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).

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

Multiple sclerosis (neurologic pain interpreted as muscular), Myalgic Encephalomyelitis (chronic fatigue syndrome), Myositis, Mixed connective tissue disease, Lupus erythematosus, Fibromyalgia syndrome, Familial Mediterranean fever, Polyarteritis nodosa, Devic's disease, Morphea, Sarcoidosis

A growing body of evidence supports that prevention is effective in reducing the effect of chronic conditions; in particular, early detection results in less severe outcomes. Clinical preventive services include screening for the existence of the disease or predisposition to its development, counseling and immunizations against infectious agents. Despite their effectiveness, the utilization of preventive services is typically lower than for regular medical services. In contrast to their apparent cost in time and money, the benefits of preventive services are not directly perceived by patient because their effects are on the long term or might be greater for society as a whole than at the individual level.

Therefore, public health programs are important in educating the public, and promoting healthy lifestyles and awareness about chronic diseases. While those programs can benefit from funding at different levels (state, federal, private) their implementation is mostly in charge of local agencies and community-based organizations.

Studies have shown that public health programs are effective in reducing mortality rates associated to cardiovascular disease, diabetes and cancer, but the results are somewhat heterogeneous depending on the type of condition and the type of programs involved. For example, results from different approaches in cancer prevention and screening depended highly on the type of cancer.

The rising number of patient with chronic diseases has renewed the interest in prevention and its potential role in helping control costs. In 2008, the Trust for America's Health produced a report that estimated investing $10 per person annually in community-based programs of proven effectiveness and promoting healthy lifestyle (increase in physical activity, healthier diet and preventing tobacco use) could save more than $16 billion annually within a period of just five years.

While risk factors vary with age and gender, most of the common chronic diseases in the US are caused by dietary, lifestyle and metabolic risk factors that are also responsible for the resulting mortality. Therefore, these conditions might be prevented by behavioral changes, such as quitting smoking, adopting a healthy diet, and increasing physical activity. Social determinants are important risk factors for chronic diseases. Social factors, e.g., socioeconomic status, education level, and race/ethnicity, are a major cause for the disparities observed in the care of chronic disease. Lack of access and delay in receiving care result in worse outcomes for patients from minorities and underserved populations. Those barriers to medical care complicate patients monitoring and continuity in treatment.

In the US, Minorities and low-income populations are less likely to access and receive preventive services necessary to detect conditions at an early stage.

The majority of US health care and economic costs associated with medical conditions are for the costs of chronic diseases and conditions and associated health risk behaviors. Eighty-four percent of all health care spending in 2006 was for the 50% of the population who have one or more chronic medical conditions (CDC, 2014).

The administration of immunotherapy, in association with chemotherapy or tumor removal, .

SPS is diagnosed by evaluating clinical findings and excluding other conditions. There is no specific laboratory test that confirms its presence. Underdiagnosis and misdiagnosis are common.

The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and cerebrospinal fluid (CSF) testing. Anti-GAD65 is found in about 80 percent of SPS patients. Anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin are also often present in blood tests. Electromyography (EMG) demonstrates involuntary motor unit firing in SPS patients. EMG can confirm the diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves. Responsiveness to diazepam helps confirm that the patient is suffering from SPS, as this decreases stiffness and motor unit potential firing.

The same general criteria are used to diagnose paraneoplastic SPS as the normal form of the condition. Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic. CT scans are indicated for SPS patients who respond poorly to therapy to determine if this is the case.

A variety of conditions have similar symptoms to SPS, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders. Tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome, Multiple sclerosis, Parkinson's disease, and Isaacs syndrome should also be excluded.

Patients' fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic, and they are sometimes suspected of malingering. It takes an average of six years after the onset of symptoms before the disease is diagnosed.

A complete recovery following immunotherapy and tumor removal. Untreated cases died within few months of onset. Some patients have a poor outcome despite sustained immunosuppression, but that is often related to tumor progression or associated with the presence of Abs directed against intracellular Ags such as GAD Abs or amphyphysin Abs, which can reflect the involvement of an additional cytotoxic T-cell mechanism in the progression of the disease.

AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the attacks, while in MS they are nearly always present and persistent.

It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS

Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria. In 2015 a new review was published by an international panel refining the previous clinical case definition but leaving the main criteria unmodified:

Absolute criteria:

1. Optic neuritis

2. Acute myelitis

Supportive criteria:

1. Brain MRI not meeting criteria for MS at disease onset

2. Spinal cord MRI with continuous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord

3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4 antigen.)

Some of the differential or comorbid medical diagnoses may include:

- achalasia – There have been cases where achalasia, a disorder of the esophagus which affects peristalsis, has been misdiagnosed as AN. It has been reported in cases where there is sub-clinical manifestation of anorexia nervosa and also in cases where the full diagnostic criteria AN have been met.

- acute pandysautonomia is one form of an autonomic neuropathy, which is a collection of various syndromes and diseases which affect the autonomic neurons of the autonomic nervous system (ANS). Autonomic neuropathies may be the result of an inherited condition or they may be acquired due to various premorbid conditions such as diabetes and alcoholism, bacterial infection such as Lyme disease or a viral illness. Some of the symptoms of ANS which may be associated with an ED include nausea, dysphagia, constipation, pain in the salivary glands, early saiety. It also affects peristalsis in the stomach. Acute pandysautonomia may cause emotional instability and has been misdiagnosed as various psychiatric disorders including hysterical neurosis and anorexia nervosa.

- Lupus: various neuropsychiatric symptoms are associated with systemic lupus erythematosus (SLE), including depression. Anorexia and weight loss also may occur with SLE and while rare it may be misdiagnosed as AN.

- Lyme disease is known as the "great imitator", as it may present as a variety of psychiatric or neurologic disorders including anorexia nervosa. "A 12 year old boy with confirmed Lyme arthritis treated with oral antibiotics subsequently became depressed and anorectic. After being admitted to a psychiatric hospital with the diagnosis of anorexia nervosa, he was noted to have positive serologic tests for Borrelia burgdorferi. Treatment with a 14 day course of intravenous antibiotics led to a resolution of his depression and anorexia; this improvement was sustained on 3 year follow-up." Serologic testing can be helpful but should not be the sole basis for diagnosis. The Centers for Disease Control (CDC) issued a cautionary statement (MMWR 54;125) regarding the use of several commercial tests. Clinical diagnostic criteria have been issued by the CDC (CDC, MMWR 1997; 46: 531-535).

- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by gastrointestinal dysmotility, severe cachexia progressive external ophthalmoplegia, post-prandial emesis (vomiting after eating), peripheral neuropathy, and diffuse leukoencephalopathy. Onset is prior to age 20 in 60% of cases. ""Miss A" was a 21-year-old Indian woman diagnosed as having treatment-resistant anorexia nervosa." It was subsequently proven to be MNGIE

- superior mesenteric artery syndrome (SMA syndrome) "is a gastrointestinal disorder characterized by the compression of the third or transverse portion of the duodenum against the aorta by the superior mesenteric artery resulting in chronic partial, incomplete, acute or intermittent duodenal obstruction". It may occur as a complication of AN or as a differential diagnosis. There have been reported cases of a tentative diagnosis of AN, where upon treatment for SMA syndrome the patient is asymptomatic.

- Addison's disease is a disorder of the adrenal cortex which results in decreased hormonal production. Addison's disease, even in subclinical form, may mimic many of the symptoms of anorexia nervosa.

- Brain tumors: There are multiple cases were the neuropsychiatric symptoms of a brain tumor were attributed to AN, resulting in misdiagnosis. The tumors in these cases were noted in various regions of the brain including the medulla oblongata, hypothalamus, pituitary gland, pineal gland and the obex.

