Acute disseminated encephalomyelitis

DEFINITIONS

ADEM has historically been an umbrella term for noninfectious acute inflammatory demyelinating events of the CNS, particularly occurring in children. Until recently, the definition of ADEM varied widely, leading to differences in the phenotypes reported. In 2007, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) proposed consensus definitions for pediatric acquired demyelinating disorders of the CNS to improve consistency in terminology.⁶ In 2013, the original definitions were updated.⁷ ADEM remains a diagnosis of exclusion, always necessitating thorough consideration of alternate diagnoses. Beyond this, the new ADEM criteria require the following:

1. A first polyfocal clinical CNS event with presumed inflammatory demyelinating cause

2. Encephalopathy (alteration in consciousness or behavior unexplained by fever, systemic illness, or postictal symptoms)

3. Brain MRI abnormalities consistent with demyelination during the acute (3 months) phase

4. No new clinical or MRI findings 3 months or more after the clinical onset

The clinical symptoms and radiologic findings of ADEM can fluctuate in severity and evolve in the first 3 months after onset. Accordingly, a second event is defined as the development of new symptoms more than 3 months after the start of the incident illness. Data to support the biological rationale for the 3-month requirement are needed.

EPIDEMIOLOGY

Population-based studies show the incidence of ADEM to be 0.3–0.6 per 100,000 per year.^16,17 Nationwide surveys of ADEM in Germany, Canada, and Great Britain report incidences of 0.1–0.3 per 100,000 children per year.^4,5,18 Incidences were higher in the northwest than in the south of the United States, possibly secondary to a geographic distribution similar to that of MS, with an increase in incidence with increasing distance from the equator.¹⁹ The median age at presentation of ADEM is 5–8 years, with male predominance.^18,20 The risk of postimmunization ADEM is significantly lower than the risk of developing ADEM following the infection itself.²¹ Considering the frequency of vaccinations and infections in young children, with up to 8 episodes of upper respiratory tract infections per year considered as normal, a chronologic association between a vaccination or an infection and ADEM does not prove causality.

PATHOLOGY

The hallmark of ADEM pathology consists of perivenular sleeves of demyelination associated with inflammatory infiltrates of myelin-laden macrophages, T and B lymphocytes, occasional plasma cells, and granulocytes.²² Lesions are of similar histologic age, and may demonstrate acute axonal injury. Larger areas of demyelination are a consequence of coalescence of numerous perivenous demyelinating lesions.²² In contrast, MS lesions are characterized by confluent demyelination associated with sheets of macrophage infiltration admixed with reactive astrocytes in completely demyelinated regions. However, transitional cases of both perivenous and confluent demyelination in the same patient have been described, suggesting a potential for misclassification even with biopsy.²² ADEM is the only disorder, aside from MS, in which the full spectrum of cortical lesions can be identified, including subpial demyelinated lesions and intracortical lesions.²² A pattern of cortical microglial activation distinct from MS, characterized by multifocal microglial aggregates, not associated with cortical demyelination, can also be found in ADEM. These diffuse cortical microglial alterations may represent the pathologic substrate of the depressed level of consciousness typically observed in patients with ADEM.²²

Whether acute hemorrhagic leukoencephalopathy (AHL) is a separate disease entity or a hyperacute severe variant of ADEM remains controversial. AHL lesions are characterized by the presence of hemorrhages, vessel fibrinoid necrosis, perivascular exudation, edema, and granulocyte infiltration, with perivascular demyelination and reactive astrocytosis typically seen later in disease evolution. A recent report of a fulminant case of AHL revealed perivenular hemorrhages, edema, and granulocytes in the absence of demyelination.²³ Perivascular astrocytes demonstrated dystrophic and swollen processes, suggesting astrocytic damage may be an early event that precedes demyelination in AHL.

