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Treatment of Acute Disseminated

Encephalomyelitis

Article in Current Treatment Options in Neurology · April 2012

DOI: 10.1007/s11940-012-0170-0 · Source: PubMed

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Current Treatment Options in Neurology (2012) 14:264–275
DOI 10.1007/s11940-012-0170-0

Neuroimmunology (R Lisak, Section Editor)

Treatment of Acute
Disseminated
Encephalomyelitis
Daniela Pohl1,*
Silvia Tenembaum2
Address
*,1Department of Neurology, Children’s Hospital of Eastern Ontario,
University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
Email: dpohl@cheo.on.ca
2
Department of Neurology, National Pediatric Hospital Dr. Juan P. Garrahan,
Combate de los Pozos 1881, Buenos Aires, 1245, Argentina
Email: silviatenembaum@gmail.com

Published online: 3 April 2012

* Springer Science+Business Media, LLC 2012

Keywords: Acute disseminated encephalomyelitis I ADEM I Inflammatory brain disease I IBD I Acquired
demyelinating syndrome I ADS I Pediatric I Children I Childhood I Adults I Diagnosis I Management I
Treatment I Therapy I Multiple sclerosis I Neuromyelitis optica I NMO I Methylprednisolone I
Corticosteroids I Intravenous immunoglobulin I IVIG I Plasma exchange I PLEX I Plasmapheresis I MRI

Opinion statement
Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating dis-
ease, characterized by an acute onset of polyfocal central nervous system (CNS) def-
icits, including encephalopathy, demonstrating multifocal lesions on MRI. ADEM is
typically a monophasic disorder, but recurrent and multiphasic courses have been
described. Furthermore, an ADEM presentation has been reported in neuromyelitis
optica (NMO) and multiple sclerosis (MS), particularly in younger children. CNS
infections, other autoimmune diseases, and neurometabolic disorders may mimic
ADEM at manifestation. There is no single test confirming the diagnosis of ADEM,
and diagnosis is based upon a combination of clinical and radiologic features and
exclusion of diseases that resemble ADEM. Therefore, a broad workup including in-
fectious, immunologic, and metabolic tests, as well as a systematic follow-up includ-
ing MRI, is indicated to establish an accurate diagnosis as a prerequisite for an
optimized treatment approach. There is a lack of evidence-based, prospective clinical
trial data for the management of ADEM. Empiric antibacterial and antiviral treatment
is standard of care until an infectious disease process is ruled out. Based on the
presumed autoimmune etiology of ADEM, the common treatment approach consists
of intravenous methylprednisolone at a dosage of 20 to 30 mg/kg per day (maxi-
mum 1 g/day) for 3 to 5 days, followed by an oral corticosteroid taper of 4 to
6 weeks. In case of insufficient response or contraindications to corticosteroids, in-
travenous immunoglobulin G (IVIG) at a dosage of 2 g/kg divided over 2 to 5 days
is a therapeutic option. For severe or life-threatening cases of ADEM, plasmapheresis
 Treatment of Acute Disseminated Encephalomyelitis Pohl and Tenembaum 265

should be considered early in the disease course. Decompressive craniectomy has

been reported as a life-saving measure for ADEM patients with intracranial hyperten-
sion. There is a lack of specific recommendations for the long-term management of
recurrent and multiphasic ADEM. In children with relapsing demyelinating events, the diag-
nosis of a chronic autoimmune CNS disease like MS or NMO should be considered.

