recent advances in ADEM

1. DR. SUMIT KAMBLE
DEPT. OF NEUROLOGY
GMC, KOTA

2.  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.

3. EPIDEMIOLOGY
 Annual incidence of ADEM is 0.4–0.8 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.

4. 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.

5. PRECEDING INFECTIOUS ILLNESSES
A. Infections B. Vaccines
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.
 Rabies.
 • Diphtheria, tetanus, pertussis.
 • Smallpox.
 • Measles.
 • Japanese B encephalitis.
 • Polio.
 • Hepatitis B.
 • Influenza.

6.  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.

7. 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, clinically, on
MRI, or both, but there may be residual deficits.

8.  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.

9.  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.

10. 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.

11. 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.

12. 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

13. 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.

14. Pathological features of acute demyelinating disorders
Feature ADEM Acute
multiple
sclerosis
Acute
haemorrhagic
leucoencephalitis
Neuromy-
elitis
optica
Perivascular infiltrates
1. Lymphocytes
2. Macrophages or
monocytes
3. Polymorphs
4. Eosinophils
++
++
--
--
++
++
--
--
++
++
++
--
++
++
++
++
Perivascular haemorrhage -- -- ++ --
Necrotising venules -- -- ++ +
Perivascular demyelination ± ± ++ ++
Axonal damage ± ± ++ ++

15. 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.

16.  Immunopathological events leading to ADEM can be
divided into two major phases-
1.Initial T cell priming and activation
2.Subsequent recruitment and effector phase

17.  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

18. CLINICAL FEATURES
 Systemic symptoms - fever, malaise, myalgias, headache,
nausea, and vomiting often precede the neurological
symptoms.
 Begin 4–21 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

19.  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.

20.  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.

21. Acute disseminated encephalomyelitis: Clinical syndromes

22. LABORATORY FEATURES
Cerebrospinal fluid-
 Increased 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 demonstrated-58%
of adult and 29% of pediatric cases
 Production of intrathecal oligoclonal IgG almost ceases as
the patient improves.

23. Electroencephalography
 Abnormalities are common but are usually non-specific.
 Mild generalised slowing, to severe generalised slowing
with infrequent focal slowing and epileptiform discharges.

24. Neuroimaging-
Computed tomography-
 Generally normal at onset and usually becomes abnormal
5–14 days later.
 Typical computed tomographic appearance is that of low
attenuation, multifocal lesions in the subcortical white
matter.

25. 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.

26. 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 .

27. 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.

28.  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

30.  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

31. 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.

32. 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

33. Acute hemorrhagic leukoencephalitis
 Considered to be hyperacute variants of ADEM, include-
1. 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.

34.  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.

35. 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.

38. TREATMENT
(1) Supportive,
(2)Specific—high-dose intravenous methyl prednisolone,
intravenous immunoglobulin (IVIg), and plasma paresis,
and
(3) Physical and rehabilitation therapy

39. 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.

41.  Immunomodulation-
Methyl Prednisolone-
 Intravenous methyl prednisolone is the first-line drug (10–
30 mg/kg/day, up to a maximum of 1 g/day) for 3–5 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.

42. Intravenous immunoglobulin (IVIg)-
 0.4 gm/kg/day for 5 days
 second-line treatment, when corticosteroids fail.
plasma exchange (PE)-
 Course of 4–6 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

43.  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.

44. 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 1–6 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.

45.  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.

47. References
 Acute Disseminated Encephalomyelitis: Current Understanding and
Controversies Semin Neurol. 2013 Feb;28(1):84-94)
 Acute disseminated encephalomyelitis Postgrad Med J 2013;79:11–17
 Neuroradiological evaluation of demyelinating disease Ther Adv
Neurol Disord. 2013 Jul; 6(4): 249–268
 Acute disseminated encephalomyelitis: Treatment guidelines Ann
Indian Acad Neurol. 2011 Jul; 14(Suppl1): S60–S64.
 Acute Disseminated Encephalomyelitis, Transverse Myelitis, and
Neuromyelitis Optica 2013, American Academy of Neurology