Key words
neuroimmunology - neuromyelitis optica spectrum disorder - NMOSD - myelin oligodendrocyte
glycoprotein - MOG - aquaporin
History and Nomenclature
As early as 1894, the French physician, Eugène Devic, described patients with concomitant
symptoms of optic neuritis and transverse myelitis, and designated it as “neuromyelitis
optica” (NMO) [1]. For a long time, the NMO was not defined as a separate entity under chronic inflammatory
CNS diseases, but as a sub-form of multiple sclerosis. This assessment was abandoned
by the turn of the millennium, when Wingerchuk and colleagues first published independent
diagnostic criteria for the disease [2]. A major contribution to this new understanding has been the discovery of antibodies
in the serum of patients; these were initially referred to as NMO immunoglobulin G
(IgG). The membrane protein aquaporin-4 (AQP4) was identified as the target structure
of these antibodies [3]
[4]. This discovery led to a revision of the diagnostic criteria with the implementation
of antibody diagnostics as a biomarker of the disease in 2006. Since in about one-third
of the patients with the clinical presentation of an NMO, such antibodies were not
detectable, a distinction was made between “seropositive” and “seronegative” NMO [5].
Conversely, antibodies to AQP4 were detectable in patients who did not have the typical
symptoms of NMO (optic neuritis and myelitis, also referred to as “classic Devic’s
syndrome”). Primarily for this reason, the concept of NMO-spectrum diseases (NMOSD)
was established and gradually expanded. With the last revision of the diagnostic criteria
in 2015, this term was rendered uniform. Its use is now recommended for the description
of all seropositive and seronegative CNS disorders with a typical distribution pattern
and clinical course [6].
Epidemiology
Basically, the NMOSD is a much rarer entity of chronic inflammatory CNS disorders
compared to multiple sclerosis (MS). The geographical distribution of prevalence and
incidence is markedly different with a significantly higher incidence in Asian, African
and South American patients compared to Caucasians.
In a relatively recent epidemiological study, a prevalence of 3.9/100 000 persons
and an incidence of 0.7/1 000 000 person-years were determined in a Caucasian population
in North America (Olmsted City, Minnesota). On the Antilles island of Martinique,
the prevalence was 10/100 000 persons and the incidence of 7.3/1 000 000 person-years.
This is consistent with a Danish survey that reported a prevalence of 4.4/100 000
inhabitants [7]
[8] in the predominantly Caucasian cohorts. Retrospective studies of (Caucasian) patients
with chronic inflammatory, demyelinating CNS disorders support these numbers, NMOSD
cases comprising approximately 1.5% of all cases in the widest sense [9]. The findings from the Caribbean population underline the fact that, as in the whole
of South America, NMOSD is much more common in the Caribbean than in Europe.
Surprisingly, in individual cohorts in Japan, the prevalence of NMOSD at 0.9/100 000
was unusually low [7]. However, it must be taken into account that in Japan often the diagnosis of “opticospinal
MS” (OSMS) is made. Although OSMS is not conclusively assigned to the NMOSD spectrum,
patients with OSMS share numerous other similarities in addition to the typical distribution
of the lesions with only occasional intracerebral demyelinating lesions. These include
a comparable course with rapid accumulation of disability; however, oligonoclonal
bands [10] are only detected in exceptional cases. However, the strongest argument for such
an association is the prevalence of AQP4 antibodies in 50% of OSMS patients [11]
[12].
Including OSMS patients, NMOSD represents approximately half of all cases of chronic
inflammatory, demyelinating CNS disorders in Asian patients [13].
For these reasons, the current consensus criteria recommend that the term OSMS be
used no longer, but that in these patients the diagnosis of an NMOSD (seronegative
or seropositive) should be made.
The age at the initial manifestation of NMOSD is on average 37.8 years, which is approximately
10 years above the mean manifestation age in MS patients. However, initial manifestations
were also observed in significantly older patients.
With a ratio of approximately 9: 1 (f: m (female to male sex ratio)), NMOSD occurs
significantly more frequently in females, especially in its seropositive forms, than
multiple sclerosis ( ratio f: m=2–3: 1 [9]
[14]. The preferential occurrence of NMSOD in women decreases in AQP4-seronegative patients
and especially with those with detectable antibodies against myelin oligodendrocyte
glycoprotein (MOG); MOG antibody-associated NMOSD forms occur even more frequently
in men (0.6: 1 (m: f)) [15].
NMOSD patients also tend to develop other antibody-mediated (or at least antibody-associated)
autoimmune diseases. Thyroid disorders (~14% of patients), Sjögren's syndrome (~20%
of patients) and myasthenia gravis (2%) [16]
[17] are the most common diseases in these patients. Overall, approximately one-third
of NMOSD patients suffer from at least one further manifest autoimmune phenomenon
with marked preference for seropositive patients (58.5% for AQP4+ patients vs. 8.6%
for AQP4-patients) [14]. The tendency to form autoantibodies is illustrated by the fact that positive antinuclear
antibodies without documented clinical manifestation are present in approximately
half of all NMOSD patients [17]. There are case reports of manifest systemic lupus erythematosus [18].
Due to the high clinical relevance and the necessity for vigilance, it must be borne
in mind that a bi-directional association exists between Myasthenia gravis and NMOSD.