Introduction
Acute disseminated encephalomyelitis (ADEM) is an
acute inflammatory demyelinating disorder of the cen-
tral nervous system (CNS) with a presumed immune-
mediated etiology. Per definition, ADEM is a polysymp-
tomatic and multifocal neurologic event with acute or
subacute onset, including encephalopathy (behavioral
change or altered consciousness) as a clinical conditio sine
qua non [1]. Brain MRI should demonstrate multifocal
lesions. ADEM is typically a monophasic disease, the ac-
tive phase lasting no longer than 3 months. If a new
ADEM event occurs 93 months after disease onset or
91 month after completing steroid treatment, it is defined
as recurrent ADEM (recurrence of initial symptoms with-
out involvement of new clinical areas) or multiphasic
ADEM (new event involving new anatomical areas of
the CNS) [1]. Whether recurrent and multiphasic ADEM
represent separate disease entities is still under debate [2].
The etiology of ADEM is obscure. Immune-mediat-
ed mechanisms are assumed to play a role in the path-
ogenesis of ADEM, and the disease is commonly
attributed to a post-infectious process, less frequently
to a post-vaccination complication [3, 4]. Perivenous
demyelination is the pathologic hallmark of ADEM,
as opposed to the more confluent demyelination seen
in multiple sclerosis (MS) [5•, 6].
ADEM usually affects children, typically in the pre-
pubertal age range, but has been described in adults as
well [7–9]. Mean age of onset for ADEM in the pediat-
ric age group is 5 to 8 years [10–13, 14•, 15–18, 19•].
The incidence of pediatric ADEM has been reported to
range from 0.1 to 0.6 per 100,000 children per year
[10–12, 14•, 20, 21].
The differential diagnosis of ADEM is broad, in-
cluding CNS infections and neurometabolic disor-
ders (especially mitochondriopathies), as well as
CNS malignancies [22, 23]. Other immune-mediated
disorders, like neurosarcoidosis, Behçet disease, sys-
temic lupus erythematodes, primary isolated CNS
angiitis, neuromyelitis optica (NMO), anti-N-methyl-
D-aspartate-receptor (NMDA-R) encephalitis, and
anti-myelin-oligodendrocyte-glycoprotein (MOG)
disease may manifest with an ADEM-like presentation
[23–30].
Progression to multiple sclerosis (MS) has been
reported in 0% to 29% of pediatric ADEM patients [13,
31–33]. Variability could however be an effect of inconsis-
tent definitions of ADEM among those studies. A recent
long-term follow-up study on children with ADEM meet-
ing the International Pediatric MS Study Group diagnostic
criteria [1] has demonstrated only a 6% risk of developing
MS after a mean follow-up duration of 9 years [19].
The clinical course of ADEM is typically monophasic,
with improvement of clinical deficits and MRI lesions
within 3 months. Although the prognosis is generally fa-
vorable, the acute phase can be severe and even life-
threatening. Fulminant courses of ADEM have been
reported and 15% to 36% of patients presenting with
ADEM may require intensive care [34, 35]. Mortality
rates range from 3% to 12% [11, 34–36] for ADEM in
general, and 10% to 25% for ADEM patients requiring
intensive care unit admission [34, 37].
In view of the spectrum of possible ADEM mimics,
the diagnostic paradigm for a patient presenting with
ADEM should be comprehensive, including a thor-
ough infectious and neurometabolic workup, cranio-
spinal MRI, cerebrospinal fluid (CSF) analysis, and
auto-antibody studies.
CSF oligoclonal immunoglobulin is absent in the ma-
jority of patients [13, 38, 39, 40]. As opposed to the typ-
ical MRI characteristics of MS, ADEM patients often show
a diffuse bilateral lesion distribution, no black holes, and
less than two periventricular lesions [41•, 42•].
Because ADEM is typically a monophasic disease, it
usually does not require long-term therapy. High-dose
corticosteroids like intravenous methylprednisolone,
followed by an oral taper, are considered as first-line
treatment for the acute phase of ADEM [3, 12, 35,
43•, 44–47]. However, there is only level IV evidence
for this treatment approach as robust therapeutic trials
are not available. The use of intravenous immuno-
globulin G (IVIG) has been reported to be beneficial
in several case studies (class IV evidence). Plasmaphe-
266 Neuroimmunology (R Lisak, Section Editor)

resis/plasma exchange (PLEX) has been shown to be
effective in aggressive demyelinating CNS disease
(class II) [48], but only few ADEM patients were in-
cluded in the two double-blind, randomized clinical
trials [49, 50]. PLEX is generally considered as a rescue
treatment for ADEM patients with fulminant disease
course and poor response to high-dose corticosteroids
[51]. Decompressive craniectomy has been reported as
a life-saving measure for ADEM patients with intracra-
nial hypertension and herniation syndrome secondary
to massive hemispheric inflammatory lesions [52–58].
Overall prognosis of ADEM patients is often favor-
able, with full recovery reported in 23% to 100% of
patients from mostly pediatric cohorts [11–13, 15, 16,
25, 31, 32, 35, 43•, 44, 59–71]. The outcome has been
reported as more severe in adult as compared to pediatric
ADEM patients [35]. The most frequent neurologic se-
quelae following an ADEM event are motor and coordi-
nation deficits, ranging from mild ataxia to hemiparesis
[38]. Impairments in cognitive and social domains with
a higher incidence of severe behavioral and emotional
problems have been observed in children who experi-
enced ADEM before 5 years of age [72].
Recurrent and multiphasic ADEM has been
reported in up to 27% of patients presenting with
ADEM [13, 19•]. Relapses usually occur within the
first 2 years after the initial manifestation [13, 19•,
73]. There are no specific treatment recommendations
for recurrent or multiphasic ADEM. Chronic immune-
mediated CNS diseases including MS and NMO have
to be ruled out in patients with a second demyelinat-
ing event after an initial ADEM attack.

