J Neurol (2015) 262:2013–2024 DOI 10.1007/s00415-015-7694-7
REVIEW
Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome Diederik L. H. Koelman • Farrah J. Mateen
Received: 21 January 2015 / Revised: 6 February 2015 / Accepted: 8 February 2015 / Published online: 13 March 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory, demyelinating disorder of the CNS. Only in the past 15 years have larger groups of patients from several geographical areas been reported for comparisons across studies. In spite of the increased recognition of ADEM, the diagnosis of ADEM remains clinical, aided by neuroimaging confirmation, because of the lack of a biological marker. The diagnosis may be difficult, given that several diseases may present similar to ADEM. The controversial existence of multiphasic forms necessitates a continuous evaluation of the diagnosis by tracking subsequent events. Despite proposed consensus criteria, the diagnostic criteria employed to characterize ADEM range widely among the largest reported cohorts to date. This review comprehensively evaluates the current knowledge and controversies that surround ADEM, with special consideration of the distinction between ADEM and other demyelinating diseases such as multiple sclerosis. In addition, we present implications of the current knowledge of ADEM for both research and clinical practice.
D. L. H. Koelman F. J. Mateen (&) Department of Neurology, Massachusetts General Hospital, 165 Cambridge Street, #627, Boston 02114, MA, USA e-mail: [email protected] D. L. H. Koelman e-mail: [email protected] D. L. H. Koelman Academic Medical Center - University of Amsterdam, Amsterdam, The Netherlands F. J. Mateen Harvard Medical School, Boston, MA, USA
Keywords Acute disseminated encephalomyelitis Autoimmune diseases Encephalopathy Postinfectious
Introduction In 1724, Clifton [1, 2] likely first described the disease currently known as acute disseminated encephalomyelitis (ADEM) in his doctoral thesis on pox at the University of Leiden, The Netherlands. He noticed the occurrence of ‘‘severe headaches, inflammation of the eyes, deceptive and inconsistent impressions [hallucinations], disrupted separations [blurred vision], convulsions, jumping of the tendons [clonus], very great weakness and eventually death itself’’ [2]. After the first contemporary description of ADEM by Anton and Wohlwill [3] and Koprowski’s [4] hypothesis in 1962 that ADEM is an autoimmune disease, the general understanding and knowledge of ADEM has significantly increased because of new diagnostic modalities such as MRI. Several cohort studies have been published on ADEM, demonstrating new insights into this inflammatory demyelinating disorder of the CNS. Only in the past 15 years have larger groups of patients with ADEM been reported from several geographical areas. However, in spite of the increased recognition of ADEM, the diagnosis of ADEM remains clinical with neuroimaging confirmation and lacks a discrete biological marker. Several diseases may present similarly to ADEM at initial presentation, making diagnosis potentially difficult. In contrast to most other demyelinating diseases, ADEM was thought to be an exclusively monophasic disorder. The controversy of multiphasic ADEM only complicates this distinction. Because most ‘mimics’ of ADEM require different treatment, accurate diagnosis is especially important.
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Characteristics
‘‘microglial’’ and ‘‘postrabies’’ vaccine encephalomyelitis, have been used to describe ADEM. These different terms emphasize the localization and histology of ADEM. The different specific triggers of ADEM have been comprehensively reviewed elsewhere with unspecified upper respiratory tract infections being common [24]. Measles was one of the first etiologies described in 1790 by Lucas [2, 25], an English surgeon from Leeds. He described urinary and fecal retention and lower limb weakness after the disappearance of a measles rash with maximal neurological deficits within 2 days, followed by full recovery within a few weeks [2].
Epidemiology
Pathogenesis
ADEM is a rare inflammatory, demyelinating disorder of the CNS. ADEM may occur at any age, but is most common during childhood [5], with an incidence in children ranging from 0.07 to 0.64 per 100,000 persons/year [5–8]. The incidence in adults has not been reported. Table 1 summarizes cohorts comprising C50 patients with an initial diagnosis of ADEM [9–17]. Of the nine cohorts presented, five focus exclusively on pediatric age groups, two focus on adults, and two focus on all age groups. The percentage of male patients was 59 % in pediatric cohorts combined [9–13, 16] and 46 % in adult cohorts combined [14, 16, 17]. The incidence of ADEM has historically been very different between countries, as after smallpox vaccination in the 1920s [18]. The incidence may even vary within countries, such as between Glasgow and Edinburgh in 1942 [19]. In a populationbased study in California, the incidence of ADEM was higher in African-American than in white non-Hispanic children [20]. There is a variant of ADEM, known as acute hemorrhagic leukoencephalopathy (AHLE) that is extremely rare, for which the epidemiology is not known.
Koprowski based his autoimmune hypothesis on the similarities of ADEM with both experimental autoimmune encephalomyelitis (EAE) and postrabies vaccination encephalomyelitis. EAE is an animal model of human CNS demyelinating diseases, which can be induced by immunization with myelin proteins and peptides in rodents. Consequently, it has been suggested that microbial infections can cause ADEM by myelin-reactive T cell activation through molecular mimicry, provoking a CNS autoimmune response. Since many cases do not have a clear history of an infectious trigger, it is also posited that ADEM may be caused by activation of pre-existing myelin-reactive T cells through a more nonspecific inflammatory process. Although ADEM is currently mostly discussed within the spectrum of demyelinating diseases because of its similarities with MS at onset, the various descriptions for ADEM suggest that ADEM may not represent one final disease process.
This review focuses on the largest published cohorts of ADEM to date, their reported risk factors for ADEM, and the proposed clinical and MRI criteria to distinguish ADEM from its mimics, with special consideration of the subsequent diagnosis of multiple sclerosis (MS). The term ADEM in this article includes all forms described in the current literature, without distinguishing between different criteria, to comprehensively evaluate the available reports and controversies.
Preceding events Preceding infection or vaccination is reported in a variable number of cases. When combining infection and vaccination as a single risk factor, among cohorts that did not mandate an antecedent trigger, seven cohorts found a mean of 67 % of cases with either preceding vaccination or infection [10, 12–16]. Some studies even use it as an inclusion criterion [9, 11, 17]. A seasonal trend, with the most common occurrence in winter and spring, has been reported, possibly due to precipitation by an infection [21–23]. Vaccination as a trigger, although frequently reported in single cases, is most likely relevant in a small subpopulation of ADEM. A preceding vaccination is reported in 5–19 % in the largest cohorts to date [10, 12, 14–17]. Besides ‘‘postinfectious’’, ‘‘parainfectious’’, and ‘‘postvaccinal’’ encephalomyelitis, other terms, such as ‘‘perivenous’’,
