Demyelination Lesion Spine Neuroradiology

biomedicines
Review
Spinal Cord Involvement in MS and Other
Demyelinating Diseases
Mariano Marrodan , María I. Gaitán and Jorge Correale *
Neurology Department, Fleni, C1428AQK Buenos Aires, Argentina; [email protected] (M.M.);
[email protected] (M.I.G.)
* Correspondence: [email protected] or [email protected]; Tel.: +54-11-5777-3200 (ext. 2704/2456)

Received: 29 April 2020; Accepted: 20 May 2020; Published: 22 May 2020
Abstract: Diagnostic accuracy is poor in demyelinating myelopathies, and therefore a challenge

for neurologists in daily practice, mainly because of the multiple underlying pathophysiologic
mechanisms involved in each subtype. A systematic diagnostic approach combining data from the
clinical setting and presentation with magnetic resonance imaging (MRI) lesion patterns, cerebrospinal
fluid (CSF) findings, and autoantibody markers can help to better distinguish between subtypes.
In this review, we describe spinal cord involvement, and summarize clinical findings, MRI and
diagnostic characteristics, as well as treatment options and prognostic implications in different
demyelinating disorders including: multiple sclerosis (MS), neuromyelitis optica spectrum disorder,
acute disseminated encephalomyelitis, anti-myelin oligodendrocyte glycoprotein antibody-associated
disease, and glial fibrillary acidic protein IgG-associated disease. Thorough understanding of
individual case etiology is crucial, not only to provide valuable prognostic information on whether
the disorder is likely to relapse, but also to make therapeutic decision-making easier and reduce
treatment failures which may lead to new relapses and long-term disability. Identifying patients
with monophasic disease who may only require acute management, symptomatic treatment,
and subsequent rehabilitation, rather than immunosuppression, is also important.
Keywords: myelitis; spinal cord; multiple sclerosis; neuromyelitis optica; acute disseminated
encephalomyelitis; myelin oligodendrocyte glycoprotein; glial fibrillary acidic protein
1. Introduction
Diagnostic accuracy in myelopathies is poor and therefore a challenge for neurologists in daily
practice, mainly due to the multiple underlying pathophysiologic mechanisms observed in this group of
disorders. In an initial approach, temporal profile (time to symptom nadir) contributes to differentiate
vascular or traumatic causes from those of metabolic, neoplastic, and infectious or inflammatory etiology.
To further assist in the identification of patients with acute vascular myelopathies for whom specific
treatment strategies may be indicated, patients whose symptoms reach maximal severity in <4 h from
onset are currently presumed to have an ischemic pathology unless proven otherwise [1]. By contrast,
inflammatory processes affecting the spinal cord produce symptoms in a subacute manner, typically
over hours or days. However, despite extensive patient work-up, a significant number of myelopathy
cases are ultimately considered idiopathic [2]. Unfortunately, the term inflammatory myelitis is still
applied to a complex and heterogeneous subgroup of post-infectious, rheumatologic, granulomatous,
paraneoplastic, and demyelinating diseases, commonly affecting the spinal cord in which substantial
overlap in clinical and imaging findings subsists. Identifying relapsing forms of disease has prognostic
implications and can guide preventive treatment. Failure to indicate appropriate treatments may
lead to new relapses and long-term disability. In contrast, patients in whom monophasic disease is
suspected may only require acute management, symptomatic treatment, and subsequent rehabilitation
Biomedicines 2020, 8, 130; doi:10.3390/biomedicines8050130 www.mdpi.com/journal/biomedicines

