Pediatrics

Acute Disseminated Encephalomyelitis (ADEM)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has acute disseminated encephalomyelitis? What are the typical findings for this disease?

The clinical appearance of acute disseminated encephalomyelitis (ADEM) is variably described in the literature but often includes some combination of the following signs/symptoms:

Initial Manifestations

Fever

Myalgias

Fatigue/malaise

Later Findings

Somnolence/altered mental status/obtundation

Nausea/vomiting

Meningeal signs

Focal weakness/hemiparesis

Ataxia

Seizures

What other disease/condition shares some of these symptoms?

ADEM is a clinical diagnosis, but in the absence of established clear and specific clinical criteria ADEM shares a great deal of overlap with numerous other diseases that cause an acute encephalopathy and should be excluded as causes including:

  • Acute infectious meningoencephalitis due to bacteria (Listeria, Streptococcus, Meningococcus) or viruses (specifically, herpes simplex virus [HSV], Epstein Barr virus [EBV], cytomegalovirus, JC virus)

  • Initial manifestation of a demyelinating disease such as multiple sclerosis or Schilder disease

  • Cerebral vasculitis

  • Immune reconstitution syndrome due to highly active antiretroviral treatment of HIV/AIDS

What caused this disease to develop at this time?

ADEM is considered to be a delayed immune overreaction to an antecedent infection, usually viral. Influenza and parainfluenza species are the most commonly found antecedent infections when a viral trigger has been identified, but published findings suggest that the viruses associated with ADEM in fact may be more ubiquitous species such as rhinoviruses, respiratory syncytial virus, or coronaviruses. Despite temporal association, ADEM is not a result of direct nervous system invasion by any pathogen but is triggered by an autoimmune response to central nervous system antigens.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There is no specific laboratory study pathognomonic for a diagnosis of ADEM, the diagnosis is made by a combination of clinical suspicion, neuroimaging findings, and the lack of a more appropriate primary diagnosis being found.

Since the clinical appearance of ADEM overlaps considerably with bacterial or viral encephalitis, an appropriate evaluation must include studies to exclude these entities.

Tests to consider should be obtained to exclude other possible (treatable) causes of findings consistent with ADEM and may include the following:

Serum toxicology screen: pediatric ingestions of prescription and illicit substances can produce acute encephalopathy and neurological symptoms that mimic ADEM. Also prescribed medications such as chemotherapy agents (tacrolimus, methotrexate, and cyclosporine) can produce an encephalopathy syndrome that mimics ADEM, which MRI and serum levels showing toxicity range findings can help establish.

Cerebrospinal fluid (CSF) studies: Include white blood cell count and protein and glucose levels, Gram stain, and bacterial culture. HSV polymerase chain reaction (PCR) should be performed as should other specific studies suggested by the history or presentation, especially the other herpes viruses (EBV, CMV, varicella-zoster virus [VZV]). CSF studies in ADEM can yield nonspecific and mild elevations in protein and white blood cell count. One should also obtain oligoclonal bands and an IgG Index, as these are reportedly more often positive in patients who will have recurrences or an ultimate diagnosis of multiple sclerosis; however, even these findings are controversial.

Aquaporin-4 antibody:This is a specific assay for neuromyelitis optica, or Devic disease. If a patient presents with optic neuritis and transverse myelitis, this serum study (and CSF if serum is not diagnostic but clinical suspicion remains high) should be obtained because these findings (e.g., optic neuritis and transverse myelitis) are atypical of ADEM.

Complete blood count with differential: This is to assess for leukocytosis and the presence of infection or an active autoimmune process.

Blood culture, urine culture, and (if available) respiratory/nasopharangeal viral panel (specifically to allow identification of influenza, parainfluenza, rhinovirus, or coronavirus species): These tests can identify possible pathogens. Given the sensitivity of commercially available respiratory viral panels, it may be possible to identify the specific viral cause that may have triggered ADEM, even in the absence of a clear viral prodrome.

Rapid plasma reagin or other serologic test to identify syphilis. If syphilis is suspected on epidemiologic or clinical grounds, this is a necessary diagnostic test. HIV should also be considered as a useful screening test in any patient with risk factors.

