Acute Disseminated Encephalomyelitis

4 Interesting Facts of Acute disseminated encephalomyelitis

1. Immune-mediated demyelinating central nervous system disorder primarily in children
2. Similar features include acute polyfocal neurologic deficits (eg, sensory loss, hemiparesis, vision disturbance typical of optic neuritis); may be difficult to differentiate from first attack of multiple sclerosis
3. Differentiating features include younger age (median is 5-8 years) and systemic symptoms (eg, fever, vomiting, meningism, drowsiness, headache); typically an isolated event that is postinfectious or post vaccinal. In addition, cerebrospinal fluid is generally negative for oligoclonal bands; MRI features that differ from those of multiple sclerosis include periventricular sparing and absence of periventricular ovoid lesions oriented perpendicular to ventricles
4. Diagnosis is clinical with neuroimaging confirmation

DEFINITION

• Acute disseminated encephalomyelitis (ADEM) is an acquired demyelinating syndrome that is often believed to be postinfectious in origin and most predominant in the pediatric population. ADEM is a clinical syndrome associated with acute-onset widespread central nervous system (CNS) inflammation. Current diagnostic criteria for ADEM include acute polyfocal neurologic deficits with the presence of encephalopathy and is supported by multifocal areas of increased T2 signal in the brain. ¹ ADEM is typically a monophasic illness. ^2 , 3 
• Some children experience evolution of new deficits within 90 days of onset, which is considered to represent a single ADEM event. New attacks, more than 90 days apart, can include a second ADEM event (multiphasic ADEM, MDEM), or more localized demyelination such as optic neuritis, transverse myelitis, or demyelination of other CNS regions. ^4 , 5 
• Approximately 50% of children with ADEM will have serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG), ⁶ and rarely may have antibodies against aquaporin-4. ⁷ Chronic relapsing disease can also occur, ³ including aquaporin 4 antibody–associated neuromyelitis optica spectrum disorder (NMOSD) or relapsing forms of MOG-associated disease (MOGAD), or rarely an ADEM attack can occur as the sentinel attack of multiple sclerosis (MS).
• Acute hemorrhagic leukoencephalitis (AHLE) is considered a more acute variant of ADEM that typically presents with similar symptoms and neurologic signs as ADEM but with a more rapidly progressive course that has multifocal hemorrhages found on imaging. ⁸

SYNONYMS

ADEM

Postinfectious encephalomyelitisView full size

ICD-10 CM CODE
G04.0	Acute disseminated encephalitis and encephalomyelitis

EPIDEMIOLOGY & DEMOGRAPHICS

• ADEM is most prevalent in school-aged children, with a mean age range at onset of 5 to 8 yr. ADEM may manifest in adulthood with a poorer prognosis relative to pediatric ADEM.
• ADEM is associated with preceding infection in most patients, and thus the higher frequency of infectious illness in childhood is thought to contribute to the greater likelihood of ADEM occurring in this age group.
• During the COVID pandemic, isolated care reports have linked the onset of pediatric and adult-onset ADEM with recent COVID infection, although no causal role for SARS-CoV-2 has been established. ^9 , 10
• Recent comprehensive studies have not demonstrated associations between ADEM and current common vaccines. ¹¹ ADEM has been reported very uncommonly following SARS-CoV-2 mRNA vaccination, but no causal relationship has been found. ⁹

Incidence of ADEM

0.1 to 0.6 per 100,000/yr

Prevalence

Prevalence studies are not available, given the transient nature of this illness in the vast majority of patients.

Predominant Sex and Age

Between 5 and 8 yr old with a slight male predominance

Peak Incidence

Winter and spring

Risk Factors

Preceding infection

Genetics

Genetic studies have failed to demonstrate genetic mutations, single nucleotide polymorphisms, or human leukocyte antigen associations for sporadic ADEM. No genetic link has been found for ADEM with MOG-immunoglobulin G (IgG) antibodies (MOGAD).