Biomedicines 2020, 8, 130 2 of 25
rather than immunosuppression. In the case of demyelinating disorders, although multiple sclerosis
(MS) is the main cause of inflammatory myelitis, other important differential diagnoses need to be
ruled out to select the best treatment strategy in individual patients [3,4]. Thorough understanding
of individual case etiology is therefore crucial, not only for correct treatment, but also to determine
patient outcome.
In this review, we describe the epidemiologic characteristics, pathophysiology, clinical and
(magnetic resonance imaging) MRI findings, treatment options and prognostic implications in MS and
other demyelinating disorders including: neuromyelitis optica spectrum disorder (NMOSD), acute
disseminated encephalomyelitis (ADEM), anti-myelin oligodendrocyte glycoprotein (MOG)-antibodies
(ab) associated disease, and glial fibrillary acidic protein (GFAP)-IgG associated disease, to provide
guidance in the diagnosis of these conditions.
A Pubmed search was conducted for articles published between 2000 and 2020, that included
the terms: “acute disseminated encephalomyelitis; “demyelinating diseases”; “glial fibrillary acidic
protein”; “multiple sclerosis”; “myelin oligodendrocyte glycoprotein”; “myelitis”; “neuromyelitis
optica”; and “spinal cord diseases”. Only those originally in English were considered. Earlier
publications were identified from references cited in the articles reviewed.
2. Multiple Sclerosis
MS is a chronic inflammatory disease of the CNS leading to demyelination, neurodegeneration,
and gliosis. It is by far the most common demyelinating disease, affecting over 2 million people
worldwide [5]. Although its etiology remains elusive, environmental factors and susceptibility
genes are now known to be involved in the pathogenesis [6]. Results from immunological, genetic,
and histopathology studies of patients with MS support the concept that autoimmunity plays a major
role in the disease [7]. In the majority of cases, the disease follows a relapsing remitting course (RRMS)
from onset, which may later convert into a secondary progressive form (SPMS). Less often, patients
show continued progression from disease debut (primary progressive MS, PPMS) [8].
Spinal cord abnormalities are common in MS and include a variety of pathological processes,
such as demyelination, neuroaxonal loss and gliosis. Ultimately these result in motor weakness with
accompanying difficulties in deambulation, spasticity, sensory disturbances, as well as bladder and
bowel dysfunction [9]. Relapsing remitting MS can cause acute myelitis presenting with sensory
loss, gait impairment, and incoordination, generally worsening over days to weeks, followed by
stabilization or recovery [10]. During progressive phases of the disease however, especially in PPMS,
slowly increasing or stuttering gait impairment due to demyelinating myelopathy is the most frequent
presentation [11]. Once gait impairment has developed, cumulative disability increase will depend on
patient age, clinical, and radiological disease activity and degree of spinal cord atrophy [12–15].
Histopathology findings in the spinal cord are characterized by significant decrease in axonal
density in normal-appearing white matter (NAWM); perivascular T-cell infiltrates are rare, but robust,
and diffuse inflammation is observed both in normal-appearing parenchyma and particularly in the
meninges. Extent of diffuse axonal loss in NAWM correlates with both MHC class II+ microglia cell
density in NAWM, and significant increase in T cell density in the meninges. Interestingly, close
interaction has been observed between T cells and MHC class II+ macrophages in spinal cord meninges
from MS patients, suggesting the meninges may form an immunological niche in which T lymphocytes
become activated and proliferate in response to antigen presentation [16]. In support of this concept,
similar findings have previously been described in experimental autoimmune encephalomyelitis [17],
raising the possibility that activated meningeal T cells, through release of soluble factors such as IFN-γ,
could instruct parenchymal macrophages/microglia to engage in neurotoxic activation programs [18].
Although spinal cord involvement has been difficult both to characterize and to quantify because
current clinical and MRI parameters lack sensitivity and specificity [19], the spinal cord was one of
four anatomical locations incorporated in a revision to McDonald diagnostic criteria for MS in 2017,
to document spatial dissemination in patients presenting clinical isolated syndrome (CIS) suggestive of
MS. Likewise, new or gadolinium-enhancing spinal cord lesions can be used to document chronological
progression [20].
Poor correlation between spinal cord injury load and clinical disability may be due to several
different factors. Spinal cord MRI is more challenging than brain imaging in patients with MS. The spine
is extremely thin and commonly subjected to ghosting artifacts (due to breathing, swallowing, and/or
pulsation of blood and cerebrospinal fluid (CSF)) [21]. The amount of bone and fat may also produce
significant artifacts, greater than those observed in brain imaging. Conventional, sagittal proton
density (PD) and T2-weighted scans, with spatial resolution of 3 × 1 × 1 mm, should be considered
the reference standard to detect MS spinal cord lesions [22,23]. Short-tau inversion recovery (STIR)
sequences seem to be more sensitive to lesion detection than T2-weighted sequences and may be
Biomedicines 2020, 8, x FOR PEER REVIEW
used to substitute PD sequences [24]. Contrast-enhanced T1-weighted images are recommended5 of if 25
T2
lesions are detected.
IVMPS treatment, but also lower risk deterioration 3 months after discharge [71,72]. For long-term
Conventional spine MRI has low sensitivity and specificity in relation to the pathological
treatment of MS, the last 2 decades have seen the development of numerous drugs aimed at
changes observed in MS [25]. Use of sagittal sections alone may underestimate lesion numbers [25].
correcting the different pathogenic mechanisms proposed in multiple sclerosis, most of which have
Axial imaging may detect more lesions than sagittal imaging [26], especially smaller ones in the spinal
been compounds targeting immune system dysfunction. Several clinical trials are currently ongoing,
cord periphery [27] and 2D or 3D T2-weighted sequences should be included in MRI protocols [21].
some using neuroprotective therapies to halt progression, others aimed at reversing neurological
Axial multiple-echo recombined gradient echo (MERGE) seems to provide greater sensitivity for cord
disability, at least in part, by repairing damaged brain and spinal cord tissue. Discussion of
lesion detection and may represent a good alternative [28]. Ultimately, combined use of sagittal and
particular disease-modifying therapies for MS is beyond the scope of this manuscript, however,
axial images
several can facilitate
comprehensive identification
reviews and location
on the subject of spinal
have recently lesions
been (Figure[73–76].
published 1A–F) [26].
Figure1.1.Multiple
Figure Multiple Sclerosis
Sclerosis myelitis.
myelitis. (A–F)
(A–F) 32-year-old
32-year-old woman
woman diagnosed
diagnosed with
with relapsing
relapsing remitting
remitting
course (RRMS) 2 years earlier, EDSS 0. (A,B) Sagittal short-tau inversion
course (RRMS) 2 years earlier, EDSS 0. (A,B) Sagittal short-tau inversion recovery (STIR) recovery (STIR) showing
showing small,
small,chronic,
focal, focal, peripheral
chronic, peripheral
lesions. (C) lesions.
Sagittal (C)post-contrast
Sagittal post-contrast
T1 weighted, T1absence
weighted, absence of
of enhancement,
enhancement,
T2 T2 lesions(D–F)
lesions are isointense. are isointense. (D–F) axial recombined
axial T2 multiple-echo T2 multiple-echo recombined
gradient gradient
echo (MERGE). (D)echo
right
(MERGE). (D) right paramedian posterior lesion corresponds to lesion framed by a box
paramedian posterior lesion corresponds to lesion framed by a box in (A). (E) left paramedian posterior in (A). (E) left
paramedian
lesion posterior
corresponds lesion framed
to lesion corresponds to lesion
by a dotted boxframed
in (A).by(F)a posterior
dotted boxlesion
in (A). (F) posterior
corresponds tolesion
lesion
corresponds to lesion framed by a dotted line in (A). (G) 46-year-old man
framed by a dotted line in (A). (G) 46-year-old man diagnosed with primary progressive multiplediagnosed with primary
progressive
sclerosis multiple
(PPMS) sclerosis
in 2011, EDSS (PPMS) in 2011,
6. Sagittal EDSS 6. framed
T2-weighted, SagittalareaT2-weighted, framedsclerosis
shows multiple area shows
(MS)
multiple sclerosis (MS) lesions
lesions and spinal cord atrophy. and spinal cord atrophy.
3. Acute
OftenDisseminated
more than oneEncephalomyelitis
demyelinating plaque is present in spinal cord MRIs from patients with MS.
The cervical
Acute spine (53–59%)encephalomyelitis
disseminated is the most common location,
(ADEM) is followed by the thoracic
an autoimmune region (20–47%)
demyelinating disorder[10].
of
the CNS, commonly affecting brain and spinal cord white matter, although deep grey matter
Lesions usually present as hyperintense on T2-weighted and isointense on T1-weighted nuclei
sequences.
(e.g., thalamus
Gadolinium and basal ganglia)
enhancement mayand
is variable alsodepends
be involved [77,78].
mainly ADEM is more
on acquisition common
timing, in children
with acute lesions
(mean age 5 to 8 years), but can occur at any age [79] with an estimated annual incidence of 0.23 to
0.40/100,000 children [80–82]. Although no clear gender predominance has been identified, slight
male preponderance has been described in some pediatric ADEM cohorts [79]. Most pediatric
ADEM cases appear to be preceded by symptoms of viral or bacterial infection, usually of the
upper-respiratory tract. Vaccination has also been reported to precede ADEM, although at much
usually enhancing during 4–8 weeks [29,30]. Most MS lesions are small in size, wedge-shaped in axial
and ovoid-shaped in sagittal views, and predominantly found in ascending sensory (i.e., posterior
column), and descending motor (i.e., corticospinal) spinal cord tracts, because of the high myelin
concentration within these fascicules [31]. Rarely, they may extend to involve central grey matter,
occupying over half the cross-sectional area of the cord. Small focal lesions may coalesce to form
more extensive ones, involving three or more segments, particularly in cases of progressive MS.
High-resolution axial MRI demonstrates these images actually result from the confluence of multiple
discrete lesions [25,32].
Spinal cord lesions, when present, are particularly helpful to discriminate MS from its radiological
mimics, which include conditions such as migraine and cerebrovascular disorders. They can also
present together with multifocal T2 lesions in brain white matter [33].
In addition to their diagnostic value, spine lesions contribute prognostic information in MS.
Asymptomatic lesions are present in approximately 35% of patients with radiological isolated
syndrome [34], in one-third of patients with CIS [35], and 83% of patients with early RRMS [36].
Interestingly, the number of asymptomatic lesions found in patients with CIS has been linked to risk of
a second clinical event at 2 and 5 years [37,38], making spine MRI advisable in CIS patient workup.
However, detection of asymptomatic spinal cord lesions during follow-up of RRMS patients was less
common than detection of asymptomatic lesions in the brain, suggesting spinal cord MRI may be less
useful than brain MRI for monitoring patients with RRMS [39]. Some authors have observed that
greater number of spinal cord lesions at MS time of diagnosis and lesional topography at time of relapse
were associated with increased relapse rates and higher risk of developing secondary progressive
MS [10,11,39].
Spinal cord atrophy (Figure 1G) present in early stages of the disease may correlate with degree
of disability and predict long term outcome [38,40]. Measuring changes in cross-sectional area
at the cervical level yields the most reproducible results and shows closest correlation to clinical
findings [41,42]. Grey matter atrophy on the other hand correlates more strongly with degree of
physical disability than other MRI parameters of brain and cord atrophy [43–45]. Notably, a significant
association between reduced cervical cord sectional diameter and disability progression has been
demonstrated in different studies, independent of brain atrophy [46–48]. Cord atrophy has also been
associated with reduction in retinal nerve layer thickness [48], suggesting it is probably part of a global
pathological process and not just determined by local damage.
Rate of atrophy is more accelerated in the spinal cord than in the brain (1.5–2.2% per year vs.
0.5–1% per year) [49,50], and in patients with SPMS than in patients with CIS or RRMS. In RRMS, cord
atrophy presents primarily in the posterior spinal cord, while in SPMS, atrophy is generalized [49].
Interestingly, regional atrophy does not seem to be influenced by focal lesion presence [51–53]. A recent
study reported that a 1% increase in the annual rate of spinal cord volume loss was associated with
a 28% risk of disability progression in the subsequent year [50]. Unfortunately, widespread use of
this parameter has so far been limited by poor reproducibility and lack of sensitivity to small changes
in the cord cross-sectional area. Since the rate of spinal atrophy over time appears to be associated
with disability progression, atrophy has been considered a secondary outcome measure in phase 3
clinical trials of progressive MS [50,51]. When it was later analyzed more thoroughly, results were
inconclusive [54–56]. This may have been due to lack of treatment efficacy, inadequate patient selection,
poor reproducibility of cord atrophy quantification, or low sensitivity of MRI techniques used to
detect small changes in cord cross-sectional area [30]. Eventually, spinal cord atrophy could also be
considered a primary outcome in phase 2 clinical trials of progressive MS. However, this will require
adequate patient selection and more precise MR imaging techniques for exact assessment.
It should be noted that neuronal loss in MS is not limited to white matter only, post mortem
studies have also shown extensive neuronal loss in gray matter of the spinal cord as well, generating
considerable interest in detection of gray matter abnormalities in MS [57]. The use of a combination of
axial fast-field echo (FFE) and phase-sensitive inversion recovery (PSIR) sequences has been proposed
to identify gray matter abnormalities in the upper cervical spinal cord [58]. However, further studies
are still necessary to verify the sensitivity of this technique. Although both double inversion recovery
(DIR) and PSIR can help distinguish focal gray matter lesions from normal-appearing tissue on sagittal
views [59,60], these are often confounded by artifacts [61,62]. Use of 3T and higher field-strength (4.7 T)
scanners as well as dedicated imaging sequences have increased MRI sensitivity for MS-associated
gray matter lesion detection in the spinal cord [63,64]. Nevertheless, greater knowledge of spinal cord
lesion pathogenesis, as well as its relationship to disability progression, still need to be established to
better define the role of spinal cord assessment in MS diagnosis and follow-up [30].
More sensitive and better standardized methods are needed to assess clinical manifestations
related to spinal cord atrophy over time, as well as monitor disease course and response to therapy.
Promising MRI techniques to study the spinal cord include myelin water imaging, magnetization
transfer imaging, diffusion tensor imaging, and magnetic resonance spectroscopy. At present however,
use of these modalities is mostly restricted to research. Automated image-acquisition techniques,
increased precision, and reduced quantification variability over time still need to be developed,
and application in the clinical setting will likely be limited to select sites with experience using
advanced imaging techniques.
Several studies have demonstrated that residual deficits persist after MS relapses affecting the
spinal cord, contributing to stepwise progression of disability. For this reason, prompt and adequate
treatment of relapses is key, although optimal regimens have to be better defined [65,66]. Unfortunately,
despite significant advances in disease-modifying treatment, management of acute MS relapses with
intravenous or oral corticosteroids has remained largely unchanged for the past 20 years [67].
Since the first prospective trial demonstrated superiority of high-dose intravenous
methylprednisolone use (IVMPS; up to 1000 mg daily) over placebo, acute MS relapses are initially
treated with IVMPS during three to five days [68]. Although faster recovery of relapses has been
documented, clinical improvement is insufficient in approximately 25% of patients after the first course
of IVMPS [69]. Aside from increasing steroid treatment dose and prolonging treatment (up to 2000 mg
daily for five additional days), use of plasma exchange (PLEX) has also been considered an alternative
option [70]. One recent study in a group of patients receiving PLEX within 6 weeks of a relapse
showed not only significantly better response rates than those of patients receiving extended IVMPS
treatment, but also lower risk deterioration 3 months after discharge [71,72]. For long-term treatment
of MS, the last 2 decades have seen the development of numerous drugs aimed at correcting the
different pathogenic mechanisms proposed in multiple sclerosis, most of which have been compounds
targeting immune system dysfunction. Several clinical trials are currently ongoing, some using
neuroprotective therapies to halt progression, others aimed at reversing neurological disability, at least
in part, by repairing damaged brain and spinal cord tissue. Discussion of particular disease-modifying
therapies for MS is beyond the scope of this manuscript, however, several comprehensive reviews on
the subject have recently been published [73–76].
3. Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating disorder of
the CNS, commonly affecting brain and spinal cord white matter, although deep grey matter nuclei
(e.g., thalamus and basal ganglia) may also be involved [77,78]. ADEM is more common in children
(mean age 5 to 8 years), but can occur at any age [79] with an estimated annual incidence of 0.23 to
0.40/100,000 children [80–82]. Although no clear gender predominance has been identified, slight male
preponderance has been described in some pediatric ADEM cohorts [79]. Most pediatric ADEM cases
appear to be preceded by symptoms of viral or bacterial infection, usually of the upper-respiratory tract.
Vaccination has also been reported to precede ADEM, although at much lower rates [83]. Some cases
have been linked to specific vaccines produced in neural tissue cultures (rabies and Japanese B
encephalitis). However, a marked drop in post vaccination ADEM has occurred since CNS tissue
culture-derived production was replaced by recombinant protein-based vaccines. Nevertheless in up

