There are no characteristic laboratory abnormalities to diagnose CFS; testing is used to rule out other conditions which could be responsible for the symptoms. When symptoms are attributable to certain other conditions, the diagnosis of CFS is excluded. As such, a diagnosis of CFS/ME is generally one of exclusion (of alternative diagnoses).

Notable definitions include:

- Centers for Disease Control and Prevention (CDC) definition (1994), the most widely used clinical and research description of CFS, is also called the Fukuda definition and is a revision of the "Holmes" or "CDC 1988" scoring system. The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.

- The ME/CFS 2003 Canadian Clinical working definition states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months".

Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in England and Wales, produced in 2007 by the National Institute for Health and Clinical Excellence (NICE).

While the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein tests may be abnormal and there may be abnormally high levels of platelets in the blood or too few red blood cells in the blood, none of these findings is a reliable indicator of the disease. A slit-lamp examination is essential. Recent work has suggested that high-resolution MRI and antibodies to inner ear antigens may be helpful. Cogan syndrome can occur in children, and is particularly difficult

to recognize in that situation.

About 10% of people who present a clinical picture of infectious mononucleosis do not have an acute Epstein–Barr-virus infection. A differential diagnosis of acute infectious mononucleosis needs to take into consideration acute cytomegalovirus infection and "Toxoplasma gondii" infections. Because their management is much the same, it is not always helpful, or possible, to distinguish between Epstein–Barr-virus mononucleosis and cytomegalovirus infection. However, in pregnant women, differentiation of mononucleosis from toxoplasmosis is important, since it is associated with significant consequences for the fetus.

Acute HIV infection can mimic signs similar to those of infectious mononucleosis, and tests should be performed for pregnant women for the same reason as toxoplasmosis.

People with infectious mononucleosis are sometimes misdiagnosed with a streptococcal pharyngitis (because of the symptoms of fever, pharyngitis and adenopathy) and are given antibiotics such as ampicillin or amoxicillin as treatment.

Other conditions from which to distinguish infectious mononucleosis include leukemia, tonsillitis, diphtheria, common cold and influenza (flu).

The cause of CVS has not been determined; there are no diagnostic tests for CVS. Several other medical conditions, such as cannabinoid hyperemesis syndrome, can mimic the same symptoms, and it is important to rule these out. If all other possible causes have been excluded, a diagnosis of CVS may be appropriate.

Once formal investigations to rule out gastrointestinal or other causes have been conducted, these tests do not need to be repeated in the event of future episodes.

The differential diagnosis of Kikuchi disease includes systemic lupus erythematosus (SLE), disseminated tuberculosis, lymphoma, sarcoidosis, and viral lymphadenitis. Clinical findings sometimes may include positive results for IgM/IgG/IgA antibodies.

For other causes of lymph node enlargement, see lymphadenopathy.

The heterophile antibody test works by agglutination of red blood cells from guinea pig, sheep and horse. This test is specific but not particularly sensitive (with a false-negative rate of as high as 25% in the first week, 5–10% in the second, and 5% in the third). About 90% of patients have heterophile antibodies by week 3, disappearing in under a year. The antibodies involved in the test do not interact with the Epstein–Barr virus or any of its antigens.

The monospot test is not recommended for general use by the CDC due to its poor accuracy.

It is diagnosed by lymph node excision biopsy.

Kikuchi disease is a self-limiting illness which has symptoms which may overlap with Hodgkin's lymphoma leading to misdiagnosis in some patients.

Antinuclear antibodies, antiphospholipid antibodies, anti-dsDNA, and rheumatoid factor are usually negative, and may help in differentiation from systemic lupus erythematosus.

There is no specific treatment for infectious mononucleosis, other than treating the symptoms. In severe cases, steroids such as corticosteroids may be used to control the swelling of the throat and tonsils. Currently, there are no antiviral drugs or vaccines available.

It is important to note that symptoms related to infectious mononucleosis caused by EBV infection seldom last for more than 4 months. When such an illness lasts more than 6 months, it is frequently called chronic EBV infection. However, valid laboratory evidence for continued active EBV infection is seldom found in these patients. The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome, or CFS. This process includes ruling out other causes of chronic illness or fatigue.

Sudden cessation of high-dose corticosteroids, opioids, barbiturates, benzodiazepines, caffeine or alcohol can induce myalgia in many respects.

