Acute disseminated encephalomyelitis

CASE

A 3-year-old girl was brought to the ED by her mother with 2 days of headaches and fatigue after returning home from a trip to Costa Rica 4 days ago.

History

The patient's mother reported that for the previous 4 days the patient had been more fussy than usual, and she had started to complain of headaches at night and early in the morning that would improve during the day. The patient subsequently had an episode of vomiting that morning, and she was tired and listless, which prompted her family to take her to the ED. On arrival, the patient stated that she had a headache, pointing to her forehead. She rated her pain a 2 on a visual version of the 0-to-10 pain intensity rating scale. Her family reported that they had left for Costa Rica about 1 month earlier. About 10 days after arriving in Costa Rica, the patient began to have fevers and urinary frequency. The patient was treated for what was presumed to be a urinary tract infection with antibiotics from a pharmacy. However, she discontinued the antibiotics after 3 days due to hives. The fevers and urinary frequency resolved, and the patient had no further fevers or other symptoms during the stay in Costa Rica. The mother reported that the patient swam in warm shallow river water, drank tap water, and interacted with cats, dogs, cattle, and horses while in Costa Rica. The patient was up-to-date on vaccinations and had no previous medical history.

Physical examination

The patient had normal vital signs and was afebrile. She appeared tired but was interactive and responded to questions. The remainder of her physical examination was unremarkable, including a normal neurologic examination without meningeal signs.

Diagnostic testing

Bloodwork revealed an elevated white blood cell count of 16,200 cells/mm3 with neutrophilic leukocytosis. The patient had a negative respiratory pathogen panel, a complete metabolic panel that was within normal limits, and a normal urinalysis. A “fast” brain MRI was obtained and showed a T2 hyperintense region identified in the medial aspect of the right brachium pontis and medial right cerebellar hemisphere. The patient was admitted to the hospital with plans to have a complete brain MRI with and without contrast the following morning. Repeat brain MRI revealed right cerebellar and middle cerebellar peduncle lesion and scattered supratentorial high T2 signal white matter lesions (Figure 1) most consistent with acute disseminated encephalomyelitis (ADEM).

F1-7FIGURE 1.:

Brain MRI FLAIR showing scattered high T2 signal white matter lesions

FB1Box 1

Infectious disease was consulted and advised further workup including a lumbar puncture with meningitis/encephalitis panel, cerebrospinal fluid (CSF) herpes simplex virus PCR, West Nile Virus IgM, Zika virus antibodies, dengue antibodies, and chikungunya antibodies.

The differential diagnosis included ADEM, multiple sclerosis (MS), optic neuritis, transverse myelitis, infectious meningitis/encephalitis, central nervous system (CNS) vasculitis, CNS malignancy, and CNS isolated hemophagocytic lymphohistiocytosis.

OUTCOME

The infectious disease workup was found to be negative. The consulting neurologist agreed that the patient's presentation and imaging were consistent with ADEM and recommended initiation of IV methylprednisolone. Once treatment was initiated, the patient began to have improvement in irritability. After 3 days of IV steroids, a repeat brain MRI with and without contrast as well as a total spine MRI was obtained, revealing widespread demyelinating disease with progression of supratentorial lesions and involvement of the cervicothoracic cord (Figure 2). IV methylprednisolone was continued for 2 more days for a total of 5 days. The neurologist recommended continuation of oral corticosteroids over a 25-day taper, and repeat brain and spine MRI with and without contrast in 4 to 6 weeks.

F2-7FIGURE 2.:

Total spine MRI showing involvement of the cervicothoracic cord

The patient showed significant improvement throughout her hospitalization and remained afebrile with stable vital signs. Her parents reported intermittent fussiness but no change in personality. On the day of discharge, the patient was ambulating around the room. She returned for repeat imaging 2 months after being discharged, and had full resolution of demyelinating lesions in the cervicothoracic cord and further reduction of demyelinating lesions in the brain.