Treatment
Diet and lifestyle
& Factors in the environment, including diet and lifestyle, may affect
the incidence and presentation of ADEM, but there is a lack of solid
epidemiologic studies.
& Vitamin D: Recent studies have implicated an association of low
levels of vitamin D with an increased risk of multiple sclerosis after a
first demyelinating event [74]. However, there have been no studies
demonstrating low vitamin D levels in patients with ADEM. Accurate
geographical incidence data for ADEM are unavailable, but to date,
the highest incidence rates have been reported from Fukuoka, Japan
(33°–34°N), and San Diego County, California, USA (32°–33°N),
whereas lower rates were surveyed in higher-latitude countries like
Canada (41°–84°N) and Germany (47°–55°N) [10–12, 14•, 20].

Pharmacologic treatment
& Acute therapy for ADEM has not been studied rigorously, either in
pediatric or in adult patients.
& Corticosteroids are generally considered as first-line therapy (class
IV) [43•, 46]. There is a wide variety in the specific steroid formu-
lation employed, as well as in the routes of administration, dosing,
and tapering regimens [38]. One retrospective, non-randomized
study of 84 children with ADEM showed a better outcome with re-
spect to Expanded Disability Status Scale (EDSS) scores in intrave-
nous methylprednisolone-treated patients as compared to those
treated with intravenous dexamethasone [13]. An increased risk of
relapse has been reported in two observational and retrospective
studies with steroid taper of 3 weeks or less [16, 32].
 Treatment of Acute Disseminated Encephalomyelitis Pohl and Tenembaum 267

& IVIG is an option for second-line treatment or if contraindications to

corticosteroids exist. It has been reported to be effective in case
reports and case series (class IV) [59, 60, 69, 75–88].
Methylprednisolone and prednisolone
Standard dosage Methylprednisolone 20–30 mg/kg (maximally 1 g) per day intravenously for
3–5 days, followed by prednisolone 1–2 mg/kg/day orally for 1–2 weeks
with subsequent tapering over 2–6 weeks.
Contraindications Hypersensitivity to drug, live vaccine or attenuated live vaccine, systemic
fungal infection, active/recent varicella, vaccinia, measles or tuberculosis
infection, cerebral malaria, ocular herpes simplex, peptic ulcer, renal
insufficiency. Caution: traumatic brain injury, congestive heart failure,
cardiac arrhythmia, hypertension, hypernatremia, hypokalemia, risk of
gastrointestinal perforation (e.g. diverticulitis, ulcerative colitis, fresh in-
testinal anastomoses), glaucoma, amebiasis, strongyloides or latent tu-
berculosis infection, recent myocardial infarction, renal impairment,
hypo- or hyperthyroidism, cirrhosis, osteoporosis, neuromuscular trans-
mission disorders (e.g. myasthenia gravis), psychiatric disorders, diabetes
mellitus.
Main side effects Serious: anaphylaxis, suppression of the hypothalamus-pituitary-adrenal
(HPA) axis, hyperglycemia, increased intraocular pressure or glaucoma, cat-
aracts, growth suppression, infection, cardiac arrest, arrhythmias, congestive
heart failure, pulmonary edema, syncope, thromboembolism, vasculitis,
osteoporosis, psychosis, gastrointestinal injury, pancreatitis, pseudotumor
cerebri, convulsions, Kaposi sarcoma, tendon rupture, Charcot-like arthrop-
athy, myopathy, angioedema. Common: increased intraocular pressure, glu-
cose intolerance, sodium/fluid retention, hypokalemia, hypertension,
edema, rash, skin atrophy, weight gain or increased appetite, emotional la-
bility, hyperhidrosis, hirsutism, menstrual irregularities, nausea, elevated
liver enzymes, headache, insomnia, paresthesia, vertigo, neuropathy.
Cost Methylprednisolone: 40 mg/vial=$12.99 (http://www.drugstore.com January
27, 2012).
Intravenous immunoglobulin G (IVIG)
Standard dosage 2 g/kg IV (total dose) given over 2–5 days.
Contraindications Hypersensitivity, IgA deficiency with antibodies against IgA (for some for-
mulations), hyperprolinemia (for some formulations). Caution with volume
depletion, cardiovascular disease, thrombophilia, renal impairment, neph-
rotoxic agents, diabetes mellitus, obesity, age over 65 years, sepsis, para-
proteinemia, migraine history, coagulation disorder, prolonged
immobilization, hyperviscosity.
Main side effects Black box warnings: IVIGs have been reported to be associated with renal
dysfunction, acute renal failure, osmotic nephrosis, and death. Patients
predisposed to acute renal failure include patients with any degree of pre-
existing renal insufficiency, diabetes mellitus, age greater than 65, volume
depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic
drugs. Especially in such patients, IVIG should be administered at the min-
imum concentration available and the minimum rate of infusion practicable.
Although these reports of renal dysfunction and acute renal failure have been
associated with the use of many of the licensed IVIG products, those con-
taining sucrose as a stabilizer accounted for a disproportionate share of the
268 Neuroimmunology (R Lisak, Section Editor)