to 26% of patients, no triggering event can be observed [84].
Histopathology findings in ADEM show perivenular inflammatory infiltrates consisting of T
cells and macrophages, associated with perivenular demyelination and relative preservation of axons
in most cases. In hemorrhagic variants, demyelination is often more widespread through the CNS,
with important neutrophilic infiltrates [79].
The pathogenesis of ADEM is still unclear. Two main hypotheses have been proposed. One,
the molecular mimicry hypothesis, suggests partial structural or amino-acid sequence homology
may exist between certain pathogens or vaccines and host CNS myelin antigens, which in turn may
activate myelin-reactive T cells, thereby eliciting a CNS-specific autoimmune response [85]. The second
hypothesis proposes CNS infection may directly prompt a secondary inflammatory cascade, leading to
blood-brain barrier rupture, exposure of CNS-antigens, and breakdown of tolerance resulting in an
autoimmune attack driven mainly by T cells [86].
Criteria for ADEM diagnosis, established in 2013 by the International Multiple Sclerosis Study
Group (IPMSSG), require the following to be present: (1) an initial polyfocal clinical CNS event of
presumed inflammatory demyelinating cause; (2) encephalopathy (alteration in consciousness or
behavior unexplained by fever, systemic illness, or post ictal symptoms); (3) brain MRI abnormalities
consistent with demyelination during the acute phase (first 3 months); (4) no new clinical or MRI
findings 3 months or more after onset [87].
Depending on the series, spinal cord involvement has been described in 20% to 54% of ADEM
patients, predominantly affecting the thoracic region [88]. Coincident brain and spinal cord lesions
are more common; isolated spinal cord ADEM is exceptional [89] and typically extends over multiple
segments, cause cord swelling, and showing variable enhancement in the acute phase. In most
ADEM patients, partial or complete resolution of MRI abnormalities occurs within a few months of
treatment [84,90]. Interestingly, ADEM patients with anti-MOG antibodies show large, more widespread
brain lesions with ill-defined borders and longitudinally extensive spinal cord lesions on MRI [91].
Lesions involving more than two segments are more frequent in adults than in children (50% vs. 27%,
respectively) [92].
No specific studies on CSF have been conducted in ADEM. Pleocytosis is typically mild, with a
high percentage of lymphocytes and monocytes [92,93] and increased protein levels (up to 1.1 g/L) in
23% to 62% of pediatric patients [94–96]. OCBs are only present in 0% to 29% of cases [79]. However,
they are usually transient as opposed to those observed in MS.
Although ADEM usually has a monophasic course, multiphasic forms have been reported
in 10–31% of patients [84,97], making differential diagnosis with MS more difficult in these cases.
Multiphasic forms are defined as new encephalopathic events consistent with ADEM, separated by a
3-month interval from the initial illness but not followed by any further event [98]. Relapsing disease
following ADEM occurring beyond a second encephalopathic event is no longer consistent with
multiphasic ADEM, but rather indicates a chronic disorder such as MS, NMOSD, or ADEM-optic
neuritis [98,99], and should prompt testing for anti-MOG ab. It is worth highlighting that progression
from ADEM to MS is relatively low, estimated at 0% to 17% in studies with follow-up periods lasting
several years [88].
Clinical presentation and outcome of ADEM in adults differs from that of children. Disease course
is worse in adults, with more than one-third of patients requiring admission to an ICU, and duration
of hospitalization can be twice as long. Outcome is also less favorable, complete motor recovery is
observed in only 15% of adults compared to 58% of children and more adult patients die, although
no difference in the occurrence of relapses or conversion to MS has been reported [92,100]. Poorer
outcomes in adults cannot be explained by differences in clinical presentation (preceding factors,
symptoms, blood and CSF parameters or radiological features are all similar). Perhaps reduced
plasticity in ageing CNS tissue is the cause, rather than a difference in pathophysiology from onset [92].
No randomized-controlled studies have been conducted on ADEM treatment. Despite the lack of
conclusive evidence, a widely accepted regimen in use today is administration of IV methylprednisolone
(30 mg/kg/day in children or 1000 mg/day in adults) for 5 days, followed by oral taper with
dexamethasone at a starting dose of 1–2 mg/kg/day, for 4–6 weeks [101,102]. Plasma exchange
is recommended for therapy-refractory patients with fulminant disease [103,104]. Beyond treatment
of the initial event, it is important to have a plan for long term follow-up to exclude a multiphasic
disorder, which would warrant further diagnostic evaluation and a different therapeutic approach.
4. Neuromyelitis Optica Spectrum-Disorder