C-reactive protein (CRP): If elevated, this study is further evidence of infection. It is not a specific finding in ADEM.

Erythrocyte sedimentation rate (ESR): If elevated, the ESR may indicate a systemic inflammatory process. This can be mildly elevated in ADEM.

Anti-nuclear antibody (ANA) screen, anticardiolipin, antiphospholipid antibodies: An elevated, significant autoantibody titer is suggestive of a systemic rheumatologic disease with neurological manifesations.

Angiotensin-converting enzyme (ACE): An elevated ACE is suggestive of a neurological manifestation of sarcoidosis, especially with other systemic findings such as lung granulomas.

Ferritin and triglycerides: An elevated fasting triglyceride level of >265 mg/dL and a serum ferritin >500 ng/ml are diagnostic of Macrophage Activation Syndrome (MAS), a rare cause of systemic autoimmune activation.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging (MRI) of the brain, with and without contrast, is the most appropriate study for confirmation of a diagnosis of ADEM. The T2 and fluid-attenuated tissue recovery (FLAIR) sequences should be obtained, as typically these will demonstrate multiple ("disseminated") lesions within the subcortical and periventricular white matter. The parietal lobe is frequently involved. Gray matter and basal ganglia lesions are not uncommon. Spinal cord involvement is seen in up to a third of cases. MRI will also establish whether there is a cerebrovascular event or other intracranial process that is precipitating an encephalopathy.

These lesions usually enhance with gadolinium administration and may have restricted diffusion. It is important to note that in several studies, lesion number and size do not necessarily correlate with the severity of the clinical picture. If a multiple sclerosis protocol sequence is available it should be obtained.

The radiologic appearance of ADEM can be indistinguishable from that of an acute manifestation of multiple sclerosis, which has led to speculation and controversy regarding whether ADEM is sometimes an initial manifestation of multiple sclerosis in children (see discussion further on)

Computed tomography (CT) of the head and brain may show hypodense lesions within the white matter, but this study is inferior to magnetic resonance imaging (MRI) in terms of resolution and sensitivity, particularly in early ADEM with small lesions. If hemorrhage is suspected, or an MRI of sufficient quality (or with anesthesia support) is not readily available, CT can provide useful data.

Electroencephalograms are not indicated unless seizures are suspected or present. Otherwise the findings in ADEM are not specific; typically diffuse slowing is noted.

Confirming the diagnosis

There are no widely accepted clinical algorithms for the diagnosis of ADEM. A proposed definition, not yet validated in a large published prospective report, was generated by the Brighton Collaboration Encephalitis Working Group and summarized in Sejvar et al (2007). It is as follows:

Level 1 of diagnostic certainty: ADEM

(a) Demonstration of diffuse or multifocal areas of demyelination by histopathology.

Level 1 of ADEM is met if criterion (a) is met or if criteria (b + c + d) are fulfilled, and no exclusion criteria are met.

OR

(b) Focal or multifocal findings referable to the central nervous system, including 1 or more of the following:

1. Encephalopathy (e.g., depressed or altered level of consciousness, lethargy, or personality change lasting >24 hours)

2. Focal cortical signs (including but not limited to aphasia, alexia, agraphia, cortical blindness)

3. Cranial nerve abnormality/abnormalities

4. Visual field defect/defects

5. Presence of primitive reflexes (Babinski sign, glabellar reflex, snout/sucking reflex)

6. Motor weakness (either diffuse or focal; more often focal)

7. Sensory abnormalities (either positive or negative; sensory level)

8. Altered deep tendon reflexes (hypo- or hyperreflexia, asymmetry of reflexes)

9. Cerebellar dysfunction, including ataxia, dysmetria, cerebellar nystagmus

AND

(c) MRI findings displaying diffuse or multifocal white matter lesions on T2-weighted, diffusion-weighted (DWI), or fluid-attenuated inversion recovery (FLAIR) sequences (± gadolinium enchancement on T1 sequences),

AND

(d) Monophasic pattern to illness (i.e., absence of relapse within a minimum of 3 months of symptomatic nadir).