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Clinical presentation ADEM presents most commonly with multifocal neurological deficits. A polysymptomatic presentation, defined as the occurrence of multiple symptoms, originating from different regions of the CNS, is often used as an inclusion criterion. In a study with a less strict inclusion criteria for ADEM (including lack of requisite abnormal brain MRI), 94 % of 176 adult patients had a polysymptomatic presentation [17]. The clinical presentation differs widely among the largest studies to date. Because differing inclusion criteria are used (Table 1), it is unclear whether differences seen between cohorts represent variations in disease patterns or non-parallel inclusion criteria for comparable reporting. Encephalopathy, often defined as altered consciousness (lethargy, stupor, coma) and/or altered behavior (irritability or confusion) as proposed by the International Pediatric MS Study Group (IPMSSG) [26], is one of the major ADEMdefining symptoms, but ranged widely in the largest cohorts from 46 to 73 % in pediatric cohorts [9–13, 16], and
52
Initial ADEM
0 (0)
Preceding vaccination
8 (15)
11 (21)
CN/brainstem
Meningismus
NR
NR
OCB
NR
Spinal cord
CSF, n (%) Pleocytosis
NR
4 (22)h
Brainstem/ cerebellar
Elevated protein
3 (17)
h
Deep gray matter
MRI abnormal
14 (78)
NR
Ataxia/cerebellar
MRI, n (%)
25 (48)
19 (37)
Headache or vomiting
9 (17)
20 (38)
Fever
Weakness/ pyramidal
38 (73)
Encephalopathy
Seizures
NRc
Polysymptomatic
Symptoms, n (%)
52 (62)
52 (100)b
Preceding infection
47 (52)
2 (4)
k
NR
NR
j
i
24 (28)
NRj
2 (17)
4 (33)h
NR
8 (67)
NR
22 (24)
24 (28)i
NR
NR
22 (26)
84 (100)b
36 (43)
37 (44)
42 (50)
34 (38) 65 (72)
29 (35)
NR
NR
41 (46)
90 (100)b
0 (0)
90 (100)b
90 (100)b
49 (54)
10 (2–16)
90
R
Idrissova et al. [11], Russia, 2003
64 (76)f
27 (32)
NR
58 (69)
84 (100)b
10 (12)
54 (64) 62 (74)
29 (56)
52 (100)b
Preceding event
5 (0–16)
84
P
Tenembaum et al. [10], Argentina, 2002
Male
Presentation, n (%) Age, years 7 (0–14) (range)
R
Type
Hung et al. [9], Taiwan, 2001
1 (2)
[50 %
[50 %
5 (10)
14 (27)h
16 (31)
h
52 (100)b
14 (27)
20 (39)
6 (12)
40 (77)
19 (37)
17 (33)
33 (63)
29 (56)
52 (100)b
4 (8)
13 (25)
17 (33)
38 (73)
6.1 (1–12)
52
P/R
Singhi et al. [12], India 2006
Table 1 Summary of published cohorts with ‡50 cases with an initial diagnosis of ADEM
20 (37)
d
9 (7)
49 (37)
70 (53)
18 (14)
83 (63)
76 (58)
132 (100)b
NR
34 (42)
7 (13)
13 (24)
25 (66)
27 (50)h
17 (31)
h
54 (100)b
NR
12 (22) 13 (24)
NR
26 (48)
3 (6)
NR
NR
NR
d
38 (70)
10 (19)
26 (48)
36 (67)
NR
26 (43)
32 (52)
18 (50)
11 (36)h
15 (48)
h
61 (100)b
12 (20)
NR
15 (25)
41 (67)
14 (23)
9 (15)
NR
33 (54)
e
61 (100)b
4 (7)
52 (85)
56 (92)
34 (56)
22 (1–65)
61
33 ([15)
P
60a
Panicker et al. [15], India, 2010
R
de Seze et al. [14], France, 2007
63 (48)g
NR
37 (28)
NR
NR
132 (100)
b
132 (100)b
NR
76 (58)
76 (58)
74 (56)
6 (\16)
132
R
Mikaeloff et al. [13], France, 2007
4 (7)
NR
81 (82)
24 (67)
60 (59)h
64 (63)
117 (100)b
26 (22)
49 (42)
56 (48)
86 (74)
27 (23)
50 (43)
52 (44)
76 (65)
117 (100)b
5 (5)
82 (72)
87 (74)
62 (53)
13.7 (0–82)
117
R
Ketelslegers et al. [16], Netherlands, 2011
44 (25)
NRj
40 (4–120)
146 (83)
NR
50 (28)
99 (56)
22 (13)
19 (11)
17 (10)
105 (60)
8 (4)
NR
48 (27)
39 (22)
163 (94)
14 (8)
162 (92)
176 (100)b
87 (49)
54 (18–80)
176
P
Marchioni et al. [17], Italy 2013
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24 (46)
0
1 (2)
0 4 (8)
8 (15)
37 (71)
Deaths
Relapses
Multiple relapses Neurological deficits
Cognitive deficits
Full recovery
75 (89)
3 (4)
0 9 (11)
8 (10)
0
80 (95)
79 (12–228)
Tenembaum et al. [10], Argentina, 2002
42 (47)
13 (14)
NR 4 (4)
11 (12)
0
NR
(12–60)
Idrissova et al. [11], Russia, 2003
27 (61)
6 (14)
1 (2) 11 (25)
4 (9)
0
43 (83)
(6–48)
Singhi et al. [12], India 2006
NR NR
87 (66)m NR
NR
0 NR
0
NR NR
9 (15)
25 (42)a
61 (100)
3 (1–12)
Panicker et al. [15], India, 2010
0
54 (100)
36 (12–120)
de Seze et al. [14], France, 2007
NR
11 (8) NR
24 (18)
0
81 (61)
65
Mikaeloff et al. [13], France, 2007
53 (50)m
NR
NR NR
20 (19)l
4 (3)
88 (75)
6 (2–169)
Ketelslegers et al. [16], Netherlands, 2011
100 (57)
NR
16 (9) NR
52 (31)
6 (3)
176 (100)
76 (24–170)
Marchioni et al. [17], Italy 2013
Inclusion or exclusion criteria
Panicker et al. reported impaired consciousness 33 (54) and behavioral disturbances 14 (23), separately
Mikaeloff et al. reported 12 patients had optic neuritis; de Seze et al. reported 7 (13) patients with optic neuritis, in addition to brainstem symptoms
Tenembaum et al. reported hemiparesis in 76 %
Tenembaum et al. reported no intrathecal OCBs
Tenembaum et al. reported signs of inflammation in CSF in 28 % as either pleocytosis or elevated protein Mean values of CSF were given: Idrissova et al. 102 cells per mL, 72 mg protein per L, Marchioni et al. 90 mg protein per L
m
Full recovery was reported after the initial event
Ketelslegers et al. reported relapses in 20 patients, seven experienced another ADEM event, seven developed ON without new other symptoms, and six experienced at least two demyelinating events and new brain MRI lesions without normalization of MRI and were diagnosed as MS
l
k
j
i
Lesions were scored separately; the higher of the two is depicted in the table: thalamus/basal ganglion: Hung et al. 3 (17)/3 (17); Singhi et al. 16 (31)/9 (17); de Seze et al. NR/17 (31); Panicker et al. 15 (48)/7 (23), brainstem/cerebellar: Hung et al. 4 (22)/2 (11); Idrissova et al. NR/4 (33); Singhi et al. 9 (17)/14 (27); de Seze et al. 27 (50)/25 (46); Panicker et al. 8 (26)/11 (36); Ketelslegers et al. 60 (59)/42 (41)
h
g
f
e
d de Seze et al. reported atypical presentation of MS, specified as consciousness alteration, hypersomnia, aphasia, hemiplegia, paraplegia, tetraplegia, seizure, vomiting, bilateral ON, or confusion, in 34 (63) of the patients
Hung et al. classified the cohort as either postinfectious encephalitis with simple, focal, localized symptomatology and/or less than three lesions in various parts of the brain on neuroimaging (n = 38) and ADEM with multifocal presentation and more than three lesions (n = 14)
c
b
de Seze et al. excluded six cases of multiphasic ADEM, specified as recurrent ADEM with recurrence of old symptoms, from the analysis. Clinical, MRI and CSF data are based on 54 patients. MS was diagnosed in 19 (32) patients if a second event occurred more than a month after the initial event with new symptoms in new clinical territory
a
R retrospective, P prospective, ADEM acute disseminated encephalomyelitis, CN cranial nerve, OCB oligoclonal bands, NR not reported, ON optic neuritis, MS multiple sclerosis
[18
Steroids treatment
Hung et al. [9], Taiwan, 2001
Months, (range)
Follow-up, n (%)
Table 1 continued
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22–52 % in adult cohorts [14, 16, 17]. The most commonly reported neurological deficit is weakness of the lower and/or upper extremities (17–77 %). Other symptoms include ataxia (10–52 %), cranial nerve palsies (11–48 %), seizures (4–48 %), fever (27–63 %), headache and/or vomiting (15–37 %), and meningeal signs (13–43 %) [9–17]. Peripheral nervous system involvement has been reported [10, 17].
2017
was reported in 83 % of patients in a cohort of 176 adults that all underwent spinal cord MRI [17]. Gadolinium enhancement of lesions is variable [27, 28]. In some cases, delay in the appearance of MRI lesions for up to 8 weeks has been reported [29] and may herald a prolonged clinical course and lack of response to glucocorticoid therapy [30]. CSF features
MRI findings The most common MRI finding is the presence of multiple bilateral T2-enhancing supratentorial white matter lesions. Accompanying lesions are often present in the thalamus and/or basal ganglia (17–63 %) and the brainstem and/or cerebellum (22–63 %) [9–17]. Spinal cord involvement
Fig. 1 Pathology in acute disseminated encephalomyelitis (a, b) and in acute hemorrhagic leukoencephalitis (c, d). Luxol fast blue, hematoxylin and eosin stains of a perivascular demyelination typical of acute disseminated encephalomyelitis in the cuneate fasciculus at C1, with moderate inflammatory reaction consisting of macrophages, T cells, and microglia (original magnification 9100), b the normal aspect of perivascular myelin (white arrow), and an area of
Analysis of the CSF is initially necessary to exclude acute CNS infection, because of the acute therapeutic implications of identifying an infection [31]. CSF usually shows inflammation (24–82 %) with pleocytosis and/or elevated protein; however, CSF findings are reported at variable time points within the clinical course of ADEM [10, 12–17].
