Chronic Fatigue Syndrome: Symptoms, Causes, Tests, Treatment

Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, ME / CFS), is a complex, multisystem disorder characterized by persistent, unexplained fatigue lasting more than six months, that does not improve with rest and worsens after physical or mental exertion. The core clinical feature is the significant worsening of symptoms even after mild activity (post-exertional malaise).

Despite scientific progress, there is still no single biomarker that definitively establishes the diagnosis of Chronic Fatigue Syndrome. The approach remains clinical, based on excluding other pathological conditions and supported by laboratory findings that reveal underlying dysfunction. Within this framework, functional medicine offers a more personalized investigative model, focusing not only on diagnosis but also on the underlying mechanisms that sustain the symptom.

In recent years, the international literature has shifted from the earlier psychosomatic approach to a biological, pathophysiological model. Contemporary reviews document disturbances in the immune system, mitochondrial function and cellular energy production, the hypothalamic-pituitary-adrenal (HPA) axis, and the gut microbiome. At the same time, significant overlap with other conditions, such as fibromyalgia and Long COVID, has been recognized. The importance of early diagnosis is fundamental, as Chronic Fatigue Syndrome may mimic or coexist with other disorders such as hypothyroidism, depression, or autoimmune diseases.

Epidemiological Data

Chronic Fatigue Syndrome is now recognized as a significant public health issue, affecting patients’ quality of life and their social and occupational functioning. According to recent international meta-analyses, the global prevalence is estimated between 0.2% and 0.4% when strict diagnostic criteria are applied, while in studies using broader criteria, the rate may reach or even exceed 1%.

In the United States, data from the period 2021 to 2022 suggest that approximately 1.3% of adults may meet the criteria for ME/CFS. In Europe, estimates typically range from 0.4% to 1%, with substantial heterogeneity across countries and depending on the recording methodology. The disease occurs:

• More frequently in women. The female-to-male ratio is approximately 2:1 to 3:1. Hormonal, immunological, and genetic factors are thought to contribute to this difference.
• Primarily between the ages of 30 and 50 years. Although it may occur in adolescents or older individuals, the average age of onset is in mid-adulthood.
• With increased risk following infections. Viral infections, such as Epstein-Barr virus, cytomegalovirus, or SARS-CoV-2, have been associated with the onset of persistent symptomatology.

As for Greece, there are no large population-based epidemiological studies using strict diagnostic criteria. However, based on international rates, it is estimated that tens of thousands of individuals in the country may experience compatible symptomatology. Clinical experience from primary care physicians indicates that a significant number of patients with chronic fatigue remain undiagnosed or receive alternative diagnoses, such as anxiety disorder or depression, without a thorough investigation of organic factors.

The COVID-19 pandemic has added a new dimension to the problem. Studies comparing ME/CFS and Long COVID highlight significant overlap in symptoms and pathophysiological mechanisms, which may likely lead to an increase in diagnosed cases in the coming years.

Early recognition and systematic laboratory investigation are critical for excluding other diseases and identifying modifiable factors.

Symptoms and Signs of Chronic Fatigue Syndrome

Chronic Fatigue Syndrome presents with a broad spectrum of symptoms, which often vary in intensity and frequency. Some are common to most patients, while others are more individualized. The heterogeneity of manifestations makes diagnosis challenging, particularly in early stages or in patients with coexisting conditions.

Core Diagnostic Features

• Persistent, unexplained fatigue lasting more than 6 months. The fatigue is severe, not related to recent overexertion, and does not substantially improve with rest. It significantly affects occupational, social, and personal functioning.
• Post-exertional malaise. This is a pathognomonic feature. Following mild physical or mental activity, symptoms may worsen and persist for days or even weeks. The deterioration is not necessarily immediate; it may occur 24 to 48 hours later.
• Non-restorative sleep. Despite adequate sleep duration, the patient awakens feeling exhausted. Circadian rhythm disturbances are frequently present.
   

Cognitive Dysfunction

• Impaired concentration and memory. The so-called brain fog includes difficulty processing information, reduced thinking speed, and short-term memory problems.
• Headaches. Often tension-type or migraine-like, with increased frequency compared to the patient’s previous history.
• Hypersensitivity to light and noise. This reflects possible neuroinflammatory involvement.
   

Musculoskeletal Symptoms

• Myalgias and arthralgias. Pain without evident inflammatory arthritis. There is often tenderness at specific points, similar to that observed in fibromyalgia.
• A feeling of heaviness in the limbs. Especially after activity.
   