- Simmond's disease (organic hypopituitarism) – "A 20-year-old Japanese man with a hypothalamic tumor which caused hypopituitarism and diabetes insipidus was mistakenly diagnosed as anorexia nervosa because of anorexia, weight loss, denial of being ill, changes in personality, and abnormal behavior resembling the clinical characteristics of anorexia nervosa"

- Brain calcification either dystrophic calcification or metastatic calcification can present with neuropsychiatric symptoms including those associated with AN and comorbid disorders such as obsessive compulsive disorder.

- cysts that occur in the central nervous system such as dermoid cysts and arachnoid cysts can cause neuropsychiatric symptoms including psychosis.

- Celiac disease is an inflammatory disorder triggered by peptides from wheat and similar grains which cause an immune reaction in the small intestine. "information on the role of the gastrointestinal system in causing or mimicking eating disorders is scarce."(Leffler DA "et al.")

- Gall bladder disease which may be caused by inflammation, infection, gallstones, obstruction of the gallbladder or torsion of the gall bladder – Many of the symptoms of gall bladder disease may mimic anorexia nervosa (AN). Laura Daly, a woman from Missouri, suffered from an inherited disorder in which the gall bladder was not properly attached; the resultant complications led to multiple erroneous diagnoses of AN. Upon performance of a CCK test, standard imaging techniques are done with the patient lying prone, in this instance it was done with the patient in an upright position. The gall bladder was shown to be in an abnormal position having flipped over the liver. The gallbladder was removed and the patient has since recovered. The treatment was performed by William P. Smedley in Pennsylvania.

- colonic tuberculosis misdiagnosed as anorexia nervosa in a physician at the hospital where she worked – "This patient, who had severe wasting, was misdiagnosed as having anorexia nervosa despite the presence of other symptoms suggestive of an organic disease, namely, fever and diarrhea"(Madani, A 2002).

- Crohn's disease: "We report three cases of young 18 to 25 year-old girls, initially treated for anorexia nervosa in a psychiatric department. Diagnosis of Crohn's disease was made within 5 to 13 years."(Blanchet C, Luton JP. 2002)"This disease should be diagnostically excluded before accepting anorexia nervosa as final diagnosis". (Wellmann W "et al.")

- hypothyroidism, hyperthyroidism, hypoparathyroidism and hyperparathyroidism may mimic some of the symptoms of, can occur concurrently with, be masked by or exacerbate an eating disorder and/or various comorbid disorders such as anxiety and depression.

- Insulinomas are (pancreatic tumors) that cause an overproduction of insulin, causing hypoglycemia. Various neurological deficits have been ascribed to this condition including misdiagnosis as an eating disorder.

- Multiple sclerosis (encephalomyelitis disseminata) is a progressive autoimmune disorder in which the protective covering (myelin sheath) of nerve cells is damaged as a result of inflammation and resultant attack by the bodies own immune system. In its initial presentation, MS has been misdiagnosed as an eating disorder.

The progression of SPS depends on whether it is a typical or abnormal form of the condition and the presence of comorbidities. Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment, but the condition usually progresses and stabilizes periodically. Even with treatment, quality of life generally declines as stiffness precludes many activities. Some patients require mobility aids due to the risk of falls. About 65 percent of SPS patients are unable to function independently. About ten percent of SPS patients require intensive care at some point; sudden death occurs in about the same number of patients. These deaths are usually caused by metabolic acidosis or an autonomic crisis.

The diagnosis may be made on the clinical features alone, along with tests to rule out other possible causes. An EEG will usually show the electrical features of epilepsy and slowing of brain activity in the affected hemisphere, and MRI brain scans will show gradual shrinkage of the affected hemisphere with signs of inflammation or scarring.

Brain biopsy can provide very strong confirmation of the diagnosis, but this is not always necessary.

The differential diagnoses of anorexia nervosa (AN) includes various types of medical and psychological conditions, which may be misdiagnosed as AN. In some cases, these conditions may be comorbid with AN because the misdiagnosis of AN is not uncommon. For example, a case of achalasia was misdiagnosed as AN and the patient spent two months confined to a psychiatric hospital. A reason for the differential diagnoses that surround AN arise mainly because, like other disorders, it is primarily, albeit defensively and adaptive for, the individual concerned.