perivascular demyelination (black arrow) (original magnification 9200), c vascular fibrinoid necrosis, microhemorrhages, marked acute inflammatory response and perivascular demyelination in the basilar part of the pons consistent with acute hemorrhagic leukoencephalitis (original magnification 9100), and d Fibrinoid necrosis of a vessel wall (original magnification 9200) (arrow)
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Oligoclonal bands (OCBs) are typically absent. However, in one study, OCBs were reported in 6 of 21 tested patients (29 %) [21]. Pathology Cerebral tissue is often not available for the diagnosis of ADEM, but histopathology of the brain is considered to be the gold standard for diagnosis [32]. Brain and spinal cord may grossly appear normal or show congestion and swelling. Microscopic findings in the brain or spinal cord usually include the characteristic perivenous sleeves of demyelination with mild perivascular inflammation (Fig. 1a, b). AHLE has perivascular demyelination, similar to ADEM, but additionally has acute inflammation, vascular fibrinoid necrosis and petechial hemorrhages (Fig. 1c, d). Treatment There are no randomized studies for the treatment of an initial clinical event of ADEM. Little is reported about the clinical outcome of ADEM without treatment. First-line treatment usually consists of IV methylprednisolone, generally 3–5 days of 20–30 mg/kg in children with a maximum dose of 1 g/day for both adults and children [33]. An oral steroid taper for 4–6 weeks commonly follows the use of IV steroids. IV immunoglobulin is often considered a secondary treatment for patients that do not respond to the initial IV steroid dose. Standard treatment for adults and pediatrics consists of 2 g/kg divided over 2–5 days [33]. A second dose of IV methylprednisolone may also be considered. Plasmapheresis (PLEX), with 3–7 exchanges, is one of the ‘‘last resort’’ treatments for ADEM patients with an unresponsive, fulminant disease, but should be considered early [31, 33]. One study showed improvement in function after PLEX in 4 of 10 patients [34]. Craniotomy in patients with intracranial swelling, mass effect and/or midline shift can be a life-saving treatment [33]. The well-known benefit of early treatment initiation in patients with clinically isolated syndrome (CIS) may be illustrative, but early initiation of disease-modifying therapy (DMTs) in a group with lower risk of progression will lead to unnecessary lifelong treatment in some patients. Yet, specific subpopulations with an initial ADEM presentation with higher rates of transition may be suitable for the same therapeutic management as patients with CIS. Clinical course and outcome The clinical course is characterized by rapid, progressive evolvement of symptoms with maximization of deficits in a couple of days, with reported means of 2–8 days [10, 17, 35]. One study estimated that approximately 25 % of
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children are admitted to the PICU after a first presentation of ADEM [36]. MRI lesions gradually resolve and clinical deficits become less prominent with time. The mortality is low, especially in childhood, with a combined prevalence in the largest cohorts of 1 of 525 (0.2 %) children and 18 of 293 (6.1 %) adults after an initial ADEM diagnosis [9–17]. However, ADEM is reported from several locations worldwide, including regions where supportive care is more limited and the mortality may be higher.
Differential diagnosis Diagnostic difficulties The diagnosis of MS is currently based on dissemination in time and space according to the McDonald 2010 criteria [37], but the initial presentation of MS may be indistinct from ADEM. Since the diagnosis of ADEM is one of exclusion and suffers from the lack of a biological marker, accurate diagnosis solely based on the first clinical demyelinating event is very limited. Distinct epidemiology Fortunately, several factors may help in distinguishing ADEM from MS. ADEM does not have a notable female predominance, in contrast to MS [5, 38]. Children less than 10 years of age are more likely to have ADEM than MS at the time of an initial demyelinating event [5, 39]. However, onset of MS has been reported at 1 year of age [40], limiting the usefulness of age as a discriminating factor. While a history of antecedent infection or vaccination is indicative of ADEM, an increased frequency of antecedent events, though to a lesser extent, has been reported in patients with a first presentation of MS [41]. Distinct presentation Clinical presentations of encephalopathy [21, 42], seizures [21, 43], fever [21, 42, 43], headache [21, 43], bilateral optic neuritis (ON) [21, 44], brainstem symptoms [42], and meningeal signs [21, 42] are reported to be statistically significantly more likely with a diagnosis of ADEM than MS. In addition, one study showed, among 176 adults with postinfectious ADEM, concomitant peripheral nervous system involvement was significantly associated with a subsequent relapse (42 vs. 25 %, p = 0.011). A study found that in 117 children with a demyelinating disease of the CNS, seizures almost exclusively occurred in patients with a polysymptomatic monophasic disease (28 vs. 3 %, p = 0.02) [43]. ON in ADEM is most commonly bilateral, while bilateral ON is less suggestive of MS [21, 44].
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Fig. 2 Neuroimaging of two patients with a first demyelinating event diagnosed as ADEM. a Axial FLAIR MRI of a 53-year-old male at symptom onset. Patient presented with weakness, nausea/vomiting, and confusion after an unspecified infection. Diagnosis after 5 years of follow-up: monophasic acute disseminated encephalomyelitis, b Axial FLAIR MRI of a 48-year-old female at symptom onset. Patient presented with gait abnormality, nausea/ vomiting and confusion. Change of diagnosis after 1 year of follow-up: multiple sclerosis
Several studies have identified anti-aquaporin-4 (AQP4) antibodies, the biomarker of neuromyelitis optica (NMO), in a subset of ADEM patients [45–50]. Neuromyelitis optica (NMO) is well recognized as a cause of a bilateral ON and may be an alternative diagnosis in many cohorts, possibly limiting the usability of bilateral ON as distinctive factor. It is not clear whether AQP4 antibody seropositive ADEM is a subset of ADEM, NMO spectrum disorder, or a separate entity. The etiologic role of the AQP4 antibody in the cases diagnosed clinically as ADEM is similarly unresolved. Distinct neuroimaging Neuroimaging of ADEM and MS at first presentation can be very similar (Fig. 2). MRI findings reported to be significantly more present in ADEM than in MS include deep gray matter lesions [14, 51–53], cortical gray matter involvement [14, 51], diffuse bilateral lesion pattern [54], and a high lesion load ([50 % abnormal brain (lesions) versus normal brain) [55]. By contrast, findings associated more often with MS than ADEM include: periventricular white matter lesions [21, 43, 51, 53, 54], juxtacortical lesions [13, 43], corpus callosum lesions (perpendicular to the long axis) [14, 21, 51–53, 55], sole presence of welldefined lesions [21, 43, 55], high number of T2-hyperintense lesions [43, 55], and presence of T1-black holes [53, 54]. A recent study comparing deep gray matter lesions between ADEM and MS found that, unlike in children, thalamic involvement in adults is not more specific for ADEM than for MS [56]. Moreover, they found that in adults, lesions in the putamen are more suggestive of ADEM and lesions in the hypothalamus are more suggestive of NMO. Brainstem lesions in ADEM are more often located in the midbrain and are more often bilateral and
symmetrical [57]. Incomplete resolution or persistence of lesions is associated with a subsequent diagnosis of MS [21]. The use of advanced imaging such as diffusion tensor imaging to differentiate ADEM has been considered [58], but no clinical recommendations can be made on its use at the present time. Distinct CSF findings Although CSF does not permit reliable differentiation, CSF more frequently shows OCBs in patients with MS than ADEM [14, 59]. CSF pleocytosis and elevated protein are thought to be more suggestive of ADEM, but can be seen in MS patients as well, especially in pediatric MS [60]. Brain biopsy Pathologically, confluent demyelination, which is typical in MS, is distinct from the perivenous sleeves of demyelination, the hallmark of ADEM [61]. The performance of brain biopsy for histopathology must be considered carefully given the morbidity that may be associated with the biopsy procedure. The major constraint of all of these distinguishing factors is the lack of specificity and the risk of not providing a DMT in patients who evolve to MS.
Controversies in current practice Re-emergence of symptoms Historically, ADEM was thought to be an exclusively monophasic disease for which any re-emergence of symptoms was not possible. In the past decades, a
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Table 2 International pediatric study group definitions for re-emergence of symptoms after an initial ADEM diagnosis [26] Diagnosis
2007
2012
Recurrent 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
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 re-emergence of prior clinical and MRI findings. Timing in relation to steroids is no longer pertinent
Multiple sclerosis
Multiple clinical episodes of CNS demyelination separated in time and space that is not consistent with the clinical features of ADEM
New non-encephalopathic clinical event 3 months or more after the initial event with new lesions on brain MRI consistent with MS
multiphasic form of ADEM has been recognized and has since been reported in numerous case reports [62]. The controversy of multiphasic ADEM has been highlighted in the different cohorts published in the last 15 years [9–17]. Studies have either excluded recurrent forms from analysis [14], classified all relapses as MS [63], did not differentiate relapses [12, 13, 17], differentiated multiphasic ADEM from MS based on clinical presentation or follow-up [9– 11], or classified relapses according to, or similar as, the IPMSSG criteria (Table 2) [16, 35, 43]. Hence, percentages of multiphasic forms have differed widely among the largest cohorts to date. Tracking subsequent events and reevaluation of the initial diagnosis is necessary to discriminate between ADEM, multiphasic ADEM, and MS. Nonetheless, one study found that in a large, broad spectrum of adult postinfectious ADEM, patients with relapses (31 %) showed a distinct clinical and neuroimaging profile compared to patients with MS. Therefore, it was emphasized that these patients were not to be confused with MS, even though 30 % of relapsing patients had more than one relapse, and thus qualified for the diagnosis of MS according to the IPMSSG criteria [17].
MS and ADEM found a significant association between encephalopathy and a pathological picture of ADEM (77 vs. 25 %, p \ 0.001), but noted 3 of 13 patients (23 %) with ADEM pathology did not present with encephalopathy [61]. It is uncertain whether the IPMSSG criteria are overly strict and lead to the under-diagnosis of ADEM. Moreover, postictal state, aphasia, visuospatial syndromes, or other causes of behavioral change may be mistaken for encephalopathy. The diagnosis of encephalopathy may be especially difficult in young pediatric patients [64]. In studies without comprehensive infectious diagnostic testing, infectious encephalitis remains a possible alternative diagnosis. Moreover, 27 % of neurologists in one survey questioned the definition or use of encephalopathy as inclusion criterion [65]. In the latest definitions, ‘‘polyfocal’’ replaced the term ‘‘polysymptomatic,’’ as polyfocal (or polyregional) assumes the involvement of multiple CNS sites, whereas a singular lesion can cause a polysymptomatic presentation. Yet, it has been suggested that although ADEM is a disseminated disease, some isolated brain stem lesions in children can retrospectively best be characterized as a localized form of ADEM [66].