Level 2 of diagnostic certainty: ADEM

(a) Focal or multifocal findings referable to the central nervous system, including one or more of the following:

10. Encephalopathy (e.g. depressed or altered level of consciousness, lethargy, or personality change lasting >24 h),

11. Focal cortical signs (including but not limited to: aphasia, alexia, agraphia, cortical blindness)

12. Cranial nerve abnormality/abnormalities

13. Visual field defect/defects

14. Presence of primitive reflexes (Babinski’s sign, glabellar reflex, snout/sucking reflex)

15. Motor weakness (either diffuse or focal; more often focal)

16. Sensory abnormalities (either positive or negative; sensory level),

17. Altered deep tendon reflexes (hypo- or hyperreflexia, asymmetry of reflexes)

18. Cerebellar dysfunction, including ataxia, dysmetria, cerebellar nystagmus,

AND

(b) Magnetic resonance imaging (MRI) findings displaying diffuse or multifocal white matter lesions on T2-weighted, diffusion-weighted imaging (DWI), or fluid-attenuated inversion recovery (FLAIR) sequences (± gadolinium enhancement on T1 sequences)

AND

(c) Insufficient follow-up time achieved to document absence of relapse within a minimum period of 3 months after symptomatic nadir.

Level 3 of diagnostic certainty: ADEM

(a) Focal or multifocal findings referable to the central nervous system, including 1 or more of the following:

19. Encephalopathy (e.g., depressed or altered level of consciousness, lethargy, or personality change lasting >24 hours)

20. Focal cortical signs (including but not limited to aphasia, alexia, agraphia, cortical blindness)

21. Cranial nerve abnormality/abnormalities

22. Visual field defect/defects

23. Presence of primitive reflexes (Babinski sign, glabellar reflex, snout/sucking reflex)

24. Motor weakness (either diffuse or focal; more often focal)

25. Sensory abnormalities (either positive or negative; sensory level)

26. Altered deep tendon reflexes (hypo- or hyperreflexia, asymmetry of reflexes)

27. Cerebellar dysfunction, including ataxia, dysmetria, cerebellar nystagmus

Level 2 of ADEM is met if criteria (a + b + c) are fulfilled and no exclusion criteria are met.

Level 3A

  • Insufficient information is available to distinguish case between acute encephalitis or ADEM; case unable to be definitively classified

Exclusion criteria for all levels of diagnostic certainty:

  • Presence of a clear alternative acute infectious or other diagnosis for illness

  • Recurrence or relapse of illness at any point following a 3-month period of clinical improvement from symptomatic nadir

  • If known, MRI findings or histopathologic data inconsistent with the diagnosis of ADEM

There is suggestion that the Callen Magnetic Resonance Imaging Criteria for Multiple Sclerosis can differentiate between ADEM and pediatric multiple sclerosis. The published sensitivity and specificity were 82% and 52%, respectively. This finding has not been verified in a large prospective study. The Callen criteria for diagnosing pediatric multiple sclerosis on MRI are as follows:

At least 2 of the following:

Five or more T2 lesions

Two or more periventricular lesions

One or more brainstem lesions

If you are able to confirm that the patient has acute disseminated encephalomyelitis, what treatment should be initiated?

There is no literature establishing a standard, proven treatment for ADEM. The Infectious Diseases Society of America recommends the use of steroids for the acute management of ADEM.

If other causes are excluded, treatment consists of immunomodulation and immune suppression.

Corticosteroids are the most widely accepted initial treatment for ADEM. The treatment dose and duration is derived from clinical experience with other demyelinating conditions. Most authors recommend intravenous methylprednisolone 20-30 mg/kg/day (up to 1000 mg maximum) daily for a treatment duration of 5 days. The optimal duration of intravenous steroid treatment is not known in children; some patients may respond robustly within 3 days of treatment, and reports suggest that clinical improvement is typically seen after 1-4 days of steroid treatments.

After high-dose methylprednisolone treatment is completed, oral corticosteroids should be given to for 4-6 weeks after completion of intravenous (IV) therapy. The initial starting dose of oral steroids is recommended at 1 mg/kg/day or a maximum starting dose of 60 mg daily of either prednisolone suspension or prednisone tablets. There is no established tapering protocol, but a reduction of 5 mg every 3-5 days days from the initial 60 mg dose would achieve the desired goal as to duration of treatment in a safe manner.

