Chronic Fatigue Syndrome: When Prolonged Fatigue Requires Medical Evaluation

Chronic fatigue doesn't always mean that a person simply needs more rest. It can be a symptom of anemia, thyroid disorders, iron or vitamin deficiencies, sleep disorders, infectious diseases, and other conditions. In some cases, your doctor may consider myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex chronic illness that significantly affects daily activities.

ME/CFS is not diagnosed by a single blood test or other laboratory test. Diagnosis is based on a characteristic combination of symptoms, medical history, physical examination, and targeted testing to rule out other causes of chronic fatigue.

What is chronic fatigue syndrome?

Chronic fatigue syndrome, or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a chronic illness that impairs a person's ability to perform normal physical, mental, occupational, educational, or social activities.

One of the defining features of ME/CFS is that symptoms are not simply explained by overexertion and do not disappear after normal rest.

The disease can vary in severity. In some people, symptoms allow them to continue their daily activities with some limitations, while in severe cases, a person may be significantly limited in their mobility and daily activities.

Main symptoms of ME/CFS

Several symptoms are of particular importance for the clinical evaluation of ME/CFS.

Decreased ability to perform usual activities and severe fatigue

The person notices that they can no longer perform the same amount of physical, intellectual, or social work that was previously normal for them.

Fatigue while:

• can be significant;
• does not occur due to unusual or excessive strain;
• does not go away completely after rest or sleep;
• lasts at least six months in adults when appropriate diagnostic criteria are applied.

It is important to distinguish this type of fatigue from normal exhaustion after a hard day at work, intense exercise, or several nights of insufficient sleep.

Post-exercise deterioration — PEM

PEM (post-exertional malaise) is one of the most characteristic symptoms of ME/CFS.

This refers to the worsening of symptoms after physical, mental, or emotional stress that was previously tolerated normally.

An important feature is that the deterioration may not occur immediately. It often becomes noticeable 12–48 hours after exertion and can last for several days or even weeks.

For example, a person may do routine housework, visit a store, spend several hours at work, or perform a significant amount of mental work, and the next day experience a sharp increase in fatigue, headaches, difficulty concentrating, pain, or other symptoms.

It is this response to stress that distinguishes ME/CFS from many other conditions that are accompanied by fatigue.

Unrefreshing sleep

Another key sign is that sleep is not providing the expected recovery.

A person may sleep for a sufficient number of hours, but wake up tired or not feel a noticeable improvement after sleep.

Difficulty falling asleep, frequent awakenings, or other sleep disturbances may also occur.

Cognitive impairment

Some people have problems with concentration, memory, information processing speed, and the ability to perform complex mental tasks.

Patients often describe this as "brain fog.".

For example, it may be more difficult for a person to:

• focus on the text;
• maintain a long conversation;
• make decisions quickly;
• remember new information;
• perform multiple tasks simultaneously.

Cognitive impairment is one of two additional symptoms, one of which must be present along with the core features of ME/CFS according to the criteria used by the CDC.

Orthostatic intolerance

The second possible additional symptom is a worsening of well-being while standing.

This may manifest itself:

• dizziness;
• weakness;
• feeling of heartbeat;
• vision changes;
• pre-unconscious state;
• worsening of other symptoms after prolonged standing or sitting.

This condition is called orthostatic intolerance.

What criteria are used for diagnosis?

According to the Institute of Medicine/National Academy of Medicine criteria, as provided by the CDC, three core symptoms are required for ME/CFS:

1. a significant decrease in the ability to perform usual activities, lasting more than six months and accompanied by new, severe fatigue that is not relieved by rest;
2. post-exercise deterioration (PEM);
3. unrefreshing sleep.

In addition, there must be at least one of two additional manifestations:

• cognitive impairment;
• orthostatic intolerance.

These criteria are used in conjunction with the patient's clinical evaluation and examination to rule out other diseases.

Why is chronic fatigue syndrome difficult to diagnose?