Neuromyelitis optica (NMO) is an inflammatory disorder, traditionally considered monophasic,
although relapsing cases have been described in which patients present optic neuritis and transverse
myelitis [105]. NMO had been considered a variant of MS until an autoantibody against the water
channel protein aquaporin-4 (AQP4), expressed abundantly on astrocyte end-feet, called AQP4-IgG
(also called NMO-IgG), was discovered in patients with NMO, and found to be absent in patients
with MS [106,107]. Incorporation of AQP4-IgG serology to revised NMO diagnostic criteria broadened
the clinical and radiological spectrum of NMO [108]. The term NMO spectrum disorders (NMOSD)
was introduced to include AQP4-IgG seropositive patients with limited forms of NMO, and at risk
of future attacks, as well as patients with cerebral, diencephalic, and brainstem lesions, or coexisting
autoimmune disease (e.g., systemic lupus erythematosus [SLE] or Sjögren syndrome [SS]) [109].
Accordingly, NMOSD was recognized as a humoral disease entity distinct from MS, and diagnostic
criteria were revised in 2015 unifying the terms NMO and NMOSD [110].
Evidence supporting a pathogenic role of AQP4-IgG comes from different sources. Complement- as
well as ab-dependent cytotoxicity [101,102] has been associated to AQP4-IgG, which when administered
along with complement and/or pathogenic T cells, promotes development of NMOSD-like CNS lesions
in rodents [111,112]. Inflammatory damage is characterized by astrocyte loss and deposition of both
immunoglobulins and complement, followed by neutrophil, monocyte, phagocyte and eosinophil
infiltration [113]. Importantly, AQP4 distribution coincides with deposition patterns of IgG, IgM, and
products of complement activation present in active NMO tissue [114,115], and MRI lesions of patients
with NMO overlap with sites of high AQP4 expression [116]. AQP4-IgG is believed to determine
internalization of the glutamate transporter EAAT2, limiting glutamate uptake from the extracellular
space into astrocytes, also resulting in oligodendrocyte damage and myelin loss [117]. Although most
strongly expressed in the CNS, AQP4 is also present in the collecting duct of the kidney, parietal cells
of the stomach, as well as in airways, salivary glands, and skeletal muscle [118]. However, peripheral
organ damage does not typically occur, probably due to the presence of complement inhibitory proteins
in these secondary target organs [119].
Despite caveats in knowledge on NMOSD epidemiology, prevalence has been estimated depending
on the study population at 0.1–4.4 cases/100,000 individuals, and annual incidence at 0.20–4.0 per
1,000,000 [120,121]. Initial clinical manifestations occur at around 40 years of age, although children
and the elderly account for 18% of cases. Female/male predominance is around 9:1, but not in children,
where equal gender distribution has been observed [32,122].
According to the most recent diagnostic criteria, core clinical characteristics can involve 1 of 6 CNS
regions, namely: optic nerve, spinal cord, area postrema of the dorsal medulla, brainstem, diencephalon,
or cerebrum [110]. Clinical presentation particularly suggestive of NMOSD diagnosis includes: bilateral
ON involving the optic chiasm with poor recovery compared to MS-ON, complete spinal cord syndrome
determining paroxysmal spasms, and area postrema clinical syndrome characterized by intractable
hiccups, or nausea and vomiting. No single clinical characteristic is pathognomonic of NMOSD,
however [110]. In AQP4-IgG seronegative patients, diagnostic criteria are more rigorous. Patients must
present at least 2 of the core clinical characteristics, and at least one of these must be: ON, longitudinally
extensive transverse myelitis (LETM), or area postrema syndrome.
Given the focus of this review, in the following sections, only aspects related to NMOSD-related
to spinal cord involvement will be addressed.
Acute transverse myelitis symptoms in NMOSD patients (motor, sensitive, and frequently
sphincter) are usually severe and bilateral, and recovery is incomplete compared to MS. Although
overlap of clinical characteristics in MS and NMOSD myelitis does occur, symptom magnitude and
disease history frequently contribute to establish differential diagnosis [30,32,120], as do certain MRI
findings. LETM is the most specific neuroimaging characteristic found in NMOSD, and is uncommon in
MS (Figure 2) [108]. Mirroring severe underlying tissue damage, lesions are generally hyperintense on
T2-weighted, and hypointense on T1-weighted sequences [30]. Extending over three or more complete
vertebral segments, they tend to localize in the center of the cord, because of the abundant AQP4
channel expression in grey matter. Lesions will usually occupy over 50% of the cross-sectional surface
area of the spine, representing a complete, rather than incomplete, form of transverse myelitis which is
more characteristic in MS. However, they also may be lateral, anterior, or posterior over the length of
the lesion and be accompanied by cord swelling. The latter, when present, can generate concern over
presence of a spinal cord tumor [123]. Chronic necrosis caused by NMOSD can in some cases result in
spinal cord cavitation and cystic myelomalacia. Small areas of strong hyperintensity, higher than that of
the surrounding cerebrospinal fluid (CSF), so-called bright spotty lesions, may be observed and could
be useful to distinguish NMOSD from MS [124]. Acute NMO lesions extensively enhance following
IV gadolinium administration. Lens-shaped ring-enhancement is detected in up to 32% of NMOSD
patients [29,125,126]. Rostral extension of cervical lesions to the area postrema is another characteristic
of NMOSD and can be helpful to distinguish it from other causes of longitudinal extensive myelopathy
such as sarcoidosis, spondylotic myelopathy with enhancement, dural arteriovenous fistula, spinal
cord infarct, and paraneoplastic myelopathy [127]. Although LETM is the most frequent form, 7–14% of
NMO-myelitis involve <3 vertebral segments. However, short forms of NMO-myelitis are followed by
LETM in ninety percent of cases. Short cord lesions should be suspected in patients with tonic spasm,
coexistence of autoimmune disease, grey matter involvement and absence of OCB. As in MS, in 7–14%
of cases, variation in presentation will be linked to time at which MRI scans are obtained [128–130].
Lesions limited to less than three segments will be detected at the beginning of disease or during
remission [131]. In contrast, patients with longstanding disease may present short but coalescing
lesions suggesting a LETM pattern [22]. Presence of a longitudinally extensive segment of cord atrophy
is another characteristic finding in support of prior NMOSD myelitis [131].
Although in NMOSD the relationship between spinal cord atrophy, disease activity and disability
is not fully known, two observations deserve mention. First, NMOSD patients predominately show
spinal cord atrophy with only mild brain atrophy, while MS patients demonstrate more brain atrophy,
especially in gray matter, suggesting a different underlying pathogenic mechanism [132]. Second, spinal
cord atrophy can occur in patients without a clinical history of myelitis or visible spinal cord lesions on
MRI, suggesting cord atrophy may be due to a diffuse underlying process. Alternatively, or perhaps in
co-contributory fashion, patients may have experienced transient or subclinical inflammatory events
not evident on conventional MRI [133].
Serum AQP4-IgG assay is the most useful test for NMOSD diagnosis. Based on criteria proposed
by the International Panel for NMOSD, approximately 73–90% of patients with NMOSD express
AQP4-IgG [134,135]. A cell-based assay (CBA) is recommended whenever possible because of its higher
sensitivity (76.7%) and very low false-positive rate (0.1%) [136,137]. Indirect immunofluorescence
assays and ELISA have less sensitivity (63–64% each), and can yield false-positive results (0.5–1.3%
for ELISA) particularly at low titers [135,137]. Ultimately, 10–27% of patients with typical clinical
and radiological features of NMOSD will not have detectable AQP4-IgG despite use of the best
available assay. Lack of a diagnostic biomarker makes management of these patients more challenging
especially of patients with monophasic disease [121,136]. Notably, using CBA, approximately 15–40%
of AQP4-IgG seronegative NMOSD patients have been reported to have detectable antibodies against
myelin oligodendrocyte glycoprotein (MOG) [137,138]. Aside from causing optico-spinal disease
resembling NMOSD, anti-MOG antibodies have been identified in patients with clinical characteristics
unlike those of patients with AQP4-IgG [32,137,139] (see below), suggesting a different underlying
pathogenesis. Occasionally, patients without detectable serum AQP4-IgG are later found to be positive,
possibly related to assay timing (antibody levels increase during exacerbations), or to impact of
immunosuppressive treatment.
Biomedicines 2020, 8, x FOR PEER REVIEW 10 of 25
Figure 2.
Figure 2. Neuromyelitis
Neuromyelitis optica
optica (NMO)
(NMO) myelitis.
myelitis. Images
Images from
from aa 58-year-old
58-year-old woman
woman withwith acute
acute
longitudinally extensive
longitudinally extensive myelitis
myelitis (C1–C7).
(C1–C7). (A)(A) Sagittal STIR showing
Sagittal STIR showing anan extensive
extensive lesion,
lesion, involving
involving
more than
more than33segments,
segments,thatthat widens
widens thethe cervical
cervical spinal
spinal cord.cord. (B) Sagittal
(B) Sagittal T1-weighted
T1-weighted sequences
sequences show
show an extensive T1-hypointense lesion. (C) T1-weighted images after contrast administration,
an extensive T1-hypointense lesion. (C) T1-weighted images after contrast administration, extensive
extensive enhancement
enhancement of cervical
of cervical lesion. (D,E)lesion. (D,E) Axialhyperintense
Axial T2-MERGE T2-MERGE areahyperintense areamore
that involves that than
involves
half
more
the than half
diameter of thethe diameter
spinal of the
cord. (E,F) spinal
Axial cord. (E,F)
T1-weighted, Axial
intense T1-weighted,
contrast enhancementintense contrast
of lateral (E)
enhancement
and of lateral
central-posterior (E) and
(F,G) central-posterior (F,G) areas.
areas.
5. Myelin
SerumOligodendrocyte Glycoprotein
AQP4-IgG concentration Antibody-Associated
is much Disease
higher than that found in CSF. The hypothesis behind
this is that most AQP4-IgG is produced in peripheral lymphoid tissues and that a favorable serum/CSF
Myelin oligodendrocyte glycoprotein, a member of the immunoglobulin superfamily, is
antibody gradient is needed for penetration into the CNS, a concept supported by the fact that
exclusively expressed on the surface of oligodendrocytes and on the outermost lamellae of myelin
commercial CBA and flow cytometry detection of AQP4-IgG is more sensitive in serum than in CSF.
sheaths in the CNS. Given its structure and location it could potentially function as a cell surface
Serum is therefore the optimal specimen for AQP4-IgG testing [140].
receptor, or cell adhesion molecule. Furthermore, its extracellular location makes it a target for
Some patients with NMOSD produce other autoantibodies in addition to AQP4-IgG, as occurs in
autoimmune ab- and cell-mediated responses, in inflammatory demyelinating diseases. Interesting
patients with SLE or SS [118]. Since LETM has also been described in patients with these conditions,
results from animal studies on MOG ab-associated demyelination lead to this antibody being
the possibility exists that NMOSD symptoms arise secondary to SLE or SS. Limited existing data in
considered a marker for MS [158,159]. However, subsequent studies in large populations of MS
this regard shows that in such patients, AQP4-IgG detection rates are similar to those observed in
patients found seropositivity prevalence in this condition was similar to that detected in other
patients with NMOSD without associated rheumatic disease, suggesting LETM in NMOSD is not
inflammatory neurological diseases, as well as to levels in control subjects, generating skepticism
secondary to SLE or SS, and these patients suffer from two independent, coexisting autoimmune
over whether these ab could be considered a true biomarker of MS [160–162]. Seminal studies using
diseases [118,141–143].
murine anti-MOG ab have highlighted the fact that ab target epitopes of native MOG are biologically
CSF pleocytosis (>50 cells/µL) or presence of neutrophils or eosinophils during NMOSD attacks
relevant in their conformational state, rather than in linearized or denatured MOG. Therefore, CBA,
may help to distinguish NMOSD from MS [123,137].CSF OCBs are usually absent, although they may
which maintains the native conformational form of the extracellular portion of MOG, is the most
sometimes be transiently detectable during an attack [123,144].Given the high morbidity associated
recommended technique to study ab levels.
with NMOSD exacerbations, the goals of pharmacotherapy are to aggressively treat acute attacks,
There is current international consensus that anti-MOG ab are important in both pediatric and
adult demyelination. Different research groups have identified seropositive MOG ab populations in
children with ADEM, particularly in recurrent forms of the disease [163–166]. Other studies later
confirmed presence of MOG ab in 25% to 30% of AQP4 seronegative NMOSD patients with
recurrent ON. Substantial differences between both diseases in histopathology, as well as in vivo
and vitro studies demonstrating a direct pathogenic role for MOG-IgG, suggest it represents a
(including the initial episode) and prevent future relapses, minimizing CNS damage and long-term
disability [145,146]. Different pathophysiologic mechanisms are known to characterize MS and NMOSD,
a finding at least partially demonstrated by the fact that exacerbations can be precipitated by fingolimod,
IFNβ and natalizumab, treatments that are effective in MS. Aside from the need for accurate diagnosis,
evaluation of occult infection or metabolic disturbances should be carried out to identify pseudo-relapses
Although there are no randomized controlled trials in large cohorts examining treatment of acute
relapses, NMOSD exacerbations are typically treated with 1 g of IVMP for 3–5 consecutive days [147,148].
Severe NMOSD relapses or patients who do not respond to treatment with IVMP may benefit from
plasma exchange (PLEX) [72,147–149]; which targets specific antibodies, complement and several
pro-inflammatory proteins [150] Early (≤5 days), aggressive treatment with PLEX is linked to better
outcome [151]. Interestingly, positive results of PLEX are obtained both in seropositive as well as
seronegative NMOSD patients [152–154]. In order to avoid relapses, different immunosuppressive
strategies are used in daily neurological practice including: oral corticosteroids, mycophenolate
mofetil or azathioprine (both oral purine analog anti-metabolites), rituximab (IV anti-CD20 monoclonal
antibody) and tocilizumab (anti-IL-6 receptor monoclonal antibody [146,147]. However, none of these
agents have been specifically approved for NMOSD treatment, and off-label use has arisen based almost
entirely on results from uncontrolled observational studies [146,147]. Recently, three new monoclonal
antibodies with different mechanisms of action and routes of administration have shown efficacy in
NMOSD patients: eculizumab (anti-complement protein C5) [155], inebilizumab (anti-CD19) [156],
and satralizumab (anti-IL-6R) [157], significantly reducing risk of new relapses compared to placebo,
particularly in AQP4-ab-positive patients, with clinical stabilization or improvement in most cases.
All these drugs demonstrated good safety and tolerability profiles with limited side effects. Future
evaluation in real-life studies will be needed though, to estimate annual relapse rates and compare
results to those of older drugs.
5. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