This same regimen (5 days IV methylprednisolone followed by 4-6 weeks of oral steroids is advised for recrudescence of ADEM (also termed multiphasic disseminated encephalomyelitis [MDEM]).

There have been studies of plasma exchange as a possible treatment of ADEM refractory to corticosteroids. This treatment should be initiated as soon as possible and could be considered as early as 3 days into steroid treatment. A total of 5-7 exchanges over 10-14 days is the reported course of treatment. Steroid treatment can and likely should continue concurrently while plasma exchange occurs.

Intravenous immunoglobulin (400-500 mg/kg) is an option for steroid-refractory cases of ADEM in which plasma exchange is contraindicated or not available. Duration of therapy reported to be effective for ADEM is 5 consecutive days. It may also have particular effectiveness when combined with steroids in atypical ADEM with a predominant involvement of the peripheral nervous system.

There are isolated reports that other treatments for demyelinating diseases such as the multiple sclerosis medications glatiramer acetate (Copaxone), cyclophosphamide, and mitoxantrone were effective treatments for patients refractory to steroids, IV immunoglobulin, and/or plasma exchange.

What are the adverse effects associated with each treatment option?

The side effects of corticosteroids are well documented and include hyperglycemia, hypertension, psychosis/mood changes, gastrointestinal ulceration/bleeding, hypokalemia, insomnia, and opportunistic infections. These side effects are thankfully uncommon and are not usually associated with a need for early termination of treatment.

There is evidence for prevention of gastrointestinal ulceration while taking corticosteroids through the routine use of H2 antagonists and proton pump inhibitors. Potassium levels should be monitored; if high-dose methylprednisolone results in hypokalemia, repletion should be instituted appropriately to avoid complications.

Plasma exchange is generally a safe and well-tolerated procedure in children. It requires surgical implantation of a catheter suitable for exchange, which has the usual surgical risks of bleeding and infection. Long term, the catheter is a potential source of infection and embolism.

There are patients in whom plasma exchange is contraindicated. Hemodynamically unstable patients or patients with cardiovascular compromise as a result of myocardial infarction, arrhythmias, or coronary artery disease are unsuitable for exchange therapy. Severe, uncorrectable coagulopathies are also a contraindication. Patients with severe hepatic failure and renal failure are also not appropriate for plasma exchange therapy.

During therapy, there are multiple complications reported, but most are easily corrected through readily available means. Hypotension and bradycardia are frequently encountered and may require fluid support. Hypocalcemia and other electrolyte abnormalities can also require intervention, and electrolytes should be monitored. Coagulopathy, anemia, and deep vein thrombosis/pulmonary embolism are also serious, potentially fatal, complications in rare instances.

IV immunoglobulin (IVIG) administration has both early and later side effects and complications, which can occur in up to 15% of patients receiving IVIG infusions. During infusion, the primary concern is prompt recognition and treatment of signs of a hypersensitivity or anaphylactic reaction, including angioedema, urticaria, hypotension, or bronchospasm, often caused by IgA deficiency. An IgA level should be obtained and reviewed before IVIG infusion.

Patients may experience relatively mild symptoms, including headache, myalgias, fever, chills, or nausea/vomiting, while receiving their infusions. Later side effects include fatigue; symptomatic hypotension, headache, and nonspecific complaints are also seen. The large volume of IVIG infusion makes it contraindicated in patients with severe cardiac failure and renal compromise. Rarely renal failure and thrombosis can be late complications of IVIG.

What are the possible outcomes of acute disseminated encephalomyelitis?

ADEM is classically considered a monophasic condition with an excellent prognosis for remission and full recovery within 1-6 months of onset. Retrospective and prospective studies agree that more than 75% of patients with ADEM can expect a full recovery. More than 90% of patients will recover fully or have a very mild disability noted at follow-up.

ADEM is not typically fatal, but there are severe cases in which the brain edema leads to herniation and without prompt treatment death. Findings that suggest a more complicated course or long-term disability include symptomatic brain edema, older age at onset, the presence of CSF oligoclonal bands, female sex, and involvement of the spinal cord or peripheral nervous system.

