RECENT ADVANCES

IN ADEM
DR. Dhanunjay
DEPT. OF NEUROLOGY

Is a demyelinating disease of the central nervous

system that typically presents as a monophasic

disorder associated with multifocal neurologic
symptoms and encephalopathy.
Usually follows an infection or vaccination.
Is characterised by multifocal white matter lesions
on neuroimaging.
Monophasic disease. Uncommonly ADEM can
relapse.

EPIDEMIOLOGY
Annual incidence of ADEM is 0.40.8 per 100,000
Commonly affects children and young adults,

probably related to the high frequency of

exanthematous and other infections and
vaccination in this age group.
No gender predominance.
Mortality and major neurological sequelae of
ADEM after varicella and rubella infections are
much lower in comparison with ADEM after
measles infection.

Postinfectious-preceded by a viral or
bacterial infection, usually in the form of a
nonspecific upper respiratory infection.
Antecedent infection could be identified in 72
-77 % of patients. most cases present in
winter and spring.
Postvaccinial- Less than 5 percent of all
ADEM cases follow immunization.

PRECEDING INFECTIOUS ILLNESSES

A. Infections

Viral
Measles, Mumps.
Influenza A or B.
Hepatitis A or B.
Herpes simplex.
Varicella, rubella. Epstein-Barr
Cytomegalovirus.
HIV.
Others
Mycoplasma pneumoniae.
Chlamydia.
Legionella.
Campylobacter.
Streptococcus.

B. Vaccines

Rabies.
Diphtheria, tetanus,

pertussis.
Smallpox.
Measles.
Japanese B encephalitis.
Polio.
Hepatitis B.
Influenza.

Risk of occurrence of ADEM is 20 times lower after

vaccination than ADEM after natural measles virus

infection.
ADEM found after measles is associated with
mortality rates as high as 25% and 25%40% of
survivors were left with permanent neurological
sequelae.

International Pediatric MS Study Group

Consensus Definitions
Monophasic ADEM
First clinical event with a presumed inflammatory
or demyelinating cause, with acute or subacute
onset that affects multifocal areas of the CNS;
Clinical presentation must be polysymptomatic
and must include encephalopathy, which is
defined as one or more of the following:
Behavioral change occurs, e.g., confusion,
excessive irritability.
Alteration in consciousness occurs, e.g., lethargy,
coma.
Event should be followed by improvement,

Patient has no history of a clinical episode with

features of a prior demyelinating event.

No other etiologies can explain the event.
New or fluctuating symptoms, signs, or MRI
findings occurring within 3 months of the inciting
ADEM event are considered part of the acute
event.
Neuroimaging shows focal or multifocal lesion(s),
predominantly involving white matter, without
radiologic evidence of previous destructive white
matter changes.

Brain MRI, with FLAIR or T2-weighted images, reveals

large (>1 to 2 cm) lesions that are multifocal,

hyperintense, and located in the supratentorial or
infratentorial white matter regions; gray matter,
especially basal ganglia and thalamus, is frequently
involved.
In rare cases, brain MR images show a large single
lesion (1 to 2 cm), predominantly affecting white
matter.
Spinal cord MRI may show confluent intramedullary
lesion(s) with variable enhancement, in addition to
abnormal brain MRI findings specified previously.

Recurrent ADEM
New event of ADEM occurs with recurrence of the
initial symptoms and signs 3 or more months after
the first ADEM event without involvement of new
clinical areas by history, examination, or
neuroimaging.
Event does not occur while on steroids and occurs
at least 1 month after completing therapy.
MRI shows no new lesions; original lesions may
have enlarged.
No better explanation exists.

Multiphasic ADEM
ADEM is followed by a new clinical event also meeting

criteria for ADEM, but involving new anatomic areas of

the CNS as confirmed by history, neurologic examination,
and neuroimaging.
Subsequent event must occur (1) at least 3 months after
the onset of the initial ADEM event and (2) at least 1
month after completing steroid therapy.
Subsequent event must include a polysymptomatic
presentation, including encephalopathy, with neurologic
symptoms or signs that differ from the initial event
(mental status changes may not differ from the initial
event).
Brain MRI must show new areas of involvement but also
demonstrate complete or partial resolution of those
lesions associated with the first ADEM event.