There are established criteria to aid in diagnosis of CVS; essential criteria are:

1. A history of three or more periods of intense, acute nausea and unremitting vomiting, as well as pain in some cases, lasting hours to days and even weeks or months

2. Intervening symptom-free or reduced-symptom intervals, lasting weeks to months

3. There are repeated cycles of periods (of varying duration) with intense/acute nausea, with or without vomiting, with or without severe pain, followed by periods of reduced symptoms, followed by gradual increase in CVS symptoms until it peaks (peak intensity is generally relative to cycle intensity).

4. There are differences between early-onset CVS (babies & children) and late onset CVS (adult).

5. Exclusion of metabolic, gastrointestinal, or central nervous system structural or biochemical disease, e.g., individuals with specific physical causes (such as intestinal malrotation)

The procedure of diagnosis for Cramp Fasciculation Syndrome (CFS) is closely aligned with the diagnosis procedure for benign fasciculation syndrome (BFS). The differentiation between a diagnosis of BFS versus CFS is usually more severe and prominent pain, cramps and stiffness associated with CFS.

Treatment is similar to treatment for benign fasciculation syndrome.

Carbamazepine therapy has been found to provide moderate reductions in symptoms.

For more severe disease, oral corticosteroids may be necessary to reduce the inflammatory response. When large amounts of steroids are required or if the disease is severe and is not responding to steroid therapy, other immunosuppressive medications often are recommended. These immunosuppressive drugs include methotrexate, cyclophosphamide, cyclosporine or azathioprine. In some cases, combinations of these medicines are prescribed. Occasionally, if the disease has damaged blood vessels, cochlear implantation may

need to be done to correct the problem.

Cinnarizine is mainly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome. Studies have shown it to produce significant improvement in hearing loss in some patients.

Carnitine palmitoyltransferase II deficiency, Conn's syndrome, Adrenal insufficiency, Hyperthyroidism, Hypothyroidism, Diabetes, Hypogonadism, postorgasmic illness syndrome (POIS).

OI is "notoriously difficult to diagnose." As a result, many patients have gone undiagnosed or misdiagnosed and either untreated or treated for other disorders. Current tests for OI (Tilt table test, autonomic assessment, and vascular integrity) can also specify and simplify treatment. (See Dr. Julian Stewart's article, "Orthostatic Intolerance: An Overview" for a more detailed description of OI tests.)

A typical method for determining the effects of the sopite syndrome is through the use of one or several questionnaires. The available questionnaires for motion sickness and sopite syndrome are described by Lawson. Two such questionnaires widely used to evaluate motion sickness are the Pensacola Diagnostic Index and the Motion Sickness Questionnaire. These questionnaires are limited, however, in that they group symptoms of drowsiness with other non-sopite related effects, such as nausea and dizziness. Motion sickness is measured based on the cumulative ratings of all these symptoms without distinguishing different levels for each effect.

A Motion Sickness Assessment Questionnaire has been developed to test the multiple dimensions of motion sickness more thoroughly; this survey defines motion sickness as gastrointestinal (involving nausea), peripheral (referring to thermoregulatory effects such as clamminess and sweating), central (involving symptoms such as dizziness and lightheadedness), and sopite-related. This questionnaire may more accurately determine how subjects experience sopite symptoms relative to other motion sickness effects. Another questionnaire designed to measure sleepiness is the Epworth Sleepiness Scale.

In various studies, about one half of the patients who seek medical treatment for symptoms of MCS meet the criteria for depressive and anxiety disorders. Because many people eliminate whole categories of food in an effort to reduce symptoms, a complete review of the patient's diet may be needed to avoid nutritional deficiencies.

Treatment may involve investigation, reassurance and explanation, and possibly specialist treatment such as antidepressants or cognitive behavioral therapy.

Functional somatic syndromes may occur in 6 to 36% of the population.

In response to a WHO call for papers at the 5th Paris Appeal Congress of Environmental Idiopathic Intolerance conference that took place in Belgium on the 18th of May, a report that was generally supportive quoted a number of international practitioners. This was provisionally accepted by the Spanish health ministry, and later found proven by a judge in the case of a plumber in the Province of Castellón

MCS is a diagnosis of exclusion, and the first step in diagnosing a potential MCS sufferer is to identify and treat all other conditions which are present and which often explain the reported symptoms. For example, depression, allergy, thyroid disorders, orthostatic syndromes, lupus, hypercalcemia, and anxiety need to be carefully evaluated and, if present, properly treated. The "gold standard" procedure for identifying a person who has MCS is to test response to the random introduction of chemicals the patient has self-identified as relevant. This may be done in a carefully designed challenge booth to eliminate the possibility of contaminants in the room. Chemicals and controls, sometimes called prompts, are introduced in a random method, usually scent-masked. The test subject does not know when a prompt is being given. Objective and subjective responses are measured. Objective measures, such as the galvanic skin response indicate psychological arousal, such as fear, anxiety, or anger. Subjective responses include patient self-reports. A diagnosis of MCS can only be justified when the subject cannot consciously distinguish between chemicals and controls, and when responses are consistently present with exposure to chemicals and consistently absent when prompted by a control.