Since NMOSD is most common in myasthenia patients after thymus resection, this differential
diagnosis should be considered in the presence of the relevant clinical symptoms.
It is unclear, however, whether presence of AQP4 antibodies without corresponding
clinical symptoms in individual cases of myasthenia patients is a meaningful indication
for screening (if necessary, prior to indicated thymus resection) [19].
Pathogenesis
The pathogenesis of NMOSD has not been conclusively clarified. By identifying the
target structure Aquaporin-4, however, there has been a gain in the understanding
of immunopathogenesis. In this article, only selected aspects, which can explain directly
clinical findings, are recapitulated.
A key role in disease development is the autoimmune-mediated destruction of astrocytes
by the immune system [20]. The formation of autoantibodies against the water channel protein Aquaporin-4 (AQP4)
represents the first step of the immunopathogenesis. This protein is expressed at
astrocyte processes involved in the construction of the blood-brain barrier. Furthermore,
AQP4 occurs more frequently in the gray matter of the spinal cord and the periaqueductal
and periventricular zones [21].
The binding of AQP4 antibodies to the astrocyte processes of the hemophilia barrier
leads to cell death of astrocytes, for which, among others, antibody-mediated complement
activation and cytotoxic T cells are responsible.
After disruption of the blood-brain barrier, inflammatory cells, in addition to lymphocytes,
typically also neutrophils and eosinophilic granulocytes, migrate into the CNS [14]. The inflammatory response leads to secondary damage of neurons and oligodendrocytes
with corresponding atrophy and demyelination, possibly by glutamate overstimulation
after increased release of this transmitter from dead astrocytes [22]
[23]
[24].
The death of astrocytes and neurons could be visualized in MRI of NMOSD patients.
The results differed markedly from MS patients with detectable, primary damage to
the oligodendrocytes [25].
In the case of NMOSD patients, the changes in the central nervous system that have
been detected so far are strictly limited to those of inflammatory origin. In the
case of MS patients, however, structural abnormalities of the white substance not
detected by MRI have also been described.
Possibly due to this, there is no generalized or localized (e. g., the thalamus) cerebral
atrophy in NMOSD patients. This can explain the absence of a chronic-progressive course
of the disease [26].
For the recruitment of the inflammatory cells in NMOSD, interleukin-6 (IL6) more frequently
found in the CSF appears to be responsible. IL6 is released, among others, by special
subgroups of T lymphocytes (Th17 cells) [27]
[28].
The involvement of Th17 cells is a possible explanation for the ineffectiveness of
different MS therapeutics in NMOSD patients, as these cells use alternative strategies
to invade the CNS compared to “conventional” T cells [29]
[30].
However, typical markers of intrathecal antibody synthesis are absent in NMOSD, up
to 90% of the patients lack oligoclonal bands. An MRZ reaction can only be detected
in isolated cases [31].
It is worth mentioning that AQP4 is also expressed in other organs, such as the placenta.
This could be an explanation for the increased rate of miscarriages and pregnancy
complications in NMOSD patients [32].
Manifestations of NMOSD
A major improvement of the revised diagnosis criteria of 2015 is the recognition that
although the optic nerve, the spinal cord and area postrema are the preferred sites
of NMOSDs manifestation, in principle they can affect all parts of the central nervous
system. Accordingly, three further manifestations were defined in addition to the
three “classical” regions. These six categories are presented briefly below.
Nervus Opticus
Optic nerve (neuritis nervi optici, ON) is one of the most frequent manifestations
of NMOSD and is therefore also listed as a “core criterion” in the new diagnostic
criteria. Even if an optic neuritis can in principle be the expression of numerous
isolated or disseminated CNS disorders, the NMOSD-ON has certain characteristic features.
The presence of bilateral manifestation is highly suspicious, but unilateral inflammation
occurs in about 80% of the cases at initial manifestation [33]. Clinically, NMOSD-ON impresses with a high degree of loss of visual acuity to blindness
and very limited recovery. Radiologically, it is often associated with long-term affection
of the corresponding optic nerve, extending into the optic chiasm. Electrophysiologically,
the visual evoked potentials often show a significant amplitude reduction. The combination
of persisting deficit and electrophysiological findings can suggest a vascular genesis
[34]. The differential diagnosis can be made more difficult by the fact that no oligoclonal
bands are detectable in a majority of NMOSD patients (see chapter “CSF Diagnostics”)
([Table 1 ]).
Relapsing, but monotopic manifestations in AQP4-negative patients, such as the chronic-relapsing
inflammatory optic neuropathy (CRION), are not as yet included in NMOSD. CRION is
characterized by severe clinical symptoms that can lead to blindness in untreated
patients and quickly responds to therapy with corticosteroids. Uni- and often bilateral
manifestations occur, and orbital pain is often very pronounced, especially in the
initial phase. Further differential diagnosis including MRI imaging is inconspicuous
with regard to disseminated inflammatory activity. The relapsing course requires in
long-term immunosuppression, the majority of the drugs listed the chapter “Therapy”
is effective [35].
Spinal Cord
Myelitic manifestations of NMOSD have a prominent position in the manifestation sites
due to the fact that they contribute significantly to the accumulation of disability
and also to the mortality.
