Since the clinical characteristics and long-term outcomes of patients with NMOSD-NOSIS remain unknown, we retrospectively evaluated such patients in comparison with NMOSD-OSIS patients. Whereas it was not clear whether all patients with NMOSD-NOSIS will eventually develop ON/MY, our research showed that the majority do (88.37%). Only 11.63% of the total patients with NMOSD-NOSIS had non-opticospinal manifestations throughout the disease course. However, the follow-up period of NMOSD-NOSIS patients who showed restricted non-opticospinal manifestations was shorter than that of NMOSD-NOSIS patients who did not develop ON/MY; thus, it is possible that these NMOSD-NOSIS patients with restricted non-opticospinal manifestations will develop ON/MY before subsequent follow-ups.
NMOSD-NOSIS is easily misdiagnosed as Wernicke encephalopathy (peri-third ventricle region involvement), GBS (medulla oblongata involvement), or digestive system diseases (area postrema involvement). As NMOSD-NOSIS patients have a high probability of developing ON/MY, it is important to recognize that NMOSD can initially present with non-opticospinal symptoms. Our study revealed that all the non-opticospinal manifestations in NMOSD were brain/brainstem symptoms. Most of the non-opticospinal manifestations were area postrema syndrome (vomiting and hiccups), acute brainstem syndrome (vertigo, diplopia), and acute diencephalic syndrome (somnolence), which are now recognized as being among the core clinical characteristics of NMOSD, in addition to ON and LETM, and have been included in the newly proposed diagnostic criteria.[5, 7] More importantly, we identified other non-opticospinal manifestations, such as ataxia, facial paralysis, facial hypoesthesia, headache, psychiatric symptoms, limb spasms, and tinnitus, and the causative lesions were located in the cerebellum, brachium pontis, thalamus, and other nonspecific parts of the brainstem. These symptoms and their responsible lesions expand our understanding of the spectrum of initial symptoms of NMOSD, which may facilitate the early recognition of NMOSD-NOSIS patients.
Both non-opticospinal symptoms and associated medullary MRI lesions, particularly in the peri-third/fourth ventricle areas (diencephalon and area postrema), were reversible in many NMOSD-NOSIS patients. Compared with opticospinal symptoms, non-opticospinal symptoms recovered better. The CR rate of non-opticospinal symptoms was higher than that of opticospinal symptoms. Most of the lesions near the third and fourth ventricles (area postrema and diencephalon) resolved during follow-up. In addition, 12 patients presented with vomiting or hiccups as initial symptoms (suggesting area postrema involvement, but brain MRI was not performed at the time of onset). During the follow-up, no area postrema lesions were found on their brain MRIs, suggesting that the area postrema lesions may have disappeared.
It is worth noting that five NMOSD-NOSIS patients had a normal appearance on brain MRI when they complained of hiccups or vomiting. It is conceivable that the early the brain imaging may have missed evolving lesions. This postulation is supported by the observation that medullary lesions were detected in a subsequent MRI in one patient who had initially presented with area postrema syndrome 6 months prior. Another possible explanation is that the lesions were too small to be detected by MRI. Therefore, if a patient complains of nausea, vomiting, or other brainstem symptoms, which cannot be explained clinically and with normal-appearing MR images, the possibility of NMOSD should always be considered, and the serum AQP4 antibody should be assessed.
The clinical characteristics of NMOSD-NOSIS patients differed from those of NMOSD-OSIS patients. NMOSD-NOSIS patients had a younger onset age and lower serum AQP4 titers than did NMOSD-OSIS patients. Although NMOSD-NOSIS patients may develop ON/MY during follow-up, the frequency of non-ON/MY relapse episodes remained higher than that in NMOSD-OSIS patients. NMOSD-NOSIS patients more commonly had brainstem lesions, more cervical and less thoracic involvement, and less frequent LETM, than did NMOSD-OSIS patients.
NMOSD-NOSIS patients had better long-term clinical outcomes. NMOSD-NOSIS patients had lower EDSS scores at follow-up and took longer to reach EDSS scores of 3.0 than did NMOSD-OSIS patients, which may be due to the following reasons: 1) The brain lesions in NMOSD-NOSIS patients were mostly concentrated in the peri-third/fourth ventricle (diencephalon and area postrema) or periependymal areas in the brainstem, avoiding the pyramidal tract, and thus had little effect on motor function. 2) NMOSD-NOSIS patients had a younger age of onset than did NMOSD-OSIS patients. Several previous studies have reported poor clinical outcomes in older-onset patients with NMOSD.[10, 11] 3) The immunopathogenesis for NMO lesions in the peri-third/fourth ventricle areas may be different from the typically destructive NMO lesions that predominate in the optic nerves or spinal cord. Immunohistochemical analyses of archival brain, spinal cord, and optic nerve tissues obtained from patients with NMO have demonstrated a novel NMO lesion phenotype in the medullary floor of the fourth ventricle (including the area postrema), which exhibits loss of AQP4 and contains inflammatory cells, but lacks demyelination or necrosis.[12, 13] Binding of NMO-IgG to AQP4 in the peri-third/fourth ventricle areas may be less efficient at activating the complement system. The peri-third/fourth ventricle areas in the brainstem are close to the cerebrospinal fluid (CSF) circulation system, and these circumventricular neural structures are devoid of a blood-brain barrier (BBB)[14, 15]. This anatomical site could thus serve as an entry point for circulating AQP4-IgG entry into the CSF. We hypothesized that the circulating AQP4 antibody entered the CSF circulation through the weak BBB in the peri-third/fourth ventricle areas, thus reducing the concentration of AQP4-IgG in the serum and nerve tissue, and relieving the inflammatory response and neurological damage in these areas. The finding that the serum anti-AQP4 titers in NMOSD-NOSIS patients were lower than those in NMOSD-OSIS patients in our study supports our point of view. This hypothesis needs further corroboration with evaluation of the CSF AQP4-IgG titers in both NMOSD-NOSIS and NMOSD-OSIS patients in the future.
Our results should be interpreted with caution in light of several limitations. One is our relatively small sample size of NMOSD-NOSIS cases. Another is that we used retrospective data from a single center, so the potential selection bias and missing data may affect the interpretations of the findings and therefore the conclusions of the study. Despite these limitations, the long-term follow-up of these cases revealed the clinical characteristics and outcomes of NMOSD-NOSIS patients to a large extent. A larger multi-center prospective study with CSF AQP4-IgG data is needed in the future.