A 1999 consensus statement recommends that MCS be diagnosed according to six standardized criteria:

1. Symptoms are reproducible with repeated (chemical) exposures

2. The condition has persisted for a significant period of time

3. Low levels of exposure (lower than previously or commonly tolerated) result in manifestations of the syndrome ("i.e." increased sensitivity)

4. The symptoms improve or resolve completely when the triggering chemicals are removed

5. Responses often occur to multiple chemically unrelated substances

6. Symptoms involve multiple-organ symptoms (runny nose, itchy eyes, headache, scratchy throat, ear ache, scalp pain, mental confusion or sleepiness, palpitations of the heart, upset stomach, nausea and/or diarrhea, abdominal cramping, aching joints).

The sopite syndrome may be difficult to test due to the nature of the symptoms. Indicators such as drowsiness, mood changes, and apathy must be observed and graded objectively. Therefore, many of the results obtained from studies of the sopite syndrome are not sufficiently repeatable for the purposes of scientific writing.

Anumonye reported treatment success with lorazepam; others found benefit with antidepressants and relaxation exercises.

There is no single test that can fully diagnose fibromyalgia and there is debate over what should be considered essential diagnostic criteria and whether an objective diagnosis is possible. In most cases, people with fibromyalgia symptoms may also have laboratory test results that appear normal and many of their symptoms may mimic those of other rheumatic conditions such as arthritis or osteoporosis. The most widely accepted set of classification criteria for research purposes was elaborated in 1990 by the Multicenter Criteria Committee of the American College of Rheumatology. These criteria, which are known informally as "the ACR 1990", define fibromyalgia according to the presence of the following criteria:

- A history of widespread pain lasting more than three months – affecting all four quadrants of the body, i.e., both sides, and above and below the waist.

- Tender points – there are 18 designated possible tender points (although a person with the disorder may feel pain in other areas as well). Diagnosis is no longer based on the number of tender points.

The ACR criteria for the classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis but have now become the "de facto" diagnostic criteria in the clinical setting. It should be noted that the number of tender points that may be active at any one time may vary with time and circumstance. A controversial study was done by a legal team looking to prove their client's disability based primarily on tender points and their widespread presence in non-litigious communities prompted the lead author of the ACR criteria to question now the useful validity of tender points in diagnosis. Use of control points has been used to cast doubt on whether a person has fibromyalgia, and to claim the person is malingering; however, no research has been done for the use of control points to diagnose fibromyalgia, and such diagnostic tests have been advised against, and people complaining of pain all over should still have fibromyalgia considered as a diagnosis.

The condition may be a sign of various disease states, including but not exclusive to the following:

- Cancers

- Lymphoma

- Leukemia

- Infections

- HIV/AIDS

- Tuberculosis

- Mycobacterium avium-intracellulare infection

- Infectious mononucleosis

- Fungal infections (histoplasmosis, coccidioidomycosis)

- Lung abscess

- Infective endocarditis

- Brucellosis

- Pneumocystis pneumonia (most often - in immunocompromised individuals)

- Endocrine disorders

- Menopause

- Premature ovarian failure

- Hyperthyroidism

- Diabetes mellitus (nocturnal hypoglycemia)

- Endocrine tumors (pheochromocytoma, carcinoid)

- Orchiectomy

- Rheumatic disorders

- Takayasu's arteritis

- Temporal arteritis

- Other

- Obstructive sleep apnea

- Gastroesophageal reflux disease

- Chronic fatigue syndrome

- Fibromyalgia

- Granulomatous disease

- Chronic eosinophilic pneumonia

- Lymphoid hyperplasia

- Diabetes insipidus

- Prinzmetal's angina

- Anxiety

- Pregnancy

- Drugs

- Antipyretics (salicylates, acetaminophen)

- Antihypertensives

- Dinitrophenol - a common side effect

- Phenothiazines

- Drug withdrawal: ethanol, benzodiazepines, heroin (and other opiates),

- Over-bundling

- Autonomic over-activity

- IBD (inflammatory bowel disease) - Crohn's disease/ulcerative colitis