Diagnostic clinical criteria
Application of IPMSSG criteria
In 2007, the IPMSSG defined the first diagnostic criteria for demyelinating diseases in children based on expert consensus. Other criteria have been published by the Brighton group [32]. The 2012 revisions of the IPMSSG criteria defined ADEM as a first polyfocal clinical demyelinating event with encephalopathy and abnormalities on MRI and does not match the criteria for dissemination in space and time for a diagnosis of MS [26]. Absence of encephalopathy or encephalopathy caused by fever leads to a diagnosis of CIS. Although absence of encephalopathy is traditionally seen as a predictor for a subsequent MSdefining event [21], one study found that encephalopathy was not a significant predictor in 50 children with an initial polyfocal demyelinating event [43]. A study that compared clinical presentation between patients with pathology of
Multiple studies found that in children, a subsequent MS diagnosis was more likely after CIS (*40 %) than after ADEM [67, 68]. Though, reported percentages of transition to MS after an initial ADEM diagnosis were 4/77 (5 %) [38], 4/47 (9 %) [68], and 3/16 (19 %) [69]. A study reported an ADEM-like onset in MS in 22 of 137 (16 %) children, and especially occurred in young children [39]. Criteria that necessitate encephalopathy have not been applied in adult patients, but a study found conversion to MS in 3 of 13 adults with encephalopathy and in 3 of 12 adults without encephalopathy at clinical onset [16]. Application of the IPMSSG criteria does not universally predict a monophasic disease. In addition, the under-identification of patients with a monophasic disease is a highly debated topic. Some patients with a monophasic disease
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Table 3 MRI criteria to predict a subsequent MS diagnosis after a first demyelinating event KIDMUSa
Barkhofb
Callenc
Verheyd
Sensitivity
Specificity
Sensitivity
Specificity
Sensitivity
Specificity
Sensitivity
Specificity
Mikaeloff et al. [55]
21
100
52
63
NR
NR
NR
NR
Neuteboom et al. [43]
49
96
60
92
NR
NR
NR
NR
Callen et al. [54]
29
100
NR
NR
81
95
NR
NR
Ketelslegers et al. [70]
11
100
61
57
75
95
NR
NR
Verhey et al. [53]
40
98
NR
NR
95
90
84
93
a
2 out of 2: (1) lesions perpendicular to long axis of corpus callosum, (2) the sole presence of well-defined lesions
b
3 out of 4: (1) C9 Lesions on T2-weighted images or 1 gadolinium enhancing lesion, (2) C3 periventricular lesions, (3) C1 juxtacortical lesion, (4) C1 infratentorial lesion c
2 out of 3: (1) absence of a diffuse bilateral lesion pattern, (2) presence of black holes, (3) C2 periventricular lesions
d
2 out of 2: (1) C1 T1-hypointense lesions, (2) C1 periventricular lesions
will likely have similar pathogenesis as those with the clinical phenotype of ADEM as proposed by the IPMSSG. Therefore, application of these criteria would lead to the study of only a subset of ADEM. Diagnostic MRI criteria Neuroimaging is not currently included in the proposed IPMSSG criteria [26]. Several others have proposed and/or investigated MRI criteria to predict progression to MS after a first demyelinating event (Table 3) [43, 53–55, 70]. Application of the Callen criteria, defined as two or more of (1) absence of a diffuse bilateral lesion pattern, (2) presence of black holes, (3) C2 periventricular lesions, is reported to have the highest sensitivity (75–95 %) for identifying those cases with an eventual diagnosis of MS after a first demyelinating attack [53, 54, 70]. In addition, a very high specificity between 90 and 95 % has been reported, [53, 54, 70] resulting in a positive prediction value of approximately 95 % [54]. However, comparison to the gold standard of tissue pathology has not been done to date. Application of the Verhey criteria, defined as the presence of both C1 T1-hypointense lesion(s) and C1 periventricular lesion(s), may be a promising alternative in predicting a subsequent MS diagnosis [53]. However, these criteria have not been thoroughly studied to date. Autoantibodies Myelin oligodendrocyte glycoprotein (MOG) may be important to the myelination of the CNS, by providing structural integrity to the myelin. Antibodies against MOG may play a role in demyelinating diseases, and may be more often present in ADEM than in MS [71]. One study attempted to establish prediction algorithms using autoantibodies to myelin peptides to distinguish ADEM from
relapsing remitting MS, but sensitivity and specificity never exceeded 90 [72]. Two studies detected high MOG IgG in serum in 40 and 44 % of 19 and 34 patients, respectively, with ADEM [73, 74]. High titers of MOG in the serum of some patients with CIS could reflect a similar pathogenesis as MOG IgG-positive ADEM patients. A recent study found that ADEM in children with MOG antibodies was associated with uniform, although not exclusive, MRI characteristics at onset and resolution of lesions and favorable clinical outcome at follow-up compared to children without MOG antibodies [75]. It has been proposed that the presence of MOG antibodies in childhood-onset ADEM may have prognostic significance, via the persistence and disappearance of antibody [76]. MOG IgG in serum may supplement the diagnostic testing of difficult ADEM cases. It may help to differentiate it from acute infectious encephalitis [77] and AQP4IgG-negative NMO cases [78]. The presence of MOG antibodies in a subset of patients with monophasic or multiphasic ADEM with concomitant, monophasic or recurrent, optic neuritis may represent a distinct clinical phenotype [79]. A recent study described antibodies against the N-Methyl-D-Aspartate receptor (NMDA-R) and voltagegated potassium channel in ADEM [80]. The presence of NMDA-R antibodies in ADEM has been described previously [81]. A large study of 691 cases with NMDA-R encephalitis identified 23 cases associated with demyelination of the CNS [82].
Implications for clinicians and future research ADEM, as a clinicopathological entity, has both core diagnostic features, such as histopathological changes, and typically recognized clinical features, such as antecedent infection. There are no absolute distinctive diagnostic
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criteria that separate it from other demyelinating diseases, most notably a first presentation of MS. This is in spite of the increased recognition of the entity, the advent of new diagnostic criteria, and the publication of several cohort studies in the past 15 years. The criteria that have been proposed by the IPMSSG have helped partially in differentiating between first demyelinating episodes of MS and ADEM. However, proscriptive application of the criteria will lead to the exclusion of an unknown proportion of patients with ADEM. Application of the IPMSSG has not yet been performed in adult-onset ADEM cases. It is possible that certain individuals have transiently altered immunity in the setting of some infections, while others have a more long-term, even lifelong, response to an initial trigger. Separating out host versus infectious factors in the diagnosis of ADEM is especially critical and little has been studied on ‘‘host’’ factors to date. It is likely that ADEM is not one single disease, but rather a syndromic presentation of several triggered pathways that lead to autoimmune demyelination in the central, and occasionally peripheral, nervous system. In a subset of cases, discovery of MOG antibody has provided optimism that ADEM may have a clinically useful biomarker in the near future. Although ADEM is rare, it has several public health implications to the wider community. Due to the association of vaccination with ADEM, even in isolated cases, the fear of ADEM may lead to unnecessary fear of routine, life-saving vaccinations. Thus, each ADEM case represents a need to fully understand the plausibility, temporality, and specificity of the relationship between a trigger and the demyelinating disease outcome. Our review synthesizes the available data on clinical cohorts of ADEM patients to date. This includes 12 cohort studies summarizing nine separate cohorts from seven separate geographic locations. Perhaps surprisingly, there are no detailed North American cohorts reported of more than 50 cases to date. Given the rarity of cases of ADEM in any one center, prospective studies and even retrospective analyses make the study of therapeutics in ADEM as difficult as diagnosis. The current standard of care is based on clinical tradition, anecdote, and retrospection (level IV) evidence. The most effective therapy for ADEM, and whether any therapy is warranted in the longer term, remains unclear. Taken together, the priorities for the study of ADEM must include validation of the diagnostic criteria, collaboration across centers, and the further study of the neuroimaging, CSF, and possibly autoimmune serological markers that have been reported to date. Further interest in long-term outcomes will be even more important as the number of DMTs for demyelinating diseases of the CNS rapidly grows.
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J Neurol (2015) 262:2013–2024 Acknowledgments We would like to thank Prof. Dr. E. T. HedleyWhyte, Department of Pathology, Massachusetts General Hospital, for reviewing and photographing the pathology images of patients with ADEM seen in Fig. 1. Conflicts of interest of interest.
The authors declare that they have no conflict
Appendix: Identification of cohorts Literature review PubMed was searched using the key term: ‘‘Acute Disseminated Encephalomyelitis’’. Results were limited to the English language. All titles that were identified during the final search that was conducted on December 1, 2014 were reviewed. Reference lists of related articles were reviewed in effort to identify additional studies. All cohorts that described more than 50 cases of ADEM were included. In case of overlap of published cohorts, the most recent cohort was selected. Cohorts that were not comprehensively described were excluded from the table, but mentioned elsewhere.
