.4,7 Approximately 75% of those impacted are women, with Hispanic, African-American and Native American groups disproportionately impacted.1,4,6 The prevalence is anticipated to double by 2030, so oral health professionals should prepare to treat a growing number of patients with ME/CFS.8
While ME/CFS has no clear cause, theories include environmental exposures and a genetic component. Many affected individuals report an infectious illness or stressful life event, followed by an acute or gradual, but progressive, shift to consistent ME/CFS symptoms. Viral infections, specifically those with respiratory impacts, have long been considered a trigger.1,2,4,9 Up to 80% of these patients report an infectious illness near their symptom onset, including herpesvirus 6, human parvovirus B19, giardia and, most commonly, the Epstein-Barr virus, which causes infectious mononucleosis. As with previous severe acute respiratory syndrome viruses, COVID-19 is the latest to be linked. Ongoing studies seek to determine if COVID-19 is a conclusive causative factor, if long-COVID and ME/CFS symptoms simply overlap, or whether they are the same illness.1,2,4,10
Environmental risk factors include stress, socioeconomic status and exposure to toxins.2 Adverse childhood events — such as poverty, neglect, abuse and mental health issues — can impact brain development and cortisol production. Genetically susceptible individuals hold their intrinsic stress threshold in the hypothalamus, which can be reduced by exposure to a virus.11–13 This dysregulation can lead to hormonal imbalances in the stress response system, which increases oxidative stress and decreases the ability to manage physical and emotional stress. Low levels of cortisol, common with post-traumatic stress disorder and adverse childhood events, can result in an exaggerated response to physical exertion and difficulties with sleep regulation.2,4,11,12 These events can significantly increase the risk and symptom severity of ME/CFS. For those with a family history of ME/CFS or a history of traumatic events, monitoring and treating cortisol or hormone imbalances may reduce the risk of developing ME/CFS.11,12
Genetic risk factors include age, female gender and genetic predisposition. The median age of onset is 33, with symptoms most commonly appearing between the ages 10 and 19 or 30 and 39. Puberty, pregnancy and menopause often precede the onset of ME/CFS.1,2,4 About one-third of those with ME/CFS have an immediate family member with the same or another immune-related condition. The etiology of ME/CFS is multifactorial and therefore not associated with one specific genetic alteration.2,4,10 Dysbiosis, a gut microbiome imbalance that can cause “leaky gut,” may also contribute to the immune response that perpetuates ME/CFS and other common inflammatory and autoimmune conditions.2,14
SIGNS, SYMPTOMS AND COMORBIDITIES
The progression of ME/CFS varies, but the fatigue, malaise and cognitive impacts remain. Many women report a worsening of their symptoms near menstruation.1,2,4 Orthostatic intolerance is common and includes difficulty standing in place without dizziness, weakness and/or tachycardia, and intolerance to alcohol and temperature extremes. In addition, PEM after physical, mental or emotional activity is one of the most disabling symptoms. A majority of those affected by this condition report reducing their work hours or not being able to work at all.4
Systemic, autoimmune and mental health comorbidities are common in this patient cohort; more than 80% of individuals with ME/CFS report at least one other medical condition.1,4 The most common comorbidities — depression, anxiety and mood disorders — affect more than half of those with fatigue syndromes.2,4,6,15 Major depression is a common misdiagnosis because ME/CFS symptoms overlap.2,11,12,15 Other comorbidities include fibromyalgia, migraines, irritable bowel syndrome and autoimmune thyroid disease.2,4,14 Many with ME/CFS report chronic pain that is challenging to manage and not relieved by nonsteroidal anti-inflammatory drugs (NSAIDs). A metabolism imbalance may contribute to neuroinflammation, central sensitization and a heightened pain response, which exacerbate the chronic pain and cognitive impacts of ME/CFS.2,10–12,16 Patients may report viral infections or a recurrence of symptoms that mimic influenza. Early studies suggest similarities and overlap of symptoms between ME/CFS and long-COVID, as both are triggered by viral infections.