Acute disseminated encephalomyelitis and related

disorders
Acute disseminated encephalomyelitis
Postinfectious.
Postvaccinial.
Acute haemorrhagic leucoencephalitis
Restricted form of acute, inflammatory demyelinating
diseases
Transverse myelitis.
Optic neuritis.
Cerebellitis.
Brain stem encephalitis.
Multiphasic form of acute disseminated
encephalomyelitis and multiple sclerosis

PATHOLOGY
Pathological hallmark - areas of perivenous

demyelination and infiltration of lymphocytes and

macrophages.
Other changes - hyperaemia, endothelial swelling,
and vessel wall invasion by inflammatory cells,
perivascular oedema, and haemorrhage.
Present in the small blood vessels of both white
and grey matter.
Postinfectious encephalomyelitis typically involves
the white matter, lesions in grey matter can also
been seen.

Pathological features of acute demyelinating

disorders
Feature

Perivascular infiltrates
1. Lymphocytes
2. Macrophages or
monocytes
3. Polymorphs
4. Eosinophils

ADE
M

Acute
multipl
e
sclerosi
s

Acute
haemorrhagic
leucoencephal
itis

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Neurom
y-elitis
optica

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+
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Perivascular
haemorrhage

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Necrotising venules

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++

Perivascular

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PATHOPHYSIOLOGY
ADEM results from a transient autoimmune

response against myelin or other autoantigens,

possibly, via molecular mimicry or by non-specific
activation of an autoreactive T cell clone.
Genetic susceptibility explains why
encephalomyelitic complications develop in only a
small minority of patients.
Human leucocyte antigen class II genes have the
most significant influence.

Immunopathological events leading to ADEM can

be divided into two major phases1.Initial T cell priming and activation

2.Subsequent recruitment and effector phase

Acute haemorrhagic leucoencephalitis is a more

severe and frequently fatal hyperacute variant of

ADEM.
Most important distinguishing feature of acute
haemorrhagic leucoencephalitis from ADEM is
necrotising vasculitis of venules.
Perivascular infiltrates consist mainly of
polymorphonuclear cells.
Perivascular haemorrhages are also common

CLINICAL FEATURES
Systemic symptoms - fever, malaise, myalgias,

headache, nausea, and vomiting often precede the

neurological symptoms.
Begin 421 days after the inciting event.
Encephalopathy- ranging from lethargy to coma.
Focal and multifocal neurological signs like
hemiparesis, cranial nerve palsies, and paraparesis.
Other commonly reported findings include
meningismus, ataxia, and varied movement disorders.
Seizure may occur in severe cases, especially in the
acute haemorrhagic form of ADEM.
Optic neuritis is often bilateral (23%) and transverse
myelopathy is often complete

43% of have peripheral nervous system (PNS)

involvement, which is usually demyelinating and

subclinical.
Most adult patients present clinically in a fashion
similar to that of children, except that there is a
relatively infrequent occurrence of headache,
fever and meningismus, and a higher frequency of
sensory deficits.
Optic neuritis is also infrequent in adult ADEM.
Restricted forms : ON, Transverse myelitis,
Cerebellitis, Brain stem encephalitis.

Recovery can begin within days .

Mortality varies between 10% and 30%, with

complete recovery in 50%.

Poor prognosis is correlated with severity and
abruptness of onset of the clinical syndrome.
Measles virus associated ADEM may carry a worse
prognosis than vaccine associated disease.