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REVIEW
Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome Diederik L. H. Koelman • Farrah J. Mateen
Received: 21 January 2015 / Revised: 6 February 2015 / Accepted: 8 February 2015 / Published online: 13 March 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory, demyelinating disorder of the CNS. Only in the past 15 years have larger groups of patients from several geographical areas been reported for comparisons across studies. In spite of the increased recognition of ADEM, the diagnosis of ADEM remains clinical, aided by neuroimaging confirmation, because of the lack of a biological marker. The diagnosis may be difficult, given that several diseases may present similar to ADEM. The controversial existence of multiphasic forms necessitates a continuous evaluation of the diagnosis by tracking subsequent events. Despite proposed consensus criteria, the diagnostic criteria employed to characterize ADEM range widely among the largest reported cohorts to date. This review comprehensively evaluates the current knowledge and controversies that surround ADEM, with special consideration of the distinction between ADEM and other demyelinating diseases such as multiple sclerosis. In addition, we present implications of the current knowledge of ADEM for both research and clinical practice.
D. L. H. Koelman F. J. Mateen (&) Department of Neurology, Massachusetts General Hospital, 165 Cambridge Street, #627, Boston 02114, MA, USA e-mail: [email protected] D. L. H. Koelman e-mail: [email protected] D. L. H. Koelman Academic Medical Center - University of Amsterdam, Amsterdam, The Netherlands F. J. Mateen Harvard Medical School, Boston, MA, USA
Keywords Acute disseminated encephalomyelitis Autoimmune diseases Encephalopathy Postinfectious
Introduction In 1724, Clifton [1, 2] likely first described the disease currently known as acute disseminated encephalomyelitis (ADEM) in his doctoral thesis on pox at the University of Leiden, The Netherlands. He noticed the occurrence of ‘‘severe headaches, inflammation of the eyes, deceptive and inconsistent impressions [hallucinations], disrupted separations [blurred vision], convulsions, jumping of the tendons [clonus], very great weakness and eventually death itself’’ [2]. After the first contemporary description of ADEM by Anton and Wohlwill [3] and Koprowski’s [4] hypothesis in 1962 that ADEM is an autoimmune disease, the general understanding and knowledge of ADEM has significantly increased because of new diagnostic modalities such as MRI. Several cohort studies have been published on ADEM, demonstrating new insights into this inflammatory demyelinating disorder of the CNS. Only in the past 15 years have larger groups of patients with ADEM been reported from several geographical areas. However, in spite of the increased recognition of ADEM, the diagnosis of ADEM remains clinical with neuroimaging confirmation and lacks a discrete biological marker. Several diseases may present similarly to ADEM at initial presentation, making diagnosis potentially difficult. In contrast to most other demyelinating diseases, ADEM was thought to be an exclusively monophasic disorder. The controversy of multiphasic ADEM only complicates this distinction. Because most ‘mimics’ of ADEM require different treatment, accurate diagnosis is especially important.
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Characteristics
‘‘microglial’’ and ‘‘postrabies’’ vaccine encephalomyelitis, have been used to describe ADEM. These different terms emphasize the localization and histology of ADEM. The different specific triggers of ADEM have been comprehensively reviewed elsewhere with unspecified upper respiratory tract infections being common [24]. Measles was one of the first etiologies described in 1790 by Lucas [2, 25], an English surgeon from Leeds. He described urinary and fecal retention and lower limb weakness after the disappearance of a measles rash with maximal neurological deficits within 2 days, followed by full recovery within a few weeks [2].
Epidemiology
Pathogenesis
ADEM is a rare inflammatory, demyelinating disorder of the CNS. ADEM may occur at any age, but is most common during childhood [5], with an incidence in children ranging from 0.07 to 0.64 per 100,000 persons/year [5–8]. The incidence in adults has not been reported. Table 1 summarizes cohorts comprising C50 patients with an initial diagnosis of ADEM [9–17]. Of the nine cohorts presented, five focus exclusively on pediatric age groups, two focus on adults, and two focus on all age groups. The percentage of male patients was 59 % in pediatric cohorts combined [9–13, 16] and 46 % in adult cohorts combined [14, 16, 17]. The incidence of ADEM has historically been very different between countries, as after smallpox vaccination in the 1920s [18]. The incidence may even vary within countries, such as between Glasgow and Edinburgh in 1942 [19]. In a populationbased study in California, the incidence of ADEM was higher in African-American than in white non-Hispanic children [20]. There is a variant of ADEM, known as acute hemorrhagic leukoencephalopathy (AHLE) that is extremely rare, for which the epidemiology is not known.
Koprowski based his autoimmune hypothesis on the similarities of ADEM with both experimental autoimmune encephalomyelitis (EAE) and postrabies vaccination encephalomyelitis. EAE is an animal model of human CNS demyelinating diseases, which can be induced by immunization with myelin proteins and peptides in rodents. Consequently, it has been suggested that microbial infections can cause ADEM by myelin-reactive T cell activation through molecular mimicry, provoking a CNS autoimmune response. Since many cases do not have a clear history of an infectious trigger, it is also posited that ADEM may be caused by activation of pre-existing myelin-reactive T cells through a more nonspecific inflammatory process. Although ADEM is currently mostly discussed within the spectrum of demyelinating diseases because of its similarities with MS at onset, the various descriptions for ADEM suggest that ADEM may not represent one final disease process.
This review focuses on the largest published cohorts of ADEM to date, their reported risk factors for ADEM, and the proposed clinical and MRI criteria to distinguish ADEM from its mimics, with special consideration of the subsequent diagnosis of multiple sclerosis (MS). The term ADEM in this article includes all forms described in the current literature, without distinguishing between different criteria, to comprehensively evaluate the available reports and controversies.
Preceding events Preceding infection or vaccination is reported in a variable number of cases. When combining infection and vaccination as a single risk factor, among cohorts that did not mandate an antecedent trigger, seven cohorts found a mean of 67 % of cases with either preceding vaccination or infection [10, 12–16]. Some studies even use it as an inclusion criterion [9, 11, 17]. A seasonal trend, with the most common occurrence in winter and spring, has been reported, possibly due to precipitation by an infection [21–23]. Vaccination as a trigger, although frequently reported in single cases, is most likely relevant in a small subpopulation of ADEM. A preceding vaccination is reported in 5–19 % in the largest cohorts to date [10, 12, 14–17]. Besides ‘‘postinfectious’’, ‘‘parainfectious’’, and ‘‘postvaccinal’’ encephalomyelitis, other terms, such as ‘‘perivenous’’,
