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Zhang et al. Neuroimmunol Neuroinflammation 2019;6:8 I http://dx.doi.org/10.20517/2347-8659.2019.06 Page 3 of 16

NMOSD patients, antibodies against myelin-oligodendrocyte-glycoprotein (MOG) rather than AQP4
antibodies are detectable. The clinical features of MOG-IgG-positive NMOSD are different from those of
the classic AQP4-IgG-positive NMOSD, and the underlying pathogenesis of the two conditions may also be
different. MOG is a glycoprotein localized on the myelin surface as well as in the cell bodies and processes
of oligodendrocytes. The MOG antibody is a subtype of IgG1, which is effective in regulating complement-
dependent cytotoxicity. MOG antibodies target myelin-forming oligodendrocytes, whereas AQP4 antibodies
damage astrocytes leading to secondary demyelination [23,24] . In terms of clinical features, MOG-IgG-positive
NMOSD tends to be monophasic, more common among men, and have a younger onset age and a better
[25]
prognosis . At present, it is unclear whether CNS demyelinating diseases mediated by MOG antibodies
should be independent of MS and NMOSD [26,27] . However, according to the revised NMOSD diagnostic
criteria in 2015, AQP4-IgG positive or negative diseases and MOG-IgG positive diseases can be classified as
[11]
NMOSD . AQP4 antibodies and MOG antibodies are mainly produced extrathecally and are therefore less
frequently found in the CSF than in the serum. AQP4 antibodies can be detected in the CSF in only 70% of
patients who are seropositive for AQP4 antibodies and in none of the patients who are seronegative for AQP4
antibodies [28,29] . Furthermore, the levels of AQP4 and MOG antibodies may vary during the course of the
disease. However, AQP4 antibody titers do not seem to predict long-term disease duration, and the serum
AQP4 antibody status does not predict immunotherapy response [30,31] .

TREATMENT OF ACUTE ATTACKS
At present, there is no cure for MS and NMOSD. The primary goal of therapy in the acute phase is to
alleviate symptoms, shorten the disease course, and prevent complications. Currently available treatments
only act on the inflammatory components of the disease process, and no therapy that can directly reverse
myelin loss or neuronal damage exists. As in other autoimmune diseases, the recommended management
strategy for patients with MS or NMOSD during the acute phase includes intravenous methylprednisolone
(IVMP) pulse therapy, plasma exchange (PE), and intravenous immunoglobulin (IVIG) [32,33] . The treatment
of acute attacks shortens the duration of relapses and reduces symptoms, but does not have long-term
neuroprotective effects [34,35] . IVMP is considered the standard treatment for acute attacks [36,37] . Mainly in
patients with contraindications to IVMP or disease that is refractory to IVMP, PE and IVIG are alternative
therapies. NMOSD lesions are associated with IgG, IgM, and complement deposition; all of these are
[38]
targeted by PE, which has a good therapeutic effect in NMOSD . Immunoadsorption (IA) can remove
immunoglobulins from the circulation, and is an alternative treatment for acute attacks [39,40] . For severe
[41]
attacks, PE and IA can be used as initial therapies . IVIG is a safe and well-tolerated immunotherapy that
could also be used as a treatment alternative for MS and NMOSD [42,43] . However, this recommendation is
based mostly on clinical experience, because of a lack of trials on IVIG monotherapy in the treatment of
[44]
acute attacks. Furthermore, IVIG probably confers no advantage over IVMP and PE . For MS, IVIG is
usually only used for patients with contraindications to IVMP and PE, as the efficacy of IVIG is uncertain.
NMOSD are humoral-mediated diseases, and therefore, therapeutic agents that inhibit B-cells or antibody
[46]
[45]
production may be effective . IVIG can reduce anti-AQP4 levels ; however, the efficacy of IVIG for acute
attacks still needs to be proven.
Corticosteroids are an important therapy in the acute phase of relapse. High-dose methylprednisolone
(0.5-1.0 g intravenously for 3-5 days) is recommended in the acute phase. The mechanisms of action
of IVMP include dampening the inflammatory cytokine cascade, inhibiting the activation of T-cells,
decreasing the expression of MHC-II molecules on antigen-presenting cells and the entry of immune
[47]
cells into the CNS, and facilitating the apoptosis of activated immune cells . Some studies have shown
that oral methylprednisolone is no worse than IVMP in terms of the clinical and radiological outcomes
of MS relapses [48-51] . The European Federation of Neurological Societies guidelines recommend an oral
[52]
methylprednisolone dose of at least 0.5 g/day for 5 days (cumulative dose, 2.5 g) . Several studies have