Acute Disseminated Encephalomyelitis (ADEM)

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Nazish Najeeb MBBS, Junaid Kalia MD

Introduction

  • Acute disseminated encephalomyelitis (ADEM)
  • Is an immune-mediated demyelinating disease of CNS
  • Involves white matter in the brain and spinal cord.
  • Grey matter (basal ganglia, thalamus, and even cortical grey matter) may be involved.

Epidemiology

  • ADEM is a rare illness
  • Estimated 1 in 125,000-250,000 individuals affected each year.
  • It mostly occurs in children (majority <10 yr, remainder 10-20yr)
  • More commonly in males than in females (male to female ratio 1.3:1)
  • More common in winter and spring

Etiology

  • Post-infection (67%)
  • Post-vaccination
  • Genetic susceptibility (rarely)

Table 1: Etiological factors of ADEM

Table 1: Etiological factors of ADEM

Pathophysiology

Two mechanism
  1. Molecular mimicry
  1. T cell-mediated inflammation

Molecular mimicry:

Antibodies formed against myelin basic protein (MBP), myelin-associated oligodendrocyte basic protein (MOBP), oligodendrocyte specific protein (OSP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), and proteolipid protein (PLP).

T cell-mediated inflammation:

Two phases:
  1. Priming and activation
  1. Recruitment and effector phase and resulting into
      • Infiltration of lymphocytes and macrophages in the small blood vessels of both white and grey matter
      • Hyperemia
      • Endothelial swelling
      • Vessel wall invasion by inflammatory cells
      • Perivascular edema
      • Hemorrhage
      • As the lesions become older, at a late stage of disease foci of fibrillary fibrosis can also be seen in adjacent brain tissue.

Clinical features

Initial Presentation

  • Fever
  • Headache
  • Fatigue
  • Meningismus
  • Malaise
  • Nausea
  • Vomiting

Neurological Signs

  1. Encephalopathy
    1. The characteristic feature of ADEM develops rapidly.
      Presents as
      • Confusion
      • Coma
      • Irritability
      • Acute cognitive dysfunction
      • Behavioral changes
  1. Other neurologic abnormalities:
      • Ataxia
      • Aphasia
      • Nystagmus
      • Optic neuritis
      • Urinary retention
      • Elevated intracranial pressure
      • Extrapyramidal signs

Diagnostic Criteria

According to the International Pediatric Multiple Sclerosis Study Group (IPMSSG), 4 diagnostic criteria are required to make a diagnosis of ADEM in children.
  • Multifocal, clinical CNS event with a presumed inflammatory demyelinating cause
  • Encephalopathy that cannot be explained by fever, systemic illness, or post-ictal fever
  • No new clinical and MRI findings 3 months or more after the onset
  • Brain MRI is abnormal with changes consistent with demyelination during the acute, 3-month phase.

Subtypes Of ADEM

  • Monophasic ADEM
    • single episode with no further demyelinating events more than 3 months after onset.
  • Multiphasic ADEM
    • Two episodes separated by at least 3 months in time. More than two episodes suggest an alternate disease process.
  • ADEM-ON
    • Any episode of ADEM plus one or more episodes of optic neuritis.
  • Acute hemorrhagic encephalomyelitis (AHEM)
    • Fulminant presentation associated with multifocal hemorrhages and necrosis.

Differential Diagnosis

  • Aseptic meningitis
  • Bell's palsy
  • Brain metastasis
  • Brucellosis
  • Cardioembolic stroke
  • Cauda equina and conus medullaris syndrome
  • Cavernous sinus syndromes
  • Central nervous system complications in HIV
  • Cerebral venous thrombosis
  • Churg-Strauss disease

ADEM and Multiple Sclerosis

It is important to diagnose a patient with either condition accurately because the approach to the treatment of the two conditions differs significantly. (Figure 1 & 2)

Table 2: Differentiating Features of ADEM and Multiple Sclerosis

Differentiating Features of ADEM and Multiple Sclerosis
Feature
ADEM
MS
Infection or vaccination
No recognizable infection or vaccination
Meningism, stupor, focal signs
Focal signs
Non progressive, monophasic
Relapsing and remitting, progressive
Diffuse, bilateral symmetrical lesions
Periventricular black holes
Recovery is rapid and often complete
Recovery is variable
 
notion image
Derived from:Bickle, I. Acute disseminated encephalomyelitis. Case study, Radiopaedia.org. (accessed on 15 Oct 2021) https://radiopaedia.org/cases/37253
notion image
Derived from: Sorrentino, S. Multiple sclerosis. Case study, Radiopaedia.org. (accessed on 15 Oct 2021) https://radiopaedia.org/cases/15764

Figure 1: (Left) ADEM, showing bilateral enhancing lesions of variable size throughout both cerebral hemispheres in the deep white matter, juxta-cortical regions, and left thalamus. (Right) MS, showing periventricular hyper intensities typical of multiple sclerosis plaques.