In NMOSD, most impressive variant of transverse myelitis extends over more than three
segments. This is designated as “longitudinally extensive transverse myelitis” (LETM)
[36]. During acute inflammation, the affected spinal cord segment usually shows marked
swelling. In addition to pronounced T2 hyperintensity in spinal MRI, lesions often
show strong contrast-enhancement after application of gadolinium.
MRI images acquired very early in the course of the disease demonstrate either multiple
short lesions that become confluent with time, or even isolated lesions that expand
correspondingly [37]. Cervical lesions often extend into the medulla oblongata. In a small longitudinal
cohort with 63 patients, one-fifth of the patients also showed cystic lesions [38]. Clinically, severe sensorimotor deficits as well as bladder and bowel dysfunction
are in the foreground. Even a single episode can lead to being permanently chained
to a wheelchair due to severe paraplegia or tetraplegia [39]. As a correlate of the severe defect with spastic paresis, MRI reveals a high degree
of atrophy of the areas the previously swollen areas (“hourglass-shaped atrophy of
the spinal cord”) after the inflammatory activity has subsided. This impressively
illustrates the functional discontinuity of the spinal cord [40] ( [Fig. 1] ).
Area Postrema and Brainstem
Area Postrema and Brainstem
In addition to the caudal medulla oblongata that is affected in the context of LETM
originating from the cervical spine, NMOSD can also primarily affect the brainstem.
The classical localization is the area postrema (due to the strong expression of aquaporin-4).
There is clinical manifestation of area postrema syndrome (APS) with persistent hiccups,
nausea and vomiting [41]. If inflammation spreads from the area postrema into the adjacent brainstem, cranial
nerve failure, vegetative dysfunction and sensorimotor deficits of the whole body
can occur. Since such severe, potentially life-threatening relapses can be induced
by an area postrema syndrome, MRI should be performed generously in NMOSD patients
with suspicious symptoms [42].
However, brainstem lesions can also primarily occur apart from the area postrema and
lead to corresponding symptoms (including oculomotor dysfunction, facial palsy, trigeminal
neuralgia) [43]. These rare lesions are summarized in the revised diagnostic criteria under the
term “acute brainstem syndrome” and distinguished from the classical area postrema
syndrome.
Diencephalon
Lesions in the area of the diencephalon, which can occur in the context of NMOSD,
are most frequently associated with disorders of sleep-wake rhythm in the sense of
symptomatic narcolepsy. Likewise, disturbances of thermoregulation may appear as an
expression of hypothalamic dysfunction or endocrinological syndromes with underlying
pituitary insufficiency. MRI correlates of these disorders are signal alterations
in the region of the hypophysis, hypothalamus or adjacent to the third ventricle [44]
[45]. These symptoms are summed up in the revised diagnosis criteria under the term “diencephalic
syndrome”.
Cerebral Hemispheres
One of the clearest changes in the diagnostic criteria of NMOSD is in relation to
the occurrence of cerebral white matter lesions. In the previous revision of the NMO
diagnostic criteria, such lesions were listed as “red flags”, if not as an exclusion
criterion for diagnosis. The only exception was leukoencephalopathy of alternative
origin, for instance, as a result of cerebral microangiopathy. Meanwhile, however,
longitudinal studies have shown that up to two-thirds of NMOSD patients also develop
inflammatory white matter lesions. There are some morphological differences compared
to MS-typical lesions. Thus, NMOSD-associated lesions are usually larger and in the
acute phase more markedly edematous [46]. These lesions are often localized subcortical and periventricular, but the latter
are not oriented perpendicularly to the lateral ventricles (like the “Dawson’s fingers”
in the MS), but align themselves parallel to this, affecting over 50% of the roof
of the ventricle. Subcortical lesions usually follow the course of corticospinal tracts.
In contrast, NMOSD is unlikely if disseminated, juxtacortical lesions are present
or the inferior temporal lobes are involved; these lesions should suggest a diagnosis
of MS [47]. Isolated cases running a fulminant course with cerebral demyelination, cerebral
edema with herniation and death have been described [48] ( [Fig. 2]).
Diagnosis Based on the Revised Diagnostic Criteria
Diagnosis Based on the Revised Diagnostic Criteria
Seropositive NMOSD
In presence of AQP4 antibodies, a diagnosis of NMO-spectrum disorder can and should
be made if one of the six sites is affected. For example, in the case of optic neuritis
and detection of AQP4 antibodies, a diagnosis of seropositive NMOSD should be strived
with all its therapeutic consequences.
The criterion of temporal dissemination in time the diagnosis of NMOSD does not exist
because of the existence of monophasic disease coureses. This appears to be meaningful
in the face of accumulation of severe disabilities during disease exacerbation and
the associated necessity to start a disease-modifying therapy quickly.
Fig. 1 MRI findings in NMOSD-associated ON and LETM of a single patient. a, b: Coronary T2 and T1Gd visualization of the optic nerve at the level of the optic
chiasm with signs of blood brain barrier disruption and edematous swelling due to
bilateral ON. c/d: Sagittal representation of the spinal cord in T2 b and T1Gd c. LETM extending over at least 9 segments with edematous swelling and barrier disorder.
e/f: Axial representation correlated to c/d: at segment Th1. Typical is the concentric affection of the spinal cord, which also
leads to the gray matter being affected. Clinically, the patient presented with high-grade
tetraplegia.