The global standard of care in ADEM is high-dose steroid treatment, and this treatment is shown in some studies to decrease disability at follow-up. However, many studies report spontaneous remission of ADEM and no statistical difference between those receiving steroid treatment and those who received no treatment. At this time, the recommendation of the Infectious Diseases Society of America is a trial of high-dose steroids, as it is a well-tolerated and low-risk intervention with suggestion of possible long-term benefit.

What causes this disease and how frequent is it?

ADEM is an uncommon disease. It is widely accepted to be a parainfectious or postinfectious phenomenon. The incidence of ADEM is reported to be in a range from 0.4 to 0.8 per 100,000. The mean age of onset reported in children is approximately 6 years, but the incidence is highest in younger children (<3 years). Boys may be affected more often than girls, with a ratio reported around 1.4:1, although some large studies do not corroborate a sex difference in ADEM.

As many as 70% of ADEM cases report an antecedent infection or vaccination. After measles, the incidence is 1 per 1000 patients. After varicella the reported incidence is 1 per 10,000 patients, and after rubella the incidence of ADEM is 1 per 20,000.

ADEM does not have a true seasonal association, but an increased incidence is reported after vaccinations and epidemics of wild-type infections such as those listed above.

There are no known genetic linkages to ADEM, as it appears to be a sporadic parainfectious phenomenon.

How do these pathogens/genes/exposures cause the disease?

Although ADEM can follow a viral infection, and probably typically does, an antecedent infection is not definitively known in most reported cases. There are several infectious species associated with a higher risk of ADEM, including measles. ADEM is the most commonly reported neurologic complication of infection with wild-type species of measles, rubella, and varicella.

Other viral infections that may be complicated by ADEM include mumps; influenza A or B; hepatitis A, B, or C; Epstein-Barr virus; acute HIV; herpes simplex virus; human herpes virus 6; coxsackievirus B; and coronavirus.

Bacterical infections can also yield ADEM as a postinfectious complication, and include group A β-hemolytic streptococci, Legionella pneumophila, Salmonella typhi, Leptospira interrogans, Mycoplasma pneumoniae, Borrelia burgdorferi, Rickettsia rickettsii, and Plasmodium falciparum.

There are some vaccinations that have been reported to be associated with an increased risk of ADEM after administration, including vaccinations for rabies, measles, Japanese encephalitis virus, poliovirus (oral preparation), tetanus, influenza, and recombinant hepatitis B.

There is no definitive model for ADEM as a complication of infection. The animal model of ADEM, also used in multiple sclerosis modeling, is the experimental autoimmune encephalomyelitis model in which experimental animals receive injections of purified brain homogenates and yield clinical and brain pathologic features similar to those of demyelinating diseases.

Based on this model and other pathologic studies, ADEM is thought to occur as a combination of autoimmunity and loss of regulation of the native immune response. In the majority of ADEM cases, it is believed that a form of "molecular mimicry" occurs, in which the preceding infection has antigens that resemble self-derived epitopes, leading to inappropriate immune activation against both invading and native structures.

Preceding infection can also disrupt the normal process of prevention of self-immunity by removing regulatory cells that would otherwise have prevented inappropriate autoimmune responses. Finally, some viruses have been shown to damage or even directly inhibit myelin, leading to identification of myelin as an appropriate immune target.

Other clinical manifestations that might help with diagnosis and management

There is a relatively rare variant of ADEM with a predominant hemorrhagic component, termed acute leukoencephalitis, characterized by cerebral edema and numerous small hemorrhages. The brain edema in this variant can be severe and require neurosurgical decompression. The outcome of this variant is generally worse; it is otherwise treated similarly to conventional ADEM.

What complications might you expect from the disease or treatment of the disease?

The side effects of treatment are discussed above, but generally there are no significant long-term sequelae of glucocorticoids or plasma exchange. The most common residual sequelae of ADEM are mild attention/cognitive deficits and mild weakness/paresis (corresponding to a score of 1-3 on the Expanded Disability Status Scale). Rarely, in less than 1% of reported cases, ADEM can cause severe brain edema leading to neurosurgical intervention or mortality.

How can acute disseminated encephalomyelitis be prevented?

There is no known effective prevention for ADEM. Although vaccination against some diseases rarely is associated with ADEM, the incidence of acquiring ADEM from infection with these same wild-type diseases is far higher than the postvaccination risk, and vaccination according to American Academy of Pediatrics guidelines is advised.