Myelin oligodendrocyte glycoprotein, a member of the immunoglobulin superfamily, is exclusively
expressed on the surface of oligodendrocytes and on the outermost lamellae of myelin sheaths in the
CNS. Given its structure and location it could potentially function as a cell surface receptor, or cell
adhesion molecule. Furthermore, its extracellular location makes it a target for autoimmune ab- and
cell-mediated responses, in inflammatory demyelinating diseases. Interesting results from animal
studies on MOG ab-associated demyelination lead to this antibody being considered a marker for
MS [158,159]. However, subsequent studies in large populations of MS patients found seropositivity
prevalence in this condition was similar to that detected in other inflammatory neurological diseases,
as well as to levels in control subjects, generating skepticism over whether these ab could be considered
a true biomarker of MS [160–162]. Seminal studies using murine anti-MOG ab have highlighted the
fact that ab target epitopes of native MOG are biologically relevant in their conformational state, rather
than in linearized or denatured MOG. Therefore, CBA, which maintains the native conformational
form of the extracellular portion of MOG, is the most recommended technique to study ab levels.
There is current international consensus that anti-MOG ab are important in both pediatric and
adult demyelination. Different research groups have identified seropositive MOG ab populations in
children with ADEM, particularly in recurrent forms of the disease [163–166]. Other studies later
confirmed presence of MOG ab in 25% to 30% of AQP4 seronegative NMOSD patients with recurrent
ON. Substantial differences between both diseases in histopathology, as well as in vivo and vitro studies
demonstrating a direct pathogenic role for MOG-IgG, suggest it represents a separate individual entity.
Anti-MOG ab are already present at disease onset, both in serum and CSF, in some patients, persisting also
during remission in the majority of patients, which argues against anti-MOG ab presence as a secondary
epiphenomenon [167–170]. Notably, serum anti-MOG ab detection is more sensitive than CSF assay.
Since these observations, an increasing number of patients with diverse phenotypes related to these
antibodies have been described. A comparison of patients with MOG ab disease to AQP4 NMOSD cases
showed the former were younger [68,169–171], did not show significant female predominance [172],
and were more commonly Caucasians; whereas AQP4-seropositive NMOSD was found predominantly
in non-Caucasian populations [173,174].
The most commonly reported presentation of anti-MOG ab-associated disease is ON, which can be
bilateral and recurrent in up to 61% of cases. Interesting, imaging of the optic nerve frequently shows
peri-optic nerve sheath contrast enhancement, extending into the surrounding soft tissue, a radiological
characteristic not observed in MS or AQP4 positive patients [175,176].
Approximately half the patients with MOG ab-associated disease present episodes involving the
spinal cord [177,178]. The most common symptoms include paraparesis, and sensory and sphincter
dysfunction. On MRI, LETM is frequent and short myelitis less common. Any segment of the spinal
cord can be affected, although lesions are more frequent in the thoracolumbar and/or conus medullaris
regions, as opposed to the more common cervicothoracic involvement observed in AQP4 ab positive
and MS myelitis cases [178,179]. Anti-MOG ab associated myelitis is hyperintense on T2-weighted
and iso-hypointense on T1-weighted sequences, showing contrast enhancement during acute phases
in up to 70% of cases [172]; Figures 3 and 4. MOG ab-related disease does not commonly result in
cord necrosis or cavitations as observed in AQP4-mediated cases [134,175,178]. Due to the predilection
for conus localization, bladder, bowel, and erectile dysfunction is observed in approximately 70%
of patients [167]. In comparison to AQP4-IgG+ NMOSD, MOG ab disease myelitis appears to more
focal and with better clinical outcome, although poor outcome with permanent disability has been
described for both conditions [156]. Notably, anti-MOG ab serum titers follow disease activity levels,
with significantly higher concentration during acute attacks than remission, further supporting the
concept of their pathogenic role [172].
Although ON and myelitis are the two most frequent forms of presentation of anti-MOG ab
disease, coexistence of brain, brainstem, or cerebellar involvement is frequent, and may even be
extensive. Nausea, vomiting, and respiratory disturbances are some of the symptoms that can be
present in cases
Biomedicines of8,brainstem
2020, involvement [177].
x FOR PEER REVIEW 12 of 25
Figure
Figure 3. Anti-myelin
3. Anti-myelin oligodendrocyte
oligodendrocyte glycoprotein
glycoprotein (MOG)(MOG)
antibody antibody
myelitis.myelitis. (a)T2-weighted
(a) Sagittal Sagittal
T2-weighted spinal MRI performed at disease onset revealed a large longitudinal centrally-located
spinal MRI performed at disease onset revealed a large longitudinal centrally-located lesion extending
lesion extending over the entire spinal cord, as well as swelling of the cord. (b) Longitudinally
over the entire spinal cord, as well as swelling of the cord. (b) Longitudinally extensive central spinal
extensive central spinal cord T2 lesion in another patient. (c) T2-hyperintense lesions extending from
cord T2 lesion in another patient. (c) T2-hyperintense lesions extending from the pontomedullary
the pontomedullary junction throughout the cervical cord to C5, in a third patient. Insets in (a) and
junction throughout the cervical cord to C5, in a third patient. Insets in (a) and C show axial sections of
C show axial sections of the thoracic cord at lesion level [172]. Figure is extracted from Jarius, S. et
the thoracic cord at lesion level [172]. Figure is extracted from Jarius, S. et al., J Neuroinflammation 2016,
al., J Neuroinflammation 2016, 13, 280 (http://creativecommons.org/licenses/by/4.0/).
13, 280 (http://creativecommons.org/licenses/by/4.0/).
T2-weighted spinal MRI performed at disease onset revealed a large longitudinal centrally-located
lesion extending over the entire spinal cord, as well as swelling of the cord. (b) Longitudinally
extensive central spinal cord T2 lesion in another patient. (c) T2-hyperintense lesions extending from
the pontomedullary junction throughout the cervical cord to C5, in a third patient. Insets in (a) and
C show
Biomedicines axial
2020, sections of the thoracic cord at lesion level [172]. Figure is extracted from Jarius, S. et
8, 130 12 of 25
al., J Neuroinflammation 2016, 13, 280 (http://creativecommons.org/licenses/by/4.0/).
Figure 4.4. Anti-MOG