Fig. 2 MRI findings of intracerebral manifestations in NMOSD. a/b: axial and sagittal T2 imaging of the brain stem in patients with area postrema syndrome
and multiple intracranial nerve deficits (including oculomotor dysfunction and dysphagia).
The cervical spinal cord also shows a section of an LETM: section of the upper cervical
region. c: Axial FLAIR representation of the dicephalon of a patient with newly diagnosed narcolepsy
and evidence of AQP4 antibodies. d: Evidence of periventricular white matter lesions in patients with known NMOSD. In
contrast to MS-typical lesions, here they run a parallel course along the ventricle.
It is important to note that cell-based detection methods should be used because they
are superior to the ELISA-based method in specificity and sensitivity. False-positive
antibody detection in cohorts with definitive diagnosis of MS was found in 1.3% of
cases in ELISA tests, whereas in similar cohorts, there were only 0.1% false-positive
results in studies using cell-based detection methods [49].
Seronegative NMOSD
In absence of antibodies against AQP4, more stringent criteria apply for classifying
an inflammatory syndrome of the CNS as NMOSD. In contrast to the seropositive variant,
there is dissemination to at least two sites necessary. At least one of which must
correspond to a “classical” site (spinal cord, optic nerve or area postrema). Furthermore,
the additional requirements for MRI findings listed in [Fig. 3] apply. Special care is required to differentiate suspected NMOSD with optic neuritis
and cerebral demyelination areas. The diagnosis of NMOSD can only be made in this
situation if the optic neuritis shows clear signs of NMOSD-ON. Due to therapeutic
consequences of the assignment of a case to either MS or NMOSD, diagnosis should be
done in consultation with specialists or by a specialized center. As already mentioned,
the diagnostic criteria do not include a criterion of dissemination in time. Accordingly,
NMOSD can not be diagnosed in seronegative patients with a monotopic manifestation
but with a relapsing course (in ~10% of patients) [14].
Fig. 3 Schematic representation of the diagnostic criteria according to Wingerchuk and colleagues
(2015 version). The individual flow diagrams show the minimum necessary findings in
the respective constellations. For seronegative NMOSD additional MRI criteria must
be met. MOG-positive NMOSD/MOG spectrum disease.
MOG-positive NMOSD/MOG spectrum disorder
In recent years, autoantibodies to the myelin oligodendrocyte glycoprotein (MOG) have
been detected in about a quarter of the AQP antibody-negative patients with clinical
suspicion of NMOSD [6]. In seropositive patients, however, they are virtually never demonstrable. In contrast
to AQP4, MOG is not an astrocytic protein, but is expressed on the surface of oligodendrocytes
and has been considered as a possible autoantigen in multiple sclerosis. Antibodies
against MOG have so far been reported mainly in children with acute demyelinating
encephalomyelitis (ADEM), where they are more frequently detectable [50]. Due to the clinical course, comparable laboratory findings and results of CSF examination
and partially comparable pathomechanisms, patients with appropriate symptoms and with
demonstrable MOG antibodies are occasionally included in the “seronegative NMOSD spectrum”.
This assignment is certainly not final at the present time; schematically, the “MOG
antibody spectrum” is often located between “classical” NMOSD, ADEM and MS.
MOG-positive patients are significantly more frequently male, mostly younger and more
frequently show positive oligoclonal bands in the CSF [6]. Spinal manifestations are less frequent, but optic neuritis occurs more frequently.
In particular, bilateral optic neuritis or involvement of the conus medullaris in
myelitis is suggestive for the presence of MOG antibodies [51]. The latter can be the trigger for significant bowel and bladder dysfunction. MOG-positive
patients were generally thought to have more favorable clinical course with better
recovery of deficits and slower accumulation of disabilities [15]. Recent retrospective data clearly indicate the opposite. Thus, the lower disability
accumulation per relapse appears to be cancelled by a higher relapse frequency. The
interval between the first and the second relapse also appears to be shorter [52]. There are also no differences in impairment of visual acuity [53]. Furthermore, approximately one-third of the patients develop brainstem involvement,
some with dramatic consequences [54]. Overall, the MOG-positive NMOSD also appears to need unrestricted and long-term
treatment.
Clinical Course
In approximately 90% of the cases, NMOSD runs a relapsing course, and in only about
10%, the disease is monophasic [6]. A second relapse occurs in 60% of patients in the first year, and in 90% of patients
within 3 years after diagnosis [2]. Often the course of NMOSD runs in “clusters” with phases of frequent exacerbation,
alternating with low activity phases.
Monophasic disease course is more common in seronegative, younger patients, but there
are no reliable predictive markers. Remarkably, the relapses in monophasic patients
are often more severe than those in patients with a relapsing form of the disease.
In view of the high relapse-associated morbidity, monophasic disease should be assumed
at the earliest after 5 years of relapse-free course [14]. With increasing effective long-term therapy, the question will arise more frequently
as to whether the degree of disease-freedom is the consequence of per se decreasing
disease activity or, whether it results from adequate immunosuppressive therapy.