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Clinical presentation ADEM presents most commonly with multifocal neurological deficits. A polysymptomatic presentation, defined as the occurrence of multiple symptoms, originating from different regions of the CNS, is often used as an inclusion criterion. In a study with a less strict inclusion criteria for ADEM (including lack of requisite abnormal brain MRI), 94 % of 176 adult patients had a polysymptomatic presentation [17]. The clinical presentation differs widely among the largest studies to date. Because differing inclusion criteria are used (Table 1), it is unclear whether differences seen between cohorts represent variations in disease patterns or non-parallel inclusion criteria for comparable reporting. Encephalopathy, often defined as altered consciousness (lethargy, stupor, coma) and/or altered behavior (irritability or confusion) as proposed by the International Pediatric MS Study Group (IPMSSG) [26], is one of the major ADEMdefining symptoms, but ranged widely in the largest cohorts from 46 to 73 % in pediatric cohorts [9–13, 16], and
52
Initial ADEM
0 (0)
Preceding vaccination
8 (15)
11 (21)
CN/brainstem
Meningismus
NR
NR
OCB
NR
Spinal cord
CSF, n (%) Pleocytosis
NR
4 (22)h
Brainstem/ cerebellar
Elevated protein
3 (17)
h
Deep gray matter
MRI abnormal
14 (78)
NR
Ataxia/cerebellar
MRI, n (%)
25 (48)
19 (37)
Headache or vomiting
9 (17)
20 (38)
Fever
Weakness/ pyramidal
38 (73)
Encephalopathy
Seizures
NRc
Polysymptomatic
Symptoms, n (%)
52 (62)
52 (100)b
Preceding infection
47 (52)
2 (4)
k
NR
NR
j
i
24 (28)
NRj
2 (17)
4 (33)h
NR
8 (67)
NR
22 (24)
24 (28)i
NR
NR
22 (26)
84 (100)b
36 (43)
37 (44)
42 (50)
34 (38) 65 (72)
29 (35)
NR
NR
41 (46)
90 (100)b
0 (0)
90 (100)b
90 (100)b
49 (54)
10 (2–16)
90
R
Idrissova et al. [11], Russia, 2003
64 (76)f
27 (32)
NR
58 (69)
84 (100)b
10 (12)
54 (64) 62 (74)
29 (56)
52 (100)b
Preceding event
5 (0–16)
84
P
Tenembaum et al. [10], Argentina, 2002
Male
Presentation, n (%) Age, years 7 (0–14) (range)
R
Type
Hung et al. [9], Taiwan, 2001
1 (2)
[50 %
[50 %
5 (10)
14 (27)h
16 (31)
h
52 (100)b
14 (27)
20 (39)
6 (12)
40 (77)
19 (37)
17 (33)
33 (63)
29 (56)
52 (100)b
4 (8)
13 (25)
17 (33)
38 (73)
6.1 (1–12)
52
P/R
Singhi et al. [12], India 2006
Table 1 Summary of published cohorts with ‡50 cases with an initial diagnosis of ADEM
20 (37)
d
9 (7)
49 (37)
70 (53)
18 (14)
83 (63)
76 (58)
132 (100)b
NR
34 (42)
7 (13)
13 (24)
25 (66)
27 (50)h
17 (31)
h
54 (100)b
NR
12 (22) 13 (24)
NR
26 (48)
3 (6)
NR
NR
NR
d
38 (70)
10 (19)
26 (48)
36 (67)
NR
26 (43)
32 (52)
18 (50)
11 (36)h
15 (48)
h
61 (100)b
12 (20)
NR
15 (25)
41 (67)
14 (23)
9 (15)
NR
33 (54)
e
61 (100)b
4 (7)
52 (85)
56 (92)
34 (56)
22 (1–65)
61
33 ([15)
P
60a
Panicker et al. [15], India, 2010
R
de Seze et al. [14], France, 2007
63 (48)g
NR
37 (28)
NR
NR
132 (100)
b
132 (100)b
NR
76 (58)
76 (58)
74 (56)
6 (\16)
132
R
Mikaeloff et al. [13], France, 2007
4 (7)
NR
81 (82)
24 (67)
60 (59)h
64 (63)
117 (100)b
26 (22)
49 (42)
56 (48)
86 (74)
27 (23)
50 (43)
52 (44)
76 (65)
117 (100)b
5 (5)
82 (72)
87 (74)
62 (53)
13.7 (0–82)
117
R
Ketelslegers et al. [16], Netherlands, 2011
44 (25)
NRj
40 (4–120)
146 (83)
NR
50 (28)
99 (56)
22 (13)
19 (11)
17 (10)
105 (60)
8 (4)
NR
48 (27)
39 (22)
163 (94)
14 (8)
162 (92)
176 (100)b
87 (49)
54 (18–80)
176
P
Marchioni et al. [17], Italy 2013
J Neurol (2015) 262:2013–2024 2015
123
123
24 (46)
0
1 (2)
0 4 (8)
8 (15)
37 (71)
Deaths
Relapses
Multiple relapses Neurological deficits
Cognitive deficits
Full recovery
75 (89)
3 (4)
0 9 (11)
8 (10)
0
80 (95)
79 (12–228)
Tenembaum et al. [10], Argentina, 2002
42 (47)
13 (14)
NR 4 (4)
11 (12)
0
NR
(12–60)
Idrissova et al. [11], Russia, 2003
27 (61)
6 (14)
1 (2) 11 (25)
4 (9)
0
43 (83)
(6–48)
Singhi et al. [12], India 2006
NR NR
87 (66)m NR
NR
0 NR
0
NR NR
9 (15)
25 (42)a
61 (100)
3 (1–12)
Panicker et al. [15], India, 2010
0
54 (100)
36 (12–120)
de Seze et al. [14], France, 2007
NR
11 (8) NR
24 (18)
0
81 (61)
65
Mikaeloff et al. [13], France, 2007
53 (50)m
NR
NR NR
20 (19)l
4 (3)
88 (75)
6 (2–169)
Ketelslegers et al. [16], Netherlands, 2011
100 (57)
NR
16 (9) NR
52 (31)
6 (3)
176 (100)
76 (24–170)
Marchioni et al. [17], Italy 2013
Inclusion or exclusion criteria
Panicker et al. reported impaired consciousness 33 (54) and behavioral disturbances 14 (23), separately
Mikaeloff et al. reported 12 patients had optic neuritis; de Seze et al. reported 7 (13) patients with optic neuritis, in addition to brainstem symptoms
Tenembaum et al. reported hemiparesis in 76 %
Tenembaum et al. reported no intrathecal OCBs
Tenembaum et al. reported signs of inflammation in CSF in 28 % as either pleocytosis or elevated protein Mean values of CSF were given: Idrissova et al. 102 cells per mL, 72 mg protein per L, Marchioni et al. 90 mg protein per L
m
Full recovery was reported after the initial event
Ketelslegers et al. reported relapses in 20 patients, seven experienced another ADEM event, seven developed ON without new other symptoms, and six experienced at least two demyelinating events and new brain MRI lesions without normalization of MRI and were diagnosed as MS
l
k
j
i
Lesions were scored separately; the higher of the two is depicted in the table: thalamus/basal ganglion: Hung et al. 3 (17)/3 (17); Singhi et al. 16 (31)/9 (17); de Seze et al. NR/17 (31); Panicker et al. 15 (48)/7 (23), brainstem/cerebellar: Hung et al. 4 (22)/2 (11); Idrissova et al. NR/4 (33); Singhi et al. 9 (17)/14 (27); de Seze et al. 27 (50)/25 (46); Panicker et al. 8 (26)/11 (36); Ketelslegers et al. 60 (59)/42 (41)
h
g
f
e
d de Seze et al. reported atypical presentation of MS, specified as consciousness alteration, hypersomnia, aphasia, hemiplegia, paraplegia, tetraplegia, seizure, vomiting, bilateral ON, or confusion, in 34 (63) of the patients
Hung et al. classified the cohort as either postinfectious encephalitis with simple, focal, localized symptomatology and/or less than three lesions in various parts of the brain on neuroimaging (n = 38) and ADEM with multifocal presentation and more than three lesions (n = 14)
c
b
de Seze et al. excluded six cases of multiphasic ADEM, specified as recurrent ADEM with recurrence of old symptoms, from the analysis. Clinical, MRI and CSF data are based on 54 patients. MS was diagnosed in 19 (32) patients if a second event occurred more than a month after the initial event with new symptoms in new clinical territory
a
R retrospective, P prospective, ADEM acute disseminated encephalomyelitis, CN cranial nerve, OCB oligoclonal bands, NR not reported, ON optic neuritis, MS multiple sclerosis
[18
Steroids treatment
Hung et al. [9], Taiwan, 2001
Months, (range)
Follow-up, n (%)
Table 1 continued
2016 J Neurol (2015) 262:2013–2024
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22–52 % in adult cohorts [14, 16, 17]. The most commonly reported neurological deficit is weakness of the lower and/or upper extremities (17–77 %). Other symptoms include ataxia (10–52 %), cranial nerve palsies (11–48 %), seizures (4–48 %), fever (27–63 %), headache and/or vomiting (15–37 %), and meningeal signs (13–43 %) [9–17]. Peripheral nervous system involvement has been reported [10, 17].
2017
was reported in 83 % of patients in a cohort of 176 adults that all underwent spinal cord MRI [17]. Gadolinium enhancement of lesions is variable [27, 28]. In some cases, delay in the appearance of MRI lesions for up to 8 weeks has been reported [29] and may herald a prolonged clinical course and lack of response to glucocorticoid therapy [30]. CSF features
MRI findings The most common MRI finding is the presence of multiple bilateral T2-enhancing supratentorial white matter lesions. Accompanying lesions are often present in the thalamus and/or basal ganglia (17–63 %) and the brainstem and/or cerebellum (22–63 %) [9–17]. Spinal cord involvement
Fig. 1 Pathology in acute disseminated encephalomyelitis (a, b) and in acute hemorrhagic leukoencephalitis (c, d). Luxol fast blue, hematoxylin and eosin stains of a perivascular demyelination typical of acute disseminated encephalomyelitis in the cuneate fasciculus at C1, with moderate inflammatory reaction consisting of macrophages, T cells, and microglia (original magnification 9100), b the normal aspect of perivascular myelin (white arrow), and an area of
Analysis of the CSF is initially necessary to exclude acute CNS infection, because of the acute therapeutic implications of identifying an infection [31]. CSF usually shows inflammation (24–82 %) with pleocytosis and/or elevated protein; however, CSF findings are reported at variable time points within the clinical course of ADEM [10, 12–17].