CLINICAL PRESENTATION

ADEM is characterized by an acute onset of encephalopathy in association with polyfocal neurologic deficits, sometimes preceded by prodromal symptoms (fever, malaise, irritability, somnolence, headache, nausea, and vomiting). The clinical course of ADEM is typically rapidly progressive, with maximal deficits within 2 to 5 days.²⁰ A severe presentation resulting in admission to an intensive care unit has been reported in 15%–25% of children with ADEM.^24,25 Frequent neurologic manifestations include pyramidal signs, ataxia, acute hemiparesis, optic neuritis or other cranial nerve involvement, seizures, spinal cord syndrome, and impairment of speech. Rarely, respiratory failure occurs due to brainstem involvement. Seizures may develop into status epilepticus.^20,26 Fever and seizures are described more frequently in ADEM compared to other acute demyelinating syndromes. Combined central and peripheral demyelination has been reported,^27,–,30 but should prompt diligent differential diagnostic workup including screening for other immune-mediated disorders, as well as for leukoencephalopathies of genetic/metabolic origin (e.g., mitochondriopathies, Krabbe disease, X-linked Charcot-Marie-Tooth disease).^31,32

NEUROIMAGING FEATURES

MRI T2-weighted and fluid-attenuated inversion recovery images typically demonstrate multiple hyperintense bilateral, asymmetric patchy and poorly marginated lesions.²⁰ Usually different sizes of lesions are seen in the same patient.³³ Tumefactive lesions with perilesional edema have been reported.³⁴ ADEM lesions typically involve the subcortical and central white matter and cortical gray–white matter junction, thalami, basal ganglia, cerebellum, and brainstem.^11,20,33,34 (figure, A–C) Spinal cord involvement has been described in up to 1/3 of patients, often demonstrating large confluent lesions extending over multiple segments, sometimes associated with cord swelling.^20,35 Gadolinium enhancement is reported in up to 30% of patients.²⁰ Main differentiating features of ADEM compared to MS are periventricular sparing and absence of periventricular ovoid lesions perpendicular to the ventricular edge (Dawson fingers).^34,–,36 The figure and table 2 summarize MRI characteristics of ADEM vs MS. There are, however, no absolute imaging criteria to differentiate ADEM from MS.

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Figure Representative images demonstrate typical MRI appearances of acute disseminated encephalomyelitis (ADEM) (A-C) and multiple sclerosis (MS) (D-F)

T2-weighted images from a patient with ADEM show bilateral diffuse, multifocal, poorly marginated, large asymmetric lesions of the white matter, basal ganglia, and cortical gray matter (A, B); coronal fluid-attenuated inversion recovery (FLAIR) image demonstrates asymmetric involvement of the thalami (C). FLAIR images from a patient with MS demonstrate multifocal, asymmetric, mostly well-defined ovoid lesions of the white matter, with periventricular predominance and sparing of the basal ganglia, on axial (D, E) and coronal (F) views.

CSF FINDINGS

CSF studies in ADEM are notable for their lack of confirmatory features. CSF leukocyte count has been described to be normal in 42%–72% of children with ADEM.^{16,20,42,–,44} Pleocytosis is typically mild, with a high percentage of lymphocytes and monocytes.^44,45 CSF protein is increased (up to 1.1 g/L) in 23%–62% of pediatric patients with ADEM.^{16,20,42,–,44} An elevated CSF IgG index has been reported in 2/54 and 3/13 children in 2 pediatric ADEM cohorts. Of note, none of these patients with elevated IgG indices had CSF oligoclonal bands (OCBs).^20,34 Indeed, most notably, OCBs are a rare phenomenon in children with ADEM diagnosed according to IPMSSG consensus definitions. Out of 53 patients described in 3 more recent case series, OCBs were only detected in one patient (1.9%).^34,42,43 In cases where CSF OCBs are detected in ADEM, they tend to manifest as mirror bands present in both serum and CSF, and would therefore not be considered as true OCBs per definition, but suggest an antibody production that is not intrathecally restricted.⁴⁶ Infectious studies of the CSF are, by definition, negative in ADEM with the caveat that the breadth and sensitivity of current infectious assays remain limited.

DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS, AND WORKUP

The diagnosis of ADEM is made on clinical grounds with MRI support. Variable clinical manifestations and lack of specific biological markers imply that the diagnosis requires exclusion of differential diagnoses. The first priority is to rule out potentially treatable CNS infections. The authors recommend gadolinium-enhanced brain and spinal cord MRI, and CSF studies including cell count, protein, lactate, IgG index, and oligoclonal IgG (in CSF and serum), in addition to screening for infectious agents, especially herpes simplex virus, enterovirus, Epstein-Barr virus, and mycoplasma. Bloodwork will typically include complete blood count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, NMO-IgG, and MOG antibodies. Extensive, specialized testing for alternative disorders is guided by red flags (table 3). An MRI-based approach to the differential diagnosis of ADEM is provided in table 4.

Differentiation of ADEM and MS is of prognostic and therapeutic importance. Children with ADEM are generally younger, and systemic symptoms such as fever, vomiting, meningism, and headache are much more common in ADEM than MS. Intrathecal oligoclonal IgG synthesis is a hallmark of MS, but atypical in ADEM. Disease activity (clinical or MRI) >3 months after ADEM onset points towards a chronic disorder like ADEM-ON, MS, or NMOSD (table 1). Discriminatory MRI features of ADEM and MS are listed in table 2.

TREATMENT

There are no randomized studies for the treatment of ADEM. Thus, management of ADEM is based on expert opinions and observational studies.^20,26,47 Despite the lack of conclusive evidence, high-dose corticosteroids are currently widely accepted as first-line therapy.⁴⁸ A typical treatment regimen consists of IV methylprednisolone at a dose of 30 mg/kg/d (maximally 1,000 mg/d) for 5 days, followed by an oral taper over 4–6 weeks with a starting dose of prednisone of 1–2 mg/kg/d. An increased risk of relapse was observed with steroid taper of ≤3 weeks.⁴⁹ IV immunoglobulin treatment has been described in case reports and small case series, mostly in combination with corticosteroids or as a second-line treatment in steroid-unresponsive ADEM.^50,51 The usual total dose is 2 g/kg, administered over 2–5 days.⁴⁷ Plasma exchange is recommended for therapy-refractory patients with fulminant disease, e.g., using 7 exchanges every other day.⁴⁷ In single case reports, patients with fulminant ADEM and cerebral edema have been treated with hypothermia or decompressive craniotomy.^52,53

OUTCOME

The majority of children with ADEM are reported to have full recovery. Typically, neurologic improvement is seen within days following initiation of treatment, and recovery to baseline will occur within weeks rather than months.⁵⁴ However, mortality rates of 1%–3% have been reported recently,^24,25 and long-term cognitive deficits have been observed, affecting attention, executive function, verbal processing, and behavior, as well as IQ scores, specifically in children with ADEM before age 5 years.^55,56

Relapsing ADEM—MDEM—has been reported, although at much lower frequency (<10%) since implementation of the 2007 ADEM criteria. It is currently under debate whether patients with relapsing ADEM represent a distinct group of children with other neuroimmunologic diseases like NMOSD or MOG-antibodies-associated disorders. ADEM as a first manifestation of MS appears to be uncommon, occurring in <10% of patients with ADEM.²⁰ Predictors of MS following ADEM and other acute demyelinating syndromes are discussed in “Pediatric acquired CNS demyelinating syndromes: Features associated with multiple sclerosis” by Hintzen et al. (p. S67).

CONTROVERSIES AND FUTURE DIRECTIONS

ADEM is possibly not a single specific disease, but an inflammatory CNS syndrome with immune-mediated demyelination and strong predilection to young children. Further delineation of potentially different etiologies for an ADEM presentation, including antibodies to CNS proteins like aquaporin or MOG, will hopefully enhance our understanding of the disease and facilitate treatment decisions. The question whether and how often ADEM can present as the first manifestation of MS is still under debate. In view of the relatively low incidence of ADEM, multicenter studies are required to provide more information with regards to pathogenesis, biomarkers, differential diagnoses, and therapeutic options, with the ultimate goal to promote efficacious and specific treatment approaches in order to optimize long-term outcomes in children with demyelinating disorders.