PHYSICAL FINDINGS & CLINICAL PRESENTATION

• •Many patients have fever due to a primary infectious source in the weeks preceding signs and symptoms of a demyelinating episode.
• •Pediatric ADEM
  • 1.A child with ADEM may first present with headache, vomiting, vision changes, gait disturbances, meningismus, and potentially seizures (seen in one third of patients).
  • 2.The hallmark and required core symptom, as its name suggests, is encephalopathy, ranging from irritability and confusion to lethargy and coma.
  • 3.The spinal cord may also be affected (transverse myelitis) with resultant motor and sensory deficits as well as potential bowel and bladder dysfunction.
  • 4.Cranial neuropathies may be present, including optic neuritis.
  • 5.The progression of disease is typically very rapid and aggressive, often requiring intensive care unit (ICU) monitoring.
• •Adult ADEM
  • 1.No consensus on diagnostic criteria have been made to this date, but the criteria listed for pediatric patients are generally applied.
  • 2.Typically worse prognosis in adults compared to children.

ETIOLOGY

There is a strong suggestion that ADEM is expressed in close proximity to recent infections, most commonly ones with upper respiratory tract infection symptoms. Like other postinfectious inflammatory conditions, it has been postulated that ADEM is the result of molecular mimicry, but definitive proof is lacking. Just as ADEM often proceeds a viral illness, it has been found to be a possible neurologic consequence of SARS-CoV-2 infection (COVID-19). ^9 , 12 The mechanism is still unknown, though it may be related to the immune dysregulation and cytokine activation caused by COVID-19. ¹³

In animal models for acquired autoimmune demyelinating diseases, experimental autoimmune encephalitis (EAE), exposure of animals to myelin protein antigens, as well as an external stimulant of cell-mediated immunity (Freund adjuvant), leads to a T cell and macrophage-mediated inflammatory infiltration and resultant demyelination. ¹⁴ Although there are many parallels between EAE and human ADEM, myelin-reactive immune cells are not easily measured nor conclusively found in the human disease, and it is not clear whether ADEM has a definitive triggering antigen exposure.

DIAGNOSIS

DIFFERENTIAL DIAGNOSIS

• •NMOSD associated with antibodies against aquaporin-4
• •MOGAD
• •MS
• •Meningitis
• •Brain mass
• •AHLE
• •CNS vasculitis
• •Hemophagocytic lymphohistiocytosis (HLH)
• •Inborn errors of metabolism or mitochondrial encephalopathy

WORKUP

• •ADEM is a clinical diagnosis and requires presence of encephalopathy as a key component as well as polyfocal deficits.
• •MRI features of multifocal white and deep gray matter lesions are not sufficient to diagnose ADEM in the absence of the key clinical features.
• •Over 90% of children with ADEM experience a monophasic illness.
• •Although ADEM can rarely be the first attack of MS, the current diagnostic criteria for MS require evidence of a non-ADEM attack as well as further evidence of clinically relapsing disease and/or MRI confirmation of dissemination of lesions in key locations in the central nervous system (CNS) and over time, typically with cerebral spinal fluid (CSF) oligoclonal bands, as delineated in the 2017 version of the international McDonald MS diagnostic criteria. ¹⁵
• •Presence of MOG antibodies (tested using a live cell-based assay and with clearly positive titers) leads to a diagnosis of MOGAD. MOGAD is monophasic in over 70% of children and MOG-IgG antibody titers do not predict relapsing forms of MOGAD.
• •Presence of AQP4-IgG antibodies, while rarely present in the context of ADEM, lead to a diagnosis of NMOSD. NMOSD is nearly always a chronic relapsing disease.
• •Chronic immunomodulation is advised for confirmed (clinically) relapsing MOGAD and for NMOSD, and well as for patients diagnosed with MS.