Accumulation of disability is strictly relapse-dependent in NMOSD patients; a chronic-progressive
form exists, if at all, only in exceptional cases [6].
Due to the severity of the disease, half of the patients get blind after 5 years and
are no longer independently mobile. In addition, 20% of patients die after 5 years.
The most frequent cause of death is respiratory failure and associated complications,
mostly as a result of cervical transverse myelitis [55]. These values have probably improved with the availability of monoclonal antibodies;
however, recent data are not available besides individual therapy test reports.
Diagnostics
As with all inflammatory syndromes of the CNS diseases, diagnosis is based primarily
on imaging and laboratory values, together with clinical findings.
MRI
In patients with suspicion of NMOSD based on history and clinical presentation, MRI
scan of the head and entire spinal cord is indicated including application of gadolinium.
Even if clinically silent manifestations are rare, MRI has a central role in differential
diagnosis. Follow-up examinations, especially in unclear cases or an with atypical
clinical course (especially in chronic progression) are useful. In contrast to MS,
regular MRI examinations to detect paraclinical disease activity are of minor importance
[6]. In line with the guideline of the German Society of Neurology (DGN) for the diagnosis
of multiple sclerosis, the imaging of the head should include native axial T2 sequences
as well as axial T1 sequences, without and with gadolinium administration. In particular,
to distinguish NMOSD from MS, a T2 sequence in sagittal plane is recommended. Imaging
of the spinal cord should include sagittal T1 sequences before and after gadolinium
application as well as a sagittal T2 sequence. Axial sequences in axial T1 and T2
sequences weighting complete the basic program. In the case of clinical suspicion
of an affection of certain specific structures (optic nerve, brain stem, etc.), appropriate
thin-sliced imaging of these structures is recommended [6].
CSF diagnosis
Lumbar puncture should be performed for the purpose of differential diagnosis. Typically,
NMOSD patients exhibit lymphogranulocytic pleocytosis with the presence of neutro-
and eosinophilic granulocytes. The cell count can increase significantly in acute
attack, values of more than 50 cells/μL have been regularly observed. Oligoclonal
bands are only detectable in 10–20% of the patients and should give rise to a more
thorough diagnostic process. A polyspecific antiviral immune response (“MRZ reaction”)
is detectable only in isolated cases [56]. This is in contrast to MS, where oligoclonal bands are detectable in over 90% of
cases [23]. Numerous other observations have been published which have a high specificity for
NMOSD, but are still of no relevance in clinical practice.
Table 1 Characteristics of optic neuritis (ON) in NMOSD and MS.
|
NMOSD
|
MS
|
|
Common manifestation
|
Uni- or bilateral
|
Unilateral
|
|
Extent of loss of vision
|
High grade, blindness possible
|
Blindness not common
|
|
MRI findings
|
Extensive lesion (>50%), extending into the optic chiasm
|
Short lesion, no involvement of the chiasm
|
|
Visual evoked potentials
|
Prolonged latency, Amplitude reduction
|
Prolonged latency
|
|
Convalescence
|
Frequently high-grade, persisting deficit
|
As a rule, good recovery
|
These include, among others, an increase in the levels of interleukin-6 and detection
of glial fibrillary acidic protein as a correlate of astrocytic damage [57]. Extensive measurements of the cytokine levels in the CSF or the determination of
AQP4 or MOG antibodies in the CSF have no confirmed value [58].
Diagnosis of AQP4 and MOG Antibodies in Serum
Diagnosis of AQP4 and MOG Antibodies in Serum
Due to the impressive specificity of a positive AQP4 antibody finding, a test should
always be carried out in case of suspicion. Three important findings are to be taken
into account in the test: firstly, the strength of a finding depends to a considerable
extent on the related diagnostic process. Secondly, AQP4 titers may drop after therapy
or in phases of low disease activity or seroconversion may even occur in a patient.
Thirdly, in patients initially seronegative, AQP4 antibodies may be detected over
time [59].
The first available tests detected AQP4 antibodies using ELISA technology. Since no
native but denatured AQP4 was used in this test method, the sensitivity was only 60%.
Cell-based methods, in which serum is incubated with AQP4-expressing cells and subsequently
evaluated by means of flow cytometry or microscopy, reach values of up to 77%. Accordingly,
only the latter methods should be applied [49].
In seronegative patients with suspicion of NMOSD, a diagnosis should be based on the
presence of MOG antibodies. Here too, cell-based test methods should be used [50].
In the case of seronegative patients with suspicion of NMOSD, the test should be repeated
with regard to AQP4 and MOG antibodies, and blood should be drawn before the start
of therapy. In individual cases, the corresponding antibodies were detectable in the
CSF in patients with inconspicuous serum findings. Accordingly, in seronegative patients
with high clinical suspicion, such CSF diagnosis may be useful [60].
Differential diagnosis
The most important differential diagnosis of NMO-spectrum disorders is multiple sclerosis.
A confirmed diagnostic classification is essential due to major differences in therapy.
It is therefore not surprising that most of the “red flags” explicitly named in the
diagnostic criteria for NMOSD of 2015 are simultaneously reliable characteristics
of MS.