Figure Anti-MOGantibody
antibodymyelitis.
myelitis. A 12-year-old
A 12-year-old girl girl
withwith relapse
relapse in thein the cervical
cervical spine.
spine. (A) (A),
sagittal
sagittal STIR, subtle and diffuse hyperintensity of the cervical spinal cord. (B), Sagittal T1-weighted,
STIR, subtle and diffuse hyperintensity of the cervical spinal cord. (B) Sagittal T1-weighted, spinal
spinal
cord is cord is isointense
isointense without without
contrast contrast enhancement.
enhancement. (C–E) axial(C–E), axial T2-weighted
T2-weighted imagessubtle
images showing showing
and
subtle and
diffuse diffuse
spinal cord spinal cord hyperintensity
hyperintensity (Courtesy
(Courtesy Dr. AngelesDr Angeles Schteinschnaider).
Schteinschnaider).
6. Glial Fibrillary
Different studyAcid Protein
groups haveAntibody-Associated
developed MRI diagnosticMyelitis
criteria to differentiate MS, from NMOSD
and from anti-MOG ab-associated disease, showing 91% sensitivity distinguishing MS from AQP4+
A novel autoimmune CNS disorder characterized by the presence of antibodies specific for glial
NMOSD, and 95% from anti-MOG ab-associated disease [173,179]. More recently, the criteria were
fibrillary acidic protein (GFAP) has recently been described. In the largest series published to date,
subtly modified to include spinal cord in the analysis, increasing sensitivity to 100% and specificity to
79%, reflecting the crucial importance of spinal cord findings in anti-MOG-ab disease. Interestingly,
this radiological criterion was particularly useful in patients with ON, a clinical presentation common
to all three diseases [180].
Patients with anti-MOG ab-associated disease were initially described as experiencing a
monophasic disease [91,140,178]. However, recent studies found a high proportion of patients presenting
relapsing disease [173,181]. Anti-MOG ab-positive patients exhibited better motor and visual outcome
compared to AQP4-IgG positive patients after the first episode [170,181].
Anti-MOG ab are present in approximately 40% of children with ADEM. In this group, most patients
develop LETM, and similar to patients without anti-MOG ab, show large, ill-defined, bilateral lesions in
the brain, which typically resolve completely, in correlation with improved clinical outcome [165,177].
MOG ab-positive patients show rapid response to steroids and plasma exchange [177], but tend
to relapse quickly after steroid withdrawal or cessation [182,183]. Therefore, slow steroid taper is
recommended to minimize chances of early relapses. In adult patients, persistent seropositivity
following initial treatment and clinical resolution is one of the main reasons to consider long
term immunosuppression with steroid-sparing agents including mycophenolate, azathioprine or
rituximab [135,169,170,184–186]. The significance of this finding is less clear in pediatric patients with
ADEM and persistence of serum anti-MOG abs.
6. Glial Fibrillary Acid Protein Antibody-Associated Myelitis

