J Neurol DOI 10.1007/s00415-015-7787-3


Olfactory dysfunction in neuromyelitis optica spectrum disorders Lin-Jie Zhang1 • Ning Zhao1 • Ying Fu1 • Da-Qi Zhang1 • Jing Wang1 Wen Qin1 • Ningnannan Zhang1 • Kristofer Wood2 • Yaou Liu1,3,4 • Chunshui Yu1 • Fu-Dong Shi1,2 • Li Yang1

Received: 19 March 2015 / Revised: 4 May 2015 / Accepted: 14 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015

Abstract Few data were available for the understanding of olfactory function in neuromyelitis optica spectrum disorders (NMOSDs). The aims of our study were to investigate the incidence of olfactory dysfunction and characterize olfactory structures, using MRI, in patients with NMOSDs. Olfactory function was evaluated by olfactometer in 49 patients with NMOSDs and 26 matched healthy controls. MRI parameters such as olfactory bulb (OB) and the olfactoryrelated gray matter volume changes were assessed. The frequency of olfactory dysfunction was 53 % in patients with NMOSDs. Olfactory detection thresholds were positively correlated with serum aquaporin-4 antibodies (fluorescent units) tested by fluorescent immunoprecipitation assay (FIPA) in NMOSDs (p = 0.009). Patients with olfactory dysfunction had smaller OB volume than did patients without olfactory dysfunction or controls (p \ 0.01). Both detection and recognition thresholds for olfaction were negatively correlated with OB volume (p = 0.018, p \ 0.01). The significant gray matter volume reduction in NMOSDs was found in the bilateral piriform cortex, & Li Yang [email protected] 1

Department of Neurology, Tianjin Neurological Institute, Radiology, Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China


Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA


Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam 1007 MB, The Netherlands


Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

orbitofrontal cortex, and parahippocampal gyri (FDR correction, p \ 0.05, cluster size [200 voxels). Our data suggested that olfactory function deficits are prevalent in patients with NMOSDs. Reduced OB and olfactory-related cortex volume may be responsible for the olfactory dysfunction. Keywords Neuromyelitis optica spectrum disorders  Olfactory dysfunction  MRI  Aquaporin 4  Olfactory bulb

Introduction Neuromyelitis optica (NMO) spectrum disorders (NMOSDs) have recently been recognized as an anti-aquaporin (AQP)-4 antibody-mediated astrocytopathy of the central nervous system. Lack of cerebral involvement, particularly during the early stage of disease, was initially proposed in NMO [1, 2]. However, accumulating evidence has revealed the involvement of various regions of the brain, both symptomatic and asymptomatic, in NMOSDs. Lesions present as a mirrored distribution of AQP-4, particularly adjacent to the ventricles [3]. Unlike in multiple sclerosis (MS), cortical lesions have not yet been detected in pathological and 7-T magnetic resonance imaging (MRI) studies on NMOSDs [4, 5]. The characteristics of these lesions are distinctive in MS, which typically involves periventricular, juxtacortical, and infratentorial regions [6]. Recognizing the different characteristics of the clinical features in NMOSDs and MS facilitates differential diagnosis of the two diseases. Optic nerve injury is very common in both MS and NMO, though differences in clinical characteristics, imaging manifestations, and optical coherence tomography of optic nerve injury have been found between them. Specifically, unilateral optic neuritis with


J Neurol

moderate visual acuity deficit, focal lesion in the anterior optical nerve, and less retinal damage after optic neuritis tend to occur in MS, whereas bilateral optic neuritis with severe visual acuity deficits, comparative lesions in the posterior optic nerve, and more retinal damage after optic neuritis often appear in NMO [7, 8]. Impaired olfactory function has been found as an early manifestation of MS [9]. Pathologic studies have confirmed that olfactory bulb (OB) and olfactory tract demyelination are frequent, early, and specific to MS [10]. In a recent study, 5 in 10 patients with NMO showed olfactory dysfunction, and the prevalence was higher in AQP-4 antibody-positive patients than in negative ones [11]. However, these interesting findings have not yet been confirmed in a large number of patients with NMOSDs. Furthermore, whether olfactory dysfunction is linked to abnormalities in corresponding brain regions and whether there is a relationship between AQP-4 antibody status and olfactory function in NMOSDs warrants further investigation. The present study was conducted to ascertain frequency of olfactory dysfunction in a relatively large number of patients with NMOSDs. Further, we explored the relationships between olfactory function and clinical characteristics, AQP4-antibody status and olfactory-related magnetic resonance imaging (MRI).