Autonomic Nervous System Dysfunction

• Orthostatic intolerance. Dizziness, lightheadedness, or tachycardia upon standing.
• Thermoregulatory disturbances. Alternating sensations of cold and heat.
   

Immunological and Systemic Symptoms

• Recurrent sore throat. Without apparent bacterial infection.
• Tenderness or swelling of lymph nodes. Usually cervical or axillary.
• Flu-like symptoms. Without fever, but with a general sense of malaise.
   

Gastrointestinal Symptoms

• Bloating, abdominal distension, altered bowel habits. Many patients meet the criteria for irritable bowel syndrome. Recent studies have associated Chronic Fatigue Syndrome with disturbances in the gut microbiome.
   

The heterogeneity of symptomatology often leads to delayed diagnosis. Many patients present across multiple specialties before the syndrome is suspected. For this reason, understanding potential underlying causes, conducting a comprehensive clinical assessment, and performing targeted laboratory investigations are essential.

Underlying Causes of Chronic Fatigue Syndrome

Chronic Fatigue Syndrome is not caused by a single factor. Instead, current research supports a multifactorial model involving the immune system, energy metabolism, the neuroendocrine axis, and the gut microbiome. Understanding these mechanisms is critical for a targeted and individualized diagnostic and therapeutic approach.

1. Persistent immune activation and low-grade inflammation. Many patients report symptom onset following viral infection, including Epstein-Barr virus, cytomegalovirus, or SARS-CoV-2. Studies demonstrate alterations in pro-inflammatory cytokines and evidence of chronic immune activation. Prolonged immune stimulation may affect central nervous system function, leading to neuroinflammation and cognitive disturbances. This state does not correspond to acute inflammation, but rather to a persistent, low-grade inflammatory environment.

2. Mitochondrial dysfunction and impaired energy metabolism. Fatigue in Chronic Fatigue Syndrome appears to be associated with disrupted cellular energy production. Research has demonstrated alterations in fatty acid oxidation, glucose utilization, and ATP synthesis. Increased oxidative stress and impaired antioxidant defenses have also been observed. When mitochondria function inadequately, even minor daily activities may result in disproportionate fatigue.

3. Dysfunction of the hypothalamic-pituitary-adrenal axis. The HPA axis regulates the stress response through cortisol production. In several patients with Chronic Fatigue Syndrome, lower cortisol levels or disturbances in its circadian rhythm have been observed. This dysfunction may affect immune balance, inflammatory response, and energy regulation. Chronic activation or exhaustion of the axis is also associated with sleep disturbances and psychosomatic burden.

4. Autonomic Nervous System dysfunction. A significant proportion of patients exhibit dysregulation of the sympathetic and parasympathetic systems. This condition leads to orthostatic intolerance, tachycardia, blood pressure fluctuations, and reduced cerebral perfusion in the upright position. Impaired hemodynamic adaptation may exacerbate post-exertional malaise and cognitive clouding.

5. Microbiome disturbances and increased intestinal permeability. In recent years, the gut microbiome has emerged as a potential regulator of both the immune and nervous systems. In patients with ME/CFS, alterations in gut bacterial composition and evidence of increased intestinal permeability have been documented. The translocation of microbial products into circulation may enhance inflammatory responses and systemically burden the organism.

6 .Genetic predisposition and epigenetic modifications. Although no specific gene has been identified as causative, studies suggest a possible genetic vulnerability that may be combined with environmental factors. Epigenetic changes, such as alterations in DNA methylation, may influence the expression of genes involved in energy metabolism and immune response.

The complexity of these mechanisms explains why Chronic Fatigue Syndrome requires a functional and individualized diagnostic approach.

Laboratory Tests for the Investigation of Chronic Fatigue Syndrome

The investigation of Chronic Fatigue Syndrome is not limited to excluding other conditions. The goal is to identify underlying biological dysfunctions associated with the deeper causes previously discussed, namely immune activation, impaired energy metabolism, hormonal dysregulation, autonomic nervous system dysfunction, and microbiome disturbances.

The diagnostic approach is structured into three levels: conventional tests, specialized functional medicine tests, and additional imaging or specialized examinations.

(a) Conventional Laboratory Tests
Conventional tests serve a dual role: first, to exclude other pathological conditions that cause fatigue, and second, to detect metabolic or inflammatory disturbances.