A novel autoimmune CNS disorder characterized by the presence of antibodies specific for
glial fibrillary acidic protein (GFAP) has recently been described. In the largest series published to
date, median symptom onset age was around 40 years, with similar incidence in both women and
men [187,188]. All patients with GFAP-IgGs reacted against the mature (α) GFAP isoform, with
only a few patients showing immunoreactivity against the immature (ε) isoform [188]. GFAP is a
cytoplasmic protein not accessible to IgG in intact cells, therefore, it is possible that immune cells
also contribute to the tissue damage observed in this condition, for example GFAP peptide-specific
CD8+ T lymphocytes [189]. Eventually other immune cells sensitive to steroids, such as microglia and
macrophages, can also play a role in the disease, acting directly, or through the release of molecules
modulating the immune response such as cytokines or chemokines [187,190–192].
Clinical phenotype of GFAP-IgG astrocytopathy is heterogeneous and still poorly defined.
The predominant clinical syndrome includes meningitis, encephalitis, and myelitis, or all three
(meningoencephalomyelitis) with or without optic disc edema [188,193,194].
Myelitis occurs in up to 68% of patients with GFAP-IgG. However, its presentation as isolated
clinical manifestation is infrequent. Despite the fact that autoimmune GFAP astrocytopathy and
NMOSD-related myelitis share some clinical features, certain differences are worth mentioning [195].
Influenza-like prodromal symptoms and bowel/bladder dysfunction are common features in GFAP-IgG
myelitis, while numbness and weakness followed by tonic spasms, frequent NMOSD symptoms, are
rare. Notably, sensory level and Lhermitte’s phenomenon are usually absent in GFAP-IgG myelitis,
which is found in the cervical or thoracic spinal cord, in central location, usually involving at least
three vertebral segments [195]. Lesions are hyperintense on T2-weighted sequences and may show
a thin and linear pattern of contrast enhancement along the course of the central canal, different to
the patchy or ring-like contrast uptake seen in NMOSD [187]. GFAP-IgG lesions have poorly-defined
margins and less cord swelling compared to AQP4-IgG myelitis [195]. Short myelitis has also been
reported in association with brain symptoms [187,194,195].
Notably, brain MRI findings significantly contribute to discriminate GFAP-IgG from other
pathologies. A striking pattern of linear radial periventricular contrast enhancement is highly specific
for GFAP-IgG-associated disease. Similar radial enhancement patterns have been described in the
cerebellum in a lower percentage of patients [184,185,193].
Anti-GFAP abs can be detected in serum in 45% of patients, but sensitivity increases to 92%
when ab are assayed in CSF [187]. Up to 50% of cases coexist with N-methyl-d-aspartate receptor
(NMDAr) antibodies or anti-AQP4 ab, and up to 34% of patients may present concomitant neoplasms,
with ovarian teratoma as the most prevalent [187]. These associations explain the diverse phenotypes
reported [187,188,194]. Marked elevation of white cells and protein are common findings in CSF, and
intrathecal oligoclonal bands may be present in 50% of patients [187].
Most reported GFAP-IgG cases show improvement in clinical, radiological, and CSF abnormalities
after receiving high-dose intravenous methylprednisolone for 3–5 days [184,192]. Although
nonresponsive-patients have been described, need for plasma exchange is significantly less frequent
compared to patients with NMOSD [193,195,196]. In one study, 50% of patients with long-term
follow-up (>24 months) had a relapsing course, 27% had a monophasic course and 23% had progressive
disease in spite of adequate treatment. Clinical relapses were frequently associated with recurrent
gadolinium enhancement on MRI and elevated CSF white cell count, with further remission observed
after restarting steroids [187].
GFAP-IgG is unlikely to be directly pathogenic, as GFAP is an intracellular protein. However,
it could be an excellent biomarker, identifying a neoplasm early on, leading to prompt and efficient
treatment and prevention of long-term disability in GFAP-IgG myelitis cases.
7. Conclusions
Overall, demyelinating myelopathies belong to a complex and heterogeneous group of diseases,
in which differential diagnosis can be difficult (Table 1). Clinical features, time-course, CSF
characteristics, specific serum assays, and brain and spinal cord MRI findings all contribute to
determine diagnosis, select the best treatment option and establish prognosis for each subtype. Early
treatment with IV steroids and PLEX is accepted in all etiologies, but more specific treatment strategies
may subsequently be adopted based on final diagnosis.
Table 1. Main features in demyelinating myelopathies of different etiology.
MS ADEM NMOSD MOG-IgG Disease GFAP-IgG Disease

