Most ADEM patients pass through only one or two episodes of fever, weakness, headache and ataxia. Furthermore, neurological symptoms such as decreased awareness, cranial nerve palsies, seizures and behavioral changes may be observed [10]. Vomiting has been reported. These bouts may last weeks; single symptoms may aggravate throughout that time while others improve.

MEM symptoms are typically of sudden onset. Many patients initially report with flu-like complaints, i.e., fever, malaise, generalized myalgia, fatigue, lymphadenopathy and symptoms concerning the upper respiratory tract. Myalgia and fatigue persist after "passing" the assumed cold and often interferes with daily tasks, particularly if physical activity is required. MEM patients tend to develop depression. Clinical examination does not reveal any anomalies of muscles, nervous system or other organ systems. Some patients still present signs of a mild to moderate upper respiratory infection, e.g., lymphadenopathy and pharyngitis. Any atypical symptoms should prompt serious consideration of differential diagnoses.

• Fatigue

  Chronic fatigue syndrome (Myalgic Encephalomyelitis) is a disorder that causes extreme long lasting fatigue that limits your ability to do ordinary daily activities. [news-medical.net]

  Reliability of a chronic fatigue syndrome questionnaire. J Chronic Fatigue Syndr. 2007 13 41 66 ,, ,, ,. et al A screening instrument for chronic fatigue syndrome: reliability and validity. J Chronic Fatigue Syndr. 1997 3 39 59 ,. [annals.org]

  A pediatric case definition for myalgic encephalomyelitis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2006;13:1-44. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. [rarediseases.org]

  Everyone feels fatigued sometimes, and many people feel fatigued a lot of the time. But, chronic fatigue syndrome isn’t just being tired. [webmd.com]

• Constitutional Symptom

  Constitutional symptoms that overlap with symptoms of ME/CFS are common in EDS. Fatigue and pain are substantial contributors to impaired quality of life in EDS ( 133, 134 ). [frontiersin.org]

• Pallor

  Many patients do not look ill, but noticeable facial pallor is sometimes apparent and often precedes the onset of extreme tiredness in the patient. The pallor can be associated with sub-orbital dark shadows. [frontiersin.org]

• Nausea

  Symptoms may include: Fatigue Fever Headache Nausea Vomiting Changes in your child's consciousness — such as seizures or in severe cases, coma — as well as behavioral changes such as irritability are also likely. [ucsfbenioffchildrens.org]

  […] of insulation around the nerves ( myelin ) within affected areas. [1] ADEM often follows viral infection, or less often, vaccinations for measles, mumps, or rubella (MMR). [2] Symptoms usually appear rapidly, beginning with fever, fatigue, headache, nausea [rarediseases.info.nih.gov]

  The symptoms of ADEM appear rapidly, beginning with encephalitis-like symptoms such as fever, fatigue, headache, nausea and vomiting, and in the most severe cases, seizures and coma. [ninds.nih.gov]

  Other symptoms may include: nausea and vomiting headache confusion weakness ataxia (unsteady walk) sensory changes, including numbness or tingling optic neuritis (trouble with vision) seizures The location of the inflammation (swelling) within the brain [childrenshospital.org]

• Dental Caries

  It can lead to rampant dental caries, exacerbation of periodontal disease, or oral candidiasis. [frontiersin.org]

• Heart Disease

  Other clinical conditions also experience non-restorative sleep and fatigue, such as FM, narcolepsy, and coronary heart disease, 101, 102 as well as a high number of otherwise healthy individuals. 103 It is plausible that there may be subgroups of such [aasmnet.org]

• Muscle Weakness

  They share some symptoms, like muscle weakness, numbness, loss of vision, and loss of balance. But MS is rare in children. Other differences can also help your doctor make the right diagnosis. [webmd.com]

  Other Myalgic Encephalomyelitis Symptoms can include: Physical Symptoms: Muscle weakness and pain, especially in the shoulders, upper arms, thighs Muscle twitching Blurred vision Numbness/pins and needles Tender swollen lymph nodes, particularly underarms [fatigueanswers.com]