Patients with ME/CFS have an increased risk for oral lesions, infection and tissue changes. Aphthous ulcers and herpes lesions are common oral signs of inflammatory or immune-related conditions and can be recurrent. Patients may also experience xerostomia and salivary gland damage. Oral candidiasis occurs frequently with immune-related conditions or during immunosuppression. Manifestations include angular cheilitis, thrush on the tongue or buccal mucosa, or redness of the palate.19–21
Higher systemic oxidative stress levels are associated with inflammation and bone loss; therefore, patients with ME/CFS are at an increased risk of periodontal disease. If PEM or depression decreases the ability to perform oral hygiene, the subsequent increase in plaque accumulation and gingival inflammation may raise periodontal disease risk. Oxidative stress released during the periodontal disease process can perpetuate attachment loss.22
Temporomandibular disorders (TMD) are another comorbidity of ME/CFS. Chronic, painful TMDs are uncommon in isolation, so they may indicate a susceptibility to other pain conditions, such as ME/CFS, migraine or fibromyalgia.5,23 Of the five common comorbidities, ME/CFS has the strongest association with TMD pain intensity and duration.24
DIAGNOSIS AND TREATMENT
Clinically established diagnostic or biomarker tests are not currently available for ME/CFS, and its molecular changes may mimic other conditions.1,2,25 Some individuals exhibit no abnormal physical findings, while orthostatic hypotension and abnormal cortisol levels are present in others.1 Many exhibit inflammatory markers, such as reduced T-cell function, persistent autoantibodies, and increased pro-inflammatory cytokines.10,14 Higher levels of oxidative stress and lower levels of antioxidants are also present. Symptom severity and infection risk increase with higher levels of inflammatory indicators. Although the tissue damage seen with autoimmune diseases is not typical in ME/CFS, the immune dysfunction indicators and autoimmune disease comorbidities support its classification as an immune-related disease.2,4,10
In 2020, a new technique that measures the expression of microRNA circulating after a stress challenge that causes PEM was introduced. When matched with patient questionnaires, 11 microRNAs corresponded with categories of disease severity. These measurements offer a pathway for developing a noninvasive diagnostic test and creating treatments that target specific genetic impacts.2,7
There is no cure and no medication that addresses all symptoms associated with ME/CFS.25 On average, only 5% of patients fully recover, with children experiencing a better prognosis than adults. High sugar and long-term high protein diets promote inflammation, while diets that are gluten-free, low sugar, rich in omega-3 fish oil, and low in polyunsaturated oils may promote gut health and reduce inflammation. A leaky-gut diet that includes antioxidants and probiotics may prove beneficial. Vitamins A and E and several micronutrients are important in promoting a healthy immune system while reducing oxidative stress and inflammation.2,14,26 Antioxidant supplements may improve cognitive and pain symptoms. In a recent study, patients taking coenzyme Q-10 and nicotinamide adenine dinucleotide + hydrogen reported higher quality sleep, reduced physical and cognitive fatigue, and improved quality of life.8
Guided exercise therapy can relieve pain and increase quality sleep and overall health in some patients with ME/CFS. Unfortunately, even mild exercise can increase symptom severity in others.1,2 Pacing is a newer management strategy to prevent overexertion and PEM. The goal of pacing is to be as active as possible without experiencing an increase in symptoms. Journaling is a useful tool to identify the healthiest balance between activity and rest.27
Additionally, ME/CFS may cause a hypersensitive perception of pain and exertion. This can contribute to the perception of a more severe illness. Cognitive behavioral therapy can provide coping strategies to address the fear and anxiety related to symptoms. In combination with physical or exercise therapy, physical fitness and mood may also improve. In contrast, if other factors are not addressed due to incorrect assumptions that ME/CFS is strictly psychosomatic, cognitive behavioral therapy can be detrimental.2,4,6
For mild symptoms, over-the-counter (OTC) pain relievers, sleep aids, cold and flu medications, vitamins, supplements, and gastrointestinal medications are often used as a first line of treatment to reduce pain, improve sleep, improve digestive health and reduce fatigue. Meditation, yoga, acupuncture, gentle massage, electrical nerve stimulation, relaxation therapy, and other types of alternative treatment have been explored to reduce chronic pain.