hepatitis; (4) treated with drugs that may affect olfactory function within the past month, such as amitriptyline, D-penicillin, and high doses of corticosteroids; (5) female during menstruation or pregnancy; (6) who could not cooperate. Demographic, clinical and lab assessment Clinical data collected in this study included demographic information and NMOSDs-related medical history (e.g., disease duration, onset time, and annual relapse rate). Each patient’s disability at the time of screening was assessed with the Expanded Disability Status Scale (EDSS), performed by two neurologists, both certified by the Neurostatus for EDSS competency. The Mini-Mental State Examination (MMSE) [12] and Beck Depressive Inventory II (BDI-II) [13] were blindly administered by a psychological specialist. Serum AQP-4 antibodies (fluorescent units, FU) were tested by fluorescent immunoprecipitation assay (FIPA). The sensitivity and specificity of the assay were 68 % (95 % CI, 62.5–73.5 %) and 100 % (95 % CI 83–100 %) [14]. The plasmids used in the assay were donations from Professor Angela Vincent and professor David Beeson, Nuffield Department of Clinical Neurosciences, University of Oxford. Olfactory evaluation

Materials and methods Participants We conducted a single-center case–control study from December 2013 to June 2014 in Tianjin, China. The study was approved by the Ethics Committee of Tianjin Medical University General Hospital, and written informed consent was obtained from each participant. Forty-nine cases of NMOSDs (37 NMO, 11 longitudinally extensive transverse myelitis, and one recurrent optic neuritis) from Tianjin Medical University General Hospital were enrolled. Twenty-six sex- and age-matched healthy controls were recruited. Inclusion criteria for patients were (1) classical NMO fulfilling the diagostic criteria [2], longitudinally extensive transverse myelitis and optic neuritis with AQP-4 antibody positive; (2) being in a remission state of the disease; (3) age more than 18 years. Exclusion criteria for all the participants were (1) medical history of nasal and paranasal cavities (inflammation, trauma, etc.) or operation, upper respiratory tract infection within the past 3 weeks, and patients with tumor under radiotherapy or chemotherapy; (2) other neurological and psychiatric diseases affecting olfactory function, such as Alzheimer’s disease, Parkinson’s disease, or schizophrenia; (3) history of smoking, allergies, endocrine disorders, or active


A T&T olfactometer (Takasago Industry, Tokyo, Japan) was used to evaluate each subject’s odor detection and recognition thresholds. This olfactometer includes five odorants: (A) b-phenyl ethyl alcohol, (B) methyl cyclopentenolone (cyclotene), (C) isovaleric acid (D) c-undecalactone, and (E) scatole, and each odorant is evaluated at eight levels (-2 to 5), except (B), which is evaluated at 7 (-2 to 4) [15]. Detection threshold is defined as the lowest concentration that subjects can reliably detect, while the recognition threshold is the lowest concentration that subjects can discern. A recognition threshold under 1.1 was defined as normal, 1.1 to 5.5 was hyposmia, and above 5.5 was anosmia [16]. Participants with hyposmia or anosmia were included in the olfactory dysfunction group. MRI data acquisition MRI scans were completed immediately after olfactory evaluation. MRI data were acquired using a 3.0-Tesla MR system (Discovery MR750, General Electric, Milwaukee, WI, USA), using an eight-channel phased array head coil. Tight but comfortable foam padding was used to minimize head motion, and earplugs were used to reduce scanner noise. Sagittal 3D T1-weighted images were acquired by a brain

J Neurol

volume (BRAVO) sequence with the following parameters: repetition time (TR) = 8.2 ms, echo time (TE) = 3.2 ms, flip angle = 12°, field of view = 256 mm 9 256 mm; matrix = 256 9 256; slice thickness = 1 mm, no gap, and 188 sagittal slices. Conventional brain MRIs (axial T1, T2 and flair images) and spinal cord MRI (sagittal T1 and T2 images) were also performed to detect visible lesions. Olfactory bulb volume measures MATLAB R2012b (MathWorks Inc., Sherborn, Mass., USA) was used to produce distinct random numbers for the patients together with controls. Two fully trained blinded observers independently performed the volumetric measurements on all participants. OB was traced at the level of cribriform plate and the descending bony wall of the sphenoidal sinus [17]. Volume of the bilateral OBs was assessed by investigators who, using ITK-SNAP 3.0.0 (http://www. itksnap.org/pmwiki/pmwiki.php), manually selected the OB from the coronal, axial, and sagittal planes; the sudden decrease in diameter was used as the proximal demarcation of the OB and beginning of the olfactory tract. The inter-observer correlation coefficient between the OB volume values obtained by two investigators was r = 0.930, p \ 0.01.