LABORATORY TESTS

• •Appropriate testing for acute infection such as meningoencephalitis.
• •CSF analysis:
  • 1.Pleocytosis due to inflammation is expected
  • 2.Oligoclonal bands present in CSF but not in serum are nonspecific, often associated with MS, and are rarely present in ADEM
• •Serum studies:
  • 1.Oligoclonal bands (required to determine whether CSF contains IgG bands not present in serum).
  • 2.Anti-MOG IgG: About half of all children with ADEM are MOG-Ab positive at presentation, ⁶ whereas almost all cases of MDEM are MOG-Ab positive. Relatively few patients have ADEM as the first presentation with MOGAD, and few of those have a chronic relapsing disease. ^6 , 16 Those that do relapse develop multiphasic MDEM, relapses involving the spinal cord, or ADEM followed by recurrent optic neuritis. ¹⁷ MOG IgG has only recently been described, and information regarding its implications is quickly expanding. ¹⁸ Testing for MOG IgG should be performed in serum as testing in CSF is not specific and not strongly associated with MOGAD.
  • 3.Anti-AQP4 IgG: A biomarker for NMOSD. The presence of these autoantibodies with either optic neuritis or transverse myelitis meets criteria for diagnosis of NMOSD. ¹⁹ NMOSD is a chronic relapsing disease, and recovery without appropriate treatment can be poor. ²⁰

IMAGING STUDIES

• •Head computed tomography (CT) is often obtained upon initial presentation to exclude other causes of neurologic disease such as space-occupying lesions. CT of the brain is relatively insensitive to white matter changes and can miss the features of ADEM. Brain and spine MRI with and without contrast is indicated:
  • 1.Brain MRI typically demonstrates disseminated T2 and FLAIR hyperintense lesions throughout the supratentorial or infratentorial white matter, the cerebral cortex, the deep gray matter, the brain stem, optic nerves, and the spinal cord. ²¹
  • 2.Lesions are bilateral, large, poorly demarcated, and diffuse, bright on T2-weighted sequences. Only about 10% of lesions in ADEM enhance on gadolinium-enhanced T1-weighted images.
  • 3.Follow-up MRI typically shows improvement and resolution of lesions several months following an episode of monophasic ADEM.

TREATMENT

• •ICU admission and monitoring is required in a large percentage of patients in the setting of a rapidly progressive course, seizures, marked encephalopathy, or ventilatory dysfunction due to spinal cord or brain stem lesions.

NONPHARMACOLOGIC THERAPY

• •Appropriate ICU interventions in the case of increased intracranial pressure, severe encephalopathy, or in ADEM patients with severe seizures.

ACUTE GENERAL Rx

• •Acute antiinflammatory therapy with intravenous corticosteroids (methylprednisolone 30 mg/kg/day, maximum of 1000 mg/day) for 3 to 5 days. ²²
• •Intravenous immunoglobulin (IVIG, 2 g/kg total divided over 2 to 5 days) or 5 to 7 plasma exchanges are offered to children failing to improve with corticosteroids.

CHRONIC Rx

• •Most patients respond to 3 to 5 days of acute corticosteroid therapy and do not require corticosteroid taper. ²³
• •Long-term steroids are not indicated, even if MOG antibodies are present.
• •Chronic immunomodulatory therapy is required for children diagnosed with NMOSD, relapsing MOGAD, or MS. Selection of immunomodulatory therapies should be in conjunction with pediatric neuroimmune experts, as reviewed in Fadda et al, 2021. ²⁴
• •Patients with a single MOG-related demyelinating event do not require chronic immunomodulatory therapy ²² ; however, there are currently no biomarkers available to predict which MOGAD patients may relapse, ²² and even silent new brain MRI lesions in the months after an initial demyelinating event do not suggest relapsing disease. ²⁴

DISPOSITION

• •ICU admission and monitoring is required in a large percentage of patients in the setting of a rapidly progressive course, seizures, marked encephalopathy, or ventilatory dysfunction due to spinal cord or brain stem lesions.

COMPLEMENTARY & ALTERNATIVE MEDICINE

• •Vitamin D insufficiency is commonly noted in children with ADEM (and other CNS inflammatory disorders), ²⁵ and it is clinical practice to ensure adherence with nutritional recommendations for vitamin D supplementation in children (typically 400 to 1000 IU per day vitamin D ₃ ).

REFERRAL

• •Neurology consultation and referral is indicated.

PEARLS & CONSIDERATIONS

• •Relapses of ADEM or new lesions on MRI is not consistent with monophasic ADEM and instead suggests either multiphasic ADEM, MOG-associated disease, NMOSD, or MS. ⁵

References

1.Krupp L.B., et al.: International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions . Mult Scler Houndmills Basingstoke Engl 2013; 19 (10): pp. 1261-1267.