Acute disseminated encephalomyelitis: Clinical

syndromes

LABORATORY FEATURES
Cerebrospinal fluidIncreased pressure, lymphocytic pleocytosis (as much as

1000/mm3, sometimes polymorphonuclear leucocytosis

initially), and raised protein (usually <1.0 mg/l).
May contain increased amounts of gamma globulin and
IgG and raised levels of myelin basic protein.
Glucose content is usually normal.
Rarely oligoclonal band of IgG may be demonstrated58% of adult and 29% of pediatric cases
Production of intrathecal oligoclonal IgG almost ceases
as the patient improves.

Electroencephalography
Abnormalities are common but are usually non-

specific.
Mild generalised slowing, to severe generalised
slowing with infrequent focal slowing and
epileptiform discharges.

NeuroimagingComputed tomographyGenerally normal at onset and usually becomes

abnormal 514 days later.

Typical computed tomographic appearance is that
of low attenuation, multifocal lesions in the
subcortical white matter.

MRI
Large, multiple, bilateral but asymmetric, poorly

demarcated, areas of increased signal on T2-weighted

and FLAIR sequences which can affect both white and
gray matter
Gray matter involvement can be neocortical or deep
gray matter (thalamus, basal ganglia).
Brainstem and cerebellum are commonly involved.
Associated edema, swelling and localized mass effect
can be seen in larger lesions.
Enhancement is not commonly encountered (10
30%), can be marginal and/or nodular in distribution .

Four imaging patterns have been proposed based on

evaluation of pediatric patients with ADEM
(1) multifocal numerous small (<5 mm) lesions,
(2) large, confluent white matter lesions with
frequent edema and mass effect,
(3) bithalamic involvement, and
(4) acute hemorrhagic encephalomyelitis (AHEM)
-T2* hypointensity within areas of T2 hyperintense
signal change.
In pediatric patients, spinal cord involvement has
been reported to potentially include long segments
(>3 vertebral segments) that are NMO-IgG negative .

Images of acute disseminated encephalomyelitis (ADEM) . T2 FLAIR

axial images were acquired during the symptomatic phase of the
disease (A) with typical poorly demarcated lesions with white matter
and grey matter involvement. There was no contrast enhancement of
any of these lesions (not shown). On follow up imaging three months
later (B) no residual signal change is noted.

In order to qualify as ADEM, lesions on MRI should be

of the same age and no new lesion should appear on

central nervous system imaging studies after the
initial clinical attack.
Corpus callosum is usually not involved in ADEM.
MRI features alone may not be able to differentiate
MS.
Features of ADEM that are unusual in MS, such as
symmetric bilateral disease, relative sparing of the
periventricular white matter, or deep gray matter
involvement.
possibility of MRI-negative ADEM has been proposed

A recent study in children suggested the presence

of any 2 of the MRI features: help to differentiate

MS from ADEM.
(1) absence of bilateral diffuse pattern;
(2) presence of black holes; and
(3) presence of 2 or more periventricular lesions
Sensitivity and specificity of these criteria is 81%

and 95%. respectively

ADVANCED NEUROIMAGING TECHNIQUES

Diffusion tensor imaging (DTI) and magnetic

transfer imaging (MTI), may provide a better

assessment of the underlying histopathology than
an increase in T2W signal on conventional MRI.
Magnetization transfer and diffusion tensor MR
imaging may also be helpful in identifying
involvement of the so-called normal-appearing
white matter ,(NAWM and NAGM)
Double inversion recovery improve detection of
cortical lesions.

MULTIPHASIC AND RECURRENT

ADEM
Although ADEM is typically a monophasic illness,

occasionally it can have biphasic or multiphasic

course.
Recurrent ADEM- there is another event 4
weeks after steroid withdrawal or 3 months after
the first episode, and both clinically and
radiologically same site is involved.
Prerequisite that patient is in complete remission
or as in a stable plateau phase of incomplete
remission

Acute hemorrhagic leukoencephalitis

Considered to be hyperacute variants of ADEM,

include1. Acute hemorrhagic leukoencephalitis (AHL)

2. Acute hemorrhagic encephalomyelitis (AHEM)
3. Acute necrotizing hemorrhagic leukoencephalitis
(ANHLE) of Weston Hurst
More rapidly progressive and more severe.
Typically follow an upper respiratory infection.
MRI may reveal diffuse white matter lesions, often
large and associated with cerebral edema.
CSF typically shows both white and red blood cells,
with increased protein concentration.