DISCUSSION

ADEM is an autoimmune process causing CNS demyelination that often involves the brain and spinal cord and occasionally affects the optic nerve. ADEM affects about 1 in 125,000 to 250,000 patients each year and accounts for 10% to 15% of cases of acute encephalomyelitis in the United States.1,2 Most cases occur in children, with a majority occurring in children under age 10 years.1

The exact mechanism of ADEM is not completely understood, but it is thought to result from inflammation triggered by a stimulus such as a viral or bacterial infection or, less commonly, vaccination.1 An autoimmune response to an infecting pathogen is thought to affect myelin autoantigens in the CNS, because of similarities in antigenic determinants between the pathogen and CNS myelin.1 Inflammatory cells including macrophages and T cells then attack endothelial cells in both white and gray matter, resulting in periventricular demyelination.2

ADEM has an acute onset, usually is monophasic, and is rapidly progressive. Nonspecific associated symptoms include fever, headache, malaise, fatigue, nausea, and vomiting. Patients also can present with signs of altered mental status including irritability, confusion, somnolence, and psychosis. In patients with spinal cord involvement, symptoms can mirror those of transverse myelitis, with motor and sensory deficits including flaccid paralysis and bowel and bladder dysfunction. Presentation also can include brainstem deficits such as dysarthria, or other neurologic abnormalities including seizures or ataxia, although this is typically seen only in very severe cases.1 When the optic nerve is involved, symptoms of optic neuritis can be present such as eye pain and vision loss.3 Most often, symptoms present 7 to 14 days after a viral infection.3

Most children with ADEM experience a self-limited course over a few weeks, with the peak of symptoms occurring within the first week of symptom onset; however, some cases can last up to 3 months.4 ADEM usually is monophasic, but in rare cases a second event may occur. These cases must be differentiated from other multiphasic demyelinating disorders such as MS.5

No specific diagnostic test or biomarker can identify ADEM. Diagnosis is made based on the presence of encephalopathy and multifocal CNS involvement after ruling out other demyelinating diseases as well as other causes of meningitis and encephalitis.1 The International Pediatric Multiple Sclerosis Study Group developed diagnostic criteria for ADEM in children in 2007 that were most recently updated in 2013. These include:

A first polyfocal CNS demyelinating event Encephalopathy (defined as behavioral changes and/or altered mental status not explained by fever) Brain MRI abnormalities consistent with demyelination during the acute phase (within 3 months) No new clinical or MRI findings 3 months or more after clinical onset of symptoms.4,6

The workup for children presenting with signs and symptoms concerning for ADEM should include a complete blood cell count, metabolic panel, inflammatory markers, antinuclear antibodies, brain and spine imaging, and cerebrospinal fluid studies including cell count, protein count, and meningitis/encephalitis PCR.4

Children with ADEM may have an elevated erythrocyte sedimentation rate and C-reactive protein level, thrombocytosis, and/or leukocytosis.1 CSF examination usually is normal, although oligoclonal bands can be seen, and mild pleocytosis (5 to 20 cell/mcL) with lymphocyte predominance is seen in 29% to 85% of patients.7

An emerging biomarker of interest in demyelination workup is the antibody response to myelin oligodendrocyte protein (MOG), a protein expressed on the surface of the CNS myelin sheath and oligodendrocytes. The presence of serum MOG-IgG has been seen in patients with ADEM and typically is not seen in those with MS.5

An emergency CT scan may be considered to rule out other potentially life-threatening causes of symptoms, but CT usually is unremarkable in patients with ADEM.1 The preferred imaging modality for evaluation of suspected ADEM is MRI of the brain and total spinal cord with and without contrast. As in the case patient, spinal cord lesions are common, although these rarely present as isolated findings without accompanying brain lesions.8 In children presenting with symptoms of optic neuritis, obtain an MRI of the orbits with and without contrast.4 Typical MRI findings include hyperintense lesions on T2-weighted fluid attenuated inversion recovery (FLAIR). Imaging may reveal a single lesion or multiple lesions throughout the white and gray matter, but most characteristically there are multiple widespread asymmetric lesions throughout the brain with indistinct margins.1 Supratentorial lesions tend to be asymmetrical; thalamic and basal ganglia lesions tend to be symmetrical. MRI findings are similar for ADEM and MS, but periventricular sparing and absence of periventricular ovoid lesions (Dawson fingers) support a diagnosis of ADEM.4 Patients with ADEM may have a normal MRI.