  Damage to white matter (brain tissue that takes its name from the white color of myelin ) may also occur, leading to neurological symptoms such as visual loss, muscle weakness, and difficulty coordinating voluntary muscle movements (such as those used [rarediseases.info.nih.gov]

• Blurred Vision

  Other Myalgic Encephalomyelitis Symptoms can include: Physical Symptoms: Muscle weakness and pain, especially in the shoulders, upper arms, thighs Muscle twitching Blurred vision Numbness/pins and needles Tender swollen lymph nodes, particularly underarms [fatigueanswers.com]

  Some patients continue to have symptoms such as blurred vision, weakness or numbness. Will my child get ADEM again? ADEM usually only occurs once, sometimes twice. [gosh.nhs.uk]

• Headache

  A 25-year-old woman presented with a fever, headache, vomiting and somnolence. Cranial magnetic resonance imaging (MRI) showed multiple lesions in the cerebellum, brainstem, cerebral cortex and subcortex. [ncbi.nlm.nih.gov]

  Typical symptoms of ADEM such as fever, headache and confusion, are not usually seen in people with MS. MRIs are helpful when distinguishing ADEM from MS. Most children with MS are treated with ongoing medication to prevent attacks. [childrenshospital.org]

  In children with ADEM, prolonged and severe headaches occur. In addition, the patient develops fevers during the ADEM course. [my.clevelandclinic.org]

  Symptoms may include: Fatigue Fever Headache Nausea Vomiting Changes in your child's consciousness — such as seizures or in severe cases, coma — as well as behavioral changes such as irritability are also likely. [ucsfbenioffchildrens.org]

• Confusion

  […] with ADEM The bottom line Several key factors in ADEM distinguish it from MS, including sudden fever, confusion, and possibly even coma. [healthline.com]

  If you notice symptoms during an infection that you think are unusual, such as confusion, changes in vision, weakness, numbness or imbalance, it is important to notify your child's doctor immediately. [childrenshospital.org]

  Symptoms can include the following: Initial symptoms (not typically seen in MS) Confusion Fever Headache Vomiting Encephalopathy symptoms These include damage to the brain and occur quickly. [childrens.com]

• Myoclonus

  Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder of subacute onset presenting as limb and truncal rigidity, muscle spasms, brainstem signs, and hyperekplexia. 1 Life-threatening, it is part of the spectrum of stiff-person [neurology.org]

  Progressive encephalomyelitis with rigidity and myoclonus (PERM) – A kind of stiff person syndrome. AIDS related encephalomyelitis, caused by opportunistic Human T-lymphotropic virus type III (HTLV-III) infection. [en.wikipedia.org]

  RECENT FINDINGS: Since the initial description in 2008 of antibodies to glycine receptors (GlyR-Abs) in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM), these antibodies have been found in PERM and in some patients with [ncbi.nlm.nih.gov]

  Progressive EM with rigidity and myoclonus is also an autoimmune-mediated disease. Patients infected with HIV may develop a demyelinating disease due to secondary infection with human T-cell lymphotropic virus. [symptoma.com]

• Focal Neurological Deficit

  A variety of focal neurologic deficits may be present, as with MS. Examination of CSF is typically normal. However, CSF can also show nonspecific findings which could suggest aseptic/viral meningitis, encephalitis, or MS. [eyerounds.org]

  Residual focal neurologic deficits remain in 4-30%. [54, 47, 58, 60, 61, 62, 55, 63, 85] Neurocognitive deficits after acute demyelinating syndromes are receiving more attention, as even children having an apparent full recovery after ADEM have demonstrated [emedicine.medscape.com]

• Intracranial Hemorrhage

  The most serious complications of the central nervous system that occur after venomous snake bite are intracranial hemorrhage and ischemic stroke.We present a rarely seen central nervous system complication, acute demyelinating encephalomyelitis, after [ncbi.nlm.nih.gov]

  […] mass Intracranial hemorrhage Metabolic leukoencephalopathy References Apak RA, Kose G, Anlar B, Turanli G, Topaloglu H, Ozdirim E. [eyerounds.org]