MRI findings of periventricular lesions, lesions in the inferior temporal lobe, “Dawson
fingers” and juxtacortical lesions, especially involving the U fibers, more likely
suggest multiple sclerosis.
The cranial MRI of NMOSD patients is usually inconspicuous, especially when patients
with symptomatic cerebral syndrome are excluded [47]. Even if due to the localization there is no suspicion of MS, cases with relevant
lesions in the cerebral cranial MRI require particularly critical evaluation.
The detection of oligoclonal bands in the CSF is more likely suggestive of multiple
sclerosis, whereas the demonstration of granulocytes in CSF suggests NMOSD. [Table 2] lists “red flags” in the differential diagnosis of the NMOSD.
Table 2 “Red flags” in NMOSD, modified according to [6].
|
Course of the disease
-
Chronic-progressive course, relapse-independent deterioration
-
Progressive worsening of suspicious symptoms over several weeks
-
Spontaneous remission of neurological deficits after a short time
|
|
Clinical and laboratory findings
-
Detection of oligoclonal bands in the CSF
-
Serologic testing of serum/CSF (e. g., HIV, syphilis, borreliosis)
-
Detection of solid or hematological tumor diseases
-
Proof of generalized or hilar lymphadenopathy
|
|
MRI findings
-
relevant lesion burden in cranial MRI, in particular with
-
Detection of MS-typical lesions (“Dawson’s fingers”)
-
Detection of cortical lesions
-
Detection of lesions of the inferior temporal lobes
-
Proof of persistent gadolinium-enhancement
-
Detection of persistent short-range lesions in the spinal cord
|
In addition to multiple sclerosis, other systemic and CNS autoimmune diseases, vasculitides,
malignomas as well as hereditary and infectious CNS diseases should be taken into
account in differential diagnosis. Attention is specially drawn to neurosarcoidosis
since it can manifest itself with NMOSD-typical symptoms such as optic neuritis and
LETM, and presents great difficulties in differential diagnosis [61].
In general, LETM as a common manifestation cannot be classified solely on the basis
of MRI findings. Corresponding cases have been documented by Trebst and colleagues
[36].
The diagnosis is sometimes made more difficult by the detection of antinuclear antibodies
in NMOSD patients [62]. Furthermore, several autoimmune diseases can also be present concomitantly. For
instance, there are reports of patients with concomitant systemic lupus erythematosus
and NMOSD [63]. [Table 3] gives a selected overview of differential diagnoses.
Table 3 Overview of selected differential diagnoses of the NMOSD.
|
Multiple Sclerosis
|
|
Autoimmune diseases
|
|
Vascular diseases
|
|
Infections
|
|
Hereditary diseases
-
Hereditary spastic paraparesis
-
Leber hereditary optic neuropathy
-
Arnold-Chiari malformation
|
|
Neoplastic diseases
-
Primary tumors of CNS
-
Metastases
-
CNS lymphomas
-
Paraneoplastic syndromes
-
Angiomas
|
|
Metabolic diseases
|
Therapy
Treatment of acute relapses
As with multiple sclerosis, there are essentially four procedures available for the
treatment of acute relapses of NMOSD: corticosteroids, plasmapheresis, immunoadsorption
and intravenous immunoglobulins.
Table 4 Overview of available acute therapies for relapses in NMOSD.
|
Medication
|
Dosage and interval
|
|
Corticosteroids [63]
|
1 g Methylprednisolone/d over 5 days, if needed escalation with 2 g Methylprednisolone/d
(latter over a maximum of 5 days)
|
|
Plasmapheresis [64]
|
5–7 cycles every other day (exchange of 1.1 to 1.5 plasma volumes per session)
|
|
Immunadsorption [64]
|
5–6 cycles on consecutive days; tryptophan or protein A-columns (adsorption of 2 to
2.5 plasma volumes per session)
|
|
Intravenous immunoglobulins [69]
[70]
|
0.4 g/kg/d over 3–5 days, maintenance dose: 0.4 g/kg once a month
|
Table 5 Overview of available long-term therapeutics for NMOSD.
|
Substance (Study reference)
|
Mechanism of action
|
Dosage and interval
|
|
Azathioprine (+low dose prednisolone 1 mg/kg/d) [74]
[76]
|
Inhibition of nucleic acid synthesis
|
2–3 mg/kg divided over 3 single doses depending on lymphocyte number ca. 75–175 mg/d
|
|
Mycophenolate mofetil [77]
|
Inhibition of nucleic acid synthesis
|
1g twice daily
|
|
Rituximab [79]
|
Depletion of CD20+ B cells
|
A) Induction with two infusions of 1000 mg each within a two-week interval. Re-administration
upon increase of peripheral B cell count, but at least every six months
B) Induction with 4 infusions of 375 mg/m² each once a week, afterwards depending
on peripheral B cell count, e.g. 1000 mg/m² within a two-week interval.
|
|
Tocilizumab [81]
[82]
|
Blockade of IL6 receptor
|
8 mg/kg once every 4 weeks
|
|
Eculizumab [83]
|
Inhibition of complement activation by binding to C5
|
600 mg/week over 4 weeks, once 900 mg in week 5 and thereafter 900 mg once every two
weeks (Duration of therapy investigated: 48 weeks)
|
Table 6 Overview of active phase III therapy studies on NMOSD, with study data registered
up to 09/2016.