Although there are few studies concerning recurrence risk and a great deal of controversy on the topic, some suggest delaying all vaccinations until 6 months after a diagnosis of ADEM to prevent a recurrence or, at the very least, prevent the unlikely event that a patient has a recurrence of ADEM coincident with a vaccination administration, since most relapses occur within 4-6 months of the initial ADEM diagnosis.

Table I.

Presenting symptoms of ADEM

Table II.

Differential diagnosis

Table III.

Criteria to distinguish MS from ADEM*

What the Evidence?

Sejvar, JJ, Kohl, KS, Bilynsky, R. "Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data". Vaccine. vol. 25. 2007. pp. 5771-92.

(The proposed clinical criteria for ADEM diagnosis are found here.)

Tunkel, AR, Glaser, CA, Bloch, KC. "The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America". Clin Infect Dis. vol. 47. 2008. pp. 303-27.

(The use of steroids for ADEM treatment is recommended in this article.)

Kaynar, L, Altuntas, F, Aydogdu, I. "Therapeutic plasma exchange in patients with neurologic diseases: retrospective multicenter study". Transfus Apher Sci. vol. 38. 2008. pp. 109-15.

(The use of plasma exchange in ADEM and other diseases is reviewed in this article.)

Shahar, E, Andraus, J, Savitzki, D. "Outcome of severe encephalomyelitis in children: effect of high-dose methylprednisolone and immunoglobulins". J Child Neurol. vol. 17. 2002. pp. 810-4.

(Justification for the use of IVIG in ADEM can be found in this and the following two articles.)

Straussberg, R, Schonfeld, T, Weitz, R. "Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins". Pediatr Neurol. vol. 24. 2001. pp. 139-43.

Ravaglia, S, Piccolo, G, Ceroni, M. "Severe steroid-resistant post-infectious encephalomyelitis: general features and effects of IVIg". J Neurol. vol. 254. 2007. pp. 1518-23.

Hoche, F, Pfeifenbring, S, Vlaho, S. "Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features". J Neural Transm. vol. 118. 2011. pp. 1311-7.

(ADEM and its connection to multiple sclerosis is discussed in this and the following articles.)

Javed, A, Khan, O.. "Acute disseminated encephalomyelitis". Handb Clin Neurol.. vol. 123. 2014. pp. 705-17.

Ketelslegers, IA, Neuteboom, RF, Boon, M. "A comparison of MRI criteria for diagnosing pediatric ADEM and MS". Neurology. vol. 74. 2010. pp. 1412-5.

Visudtibhan, A, Tuntiyathorn, L, Vaewpanich, J. "Acute disseminated encephalomyelitis: a 10-year cohort study in Thai children". Eur J Paediatr Neurol. vol. 14. 2010. pp. 513-8.

Wender, M.. "Acute disseminated encephalomyelitis (ADEM)". J Neuroimmunol. vol. 231. 2011. pp. 92-9.

Zettl, UK, Stüve, O, Patejdl, R.. "Immune-mediated CNS diseases: a review on nosological classification and clinical features". Autoimmun Rev. 2011 May 18.

Ongoing controversies regarding etiology, diagnosis, treatment

There remains considerable controversy regarding the risk of multiple sclerosis development after ADEM. Virtually all studies of ADEM identify patients who present with relapses, sometimes with new lesions on MRI and CSF findings. The controversy about these patients is whether ADEM is always monophasic or whether relapses truly represent a second occurrence of ADEM (which some propose as the variant MDEM), or whether the initial ADEM was in fact the first herald (or clinically isolated syndrome) of a diagnosis of multiple sclerosis. ADEM relapses and recurrence rates are reported between 5 and 21%.

ADEM recurrences exist in less than 25% of ADEM cases (range: 12%-25%), and the published risk of ultimately meeting criteria for multiple sclerosis after ADEM is as high as 40%. The presence of spinal or peripheral lesions and persistent oligoclonal bands are risks for multiple sclerosis. It is therefore not appropriate to discuss a long-term risk of multiple sclerosis at initial diagnosis of ADEM unless atypical features such as peripheral involvement are present. This is an evolving topic and remains heavily debated in the pediatric literature.

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