The problem is that fatigue, difficulty concentrating, headaches, sleep problems, and pain can occur with a wide range of other illnesses.

Similar symptoms may occur with:

• anemia;
• iron deficiency;
• thyroid dysfunction;
• vitamin B12 deficiency or folate;
• sleep disorders;
• some infectious diseases;
• metabolic disorders;
• liver or kidney diseases;
• autoimmune diseases;
• other states.

Therefore, before diagnosing ME/CFS, a doctor evaluates the history, symptoms, examination results, and laboratory tests.

Is there a test for chronic fatigue syndrome?

No. There is currently no specific laboratory test that confirms ME/CFS.

Researchers are studying various biological features of the disease, but none of the proposed biomarkers yet have sufficient sensitivity and specificity to be used as a stand-alone diagnostic test.

Therefore, laboratory research has a different task - help identify or rule out other causes of symptoms.

What tests can be prescribed for prolonged fatigue?

The list of tests is determined on an individual basis. The CDC lists a number of laboratory tests that may be used in the evaluation of a person with suspected ME/CFS.

Among them:

• complete blood count with leukocyte formula;
• erythrocyte sedimentation rate;
• C-reactive protein;
• fasting glucose;
• electrolytes;
• creatinine and other indicators of kidney function;
• calcium and phosphorus;
• liver function tests;
• total protein;
• albumin;
• TSH and free thyroxine (FT4);
• ferritin;
• serum iron;
• transferrin saturation;
• celiac disease screening;
• general urine analysis.

Depending on the clinical situation, the doctor may additionally prescribe vitamin B12, folic acid, vitamin D, or other tests.

For example, if complete blood count shows anemia, additional tests may be needed to determine its cause, including iron metabolism, B12, and folate levels.

If there is reason to suspect an autoimmune disease, the doctor may prescribe appropriate autoimmune markers. However, conducting a large set of tests without clinical indications is impractical due to the risk of incidental or false-positive results.

What role do ferritin, TSH, B12, and vitamin D tests play?

Certain laboratory parameters are particularly often considered during the differential diagnosis of chronic fatigue.

Ferritin helps assess iron stores. Iron deficiency can be accompanied by fatigue and decreased performance.

TSH and FT4 used to assess thyroid function. Thyroid dysfunction can be accompanied by fatigue, weight changes, drowsiness, difficulty concentrating, and other symptoms.

Vitamin B12 and folic acid may be important in evaluating the causes of anemia and some neurological or cognitive complaints.

Vitamin D sometimes included in laboratory testing depending on the clinical situation and local approaches to patient assessment.

However, none of these indicators individually confirm or exclude ME/CFS.

Should I be tested for EBV, CMV, and other viruses?

ME/CFS begins after an infection in some people, but this does not mean that a persistent active infection with Epstein-Barr virus, cytomegalovirus, or another virus is the cause of symptoms in every patient.

Therefore, tests for specific infections are prescribed if there are clinical grounds, and not as a universal panel for all people with chronic fatigue.

If the history, symptoms, or examination results suggest an infectious disease, the doctor may order appropriate tests.

What is known about the causes of ME/CFS

The exact cause of ME/CFS remains unknown.

Scientific research is investigating various mechanisms and possible factors associated with the development of the disease. In some people, symptoms begin after an infection, but other possible triggers have also been described.

At the same time, there is currently no sufficient evidence to suggest that ME/CFS is caused by one specific virus, mitochondrial dysfunction, hormonal changes, or specific cytokine levels.

Therefore, such mechanisms should be considered as a subject of research, rather than as established causes of disease.

Chronic Fatigue Syndrome and Long COVID

After COVID-19, some people may experience prolonged fatigue, concentration problems, sleep disturbances, pain, and post-exercise deterioration.

These symptoms can overlap with those of ME/CFS, so when evaluating someone with persistent symptoms after COVID-19, a doctor may consider ME/CFS as a possible condition.