|
Study
|
Drug studied
|
Mechanism of action
|
Benchmark data
|
Identification number (Clinicaltrials.gov)
|
|
“PREVENT”
|
Eculizumab/Placebo
|
Inhibition of complementactivation by binding to C5
|
Completion planned 12/2016 (132 Patients), only AQP4+
|
NCT01892345
|
|
„N-MOmentum“
|
MEDI-551/Placebo
|
Depletion of CD19+ B cells
|
Completion planned 04/2020 (212 Patients), AQP4+/−
|
NCT02200770
|
|
SA-237 (Monotherapy)
|
SA-237/Placebo
|
Blockade of IL6 receptor
|
Completion planned 03/2019 (90 Patients), AQP4+/−
|
NCT02073279
|
|
“Sakura-SKY” (Add-on-Therapy)
|
SA-237/Placebo
|
Blockade of IL6 receptor
|
Completion planned 06/2020 (70 Patients), AQP4+/−
|
NCT02028884
|
High-dose administration of intravenous corticosteroids (1 g/d methylprednisolone
over 5 days) is currently the most frequently used therapy for acute attacks [64]
[65]. In the absence of improvement after therapy with 1 g/d methylprednisolone, a further
cycle of 2 g/d can be added on for a further 5 days. Ulcer and thrombosis prophylaxis
are essential.
Alternatively, plasmapheresis or immunoadsorption can be carried out. Both methods
have shown comparable efficacy. The selection can accordingly be oriented, besides
availability, to the side effects/to the side effects profile profile (necessity of
having to substitute foreign blood components after plasmapheresis, stronger affection
of the coagulation function after plasmapheresis). The effect of plasmapheresis or
immunoadsorption is not categorically different in seropositive or seronegative patients
[66].
In a recent retrospective study of the NEMOS study group, it was found that there
was complete remission in only 21.6% of the patients and partial remission in 72.4%
of the patients after all therapeutic procedures had been exhausted. It is astonishing
that already 19.1% of the patients achieved complete remission after the first of
up to five therapy courses. Plasma exchange methods have led to improved symptom control
especially in patients with acute myelitis. The positive effect of plasma exchange
decreased with the increase in previously undergone therapy procedures. These data
were not significant when comparing all kinds of relapses but other studies support
the estimation that plasma exchange is superior [65]
[67]. Individual studies also showed a cumulative effect of combined steroid pulse and
apheresis treatment (for example plasma exchange and infusion of corticosteroids on
alternating days) [68].
Intravenous immunoglobulins (IVIG) are currently only used in exceptional cases for
the treatment of relapses, as for instance in children. Currently there are no larger
studies, but patients are being recruited for a study on the treatment of acute transverse
myelitis with IVIG [69]. Different case series have documented the positive effects of IVIG so that its
use as second-line therapy can be justified (0.4 g/kg for five consecutive days) [70]. On the one hand, the therapy should be carried out only after plasma exchange has
been completed because efficacy is not clearly established and there is the risk of
leaching. Individual studies in pediatric patients showed a positive effect of IVIG
in maintenance therapy (dose: 0.4 g/kg bw every 4 weeks) [71] ( [Table 4]).
Disease-modifying therapy
Contrasting the 15 approved medications for the treatment of MS, there is no approved
drug for the treatment of NMOSD. This is mainly due to the absence of relevant randomized,
placebo-controlled trials. In addition to the rarity of the disease, other factors
contribute to this situation. On the one hand, approval authorities usually do not
recognize comparative studies between several unauthorized medications. On the other
hand, there are significant ethical concerns about placebo-controlled studies in the
face of threat of severe impairment after a single relapse. For the first time, different
drugs are tested in controlled clinical trials. Different methods, for instance, asymmetric
randomization in favor of the study medication, definition of the first relapse as
clinical end point or narrow time limitation of the study medication, were used for
risk minimization [72].
With the exception of mitoxantrone, rituximab and azathioprine, most drugs known from
MS therapy are either ineffective (e. g., glatiramer acetate) or even counterproductive
(e. g., interferon-beta, fingolimod, natalizumab, alemtuzumab). Under no circumstances
should they be used in the therapy of NMOSD. Instead, classical immunosuppressants
and various monoclonal antibodies are prefered in treatment of NMOSD [73].
As a rule, according to how well a drug is clinically established, three categories
of drugs can be defined: (1) “established” drugs with longer experience in off-label
use, (2) medication successfully used in individual cases, (3) drugs currently being
tested in studies.
Even though a wide range of drugs has already been used in the therapy of NMOSD, the
greatest amount of experience is available in relation to azathioprine, mycophenolate
mofetil and rituximab. Accordingly, these drugs are regarded as first choice drugs.
In some cases, the recommendation is made to use azathioprine and mycophenolate mofetil
for “mild” forms and rituximab for “highly active” forms of the disease. However,
in view of the risk of mortality, such considerations should be left to a specialized
center.