Anorexia Nervosa is a psychological disorder characterized by extremely reduced intake of food. People suffering from Aneroxia Nervosa have a low self-image and consider themselves overweight.

Common behaviors and signs of someone suffering from AN:

- Forcing oneself to vigorously exercise even in adverse conditions or when their health does not permit it.

- Forcing own self to urinate and excrete waste product from the body.

- Using substituted amphetamines (stimulants that can reduce appetite) to reduce appetite.

- Skin turning yellow

Myelitis has an extensive differential diagnosis. The type of onset (acute versus subacute/chronic) along with associated symptoms such as the presence of pain, constitutional symptoms that encompass fever, malaise, weight loss or a cutaneous rash may help identify the cause of myelitis. In order to establish a diagnosis of myelitis, one has to localize the spinal cord level, and exclude cerebral and neuromuscular diseases. Also a detailed medical history, a careful neurologic examination, and imaging studies using magnetic resonance imaging (MRI) are needed. In respect to the cause of the process, further work-up would help identify the cause and guide treatment. Full spine MRI is warranted, especially with acute onset myelitis, to evaluate for structural lesions that may require surgical intervention, or disseminated disease. Adding gadolinium further increases diagnostic sensitivity. A brain MRI may be needed to identify the extent of central nervous system (CNS) involvement. Lumbar puncture is important for the diagnosis of acute myelitis when a tumoral process, inflammatory or infectious cause are suspected, or the MRI is normal or non-specific. Complementary blood tests are also of value in establishing a firm diagnosis. Rarely, a biopsy of a mass lesion may become necessary when the cause is uncertain. However, in 15–30% of people with subacute or chronic myelitis, a clear cause is never uncovered.

Some medical practitioners are open to a patient's personal research, as this can open lines of communication between doctors and patients, and prove valuable in eliciting more complete or pertinent information from the patient about their present condition.

Other doctors express concern about patients who self-diagnose on the basis of information obtained from the Internet when the patient demonstrates an incomplete or distorted understanding of other diagnostic possibilities and medical likelihoods. A patient who exaggerates one set of symptoms in support of their self-diagnosis while minimizing or suppressing contrary symptoms can impair rather than enhance a doctor's ability to reach a correct diagnosis.

The CDC MMWR report advised, "To prevent infections in general, persons should stay home if they are ill, wash their hands often with soap and water, avoid close contact (such as touching and shaking hands) with those who are ill, and clean and disinfect frequently touched surfaces."

Unlike polio, acute flaccid myelitis can not currently be prevented with a vaccine.

Diagnostic testing in a possible paraneoplastic syndrome depends on the symptoms and the suspected underlying cancer.

Diagnosis may be difficult in patients in whom paraneoplastic antibodies cannot be detected. In the absence of these antibodies, other tests that may be helpful include MRI, PET, lumbar puncture and electrophysiology.

Diagnosis of tumefactive MS is commonly carried out using magnetic resonance imaging (MRI) and proton MR spectroscopy (H-MRS). Diagnosis is difficult as tumefactive MS may mimic the clinical and MRI characteristics of a glioma or a cerebral abscess. However, as compared to tumors and abscesses, tumefactive lesions have an open-ring enhancement as opposed to a complete ring enhancement. Even with this information, multiple imaging technologies have to be used together with biochemical tests for accurate diagnosis of tumefactive MS.

Tumefactive demyelination is distinguished from tumor by the presence of multiple lesions, absence of cortical involvement, and decrease in lesion size or detection of new lesions on serial imaging

In the US, neuroborreliosis is typically treated with intravenous antibiotics which cross the blood–brain barrier, such as penicillins, ceftriaxone, or cefotaxime. One relatively small randomized controlled trial suggested ceftriaxone was more effective than penicillin in the treatment of neuroborreliosis. Small observational studies suggest ceftriaxone is also effective in children. The recommended duration of treatment is 14 to 28 days.