• Complete Blood Count: Evaluates anemia, leukocytosis, or other hematologic abnormalities that may account for fatigue or underlying inflammation.
• Ferritin: Indicator of iron stores. Even in the absence of overt anemia, low ferritin may be associated with exhaustion and reduced endurance.
• Vitamin B12: Essential for neurological function and hematopoiesis. Low levels are associated with fatigue, memory disturbances, and paresthesias.
• Vitamin D, 25 OH: Regulates immune and musculoskeletal functions. Deficiency is associated with myalgias and increased inflammatory activity.
• TSH, FT3, FT4: Assessment of thyroid function. Hypothyroidism is a common cause of chronic fatigue.
• Insulin Resistance, HOMA-IR: Assessment of metabolic balance and possible insulin resistance, which affects energy efficiency.
   

(b) Functional Medicine Tests
Functional medicine tests focus on investigating mechanisms that are not always reflected in basic laboratory testing. The aim is to map metabolic, hormonal, and immunological imbalances.

• ImmuneScan® Th1 / Th2 / Th17 Balance Assessment: This test evaluates the functional balance among major T-helper lymphocyte subsets. In Chronic Fatigue Syndrome, international literature has shown that immune shifts or imbalances between Th1 and Th2 responses are frequently observed, along with involvement of the Th17 axis associated with chronic inflammation.
• Omega Fatty Acids Comprehensive Profile ΩmegaScan®: Assesses the balance between omega-3 and omega-6 fatty acids, which influences inflammatory response. Imbalance may sustain chronic low-grade inflammation.
• Oxidative Stress Markers DetoxScan®: Chronic immune activation is accompanied by increased free radical production. Evaluation of total oxidative load and antioxidant capacity reflects the metabolic imprint of inflammation and guides antioxidant therapy.
• Intracellular ATP - Adenosine Triphosphate: Assesses cellular ATP production capacity and availability. It enables quantitative evaluation of energy sufficiency and mitochondrial functional capacity. In patients with Chronic Fatigue Syndrome, reduced production or impaired ATP utilization is often documented.
• MitoStress: Specialized analysis of mitochondrial performance under metabolic stress conditions. It evaluates respiratory chain function and the capacity for cellular adaptation to increased energy demands. Particularly useful in patients with marked post-exertional deterioration.
• Urinary Metabolomic Analysis, MetaBolomiX™: Detects metabolic intermediates of the Krebs cycle, mitochondrial function, and detoxification pathways. It may reveal impaired energy production, B-complex vitamin deficiencies, and increased oxidative stress. It is particularly useful in cases with pronounced post-exertional malaise.
• Trace Elements Profile, Metals & Traces®: Assesses intracellular deficiencies of magnesium, zinc, and other micronutrients involved in mitochondrial function, as well as neuromuscular and autonomic regulation.
• AdrenalScan®: Through assessment of circadian cortisol rhythm and DHEA-S measurement, it allows evaluation of hypothalamic-pituitary-adrenal axis dysfunction, particularly in cases of sleep disturbances and reduced stress resilience.
• Functional Gut Microbiome Assessment, EnteroScan®: Analyzes bacterial strain composition, the presence of dysbiosis, and markers of intestinal permeability and inflammation. Important in patients with concomitant gastrointestinal symptoms and systemic inflammation.
• Comprehensive Methylation Capacity Profile: Evaluates functional methylation capacity, a key biochemical mechanism influencing energy production, inflammatory regulation, and neurotransmitter synthesis. In Chronic Fatigue Syndrome, disturbances in the methylation cycle may further burden mitochondrial function and oxidative stress.

The combined evaluation of the above tests allows the development of a personalized intervention plan targeting the mechanisms sustaining fatigue.

(c) Additional Tests and Imaging Methods

• Tilt Table Test: Diagnostic test for orthostatic hypotension or postural orthostatic tachycardia syndrome (POTS).
• Brain Magnetic Resonance Imaging (MRI): Exclusion of structural neurological pathology.
• Thyroid Ultrasound: Imaging of morphological thyroid abnormalities.
• Sleep Study: Assessment for sleep apnea syndrome or other sleep disorders.

Comprehensive investigation is not solely diagnostic in nature. It forms the foundation for targeted therapeutic interventions. In the next section, the available therapeutic approaches, both conventional and natural, will be analyzed.

Therapeutic Approaches to Chronic Fatigue Syndrome

The management of Chronic Fatigue Syndrome is multidimensional and individualized, as there is no specific treatment that eliminates the condition. The goal is symptom relief, improvement of functionality, and support of the underlying pathophysiology. Strategies include conventional (pharmacological and non-pharmacological) approaches, as well as natural therapies with emphasis on nutrition, lifestyle, and supportive supplementation, aiming to restore energy balance.