Most MRI lesions resolve within 18 months in patients with ADEM. New lesions or relapses may indicate the development of MS, especially if seen after 6 months or recurrent multiphasic ADEM.3 Monophasic ADEM is not associated with development of new lesions more than 3 months after disease presentation. Patients should be reassessed with follow-up MRIs every 2 to 3 months for up to 12 months to rule out ongoing disease.4

EEG may reveal a disturbed sleeping pattern with background slowing of electrical activity, but findings typically are nonspecific.1

Because of the lack of conclusive evidence and randomized studies, management of ADEM is based on observational studies and expert opinions.4 Strongly consider empiric antibiotic and antiviral treatment while diagnostic evaluation is pending.7 The recommended treatment for ADEM is immunosuppression with high-dose IV glucocorticoids for 3 to 5 days, followed by a course of oral corticosteroids tapered over 4 to 6 weeks.6 If a patient does not respond well to the corticosteroids, IV immune globulin (IVIG), plasma exchange, and cyclophosphamide are secondary treatment options.1 Beyond treatment of the initial disease, clinicians should have a plan for long-term follow-up to exclude a multiphasic disorder that would warrant further evaluation.7

Most children with ADEM have a full recovery after treatment; mortality is below 3% during the acute demyelinating episode.4 The timeline to recovery from ADEM is not well defined, which is likely because studies use a variety of outcome measures in assessing these patients. Improvement of neurologic symptoms typically is seen within a few days of initiation of treatment, and recovery to baseline typically occurs within weeks.4 However, long-term cognitive deficits have been reported, more commonly in children who develop ADEM before age 5 years.4 These deficits can include clumsiness, ataxia, hemiparesis, and blindness.6 Other subtle deficits including excessive fatigue and decreased exercise capacity have been seen in close to 50% of patients with ADEM assessed 40 months after onset.4 Relapsing ADEM is rare, as is ADEM as an initial presentation of MS, occurring in less than 10% of patients with ADEM.4

CONCLUSION

ADEM is an acute autoimmune process causing CNS demyelination, and most often occurs in children after a viral infection. It is typically monophasic; therefore, patients presenting with multiple episodes must be further evaluated for other demyelinating processes such as MS. Diagnosis is made based on observation of specific clinical symptoms and MRI findings. Prompt recognition and brain imaging is warranted for ideal treatment and optimal patient outcomes. Recommended treatment includes immunosuppression with corticosteroid administration. Most children with ADEM have a full recovery after treatment.

REFERENCES 1. Anilkumar AC, Foris LA, Tadi P. Acute disseminated encephalomyelitis (ADEM). www.ncbi.nlm.nih.gov/books/NBK430934. Accessed March 25, 2022. 2. Neeki MM, Au C, Richard A, et al. Acute disseminated encephalomyelitis in an incarcerated adolescent presents as acute psychosis. Pediatr Emerg Care. 2019;35(2):e22–e25. 3. Stonehouse M, Gupte G, Wassmer E, Whitehouse WP. Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians. Arch Dis Child. 2003;88(2):122–124. 4. Pohl D, Alper G, Haren KV, et al. Acute disseminated encephalomyelitis. Neurology. 2016;87(9 suppl 2):S38–S45. 5. Neuteboom R, Wilbur C, Pelt DV, et al. The spectrum of inflammatory acquired demyelinating syndromes in children. Semin Pediatr Neurol. 2017;24(3):189–200. 6. Gray MP, Gorelick MH. Acute disseminated encephalomyelitis. Pediatr Emerg Care. 2016;32(6):395–400. 7. Cole J, Evans E, Mwangi M, Mar S. Acute disseminated encephalomyelitis in children: an updated review based on current diagnostic criteria. Pediatr Neurol. 2019;100:26–34. 8. Burton KLO, Williams TA, Catchpoole SE, Brunsdon RK. Long-term neuropsychological outcomes of childhood onset acute disseminated encephalomyelitis (ADEM): a meta-analysis. Neuropsychol Rev. 2017;27(2):124–133.

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