total number. Serious: hypersensitivity/anaphylactic reaction, Stevens-

Johnson syndrome, erythema multiforme, nephrotoxicity, hyperprotei-
nemia, pseudohyponatremia, hyperviscosity, thromboembolism, aseptic
meningitis, hemolytic anemia, transfusion-related acute lung injury, viral
transmission risk (blood product). Common: headache, cough, injection
site reaction, nausea/vomiting, rash/urticaria, fever/chills/rigors, flushing,
back pain, fatigue, chest tightness, muscle cramps, blood pressure labil-
ity, upper respiratory infection.
Cost Varies depending on location and patient weight, generally over $75 per
gram.

Interventional procedures

Plasmapheresis
Plasmapheresis is a non-selective immune procedure that separates the
plasma from the corpuscular blood components (pathogenic antibodies,
complement, and cytokines) either by centrifugation or by membrane
filtration. The therapeutic effect of plasmapheresis procedures in auto-
immune diseases is mainly based on a modulation of the humoral
immune system [89].
The procedure has been recently established as possibly effective and
may be considered as escalation therapy for steroid-unresponsive acute
fulminant demyelinating CNS diseases including ADEM, MS, NMO, and
transverse myelitis (TM), with class II evidence [48]. Plasmapheresis has
been reported as escalation therapy in a small number of severe cases of
ADEM in adults and pediatric patients [90–95].
Standard procedure 5–7 exchanges every other day with a 1:1 exchange.
Contraindications Hypersensitivity to agents used in PLEX.
Complications Moderate to severe anaemia, symptomatic hypotension, risk of hypocalce-
mia, immune suppression, potential transfusion reactions or transmission of
transfusion-related diseases, and heparin-associated thrombocytopenia.
Caution with severe bleeding diathesis (line insertion may be associated with
bleeding). Catheter-related complications (line infections, line thrombosis,
pneumothorax). Minor risk of infection if human albumin is used as re-
placement.
Special points Use caution in young children, as significant volume shifts may result from
the use of plasmapheresis, leading to possible hemodynamic instability.
Costs Medical costs are mainly procedural, including replacement with human
albumin.

Surgery

Craniectomy
Decompressive craniectomy has been demonstrated as an effective mo-
dality in reducing intracranial pressure (ICP) in emergency situations
usually in the context of stroke and severe head injuries.
Surgical decompression has been performed in pediatric and adult
 Treatment of Acute Disseminated Encephalomyelitis Pohl and Tenembaum 269

patients with fulminant variants of ADEM with evidence of continued

clinical deterioration due to increased ICP, unresponsive to conventional
medical treatment and critical care measures (level IV) [52–58].
Efficacy of craniectomy in the treatment of fulminant variants of
ADEM associated with elevated ICP has not been tested in prospective
clinical trials.
Standard procedure Hemicraniectomy, posterior fossa craniectomy, subtotal uni- or bilateral
frontal craniectomies with duraplasty.
Contraindications There is a trend toward a high incidence of mortality or persistent vegetative
state despite aggressive therapy in patients with very low Glasgow Coma
Scale (GCS). However, the recommendation to avoid surgical procedure in
patients with GCS less than 5 remains debatable [96].
Complications Major: Hydrocephalus, subdural hematoma, extradural hematoma, osteo-
myelitis, permanent neurological deficits, neuropsychological impairment.
Minor: Seizures, CSF leaks, subgaleal fluid collection, surgical site infection,
transient neurological deficits.
Cost Unavailable.