ADEM workup basically aims at distinguishing ADEM and multiple sclerosis [11]. If a patient presents with the above described symptoms and anamnesis reveals an infectious disease or immunization within three weeks before presentation, ADEM should be considered. Symptoms tend to worsen initially and persist for more than a few days. In order to rule out differential diagnoses for neurological symptoms, neuroimaging and laboratory analysis of cerebrospinal fluid should be carried out. Magnetic resonance imaging is the technique of choice to achieve the former. Images usually show disseminated white matter lesions. Cerebrospinal fluid is obtained by means of a lumbar puncture and does generally present none to mild pathological alterations.

MEM has been an exclusion diagnosis for a long time. This is principally due to the fact that neither clinical examination nor laboratory analysis of samples obtained from MEM patients reveals any alteration. Diagnostic imaging of the brain, analyses of blood samples (hemogram and complete blood chemistry) and cerebrospinal fluid should be realized to rule out differential diagnoses. Cardiovascular and endocrinological pathologies, notably those affecting hypothalamus, pituitary gland and adrenal glands, may cause fatigue and should be considered to this end. General weakness and malaise may also be triggered by a variety of infectious diseases and autoimmune processes. It is important to maintain objectivity to avoid overestimation of non-significant changes.

• White Matter Lesions

  MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. [ncbi.nlm.nih.gov]

  Multiple lesions in the deep and subcortical white matter are common, which is characteristic of demyelination (gray matter lesions sometimes accompany white matter lesions, especially among children). [myelitis.org]

  Direct imaging of the optic nerve with a gadolinium-enhanced MRI of the brain and orbits is a more sensitive means to diagnose optic neuritis in these patients diffuse white matter lesions, often large and associated with cerebral edema White matter lesions [slideshare.net]

  Thus, MS typically shows demyelinating lesions of varying ages on MRI. MRI in ADEM typically exhibits lesions of the same age. MS typically exhibits demyelination of the deep or periventricular white matter. [eyerounds.org]

  Images usually show disseminated white matter lesions. Cerebrospinal fluid is obtained by means of a lumbar puncture and does generally present none to mild pathological alterations. MEM has been an exclusion diagnosis for a long time. [symptoma.com]

Due to the low incidence of ADEM, therapeutic recommendations based on controlled clinical trials are very rare. The assumption that ADEM is an autoimmune disorder usually makes immunosuppressive medication the treatment of choice. Therapy aims at reducing inflammation and demyelination during an acute episode and to accelerate recovery. In order to achieve this, high-dose corticosteroids such as methylprednisolone are administered intravenously for up to one week. Treatment is continued with oral medication and tapered off. Similar to treatment of multiple sclerosis, patients that do not respond to corticosteroids may be treated with intravenous immunoglobulin in the course of up to one week. They may also benefit from plasmapheresis. This procedure should be repeated every other day for up to two weeks and should also reduce the autoimmune response. Very few ADEM patients don't respond to any of the aforementioned therapeutic approaches and require administration of cytostatic drugs like cyclophosphamide.

Stress reduction, behavioral therapy as well as symptomatic treatment are the mainstays of MEM therapy. The latter may consist in application of analgesics, antidepressants and sedatives if so needed. Many patients improve with relaxation techniques. Sleeping disorders and depression should be treated in a multidisciplinary approach, i.e., with medication and psychotherapy. Graded exercise therapy may prove helpful to relieve stress, depression and pain. Physical activity should be included little by little in the patient's everyday life. Immunosuppressive therapy has not proven effective to treat MEM.

Most ADEM patients fully recover within a few months [9]. Another significant share of patients achieves partial recovery and maintains minor disabilities. However, ADEM is also associated with a mortality of up to 5%. In this context, sudden onset of severe symptoms, absence of fever and lack of response to therapy are unfavorable prognostic factors. Prognosis is generally poorer for those few adult patients diagnosed with ADEM. Children have a good prognosis.