2.Pavone P., et al.: Acute disseminated encephalomyelitis: a long-term prospective study and meta-analysis . Neuropediatrics 2010; 41 (6): pp. 246-255.

3.Anlar B., et al.: Acute disseminated encephalomyelitis in children: outcome and prognosis . Neuropediatrics 2003; 34 (4): pp. 194-199.

4.Tenembaum S., et al.: Acute disseminated encephalomyelitis . Neurology 2007; 68 (16 Suppl 2): pp. S23-S36.

5.Krupp L.B., et al.: Consensus definitions proposed for pediatric multiple sclerosis and related disorders . Neurology 2007; 68 (Suppl 2)16): pp. S7-S12.

6.Waters P., et al.: Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes . JAMA Neurol 2020; 77 (1): pp. 82-93.

7.Lana-Peixoto M.A., Talim N.: Neuromyelitis optica spectrum disorder and anti-MOG syndromes . Biomedicines 2019; 7 (2): pp. 42.

8.Grzonka P., et al.: Acute hemorrhagic leukoencephalitis: a case and systematic review of the literature . Front Neurol 2020; 11: pp. 899.

9.Parsons T., et al.: COVID-19-associated acute disseminated encephalomyelitis (ADEM) . J Neurol 2020; 267 (20): pp. 2799-2802.

10.Novi G., et al.: Acute disseminated encephalomyelitis after SARS-CoV-2 infection [published correction appears in Neurol Neuroimmunol Neuroinflamm 15;8(1), 2020 . Neurol Neuroimmunol Neuroinflamm 2020; 7 (5): pp. e797.

11.Baxter R., et al.: Acute demyelinating events following vaccines: a case-centered analysis . Clin Infect Dis Off Publ Infect Dis Soc Am 2016; 63 (11): pp. 1456-1462.

12.Montalvan V., et al.: Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review . Clin Neurol Neurosurg 2020; 194: pp. 105921.

13.Giamarellos-Bourboulis E.J., et al.: Complex immune dysregulation in COVID-19 patients with severe respiratory failure . Cell Host Microbe 2020; 27 (6): pp. 992-1000. e3 .

14.Hasseldam H., et al.: Oxidative damage and chemokine production dominate days before immune cell infiltration and EAE disease debut . J Neuroinflammation 2016; 13 (1): pp. 246.

15.Thompson A.J., et al.: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria . Lancet Neurol 2018; 17 (2): pp. 162-173.

16.Fadda G., et al.: Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care . Lancet Neurol 2021; 20 (2): pp. 136-149.

17.Jurynczyk M., et al.: Clinical presentation and prognosis in MOG-antibody disease: a UK study . Brain J Neurol 2017; 140 (12): pp. 3128-3138.

18.Jarius S., et al.: MOG encephalomyelitis: international recommendations on diagnosis and antibody testing . J Neuroinflammation 2018; 15: pp. 134.

19.Wingerchuk D.M., et al.: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders . Neurology 2015; 85 (2): pp. 177-189.

20.Paolilo RB et al: Treatment and outcome of aquaporin-4 antibody–positive NMOSD: a multinational pediatric study. Neurol Neuroimmunol Neuroinflammation 7(5), 2020, https://doi.org/10.1212/NXI.0000000000000837 .

21.Marin S.E., Callen D.J.A.: The magnetic resonance imaging appearance of monophasic acute disseminated encephalomyelitis . Neuroimaging Clin N Am 2013; 23 (2): pp. 245-266.

22.Hacohen Y., Banwell B.: Treatment approaches for MOG-Ab-associated demyelination in children . Curr Treat Options Neurol 2019; 21 (1): pp. 2.

23.Dale R.C., et al.: Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children . Brain J Neurol 2000; 123 (Pt 12): pp. 2407-2422.

24.Fadda G., et al.: Silent new brain MRI lesions in children with MOG-antibody associated disease . Ann Neurol 2021; 89 (2): pp. 408-413.

25.Koduah P., et al.: Vitamin D in the prevention, prediction and treatment of neurodegenerative and neuroinflammatory diseases . EPMA J 2017; 8 (4): pp. 313-325.