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Page 8 Bozzetti et al. Neuroimmunol Neuroinflammation 2021;8:1-13 I http://dx.doi.org/10.20517/2347-8659.2020.26

increase in NfL levels over time on repeated measurements. Although data on the difference of NfL levels
between patients with a progressive vs. relapsing course are divergent, a recent systematic review confirmed
that among subjects with a progressive course, higher levels are observed in those with increased clinical
and radiological evidence of disease activity. The impact of disability and the possible role of NfL in
predicting future disability is still debated. Finally, treatments with DMTs including natalizumab, rituximab,
fingolimod, ocrelizumab, and mitoxantrone seem to affect plasma NfL levels. Unestablished treatments,
[66]
first-line DMTs, or neuroprotective treatments seem less effective in influencing NfL values .
NFL IN NMOSD AND RELATED DISORDERS
NMOSD is an inflammatory CNS syndrome currently diagnosed on the basis of clinical, neuroimaging
[2]
and laboratory features . The most typical presentations of NMOSD include acute (usually bilateral) optic
neuritis with severe visual acuity impairment and longitudinally extensive transverse myelitis (LETM),
typically presenting with severe symptoms including paraplegia, bowel/bladder dysfunctions, and sensory
loss [67,68] . However, unilateral optic neuritis, short-segment myelitis and other limited forms of neurological
[69]
syndromes do not exclude NMOSD diagnosis . The course is usually relapsing (90%), with increasing
[70]
burden of impairment resulting from incomplete attack recovery , and it is influenced in particular by
[71]
onset age, onset phenotype, and ethnicity . In most patients with a diagnosis of NMOSD, AQP4-Abs
[2]
are detectable in serum, reflecting the autoimmune pathogenesis of the disease . However, seronegative
cases are also part of the spectrum, and often represent a diagnostic challenge, with unpredictable disease
course and final outcome. The development of cell-based assays using transfected cells and a full-length
[72]
[7]
conformationally intact MOG has allowed the identification of serum and, more rarely, CSF antibodies
to MOG in a proportion of patients with NMOSD. However, the clinical spectrum associated with MOG-
Abs encompasses a broadening range of phenotypes, including NMOSD and partial forms of the disease
(prevalent in adults) and ADEM (prevalent in children) [73-76] .

In cases positive for MOG-Abs, isolated optic neuritis (ON) is the most common onset presentation (55%-
64%), with simultaneous bilateral involvement in 34%-42% of patients [76-78] , followed by acute transverse
myelitis (22%-37%), which typically presents as a LETM with enhancement with blurred margins, the
so called “cloud-like enhancement”. Simultaneous ON and myelitis (8%) , an ADEM-like presentation
[79]
[78]
particularly in children, and, more rarely, brainstem presentations and encephalitis [77,80] are other clinical
phenotypes associated with MOG-Abs positivity. Disease course can be either monophasic or relapsing
(30%-70% of cases), with relapses occurring most frequently in the first year after onset and influenced
by acute treatment choices [76,78] . Relapses are considered less common in this condition than in AQP4-
[81]
Abs-positive NMOSD, manifest more common with ON, and have a great impact on disability . Up to
now, only monitoring of MOG-Abs titer has been proposed as a possible predictor of disease course. In
particular, disappearance of MOG-Abs in serum is considered prognostic of cessation of relapses [77,82] ,
although seropositivity can be maintained over years even without clinical activity . On the other hand,
[83]
MOG-Abs titer at onset does not predict the future disease course in terms of risk of relapses or final
outcome . As a consequence, antibody titers can help treatment decisions but do not seem reliable enough
[84]
to be used in the clinical setting for patients’ management. MOG-Abs related disorders usually have a
favorable prognosis, with a full/good recovery observed in 78% of cases. However, patients can be left with
significant sphincter/erectile dysfunction, cognitive impairment, and poor visual acuity, mainly driven
by onset attack. Good recovery is more frequent in cases with unilateral ON or ADEM and in younger
[78]
patients .
For the aforementioned characteristics of NMOSD and related conditions, it is evident that there is a need
to improve prediction of disease course and short-/long-term prognosis.

Previous reports described astrocytic damage as a primary pathologic process in NMOSD, which is
[85]
supported by the presence of AQP4-Abs in the serum of most patients (68%-91%) . These antibodies