Prognosis for MEM patients is less favorable than for those diagnosed with ADEM. Although in most cases, an improvement can be observed, complete recovery is rare. If achieved, it takes years to get there. Knowledge gaps regarding etiology and pathogenesis may be the cause of ineffective therapeutic approaches that, in turn, result in a poorer outcome.

ADEM or post-infectious EM is most frequently related to viral infections, particularly those with herpes simplex virus, cytomegalovirus and Epstein-Barr virus, all of them pertaining to the family of herpesviridae. Before the incidence of measles has been significantly reduced by means of vaccination programs, the corresponding representant of the family of paramyxoviridae had been most commonly detected in ADEM patients. Various viral pathogens accounting for respiratory and gastrointestinal tract infections may also cause EM. Mycoplasma have been associated with ADEM and prove that bacterial infections may also trigger the disease. However, in most cases, the causative agent is no longer identifiable when patients are diagnosed with ADEM.

ADEM has repeatedly been reported to occur after vaccination against rabies, varicella, measles, rubella, tetanus, diphtheria, pertussis, poliomyelitis and a variety of other diseases.

Until first onset of ADEM symptoms, up to three weeks may have past, but much shorter periods of time have also been reported. In some cases, even longer intervals have been described. These data have to be interpreted with care because it is not always possible to prove a causal relation between the assumed primary infection or vaccination and ADEM.

According to current knowledge, the above mentioned pathogens or vaccines may provoke ADEM only in predisposed individuals. Genetic factors influencing immune cell function may play a major role to this end [7].

Etiology and pathogenesis of MEM are not completely understood. Although there are definitely alterations regarding the function of central nervous system and immune system, these have not yet been defined in detail. This fact complicates a targeted search for possible causes. An autoimmune response, possibly triggered or enhanced by infection, is currently assumed, but this hypothesis requires further corroboration. To date, a genetic predisposition cannot be ruled out. Additionally, environmental factors may act as modulators.

Incidence rates for ADEM have been repeatedly estimated to be below or around 0.5 per 100,000 individuals.

Whereas an increased incidence among Caucasians and males has been suggested, these theories can currently not be confirmed. ADEM may be developed by individuals pertaining to all races and both genders.

ADEM is most frequently diagnosed in children aged less than 10 years. The remaining share of ADEM patients is in their second decade of life. ADEM is rarely diagnosed in adults.

It has been proposed that ADEM incidence is higher in temperate climates than in subtropical and tropical regions. Because seasonal fluctuations have also been observed - ADEM is more frequently diagnosed during the cold and damp season -, it is tempting to speculate that climate does affect ADEM incidence. However, these observations may merely be a reflection of seasonal variations regarding the incidence of ADEM-triggering diseases.

Less epidemiological data is available regarding MEM. Its prevalence has been estimated to be as high as 1% in the United States. Presumably, females are affected more frequently than males. A racial predilection has not been noted. The disease is most often diagnosed in patients during their fourth to sixth decade of life.

While clinically, ADEM may resemble multiple sclerosis, there are histopathologic differences that may be recognized upon analysis of biopsy samples. Both are demyelinating diseases and thus associated with lesions of the myelin sheaths. In multiple sclerosis, gliosis turns an active plaque into an inactive one. The glial scar also impairs re-myelinization by oligodendrocytes. This is not the case in ADEM and may serve as an explanation for the fact that ADEM patients usually recover completely. Also, myelin lesions are usually less extensive and rather patchy in ADEM. Axonal fragmentation is rare, most axons are preserved. Infiltration with mononuclear cells is typical and can mainly be detected in perivascular regions [8].

As has been mentioned above, autoimmune mechanisms, pathogenic microorganisms, genetic predisposition and environmental factors may all play a role in MEM. Endocrinological alterations affecting the function of hypothalamus, pituitary gland and adrenal glands seem to contribute significantly to chronic fatigue. Furthermore, functional differences regarding the autonomous nervous system and an increased vagotone may add to exhaustion. Stress is likely an important environmental factor that may trigger episodes of myalgia, headache and weariness. Nutrient deficiencies and sleeping disorders are likely to affect onset and persistence of MEM.