(a) Conventional Therapeutic Interventions

• Pharmacological Support: Although there is no specific medication approved for Chronic Fatigue Syndrome, in certain cases targeted pharmacological interventions are used to address specific symptoms:
  • Low-dose antidepressants, for pain management and sleep regulation, mainly in patients with coexisting depression or fibromyalgia.
  • Vasoconstrictors or beta-blockers, in patients with orthostatic tachycardia (POTS).
  • Sleep-regulating medications, in cases of resistant insomnia.
  • Antivirals, in selected cases with documented persistent viral infection.
• Cognitive Behavioral Therapy (CBT): Has been shown to be helpful in many patients. It aims to improve symptom management, address negative beliefs, and break the anxiety-fatigue cycle.
• Graded Exercise Therapy: Although it may help in carefully selected patients, it is important to emphasize that the approach of gradually increasing exercise is no longer applied uniformly, as in many patients it worsens post-exertional malaise.
   

(b) Natural Therapies
Functional Medicine proposes natural and supportive therapies aimed at restoring homeostatic mechanisms rather than merely suppressing symptoms.

• Nutrition: Nutritional intervention in Chronic Fatigue Syndrome aims to reduce low-grade inflammation, improve mitochondrial function, regulate glycemic stability, and support the microbiome. Blood sugar stability is critical, as abrupt glucose fluctuations burden the stress axis and mitochondrial function. In cases of documented dysbiosis, an individualized nutritional strategy may be required, including temporary restriction of foods that aggravate gastrointestinal symptoms. An anti-inflammatory dietary pattern is recommended, with emphasis on:
  • fresh vegetables and low-glycemic-load fruits
  • high-quality protein
  • monounsaturated and omega-3 fatty acids
  • limiting processed carbohydrates and sugar
• Lifestyle: Gradual improvement is based on stability rather than overexertion. Energy management is a cornerstone of treatment. The following are recommended:
  • Sleep: Establishing a consistent sleep schedule, avoiding blue light before bedtime, and using melatonin where indicated.
  • Stress management: Techniques such as diaphragmatic breathing, yoga, gentle meditation, or mindfulness improve HPA axis regulation.
  • Activity pacing: A technique for balancing daily energy expenditure and preventing post-exertional worsening.
• Supplements: The use of supplements must be individualized, based on laboratory findings, and guided by an appropriate healthcare professional. The following are indicative examples:
  • Coenzyme Q10: Supports the mitochondrial respiratory chain and ATP production. Possible mild gastrointestinal disturbances.
  • Magnesium: Participates in more than 300 enzymatic reactions, including energy production. High doses may cause diarrhea.
  • B-complex vitamins: Involved in energy metabolism and neurological function. Dosage is individualized.
  • Omega-3 fatty acids: Contribute to the regulation of inflammatory response.
  • Probiotics: Useful in cases of dysbiosis. Strain selection should be based on microbiome findings.
• Herbal Therapies: Certain adaptogenic herbs, such as Rhodiola rosea or Ashwagandha, have been studied for supporting stress resilience and regulating the HPA axis. They should be used with caution in patients with thyroid disorders or autoimmune diseases. Dosage depends on the extract and requires medical supervision.

In Conclusion

Chronic Fatigue Syndrome is not merely a prolonged feeling of tiredness, but a complex, multisystem disorder associated with immune dysregulation, mitochondrial dysfunction, hormonal imbalance, and disturbances of the gut-brain axis.

Effective management requires targeted and individualized laboratory investigation so that therapeutic intervention is based on real biological findings rather than general assumptions. Functional medicine offers the opportunity for this in-depth mapping, paving the way for more effective and personalized care.

References

1. Komaroff AL, Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol Med. 2021;27(9):895-906.
2. Renz-Polster H, Tremblay M-E, Bienzle D and Fischer JE (2022) The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front. Cell. Neurosci. 16:888232.
3. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146.
4. Nacul L, Authier FJ, Scheibenbogen C, et al. European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe. Medicina (Kaunas). 2021;57(5):510. Published 2021 May 19.
5. Fluge Ø, Tronstad KJ, Mella O. Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Clin Invest. 2021;131(14):e150377.
6. Fan J, Jiao J, Chang HQ, Zhong DL, Liu XB, Li J, Chen LM, Jin RJ, Wu X. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management. J Transl Med. 2025 Dec 9;24(1):62.

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