For azathioprine, several studies with approximately 100 patients each showed significant
reduction in the relapse rate and disability accumulation [74]
[75]. The high dropout rate of around 60% after two years, usually due to side effects,
as for example elevated liver enzymes, appears to limit its use. Due to the delayed
onset of drug effect, overlapping therapy with oral prednisone appears to be useful
after steroid pulse [76].
Mycophenolate mofetil (MMF) was effective in several smaller studies with up to 59
patients [77]. Randomized prospective studies, which allow a definite statement compared to azathioprine,
are not available. However, the fact that therapy dropouts were rarer during the observation
period than in the case of azathioprine speaks in its favor.
There are also positive data in support of the use of anti-CD20 antibody rituximab
in NMOSD patients. Numerous studies showed a significant reduction in the rate of
relapses and accumulation of disability. Long-term data of up to 67 months are available
for this drug [78]
[79]. Overall, its efficacy is superior to azathioprine and MMF, which is why its use
in “severe disease course” is recommended [80]. Because a priori the risk of rapid disability accumulation is already high after
a single relapse event in NMOSD, we tend to use primarily rituximab, particularly
in seropositive patients. We believe that this approach is supported by the lack of
reliable prognostic markers.
In particular, with regard to rituximab, there are two treatment schemes both of which
are equally effective: Scheme (1) was originally designed for the treatment of lymphoma.
Despite the higher amount of drug used, it lacks superiority compared to scheme (2).
As costs of this off-label use have to be negotiated with the health insurance, scheme
(1) has largely been abandoned in Germany.
Maintenance therapies should be performed when there is a renewed increase of CD19+ B
cells or CD27+ memory B cells in the peripheral blood, but at the latest after 6 months
in each case. Various biomarkers, such as the FCGR3A polymorphism, associated with
a poorer response to therapy, are not currently established in the clinical routine
[79].
Tocilizumab is the second successfully used monoclonal antibody. Tocilizumab binds
to the IL6 receptor, without activating it and thus blocks the proinflammatory effect
of the cytokine IL6. In 2013, first positive data were published [81] and in 2015, the drug was found to be effective in a small study of 8 rituximab-refractory
8 patients [82]. Usually 8 mg/kg body weight is infused every 4 weeks ( [Table 5]).
Eculizumab, which intervenes in the complement cascade by binding to the protein C5,
is an option as well; data, however, are sparse but positive. In 2013, an open-label
study with 14 patients observed over a period of 48 weeks reported disease stabilization
[83]. Under treatment with eculizumab, there was a significantly increased susceptibility
to meningococcal meningitis. Accordingly, in addition to high clinical vigilance,
the administration of a protective vaccination and/or an antibiotic prophylaxis according
to summary of product characteristics (SMPC) is indicated.
Current therapies of NMOSD and Perspectives
Current therapies of NMOSD and Perspectives
Although, as stated at the beginning of the previous section, clinical studies on
the implementation of therapies in NMOSD remain difficult, several large-scale Phase
III trials are recruiting patients.
As a consequence of the positive but highly preliminary results of an open-label study
of eculizumab, the manufacturer initiated a phase III study, which is expected to
deliver first data by the end of 2016. However, only AQP4-seropositive patients were
included. Eculizumab was added to an existing immunosuppression – with the exception
of rituximab.
In the N-MOMENTUM study, patients are randomized 3: 1 to MEDI-551, a B cell-depleting
antibody directed against CD19. The therapy duration is limited to 197 days, followed
by the option to participate in an extension study [72].
Two studies were started to evaluate the IL6 receptor antibody SA-237, which is a
derivative of tocilizumab and has an approximately fourfold longer half-life. In the
first phase III trial, 70 patients are scheduled to receive either SA-237 as monotherapy
or placebo. The parallel-running Sakura-SKY study randomizes 90 patients to SA-237
or placebo under continuation of the existing immunosuppressive therapy. The results
of the studies on MEDI-551 and SA-237 are not expected to be available until 2019
at the earliest.
Other therapeutics are in early stages of development, such as the monoclonal antibody
aquaporumab, which binds to AQP4 and prevents the interaction of the protein with
endogenous AQP4 antibodies and the resulting cell damage [84]. However, no clinical trials have yet been registered with this antibody. Ublituximab
is another B-cell depleting antibody in Phase I trial (NCT02276963) ( [Table 6]).
Conclusion for Practice
By revising the diagnostic criteria, the term neuromyelitis optica (NMO) is being
increasingly replaced by NMO-spectrum diseases (NMOSD). In the future, the new term
will cover a broader range of clinical presentations with presumably comparable immunopathogenesis.
The “MOG Antibody Spectrum”, a new entity crystallized out of diseases, has its own
biomarker and partly already included in the NMO spectrum. However, monotopic presentations
such as isolated, relapsing transverse myelitis or chronic recurrent inflammatory
optic neuritis are not (yet) included in this spectrum. For the first time, controlled
therapies have been initiated for NMOSD patients, but results are still pending.
The initial diagnosis should include spinal and cranial MRI images as well as CSF
and laboratory diagnostics. Special attention should be paid to cell-based antibody
diagnosis. Following acute therapy where necessary, NMOSD patients should be referred
to a specialized center for further diagnosis and implementation of long-term immune
therapy concepts. Taking up contact to national or international study groups (e.g.,
german NMO study group (www.nemos-net.de)) is recommended.