Investigation

Non-specific

  • Leucocytosis, predominately lymphocytosis
  • Raised platelets
  • Raised CRP and ESR

Viral cultures and serology

  • Culture of throat, nasopharynx, stool, and CSF
  • Serology testing for a variety of agents such as influenza, EBV, herpes, and mycoplasma, etc.

Cerebrospinal fluid

  • Raise RBC and WBC
  • Increase protein concentration
  • Increase myelin basic protein
  • Rarely elevated IgG index
  • Oligoclonal bands in up to 29 % of cases

Imaging

MRI

  • ADEM lesion characteristics
    • Bilateral
    • It may be symmetric or asymmetric
    • Poorly marginated
    • The periventricular area is spared (which is involved commonly in MS)
    • Located in deep and subcortical and central white matter, cortical gray-white matter junction, and deep gray matter of the basal ganglia, thalami, cerebellum, brainstem.
  • Best modality used in the diagnosis of ADEM and is best defined in T2, FLAIR &
    • T2-weighted images
    • Fluid-attenuated inversion recovery (FLAIR) sequences
    • Proton density, or echo-planar trace diffusion techniques

CT scan

  • most often unremarkable
  • In later stages, ADEM may appear as focal or multifocal regions of white matter damage.

Electroencephalography

  • Disturbed sleep pattern
  • Focal or generalized slowing of electrical activity, typical of encephalopathy
  • Seizure activity may also be noted

Management

Medical

Anti-microbial

  • Antibiotic or Acyclovir until an infectious agent is ruled out

Corticosteroids

  • High dose IV methylprednisolone 30 mg/kg/day up to a maximum dose of 1000 mg per day for 3-5 days
  • Oral treatment at dose of 1-2 mg/kg/day is continued and gradually tapered over a period of 4-6 weeks to reduce risk of relapse

Intravenous immunoglobulin

  • 1gm/kg/day IV for 2-5 days

Indication for IVIG use:

  • Recommended for <1 year age
  • No response to steroids in 48-72 hours
    • Induction Dose up to 2 g/kg in 2 to 5 divided doses.
    • Follow‐up Dose -1 g/kg followed by a second dose (if required) after 4 to 6 weeks for extended monophasic ADEM
  • Recurrent cases
    • Induction Dose up to 2 g/kg in 2–5 divided doses
    • Maintenance Dose ‐ 1 g/kg, 4–6 weekly
  • Acute hemorrhagic leucoencephalitis, AHLE

Plasmapheresis

  • Recommended for patient not responding to both steroid and IVIG

Surgical

  • Surgical intervention is indicated in cases of elevated intracranial pressure and hemorrhagic brain purpura as a result of AHLE by
    • Lumboperitoneal shunt
    • Bilateral optic nerve decompression
    • Decompression of the intracranial fossae by unroofing of the cranium
    • Rehabilitation

    • <5 years age show excellent recovery
    • Early rehabilitation program is required in case of cognitive impairment, epilepsy, visual and motor deficits (weakness, spasticity, ataxia), and impairment in speech

Prognosis

  • Children with ADEM show a slow and complete recovery in four to six weeks
  • Adults with ADEM have increased rates of hospitalization, intensive care unit admission, and mortality compared to pediatric patients
  • 60 % do not show any neurologic deficits.
  • Neurologic deficits present in the form of transverse myelitis, behavioral problems, and cognitive impairment mostly in <5 years old.

Further Reading

  1. Anilkumar AC, Foris LA, Tadi P. Acute Disseminated Encephalomyelitis. [Updated 2021 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430934/
  1. Garg RK. Acute disseminated encephalomyelitis. Postgraduate Medical Journal 2003;79:11-17.