perivascular demyelination (black arrow) (original magnification 9200), c vascular fibrinoid necrosis, microhemorrhages, marked acute inflammatory response and perivascular demyelination in the basilar part of the pons consistent with acute hemorrhagic leukoencephalitis (original magnification 9100), and d Fibrinoid necrosis of a vessel wall (original magnification 9200) (arrow)
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Oligoclonal bands (OCBs) are typically absent. However, in one study, OCBs were reported in 6 of 21 tested patients (29 %) [21]. Pathology Cerebral tissue is often not available for the diagnosis of ADEM, but histopathology of the brain is considered to be the gold standard for diagnosis [32]. Brain and spinal cord may grossly appear normal or show congestion and swelling. Microscopic findings in the brain or spinal cord usually include the characteristic perivenous sleeves of demyelination with mild perivascular inflammation (Fig. 1a, b). AHLE has perivascular demyelination, similar to ADEM, but additionally has acute inflammation, vascular fibrinoid necrosis and petechial hemorrhages (Fig. 1c, d). Treatment There are no randomized studies for the treatment of an initial clinical event of ADEM. Little is reported about the clinical outcome of ADEM without treatment. First-line treatment usually consists of IV methylprednisolone, generally 3–5 days of 20–30 mg/kg in children with a maximum dose of 1 g/day for both adults and children [33]. An oral steroid taper for 4–6 weeks commonly follows the use of IV steroids. IV immunoglobulin is often considered a secondary treatment for patients that do not respond to the initial IV steroid dose. Standard treatment for adults and pediatrics consists of 2 g/kg divided over 2–5 days [33]. A second dose of IV methylprednisolone may also be considered. Plasmapheresis (PLEX), with 3–7 exchanges, is one of the ‘‘last resort’’ treatments for ADEM patients with an unresponsive, fulminant disease, but should be considered early [31, 33]. One study showed improvement in function after PLEX in 4 of 10 patients [34]. Craniotomy in patients with intracranial swelling, mass effect and/or midline shift can be a life-saving treatment [33]. The well-known benefit of early treatment initiation in patients with clinically isolated syndrome (CIS) may be illustrative, but early initiation of disease-modifying therapy (DMTs) in a group with lower risk of progression will lead to unnecessary lifelong treatment in some patients. Yet, specific subpopulations with an initial ADEM presentation with higher rates of transition may be suitable for the same therapeutic management as patients with CIS. Clinical course and outcome The clinical course is characterized by rapid, progressive evolvement of symptoms with maximization of deficits in a couple of days, with reported means of 2–8 days [10, 17, 35]. One study estimated that approximately 25 % of
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children are admitted to the PICU after a first presentation of ADEM [36]. MRI lesions gradually resolve and clinical deficits become less prominent with time. The mortality is low, especially in childhood, with a combined prevalence in the largest cohorts of 1 of 525 (0.2 %) children and 18 of 293 (6.1 %) adults after an initial ADEM diagnosis [9–17]. However, ADEM is reported from several locations worldwide, including regions where supportive care is more limited and the mortality may be higher.
Differential diagnosis Diagnostic difficulties The diagnosis of MS is currently based on dissemination in time and space according to the McDonald 2010 criteria [37], but the initial presentation of MS may be indistinct from ADEM. Since the diagnosis of ADEM is one of exclusion and suffers from the lack of a biological marker, accurate diagnosis solely based on the first clinical demyelinating event is very limited. Distinct epidemiology Fortunately, several factors may help in distinguishing ADEM from MS. ADEM does not have a notable female predominance, in contrast to MS [5, 38]. Children less than 10 years of age are more likely to have ADEM than MS at the time of an initial demyelinating event [5, 39]. However, onset of MS has been reported at 1 year of age [40], limiting the usefulness of age as a discriminating factor. While a history of antecedent infection or vaccination is indicative of ADEM, an increased frequency of antecedent events, though to a lesser extent, has been reported in patients with a first presentation of MS [41]. Distinct presentation Clinical presentations of encephalopathy [21, 42], seizures [21, 43], fever [21, 42, 43], headache [21, 43], bilateral optic neuritis (ON) [21, 44], brainstem symptoms [42], and meningeal signs [21, 42] are reported to be statistically significantly more likely with a diagnosis of ADEM than MS. In addition, one study showed, among 176 adults with postinfectious ADEM, concomitant peripheral nervous system involvement was significantly associated with a subsequent relapse (42 vs. 25 %, p = 0.011). A study found that in 117 children with a demyelinating disease of the CNS, seizures almost exclusively occurred in patients with a polysymptomatic monophasic disease (28 vs. 3 %, p = 0.02) [43]. ON in ADEM is most commonly bilateral, while bilateral ON is less suggestive of MS [21, 44].
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Fig. 2 Neuroimaging of two patients with a first demyelinating event diagnosed as ADEM. a Axial FLAIR MRI of a 53-year-old male at symptom onset. Patient presented with weakness, nausea/vomiting, and confusion after an unspecified infection. Diagnosis after 5 years of follow-up: monophasic acute disseminated encephalomyelitis, b Axial FLAIR MRI of a 48-year-old female at symptom onset. Patient presented with gait abnormality, nausea/ vomiting and confusion. Change of diagnosis after 1 year of follow-up: multiple sclerosis
Several studies have identified anti-aquaporin-4 (AQP4) antibodies, the biomarker of neuromyelitis optica (NMO), in a subset of ADEM patients [45–50]. Neuromyelitis optica (NMO) is well recognized as a cause of a bilateral ON and may be an alternative diagnosis in many cohorts, possibly limiting the usability of bilateral ON as distinctive factor. It is not clear whether AQP4 antibody seropositive ADEM is a subset of ADEM, NMO spectrum disorder, or a separate entity. The etiologic role of the AQP4 antibody in the cases diagnosed clinically as ADEM is similarly unresolved. Distinct neuroimaging Neuroimaging of ADEM and MS at first presentation can be very similar (Fig. 2). MRI findings reported to be significantly more present in ADEM than in MS include deep gray matter lesions [14, 51–53], cortical gray matter involvement [14, 51], diffuse bilateral lesion pattern [54], and a high lesion load ([50 % abnormal brain (lesions) versus normal brain) [55]. By contrast, findings associated more often with MS than ADEM include: periventricular white matter lesions [21, 43, 51, 53, 54], juxtacortical lesions [13, 43], corpus callosum lesions (perpendicular to the long axis) [14, 21, 51–53, 55], sole presence of welldefined lesions [21, 43, 55], high number of T2-hyperintense lesions [43, 55], and presence of T1-black holes [53, 54]. A recent study comparing deep gray matter lesions between ADEM and MS found that, unlike in children, thalamic involvement in adults is not more specific for ADEM than for MS [56]. Moreover, they found that in adults, lesions in the putamen are more suggestive of ADEM and lesions in the hypothalamus are more suggestive of NMO. Brainstem lesions in ADEM are more often located in the midbrain and are more often bilateral and
symmetrical [57]. Incomplete resolution or persistence of lesions is associated with a subsequent diagnosis of MS [21]. The use of advanced imaging such as diffusion tensor imaging to differentiate ADEM has been considered [58], but no clinical recommendations can be made on its use at the present time. Distinct CSF findings Although CSF does not permit reliable differentiation, CSF more frequently shows OCBs in patients with MS than ADEM [14, 59]. CSF pleocytosis and elevated protein are thought to be more suggestive of ADEM, but can be seen in MS patients as well, especially in pediatric MS [60]. Brain biopsy Pathologically, confluent demyelination, which is typical in MS, is distinct from the perivenous sleeves of demyelination, the hallmark of ADEM [61]. The performance of brain biopsy for histopathology must be considered carefully given the morbidity that may be associated with the biopsy procedure. The major constraint of all of these distinguishing factors is the lack of specificity and the risk of not providing a DMT in patients who evolve to MS.
Controversies in current practice Re-emergence of symptoms Historically, ADEM was thought to be an exclusively monophasic disease for which any re-emergence of symptoms was not possible. In the past decades, a
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Table 2 International pediatric study group definitions for re-emergence of symptoms after an initial ADEM diagnosis [26] Diagnosis
2007
2012
Recurrent 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
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 re-emergence of prior clinical and MRI findings. Timing in relation to steroids is no longer pertinent
Multiple sclerosis
Multiple clinical episodes of CNS demyelination separated in time and space that is not consistent with the clinical features of ADEM
New non-encephalopathic clinical event 3 months or more after the initial event with new lesions on brain MRI consistent with MS
multiphasic form of ADEM has been recognized and has since been reported in numerous case reports [62]. The controversy of multiphasic ADEM has been highlighted in the different cohorts published in the last 15 years [9–17]. Studies have either excluded recurrent forms from analysis [14], classified all relapses as MS [63], did not differentiate relapses [12, 13, 17], differentiated multiphasic ADEM from MS based on clinical presentation or follow-up [9– 11], or classified relapses according to, or similar as, the IPMSSG criteria (Table 2) [16, 35, 43]. Hence, percentages of multiphasic forms have differed widely among the largest cohorts to date. Tracking subsequent events and reevaluation of the initial diagnosis is necessary to discriminate between ADEM, multiphasic ADEM, and MS. Nonetheless, one study found that in a large, broad spectrum of adult postinfectious ADEM, patients with relapses (31 %) showed a distinct clinical and neuroimaging profile compared to patients with MS. Therefore, it was emphasized that these patients were not to be confused with MS, even though 30 % of relapsing patients had more than one relapse, and thus qualified for the diagnosis of MS according to the IPMSSG criteria [17].
MS and ADEM found a significant association between encephalopathy and a pathological picture of ADEM (77 vs. 25 %, p \ 0.001), but noted 3 of 13 patients (23 %) with ADEM pathology did not present with encephalopathy [61]. It is uncertain whether the IPMSSG criteria are overly strict and lead to the under-diagnosis of ADEM. Moreover, postictal state, aphasia, visuospatial syndromes, or other causes of behavioral change may be mistaken for encephalopathy. The diagnosis of encephalopathy may be especially difficult in young pediatric patients [64]. In studies without comprehensive infectious diagnostic testing, infectious encephalitis remains a possible alternative diagnosis. Moreover, 27 % of neurologists in one survey questioned the definition or use of encephalopathy as inclusion criterion [65]. In the latest definitions, ‘‘polyfocal’’ replaced the term ‘‘polysymptomatic,’’ as polyfocal (or polyregional) assumes the involvement of multiple CNS sites, whereas a singular lesion can cause a polysymptomatic presentation. Yet, it has been suggested that although ADEM is a disseminated disease, some isolated brain stem lesions in children can retrospectively best be characterized as a localized form of ADEM [66].