Several studies from Europe have suggested oral doxycycline is equally as effective as intravenous ceftriaxone in treating neuroborreliosis. Doxycycline has not been widely studied as a treatment in the US, but antibiotic sensitivities of prevailing European and US isolates of "Borrelia burgdorferi" tend to be identical. However, doxycycline is generally not prescribed to children due to the risk of bone and tooth damage.

Discreditied or doubtful treatments for neuroborreliosis include:

- Malariotherapy

- Hyperbaric oxygen therapy

- Colloidal silver

- Injections of hydrogen peroxide and bismacine

A positive diagnosis test for thiamine deficiency can be ascertained by measuring the activity of the enzyme transketolase in erythrocytes (Erythrocyte Transketolase Activation Assay). Thiamine, as well as its phosphate derivatives, can also be detected directly in whole blood, tissues, foods, animal feed, and pharmaceutical preparations following the conversion of thiamine to fluorescent thiochrome derivatives (Thiochrome Assay) and separation by high-performance liquid chromatography (HPLC). In recent reports, a number of Capillary Electrophoresis (CE) techniques and in-capillary enzyme reaction methods have emerged as potential alternative techniques for the determination and monitoring of thiamine in samples.

The normal thiamine concentration in EDTA-blood is about 20-100 µg/l.

In the classic presentation of the disease death usually occurs within 3 years, however there are rarely both fast and slower progressions. Faster deterioration in cases of acute fulminant SSPE leads to death within 3 months of diagnosis.

If the diagnosis is made during stage 1 of the SSPE infection then it may be possible to treat the disease with oral isoprinosine (Inosiplex) and intraventricular interferon alfa, but the response to these drugs varies from patient to patient. However, once SSPE progresses to stage 2 then it is universally fatal in all occurrences. The standard rate of decline spans anywhere between 1–3 years after the onset of the infection. The progression of each stage is unique to the sufferer and cannot be predicted although the pattern or symptoms/signs can be.

Although the prognosis is bleak for SSPE past stage 1, there is a 5% spontaneous remission rate—this may be either a full remission that may last many years or an improvement in condition giving a longer progression period or at least a longer period with the less severe symptoms.

MRI diagnosis is based on lesions that are disseminated in time and space, meaning that there are multiple episodes and consisting of more than one area. There are two kinds of MRI used in the diagnosis of tumefactive MS, T1-weighted imaging and T2-weighted imaging. Using T1-weighted imaging, the lesions are displayed with low signal intensity, meaning that the lesions appear darker than the rest of the brain. Using T2-weighted imaging, the lesions appear with high signal intensity, meaning that the lesions appear white and brighter than the rest of the brain. When T1-weighted imaging is contrast-enhanced through the addition of gadolinium, the open ring enhancement can be viewed as a white ring around the lesion. A more specific MRI, Fluid attenuation inversion recovery (FLAIR) MRI show the signal intensity of the brain. Subjects with tumefactive multiple sclerosis may see a reduction of diffusion of the white matter in the affected area of the brain.

During the acute stage, treatment is aimed at reducing the inflammation. As in other inflammatory diseases, steroids may be used first of all, either as a short course of high-dose treatment, or in a lower dose for long-term treatment. Intravenous immunoglobulin is also effective both in the short term and in the long term, particularly in adults where it has been proposed as first-line treatment. Other similar treatments include plasmapheresis and tacrolimus, though there is less evidence for these. None of these treatments can prevent permanent disability from developing.

During the residual stage of the illness when there is no longer active inflammation, treatment is aimed at improving the remaining symptoms. Standard anti-epileptic drugs are usually ineffective in controlling seizures, and it may be necessary to surgically remove or disconnect the affected cerebral hemisphere, in an operation called hemispherectomy. This usually results in further weakness, hemianopsia and cognitive problems, but the other side of the brain may be able to take over some of the function, particularly in young children. The operation may not be advisable if the left hemisphere is affected, since this hemisphere contains most of the parts of the brain that control language. However, hemispherectomy is often very effective in reducing seizures.