Bibliography

  1. Murthy JM, Yangala R, Meena AK, et al. Acute disseminated encephalomyelitis: clinical and MRI study from South India. J Neurol Sci. 1999;165:133–8.
  1. Garg RK. Acute disseminated encephalomyelitis.Postgraduate Medical Journal 2003;79:11-17.
  1. Scully RE, Mark EJ, McNeely WF, et al. Case records of the Massachusetts General Hospital, case 37–1995. N Engl J Med. 1995;333:1485–92.
  1. Stefansson K, Hedley-Whyte ET. Case records of the Massachusetts General Hospital, case 8−1996—a 28 years old woman with the rapid development of a major personality change and global aphasia. N Engl J Med.1996;334:715–21.
  1. Van Bogaert L. Post-infectious encephalomyelitis and multiple sclerosis: the significance of perivenous encephalomyelitis. J Neuropathol Exp Neurol. 1950;9:219–49.
  1. Allen IV. Demyelinating diseases. Greenfield’s neuropathology.4th Ed. In: Adams JH, Corsellis JAN, Duchen LW, eds. London: Edward Arnold, 1984: 338–84.
  1. Callen D.J, Shroff M.M, Branson H.M., Li D.K, Lotze T, Stephens D, Banwell B.L. Role of MRI in the differentiation of ADEM from MS in children. Neurology2009, 72, 968–973.
  1. Ketelslegers I.A, Neuteboom R.F, Boon M, Catsman-Berrevoets C.E, Hintzen R.Q. A comparison of MRI criteria for diagnosing pediatric ADEM and MS. Neurology2010, 74, 1412–1415.
  1. Kawanaka Y, Ando K, Ishikura R, Katsuura T, Wakata Y, Kodama H, Takaki H, Takada Y, Ono J, Yamakado K. Delayed appearance of transient hyperintensity foci on T1-weighted magnetic resonance imaging in acute disseminated encephalomyelitis. Jpn J Radiol. 2019 Apr;37(4):277-282.
  1. Anand KS, Agrawal AK, Garg J, Dhamija RK, Mahajan RK. Spectrum of neurological complications in chikungunya fever: experience at a tertiary care centre and review of literature. Trop Doct. 2019 Apr;49(2):79-84.
  1. Codjia P, Ayrignac X, Carra-Dalliere C, Cohen M, Charif M, Lippi A, Collongues N, Corti L, De Seze J, Lebrun C, Vukusic S, Durand-Dubief F, Labauge P., SFSEP and OFSEP. Multiple sclerosis with atypical MRI presentation: Results of a nationwide multicenter study in 57 consecutive cases. Mult Scler Relat Disord. 2019 Feb;28:109-116.
  1. VAN BOGAERT L. Post-infectious encephalomyelitis and multiple sclerosis; the significance of perivenous encephalomyelitis. J Neuropathol Exp Neurol. 1950 Jul;9(3):219-49.
  1. Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF. Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis. 2010 Feb;133(Pt 2):333-48.
  1. Anilkumar AC, Foris LA, Tadi P. Acute Disseminated Encephalomyelitis. [Updated 2021 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.Available from: https://www.ncbi.nlm.nih.gov/books/NBK430934/
  1. Ozgen Kenangil G, Ari BC, Guler C, Demir MK. Acute disseminated encephalomyelitis-like presentation after an inactivated coronavirus vaccine [published online ahead of print, 2021 May 20]. Acta Neurol Belg. 2021;1-3. doi:10.1007/s13760-021-01699-x
  1. Schirmer L, Srivastava R, Hemmer B. To look for a needle in a haystack: the search for autoantibodies in multiple sclerosis. Mult Scler J. 2014;20(3):271-279.
  1. Krupp LB, Tardieu M, Amato MP, 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 J. 2013;19(10):1261-1267.
  1. Granget E, Milh M, Pech-Gourg G, et al. Life-saving decompressive craniectomy for acute disseminated encephalomyelitis in a child: a case report. Childs Nerv Syst. 2012;28(7):1121-1124.
  1. Langley L, Zeicu C, Whitton L, et alAcute disseminated encephalomyelitis (ADEM) associated with COVID-19BMJ Case Reports CP 2020;13:e239597.
  1. Pohl, D.; Tenembaum, S. Treatment of Acute Disseminated Encephalomyelitis. Curr. Treat. Options Neurol. 2012, 14, 264–275.
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