Although infectious diseases as well as vaccination may presumably trigger ADEM, more severe forms of the disease are usually related to the former. Indeed, infection with measles virus has been the most frequent cause of ADEM before extensive immunization programs were applied to reduce the incidence of that disease. Thus, immunization can be recommended as a measure to avoid post-infectious ADEM.

No specific measures can be recommended to prevent MEM.

Encephalomyelitis (EM) is a very general term that refers to an inflammation of the brain and the spinal cord. EM does not constitute an own entity but is rather a finding characteristic for a variety of diseases. In this context, acute disseminated EM (ADEM) and myalgic EM (MEM) may serve as examples to explain possible pathogenetic differences regarding the general condition of EM. It would go beyond the scope of this article to discuss any known form of EM, but for the sake of completeness, some more shall be mentioned here:

• EM induced by auto-antibodies against the myelin oligodendrocyte glycoprotein. This is a demyelinating disorder of autoimmune etiology. While this condition is sometimes referred to as MOG-antibody-associated EM, similar pathogenic mechanisms may account for neural damage in multiple sclerosis [1] [2]. Indeed, multiple sclerosis may also be designated EM disseminata [3].
• Progressive EM with rigidity and myoclonus is also an autoimmune-mediated disease [4].
• Patients infected with HIV may develop a demyelinating disease due to secondary infection with human T-cell lymphotropic virus [5].
• Zoonotic EM, e.g., those triggered after infection with Western, Eastern or Venezuelan equine EM virus. They may be transmitted by mosquitos.

ADEM has been proposed to be triggered by viral infection and is sometimes also referred to as post-infectious EM [6]. It is a demyelinating disease of autoimmune cause. ADEM is characterized by a sudden onset of neurological and general symptoms. It may not be easy to distinguish ADEM from EM disseminata, but contrary to the latter, the former is self-limiting. Erroneous diagnosis of ADEM as EM disseminata have been reported.

MEM is marked by severe mental and physical fatigue. Chronic fatigue syndrome is another term that refers to the same disease. As of yet, its etiology is not completely understood, but infectious and autoimmune factors have been proposed as possible triggers. Functional impairment of the central nervous system presumably results from metabolic alterations and electrolyte imbalances between intra- and extracellular compartments. Diagnosis of MEM is difficult because of persisting knowledge gaps in etiology and pathogenesis and lack of markers. For a long time, MEM has been diagnosed by exclusion of other disorders.

Encephalomyelitis (EM) is a general term that refers to any inflammation of the brain and spinal cord. Such an inflammation may develop in the course of a variety of disorders. Treatment should always be adjusted to the specific cause.

Here, some examples shall be given to illustrate differences between distinct types of EM.

• Acute disseminated EM is an autoimmune disorder, i.e., the patient's immune system attacks endogenous structures. It is usually related to an infection that occurred weeks before. Before extensive immunization programs against measles were implemented, this disease was the most common trigger for acute disseminated EM. And although some cases have been associated with vaccinations themselves, immunization is the best preventive measure against this disease. Typical symptoms are fever, weakness, headache and loss of coordination. Most patients recover completely, but in some cases, neurologic deficits may persist.
• Clinically, there are some similarities between acute disseminated EM and multiple sclerosis. In fact, multiple sclerosis is another form of EM and is sometimes also referred to as disseminated EM.
• The concept of an autoimmune disorder also applies to MOG-antibody-associated EM. Here, the patient's immune system produces antibodies against myelin, the substance that surrounds the axons of nerve cells.
• Progressive EM with rigidity and myoclonus is also an autoimmune-mediated disease.
• Myalgic EM is also called chronic fatigue syndrome and manifests in form of severe fatigue, muscle pain and depression after what seems like a usual flu. The precise causes of this disease are not yet understood. Treatment comprises stress reduction, psychotherapy and medication to relieve acute symptoms.
• Patients with a weakened immune system due to infection with HIV may develop an AIDS-related EM after secondary infection with human T-cell lymphotropic virus.
• Rarely, infectious diseases transmitted by mosquitos to horses may also be diagnosed in men.

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