Physical/speech therapy and exercise

Physical therapy
Usage Improvement of gait, balance, muscle strength.
Contraindications No contraindications.
Special points Physical therapy may be necessary after a severe ADEM event, in patients
suffering from motor deficits or difficulties in coordination skills.
Cost Varies depending on location and duration of the required physical therapy.
In North America, costs for one physiotherapy session could be estimated at
$100 to $200.
Speech therapy
Speech disturbances associated with ADEM have been reported occa-
sionally as transient or persisting language deficits, particularly in the
youngest age group [64]. Cerebellar mutism has been observed as well in
ADEM patients with predominant cerebellar involvement [97]. The
presence of subtentorial demyelinating lesions on brain MRI scans has
been identified in one half of children with ADEM in one study [33].
Neurocognitive and speech disturbances may be significant, despite
limited residual physical disability on follow-up after an ADEM event.
Usage Improvement of receptive and expressive language, articulation, and fluency
of speech.
Contraindications No contraindications.
Special points Speech and language therapy should be considered as important aspects of
treatment for patients with residual speech disturbances.
Cost Varies depending on location and duration of the required speech therapy. In
North America, costs for one visit could be estimated at $100 to $200.
270 Neuroimmunology (R Lisak, Section Editor)

Exercise
Exercise as an intervention for pediatric patients with ADEM has not
been evaluated.
Usage May be used to improve muscle strength in patients with temporary loss of
motor skills.
Special points May need guidance from a physiotherapist or personal trainer to plan an
exercise program according to age and needs of each patient.
Cost Varies depending on location, duration and facilities used for exercise.

Other treatments
Immunosuppressive drugs
& The use of cyclophosphamide has been reported in few adult patients
showing steroid-unresponsive variants of ADEM (level IV) [8, 40,
98]. There is no report on the use of immunosuppressive drugs in
pediatric patients with ADEM. However, safety and tolerability data
for cyclophosphamide are available from one study in children with
aggressive MS refractory to first-line therapies [99].
Cyclophosphamide
Standard dosage Optimal dosing has not been established. 500–1000 mg/m2 either as
single dose or as induction regimen administered on day 1, 2, 4, 6, and
8 has been reported for demyelinating diseases including ADEM, MS and
TM [46, 99, 100].
Contraindications Hypersensitivity to drug. Severe bone marrow depression/leucopenia, im-
munodeficiency, BCG (live intravesical), nasal influenza vaccines, live
vaccinia/smallpox vaccine, pregnancy, breastfeeding. Caution: cardiac,
hepatic or renal impairment, leucopenia, thrombocytopenia, recent ra-
diation therapy, recent cytotoxic drug use, adrenalectomy (dose adjust-
ments may be necessary).
Main side effects Serious: secondary malignancy, sterility (irreversible or transient), hemor-
rhagic cystitis, urinary bladder fibrosis, congestive heart failure, hemorrhagic
myocarditis, immunosuppression, infection, anaphylaxis, Stevens-Johnson
syndrome, toxic epidermal necrolysis, anemia, leucopenia, thrombocytope-
nia, interstitial pulmonary fibrosis, SIADH, osteoporosis.
Common: post-infusion nausea and emesis, alopecia, sterility, amenorrhea,
nausea, vomiting, anorexia, diarrhea, stomatitis, hemorrhagic cystitis, rash,
headache.
Special points Contraceptive measures during treatment are recommended for postpubertal
patients of both sexes.
Cost Varies depending on location, and it should include the cost of hospitali-
zation, which is common practice during administration.

Emerging therapies
& The use of emerging therapies for MS has not been reported in
patients with acute demyelinating diseases like ADEM.
 Treatment of Acute Disseminated Encephalomyelitis
Disclosure
No conflicts of interest relevant to this article were reported.
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