Estimated F:M ratio 3:1 1:1 9:1 1.3:1 1:1
Age * (yrs) 30 6 37 33 40
Sensory loss, gait impairment, Paraparesis, sensory symptoms Sensory symptoms,
Myelitis clinical features Transverse myelitis Transverse myelitis
weakness, sphincter involvement and sphincter involvement sphincter disfunction
Relapsing (85%) or Typically monophasic Monophasic (58%) or Relapsing (50%), monophasic
Clinical course Relapsing (90%)
progressive (15%) (69–90%) relapsing (42%) (27%) or progressive (23%)
Serum AQP4-IgG. Anti-GFAP ab + in serum or CSF
Serology findings Not relevant Not relevant coexistence with other systemic disease Serum MOG-IgG (Serum Anti-AQP4-IgG and/or
antibodies (ANA, SSA or SSB). anti-NMDAr ab coexistence,
0% to 29% Up to 30%
Presence of OCB 80–95% Up to 12% Up to 50%
(usually transient) (usually transient)
Mild pleocytosis and Pleocytosis (neutrophils and
Generally normal or mild Normal or slightly Marked elevation of white blood
CSF increased proteins up eosinophils can be found) and mild
inflammatory changes inflammatory changes cells and elevated protein levels
to 62% elevated proteins
Dawson fingers, lesions Non–specific supratentorial
perpendicular to ventricles Subcortical or deep gray subcortical or small deep white
Periependimal lesions
Cortical/yuxtacortical lesions matter bilateral, matter foci. Occasionally T2
Tumefactive lesions
Perivenular sometimes poorly-defined lesions in brainstem, and Linear radial periventricular
Brain MRI Involvement of corticospinal tract
Nodular or ring/open-ring Simultaneous infratentorial regions contrast enhancement pattern
Marked enhancement, ‘cloud like’
enhancing lesions enhancement with Anterior bilateral ON with
Bilateral, long optic nerve enhancement
Unilateral short optic gadolinium perineural optic nerved
nerve enhancement enhancement
Small, peripheral, LETM or multiple short Central LETM
LETM or short myelitis, frequent
posterolateral lesions segment myelitis Edematous
conus medullaris involvement
Spinal cord MRI Less than 3 segments Edematous lesions and Necrosis or cavitation LETM Central lesions
Linear gadolinium enhancement
Gadolinium enhancement during gadolinium enhancement Gadolinium enhancement in
of the ependymal canal
acute phase in acute phase acute phase
Ab: antibodies, ADEM: acute disseminated encephalomyelitis, AQP4: Aquaporin 4, F: female, GFAP: glial fibrillary acid protein, LETM: longitudinally extensive transverse myelitis,
M: male, MOG: myelin oligodendrocyte glycoprotein, MRI: magnetic resonance imaging, MS: multiple sclerosis, NMDAr: N-Methyl-d-aspartate receptor, NMOSD: neuromyelitis optica
spectrum disorder, OCB: oligoclonal bands. * estimated media.
Author Contributions: M.M. contributed to draft the original manuscript, design the figures, revise the draft
and provide important intellectual contributions. M.I.G. contributed to draft the original manuscript, design
the figures, revise the draft and provide important intellectual contributions. J.C. contributed to the conception
and design of the manuscript, draft the original manuscript, revise the draft, provide important intellectual
contributions, and supervised the writing of the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: This study was supported by an internal grant from FLENI (J.C.).
Acknowledgments: We thank Angeles Schteinschnaider for providing Figure 4 and Ismael L. Calandri for
providing the graphical abstract.
Conflicts of Interest: M.M. has nothing to disclose. M.I.G. has received reimbursement for developing educational
presentations, from Merck Argentina, Biogen Argentina, Sanofi-Genzyme Argentina, Bayer Inc Argentina
and Novartis Argentina, and has received travel/accommodations stipends from Merck Argentina, Biogen
Argentina, Roche Argentina, Novartis Argentina, and TEVA Argentina. J.C. is a board member of Merck-Serono
Argentina, Biogen-Idec LATAM, Merck-Serono. LATAM, Novartis and Genzyme global. Correale has received
reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM,
Biogen-Idec Argentina, Genzyme Argentina, and Novartis Argentina and Roche Argentina as well as professional
travel/accommodations stipends. The funders had no role in the design of the study; in the collection, analysis,
or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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Demyelination Lesion Spine Neuroradiology

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Demyelination Lesion Spine Neuroradiology

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biomedicines

Abstract: Diagnostic accuracy is poor in demyelinating myelopathies, and therefore a challenge

Biomedicines 2020, 8, 130; doi:10.3390/biomedicines8050130 www.mdpi.com/journal/biomedicines

3. Acute Disseminated Encephalomyelitis

culture-derived production was replaced by recombinant protein-based vaccines. Nevertheless in up

4. Neuromyelitis Optica Spectrum-Disorder

5. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

Figure 4.4. Anti-MOG

6. Glial Fibrillary Acid Protein Antibody-Associated Myelitis

Table 1. Main features in demyelinating myelopathies of different etiology.

MS ADEM NMOSD MOG-IgG Disease GFAP-IgG Disease

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