Clinical Features

ADEM is usually a monophasic disease with acute onset. However, hyperacute and subacute cases as well as multiphasic and recurrent cases have been described [14]. Patients with ADEM are mostly children with mean age between 5 and 8 years old [2, 3]. The clinical manifestations depend on the location, severity, and extent of the lesions. Clinical feature usually commences 1-4 weeks following the infection. Encephalopathy, defined as altered sensorium ranging from drowsiness to coma or just behavioral changes in the absence of fever, systemic illness, or seizure, is the key manifestation required for the diagnosis of ADEM [1]. Other neurologic presentations including headache, fever, and seizures (35%) are among the common clinical manifestations. Uncommonly and depending on the location of the demye- linating lesions, optic neuritis, myelitis, ataxia, weakness and sensory abnormalities, abnormal involuntary movements, ataxia, falls, aphasia (uncommonly), cranial nerve palsies (apart from optic nerves), and general presentations of meningitis and encephalitis can occur. Respiratory compromise can occur if brain stem is affected. A number of patients with ADEM also develop neuropsychiatric syndrome. Signs of long tract involvement such as hyperactive reflexes as well as the presence of clonus and extensor plantar responses are also commonly present. Nevertheless, peripheral nervous system demyelination is not unusual in pediatric and adult patients [3]. The neurological manifestations of ADEM tend to fluctuate and evolve during the first 3 months of onset; thus, recurrence should not be considered before 3 months. According to the revised International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria in 2012, this is irrespective of corticosteroid use (Table 7.1) [1]. A key exclusionary criterion is the lack of clinical or imaging evidence of prior CNS lesions [6].

Table 7.1 Comparison of 2007 and 2012 definitions for pediatric acute demyelinating disorders of the central nervous system (CNS)





A first monofocal or multifocal CNS demyelinating event; encephalopathy absent

A first monofocal or multifocal CNS demyelinating event; encephalopathy is absent, unless due to fever



A first polysymptomatic clinical event, with presumed inflammatory cause that affects multifocal areas of the CNS Encephalopathy is present MRI typically shows large,

> 1-2 cm white matter lesion; gray matter involvement (thalamus or basal ganglia) is frequent

New or fluctuating symptoms, signs, or MRI findings within 3 months of the incident ADEM are part of the acute event

A first polyfocal clinical CNS event with presumed inflammatory cause Encephalopathy that cannot be explained by fever is present MRI typically shows diffuse, poorly demarcated, large, 1-2 cm lesions involving predominantly the cerebral white matter; TI hypointense white matter lesions are rare; deep gray matter (e.g., thalamus or basal ganglia) can be present

No new symptoms, signs, or MRI findings after 3 months of the incident ADEM



New event of ADEM with a recurrence of the initial symptoms and signs, three or more months after the first ADEM event

Now subsumed under multiphasic ADEM



New event of ADEM, but involves new anatomic areas of the CNS and must occur at least 3 months after the onset of the initial ADEM event and at least 1 month after completing steroid therapy

New event of ADEM 3 months or more after the initial event that can be associated with new or reemergence of prior clinical and MRI findings. Timing in relation to steroids is no longer pertinent


Any of the following:

Multiple clinical episodes of CNS demyelination separated in time and space Single clinical event which is associated with 2001 McDonald Brain MRI criteria3 for DIS and subsequent changes on MRI consistent with criteria 2001 McDonald criteria for DIT [4]

An episode consistent with the clinical features of ADEM cannot be considered as the first event of MS

Any of the following:

Two or more nonencephalopathic CNS clinical events separated by more than 30 days, involving more than one area of CNS Single clinical event and MRI features rely on 2010 Revised McDonald criteriab for DIS and DIT [4] (but criteria relative for DIT for a single attack and single MRI only apply to children >12 years and only apply to cases without an ADEM onset)

ADEM followed 3 months later by a nonencephalopathic clinical event with new lesions on brain MRI consistent with MS


Table 7.1 (continued)





All are required:

Optic neuritis Acute myelitis

At least one of two supportive criteria

Contiguous spinal cord MRI lesion >3 vertebral segments Anti-aquaporin-4 IgG seropositive status

All are required:

Optic neuritis Acute myelitis

At least two of three supportive criteria

Contiguous spinal cord MRI lesion >3 vertebral segments Brain MRI not meeting diagnostic criteria for MS

Anti-aquaporin-4 IgG seropositive status

ADEM acute disseminated encephalomyelitis, CIS clinically isolated syndrome, CNS central nervous system, DIS dissemination in space, DIT dissemination in time, MRI magnetic resonance imaging, MS multiple sclerosis, NMO neuromyelitis optica

aThe 2001 McDonald MRI criteria for DIS require three of the following four MRI features: >9 T2 lesions or 1 gadolinium-enhancing lesions, >3 periventricular lesions, >1 infratentorial lesion(s), and >1 juxtacortical lesion(s). The DIT criteria require subsequent white matter lesions whose timing depends on the temporal relation of the initial MRI with the onset of the clinical symptoms

bThe 2010 Revised McDonald MRI criteria for DIS require the presence of at least two of the following four criteria: >1 lesion in each of the four locations; periventricular, juxtacortical, infratentorial, and spinal cord. The 2010 Revised McDonald MRI criteria for DIT can be satisfied either by the emergence of newT2 lesions (with or without enhancement) on serial scan(s) or can be met on a single baseline scan if there exists simultaneous presence of a clinically silent gadoliniumenhancing lesion and a nonenhancing lesion

While ADEM is generally considered a monophasic disease, patients with ADEM and multiphasic course or recurrent attacks exist as mentioned above [1]. According to the revised IPMSSG criteria, recurrent ADEM is now subsumed under multiphasic ADEM. Thus, multiphasic ADEM is now defined as new event of ADEM 3 months or more after the initial event that can be associated with new or reemergence of prior clinical and MRI findings [1].

After publishing the initial IPMSSG in 2007, few prospective studies are conducted to evaluate the predictive value of such criteria in predicting relapse of the first episode of ADEM to MS. For this to occur, the second episode was defined as nonencephalopathic event with new MRI finding consistent with dissemination in space occurring at least 3 months after the first episode. A second relapse consistent with MS rather than multiphasic ADEM was detected in 2-18%. Of all relapses, 80% occurred with 2 years of the first event [2, 4].

Acute hemorrhagic leukoencephalitis (AHLE) is rare variant of ADEM (< 2%) commonly presenting with fever, neck stiffness, seizures, and/or focal neurological deficits following upper respiratory infection with more rapid progression within days leading to coma and death in some cases due to increased cerebral edema and herniation if untreated urgently. It is considered the most aggressive of all demyelinating diseases. Areas of hemorrhage and necrosis along a massive white matter involvement are evident on the MRI. Many cases are diagnosed on postmortem autopsy [7].

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