Diagnostic clinical criteria
Application of IPMSSG criteria
In 2007, the IPMSSG defined the first diagnostic criteria for demyelinating diseases in children based on expert consensus. Other criteria have been published by the Brighton group [32]. The 2012 revisions of the IPMSSG criteria defined ADEM as a first polyfocal clinical demyelinating event with encephalopathy and abnormalities on MRI and does not match the criteria for dissemination in space and time for a diagnosis of MS [26]. Absence of encephalopathy or encephalopathy caused by fever leads to a diagnosis of CIS. Although absence of encephalopathy is traditionally seen as a predictor for a subsequent MSdefining event [21], one study found that encephalopathy was not a significant predictor in 50 children with an initial polyfocal demyelinating event [43]. A study that compared clinical presentation between patients with pathology of
Multiple studies found that in children, a subsequent MS diagnosis was more likely after CIS (*40 %) than after ADEM [67, 68]. Though, reported percentages of transition to MS after an initial ADEM diagnosis were 4/77 (5 %) [38], 4/47 (9 %) [68], and 3/16 (19 %) [69]. A study reported an ADEM-like onset in MS in 22 of 137 (16 %) children, and especially occurred in young children [39]. Criteria that necessitate encephalopathy have not been applied in adult patients, but a study found conversion to MS in 3 of 13 adults with encephalopathy and in 3 of 12 adults without encephalopathy at clinical onset [16]. Application of the IPMSSG criteria does not universally predict a monophasic disease. In addition, the under-identification of patients with a monophasic disease is a highly debated topic. Some patients with a monophasic disease
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2021
Table 3 MRI criteria to predict a subsequent MS diagnosis after a first demyelinating event KIDMUSa
Barkhofb
Callenc
Verheyd
Sensitivity
Specificity
Sensitivity
Specificity
Sensitivity
Specificity
Sensitivity
Specificity
Mikaeloff et al. [55]
21
100
52
63
NR
NR
NR
NR
Neuteboom et al. [43]
49
96
60
92
NR
NR
NR
NR
Callen et al. [54]
29
100
NR
NR
81
95
NR
NR
Ketelslegers et al. [70]
11
100
61
57
75
95
NR
NR
Verhey et al. [53]
40
98
NR
NR
95
90
84
93
a
2 out of 2: (1) lesions perpendicular to long axis of corpus callosum, (2) the sole presence of well-defined lesions
b
3 out of 4: (1) C9 Lesions on T2-weighted images or 1 gadolinium enhancing lesion, (2) C3 periventricular lesions, (3) C1 juxtacortical lesion, (4) C1 infratentorial lesion c
2 out of 3: (1) absence of a diffuse bilateral lesion pattern, (2) presence of black holes, (3) C2 periventricular lesions
d
2 out of 2: (1) C1 T1-hypointense lesions, (2) C1 periventricular lesions
will likely have similar pathogenesis as those with the clinical phenotype of ADEM as proposed by the IPMSSG. Therefore, application of these criteria would lead to the study of only a subset of ADEM. Diagnostic MRI criteria Neuroimaging is not currently included in the proposed IPMSSG criteria [26]. Several others have proposed and/or investigated MRI criteria to predict progression to MS after a first demyelinating event (Table 3) [43, 53–55, 70]. Application of the Callen criteria, defined as two or more of (1) absence of a diffuse bilateral lesion pattern, (2) presence of black holes, (3) C2 periventricular lesions, is reported to have the highest sensitivity (75–95 %) for identifying those cases with an eventual diagnosis of MS after a first demyelinating attack [53, 54, 70]. In addition, a very high specificity between 90 and 95 % has been reported, [53, 54, 70] resulting in a positive prediction value of approximately 95 % [54]. However, comparison to the gold standard of tissue pathology has not been done to date. Application of the Verhey criteria, defined as the presence of both C1 T1-hypointense lesion(s) and C1 periventricular lesion(s), may be a promising alternative in predicting a subsequent MS diagnosis [53]. However, these criteria have not been thoroughly studied to date. Autoantibodies Myelin oligodendrocyte glycoprotein (MOG) may be important to the myelination of the CNS, by providing structural integrity to the myelin. Antibodies against MOG may play a role in demyelinating diseases, and may be more often present in ADEM than in MS [71]. One study attempted to establish prediction algorithms using autoantibodies to myelin peptides to distinguish ADEM from
relapsing remitting MS, but sensitivity and specificity never exceeded 90 [72]. Two studies detected high MOG IgG in serum in 40 and 44 % of 19 and 34 patients, respectively, with ADEM [73, 74]. High titers of MOG in the serum of some patients with CIS could reflect a similar pathogenesis as MOG IgG-positive ADEM patients. A recent study found that ADEM in children with MOG antibodies was associated with uniform, although not exclusive, MRI characteristics at onset and resolution of lesions and favorable clinical outcome at follow-up compared to children without MOG antibodies [75]. It has been proposed that the presence of MOG antibodies in childhood-onset ADEM may have prognostic significance, via the persistence and disappearance of antibody [76]. MOG IgG in serum may supplement the diagnostic testing of difficult ADEM cases. It may help to differentiate it from acute infectious encephalitis [77] and AQP4IgG-negative NMO cases [78]. The presence of MOG antibodies in a subset of patients with monophasic or multiphasic ADEM with concomitant, monophasic or recurrent, optic neuritis may represent a distinct clinical phenotype [79]. A recent study described antibodies against the N-Methyl-D-Aspartate receptor (NMDA-R) and voltagegated potassium channel in ADEM [80]. The presence of NMDA-R antibodies in ADEM has been described previously [81]. A large study of 691 cases with NMDA-R encephalitis identified 23 cases associated with demyelination of the CNS [82].
Implications for clinicians and future research ADEM, as a clinicopathological entity, has both core diagnostic features, such as histopathological changes, and typically recognized clinical features, such as antecedent infection. There are no absolute distinctive diagnostic
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criteria that separate it from other demyelinating diseases, most notably a first presentation of MS. This is in spite of the increased recognition of the entity, the advent of new diagnostic criteria, and the publication of several cohort studies in the past 15 years. The criteria that have been proposed by the IPMSSG have helped partially in differentiating between first demyelinating episodes of MS and ADEM. However, proscriptive application of the criteria will lead to the exclusion of an unknown proportion of patients with ADEM. Application of the IPMSSG has not yet been performed in adult-onset ADEM cases. It is possible that certain individuals have transiently altered immunity in the setting of some infections, while others have a more long-term, even lifelong, response to an initial trigger. Separating out host versus infectious factors in the diagnosis of ADEM is especially critical and little has been studied on ‘‘host’’ factors to date. It is likely that ADEM is not one single disease, but rather a syndromic presentation of several triggered pathways that lead to autoimmune demyelination in the central, and occasionally peripheral, nervous system. In a subset of cases, discovery of MOG antibody has provided optimism that ADEM may have a clinically useful biomarker in the near future. Although ADEM is rare, it has several public health implications to the wider community. Due to the association of vaccination with ADEM, even in isolated cases, the fear of ADEM may lead to unnecessary fear of routine, life-saving vaccinations. Thus, each ADEM case represents a need to fully understand the plausibility, temporality, and specificity of the relationship between a trigger and the demyelinating disease outcome. Our review synthesizes the available data on clinical cohorts of ADEM patients to date. This includes 12 cohort studies summarizing nine separate cohorts from seven separate geographic locations. Perhaps surprisingly, there are no detailed North American cohorts reported of more than 50 cases to date. Given the rarity of cases of ADEM in any one center, prospective studies and even retrospective analyses make the study of therapeutics in ADEM as difficult as diagnosis. The current standard of care is based on clinical tradition, anecdote, and retrospection (level IV) evidence. The most effective therapy for ADEM, and whether any therapy is warranted in the longer term, remains unclear. Taken together, the priorities for the study of ADEM must include validation of the diagnostic criteria, collaboration across centers, and the further study of the neuroimaging, CSF, and possibly autoimmune serological markers that have been reported to date. Further interest in long-term outcomes will be even more important as the number of DMTs for demyelinating diseases of the CNS rapidly grows.
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J Neurol (2015) 262:2013–2024 Acknowledgments We would like to thank Prof. Dr. E. T. HedleyWhyte, Department of Pathology, Massachusetts General Hospital, for reviewing and photographing the pathology images of patients with ADEM seen in Fig. 1. Conflicts of interest of interest.
The authors declare that they have no conflict
Appendix: Identification of cohorts Literature review PubMed was searched using the key term: ‘‘Acute Disseminated Encephalomyelitis’’. Results were limited to the English language. All titles that were identified during the final search that was conducted on December 1, 2014 were reviewed. Reference lists of related articles were reviewed in effort to identify additional studies. All cohorts that described more than 50 cases of ADEM were included. In case of overlap of published cohorts, the most recent cohort was selected. Cohorts that were not comprehensively described were excluded from the table, but mentioned elsewhere.
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