Multiphasic ADEM- one or more ADEM relapses

including encephalopathy and multifocal deficits

involving new areas of the neuraxis on MRI and
neurologic examination.
Episodes are related to the ongoing active disease
and is probably due to persistent antigen/epitope
progression and these episodes occur in relation
to the initial episode.

DIFFERENTIAL DIAGNOSIS

1.Monophasic ADEM has to be differentiated from

the first attack of MS

Schwarz et al, in a cohort of 40 patients who were
initially diagnosed as having ADEM, noted that
35% developed clinically definite multiple
sclerosis over a mean observation period of 38
months.
50% of the patients with ADEM have MRI
suggestive of multiple sclerosis.
2. Bacterial and viral meningitis or encephalitis.

TREATMENT
(1) Supportive,
(2)Specifichigh-dose intravenous methyl
prednisolone, intravenous immunoglobulin (IVIg),
and plasma paresis, and
(3) Physical and rehabilitation therapy

Supportive Care
Airway protection in patients with altered mental

status and mechanical ventilation if required.

Antiseizure medication in patients with seizures,
Correction of fluid and electrolyte disturbances,
and
prophylactic anticoagulation for prevention of
deep vein thrombosis in patients with high risk.

ImmunomodulationMethyl PrednisoloneIntravenous methyl prednisolone is the first-line

drug (1030 mg/kg/day, up to a maximum of 1
g/day) for 35 days.
Full recovery has been reported in 50%80% of
patients.
Oral corticosteroid treatment is continued with
gradual tapering over 6 weeks to reduce the risk of
relapses.
Any type of vaccination should be avoided during
the first 6 months following recovery.

Intravenous immunoglobulin (IVIg)0.4 gm/kg/day for 5 days

second-line treatment, when corticosteroids fail.

plasma exchange (PE)Course of 46 PEs have been shown to be

associated with moderate to marked and sustained
improvement.
Predictors associated with improvement include
male sex, preserved reflexes, and early initiation of
treatment

Choice of second-line treatment is individualized,

depending on the severity of the disease,

complications, and comorbidities.
IVIg may be more effective in patients with
peripheral nervous system involvement and PE in
patients with tumefactive demyelination.
Cyclophosphamide and hypothermia have been
used with success in patients with fulminant
ADEM.

PROGNOSIS
Long-term prognosis of this entity depends on the

etiology.
Postmeasles patients have higher mortality rate and
significant morbidity in survivors.
Prognosis of nonmeasles cases is favorable ,full
recovery in 50%75% of patients, in 16 months of
follow up.
Most common sequelae are focal motor deficits,
ranging from mild ataxia to hemiparesis.
Hyperacute onset, severe neurologic deficits as a
result of aggressive disease, and unresponsiveness to
steroids are poor prognostic indicators.

Largest follow up series of 40 adult patients (15

68 years, mean 33.5 years) with ADEM, 14

patients developed clinically definite multiple
sclerosis.
Out of the remaining 26 patients with a final
diagnosis of ADEM, two patients died, nine had
minor residual deficits, three had moderate
deficits, and 12 patients had no remaining
symptoms.

THANK
YOU

References
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Acute disseminated encephalomyelitis Postgrad Med J

2013;79:1117
Neuroradiological evaluation of demyelinating disease Ther Adv

Neurol Disord. 2013 Jul; 6(4): 249268

Acute disseminated encephalomyelitis: Treatment guidelines Ann

Indian Acad Neurol. 2011 Jul; 14(Suppl1): S60S64.

Acute Disseminated Encephalomyelitis, Transverse Myelitis, and

Neuromyelitis Optica 2013, American Academy of Neurology