When OTC medications do not address severe joint and muscle pain, prescription NSAIDs or narcotics can provide relief; however, the possibility of addiction should be assessed. Anticonvulsants may be prescribed for nerve pain and sleep, and antivirals can also help ease chronic pain.25,28
Targeting neurotransmitters with antipsychotic and antidepressant medications provides moderate benefits in decreasing depression, improving mood, increasing sleep quality, and reducing fatigue. They have also shown efficacy in mitigating brain fog and pain, and enhancing concentration.2,29,30 Attention-deficit/hyperactivity disorder and narcolepsy medications also help diminish brain fog. Selective serotonin reuptake inhibitors provide palliative care, but do not address the underlying immune system malfunction.1,2,25 Options to improve sleep also consist of sedative and insomnia medications.
Immunosuppressive medications and those aimed at autoantibodies can relieve ME/CFS symptoms. Monoclonal antibodies targeting B-cell production and autoantibodies immune response significantly reduce symptoms in some patients. While immunotherapy treatment options are available, their off-label use for ME/CFS can obstruct insurance coverage. As future microRNAs and biomarker tests are developed, specific genetic contributions will be identified to create tailored treatment approaches.2,4,10,25
REFERRAL AND DENTAL MANAGEMENT
Undiagnosed patients with ME/CFS symptoms should be referred to their primary care physician, who can initiate tests and referrals to rule out anemia, endocrine issues, sleep disorders, and other contributing factors. Advising patients to journal their sleep patterns, as well as the type, severity and longevity of each symptom, and how symptoms affect their daily life will provide additional diagnostic information.1,6
Patients with unexplained pain and fatigue often face challenges explaining, diagnosing and treating their conditions. Open communication and empathy are important steps in validating and addressing patients’ concerns. Schedule patients on the day or time of day when they usually feel their best and have transportation if they do not drive. Manage muscle pain with headrest and chair positions at a supportive angulation, along with any needed cushion or pillow. Consider a referral to a TMD or pain specialist. Clinicians may also consider using a bite block, and shortening dental appointments to minimize pain. Supine chair positioning may reduce dizziness, and the patient may want to sit briefly prior to standing to avoid orthostatic hypotension.1,23
Dental appointments can be mentally and physically taxing for this population. If light and sound sensitivity or frequent headaches are reported, tinted glasses and headphones or earplugs can reduce dental office stimuli. Information processing time is the most prominent cognitive deficit, so allow additional time for patients to process information and ask questions. For those with memory impairments, written recommendations can reinforce the key points of patient discussions.1 Surgery can exacerbate ME/CFS symptoms, so this is an important consideration when explaining risks during treatment planning.4
The severity of ME/CFS symptoms may influence the development of oral manifestations. For those experiencing recurrent aphthous ulcers, vitamin B12 supplements can help with prevention. Topical corticosteroids can reduce inflammation, and topical or NSAID pain relievers can reduce the discomfort associated with these outbreaks.20 Antifungal medications are used to treat candidiasis. Treatment of immune-related conditions may increase the risk for infection and neoplastic tissue changes, so diligence is crucial to identify tissue changes; if warranted, patients should be referred to an oral pathologist or oral surgeon.19 Increased preventive recare intervals and powered adjuncts — such as an electric toothbrush or water flosser for effective plaque removal — can help reduce inflammation and periodontal disease risk. Nutritional counseling is a critical component of patient education in the management of xerostomia and promotion of optimal oral health. Providers should consider caries risk in determining the appropriate supplemental therapeutic recommendations, as many of the pharmaceutical agents used to treat the symptoms of ME/CFS may cause xerostomia.31 The use of topical fluoride agents, xylitol, and nonfluoridated remineralization systems, whether dispensed OTC or via prescription, is highly recommended.
Oral health professionals are encouraged to support patients with ME/CFS and recognize when they may be experiencing symptoms that require medical referral. As with any patient dealing with long-term fatigue or pain, dental teams should strive to be empathetic to the challenges these individuals face and provide supportive oral care.
- Bateman L, Bested AC, Bonilla F, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:2861–2878.
- Deumer US, Varesi A, Floris V, et al. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): an overview. J Clin Med. 2021;10:4786.
- Johnston S, Brenu EW, Staines D, Marshall-Gradisnik S. The prevalence of chronic fatigue syndrome/myalgic encephalomyelitis: a meta-analysis. Clin Epidemiol. 2013;5:105.
- Chu L, Valencia IJ, Garvert DW, Montoya JG. Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome. Front Pediatr. 2019;7:12.
- Kato K, Sullivan PF, Evengård B, Pedersen NL. Premorbid predictors of chronic fatigue. Arch Gen Psychiatry. 2006;63:1267.
- Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;160:221–236.
- Nepotchatykh E, Elremaly W, Caraus I, et al. Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology. Sci Rep. 2020;10:19620.
- Castro-Marrero J, Segundo MJ, Lacasa M, Martinez-Martinez A, Sentañes RS, Alegre-Martin J. Effect of dietary coenzyme Q10 plus NADH supplementation on fatigue perception and health-related quality of life in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a prospective, randomized, double-blind, placebo-controlled trial. Nutrients. 2021;13:2658.
- Wong TL, Weitzer DJ. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) — a systemic review and comparison of clinical presentation and symptomatology. Medicina. 2021;57:418.
- Sotzny F, Blanco J, Capelli E, et al. Myalgic encephalomyelitis/chronic fatigue syndrome — evidence for an autoimmune disease. Autoimmun Rev. 2018;17:601–609.
- Heim C, Wagner D, Maloney E, et al. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry. 2006;63:1258.
- Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009;66:72.
- Mackay A. A paradigm for post-COVID-19 fatigue syndrome analogous to ME/CFS. Front Neurol. 2021;12:701419.
- Varesi A, Deumer US, Ananth S, Ricevuti G. The emerging role of gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): current evidence and potential therapeutic applications. J Clin Med. 2021;10:5077.
- Lamers F, Hickie I, Merikangas, KR. Prevalence and correlates of prolonged fatigue in a U.S. sample of adolescents. Am J Psychiatry. 2013;170:502–510.
- Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci. 2021;118:e2024358118.
- Bornstein SR, Voit-Bak K, Donate T, et al. Chronic post-COVID-19 syndrome and chronic fatigue syndrome: is there a role for extracorporeal apheresis? Mol Psychiatry. 2022;27:34–37.
- Sandler CX, Wyller VBB, Moss-Morris R, et al. Long COVID and post-infective fatigue syndrome: a review. Open Forum Infect Dis. 2021;8:ofab440.
- Bandara HMHN, Samaranayake LP. Viral, bacterial, and fungal infections of the oral mucosa: types, incidence, predisposing factors, diagnostic algorithms, and management. Periodontol 2000. 2019;80:148–176.
- Mays JW, Sarmadi M, Moutsopoulos NM. Oral manifestations of systemic autoimmune and inflammatory diseases: diagnosis and clinical management. J Evid Based Dent Pract. 2012;12:265–282.
- Woo SB, Schacterle RS, Komaroff AL, Gallagher GT. Salivary gland changes in chronic fatigue syndrome: a case-controlled preliminary histologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:82–87.
- Sczepanik FSC, Grossi ML, Casati M, et al. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000. 2020;84:45–68.
- Robinson LJ, Durham J, Newton JL. A systematic review of the comorbidity between temporomandibular disorders and chronic fatigue syndrome. J Oral Rehabil. 2016;43:306–316.
- Dahan H, Shir Y, Velly A, Allison P. Specific and number of comorbidities are associated with increased levels of temporomandibular pain intensity and duration. J Headache Pain. 2015;16:47.
- Castro-Marrero J, Sáez-Francàs N, Santillo D, Alegre J. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: All roads lead to Rome: therapy and management in CFS/ME. Br J Pharmacol. 2017;174:345–369.
- Dawson DR, Branch-Mays G, Gonzalez OA, Ebersole JL. Dietary modulation of the inflammatory cascade. Periodontol 2000. 2014;64:161–197.
- Goudsmit EM, Nijs J, Jason LA, Wallman KE. Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document. Disabil Rehabil. 2012;34:1140–1147.
- Theoharides TC, Asadi S, Weng Z, Zhang B. Serotonin-selective reuptake inhibitors and nonsteroidal anti-inflammatory drugs — important considerations of adverse interactions especially for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome. J Clin Psychopharmacol. 2011;31:403–405.29.
- Crosby LD, Kalanidhi S, Bonilla A, Subramanian A, Ballon JS, Bonilla H. Off label use of aripiprazole shows promise as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a retrospective study of 101 patients treated with a low dose of aripiprazole. J Transl Med. 2021;19:50.
- Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015;29:459–525.
- Millsop JW, Wang EA, Fazel N. Etiology, evaluation, and management of xerostomia. Clin Dermatol. 2017;35:468–476.