At the same time Long COVID and ME/CFS are not the same diagnoses. The post-COVID state can include a wide range of symptoms and manifestations, and ME/CFS is diagnosed using appropriate clinical criteria.

How ME/CFS is treated and controlled

There is currently no treatment that addresses the cause of ME/CFS or guarantees recovery. Medical care is primarily aimed at controlling the most severe symptoms, maintaining functioning, and preventing the condition from getting worse.

Pacing — control of physical and mental stress

One of the key approaches is pacing, or individual activity management.

Its goal is to determine the limits of physical and mental exertion that a person can tolerate without a pronounced exacerbation of symptoms, and to plan activities taking these limits into account.

This is of particular importance for the prevention of PEM.

It is important not to systematically try to «push through» fatigue with increased exercise. Standard recommendations for vigorous exercise for healthy people are not suitable as a one-size-fits-all strategy for ME/CFS and may worsen symptoms.

Working with sleep disorders

If a person has insomnia, frequent awakenings, or other sleep problems, a doctor will evaluate possible causes and refer them to a sleep specialist if necessary.

Even improving sleep quality won't necessarily eliminate all symptoms of ME/CFS, but treating a specific sleep disorder may improve overall symptoms.

Pain control

ME/CFS can cause muscle and joint pain, headaches, and increased sensitivity to touch.

The tactics depend on the nature and intensity of the pain, other diseases and medications that the person is taking. The doctor selects the treatment individually.

Orthostatic symptoms

If dizziness or weakness occurs or worsens when standing, the doctor may evaluate your heart rate, blood pressure, and other indicators.

If necessary, additional testing is performed to determine the cause of these symptoms.

Do vitamins and supplements help?

There is no universal supplement that is proven to cure ME/CFS.

Vitamins or minerals may be needed if laboratory testing or dietary history indicate a deficiency. In such a situation, correction of the deficiency is carried out according to the doctor's recommendations.

You should not take large doses of vitamins, minerals, or other supplements just because you have chronic fatigue. Some supplements may interact with medications or cause unwanted effects.

When to see a doctor

You should see a doctor if your fatigue:

• lasts for a long time;
• significantly reduces working capacity;
• does not go away after normal sleep and rest;
• accompanied by impaired concentration or memory;
• combined with dizziness in an upright position;
• noticeably increases after physical or mental exertion;
• accompanied by other symptoms that cause concern.

It's important not to self-diagnose ME/CFS. Chronic fatigue has many possible causes, some of which are treatable.

What tests can be taken for prolonged fatigue?

If the doctor deems laboratory testing necessary, the set of tests depends on the symptoms and medical history.

Among the studies that can be used to look for other causes of fatigue:

• complete blood count;
• ferritin;
• iron and other indicators of iron metabolism;
• TSH;
• free T4;
• glucose;
• liver function tests;
• kidney function indicators;
• electrolytes;
• C-reactive protein;
• vitamin B12;
• folic acid;
• vitamin D;
• other studies - according to indications.

The specific list is determined by your doctor after evaluating your symptoms. Normal baseline test results do not rule out ME/CFS, as lab tests are primarily used to look for other possible causes of your symptoms.

It is important to remember

Chronic fatigue syndrome is not just feeling tired after a busy day. ME/CFS is characterized by a combination of significant reduction in activity, severe fatigue that does not go away with rest, post-exertional deterioration and unrefreshing sleep, as well as cognitive or orthostatic symptoms.

There is no specific test that confirms ME/CFS, so lab tests are used primarily to look for other conditions that may explain the fatigue or make you feel worse.

If prolonged fatigue significantly affects daily life, the right approach begins not with finding a single «chronic fatigue test,» but with a comprehensive assessment of symptoms and possible causes.

Author: Ulyana Anatolyivna Dzyuba

Director of Medi Lab Plus LLC, a doctor of the highest category. Has over 45 years of practical experience in medicine and laboratory diagnostics. Founder and head of the laboratory since 2007. More details…