Statistical analysis The results are expressed as mean ± standard deviation (SD) for continuous variables and probability (percent) for categorical variables. Inter-group differences were compared descriptively using Chi squared tests or Fisher’s exact test for categorical measures, ANOVA for continuous measures among three groups, Student’s t test for two groups, and Mann–Whitney U test for ordinal variables. Pearson correlation analysis was conducted to assess factors that may contribute to the occurrence of olfactory dysfunction. Statistical significance was determined at p \ 0.05. Statistical analysis and figures were performed using Statistical Package for the Social Sciences (SPSS 16.0, SPSS Inc., USA) and GraphPad Prism Version 5 (San Diego, USA). Structural image data statistical analysis was conducted as follows: Voxel-based independent two-sample t-test with age and gender as nuisance variables were performed to identify brain regions with significant group differences in GMV between controls and NMOSDs, and between NMOSDs with and without olfactory dysfunction within olfactory-related cortices (including bilateral amygdala, piriform cortex, parahippocampal gyri and orbitofrontal cortex). Multiple comparisons were corrected using a false discovery rate (FDR) method with a corrected threshold of p \ 0.05, cluster size [200 voxels.

GM, WM, and olfactory-related GM volume analysis

Results Voxel-based morphometry (VBM) was used to assess gray matter volume (GMV) alteration in olfactory-related regions among controls and patients with and without olfactory dysfunction. The GMV of each voxel was processed using VBM8 toolbox (http://dbm.neuro.uni-jena. de/vbm/), incorporated in SPM8 (http://www.fil.ion.ucl.ac. uk/spm/) running under MATLAB R2012b. T1 images were normalized and segmented into GM, WM, and cerebrospinal fluid (CSF). The GM concentration map was first registered into the Montreal Neurological Institute (MNI) space using an affine transformation, and then the images were non-linearly normalized using the diffeomorphic anatomical registration through the exponentiated Lie algebra (DARTEL) technique and were resampled to a voxel size of 1.5 mm 9 1.5 mm 9 1.5 mm. The non-linear determinants derived from the previous step were then multiplied by the GM concentration map to yield the GMV of each voxel. Finally, a 6 mm 9 6 mm 9 6 mm, full width at half maximum (FWHM) Gaussian kernel was used to smooth the images. After spatial preprocessing, the normalized, modulated, and smoothed GMV maps were used for statistical analysis [18]. Olfactory-related GM masks were picked up referring to the anatomical automatic labeling (AAL) brain atlas.

Demographic, clinical, and olfactory function in patients with NMOSDs There were no significant differences between patients with NMOSDs and healthy controls in age, gender, education year, and handedness (Table 1). Forty-two (85.7 %) patients were AQP-4 antibody positive (30 in 37 NMO, 11 longitudinally extensive transverse myelitis, and 1 recurrent optic neuritis). MMSE scores were significantly lower and BDI scores were significantly higher in patients with NMOSDs than healthy controls. Only three patients subjectively complained about declines in olfactory function. In patients with NMOSDs, recognition threshold, but not detection, threshold was higher compared to controls (Table 2). Twenty-six patients (53 %, 19 NMO, 7 recurrent longitudinally extensive transverse myelitis) demonstrated olfactory dysfunction, and among them, only one patient with NMO presented with anosmia. The other 23 patients and 26 controls had no olfactory dysfunction. In order to explore the potential impact factors on olfactory (dys)function, we divided patients with NMOSDs into two groups: patients with and without olfactory dysfunction (Table 3).


J Neurol Table 1 Characteristics of patients with NMOSDs and healthy controls

NMOSDs (n = 49)

HC (n = 26)

p NA

Age at onset, year

40.8 (13.3)


Age at test, year

47.6 (12.1)

45.3 (11.1)


Gender, female/male




Education, year

11.2 (3.9)

12.5 (2.5)


Handedness, right/left




Disease duration, year

7.1 (7.0)



Annual relapse rate

0.71 (0.51)



Median EDSS at latest follow-up (range)

4.0 (0.0, 8.5)a



AQP-4 antibody positive, no. (%)

42 (85.7 %)



AQP-4 antibody positive, no./NMO no.




AQP-4 antibody positive, no./LETM no.




AQP-4 antibody positive, no./ON no.




Segments of spinal cord lesion

8.3 (4.9)




15.7 (11.1)

5.7 (4.5)



27.1 (1.6)

28.7 (3.4)


Values are mean (SD) unless otherwise indicated a

One patient with lower limb fracture, so EDSS score was not assessed. NMOSDs neuromyelitis optica spectrum disorders, HC healthy controls, No. number, EDSS Expanded Disability Status Scale, AQP-4 aquaporin-4, LETM longitudinally extensive transverse myelitis, ON optic neuritis, BDI Beck Depression Inventory, MMSE Mini-Mental State Examination, SD standard deviation

Table 2 Olfactory Threshold of Patients with NMOSDs and Healthy Controls

Median detection threshold (range) Median recognition threshold (range)

NMOSDs (n = 49)

HC (n = 26)


NMOSDs with ODF (n = 26)

NMOSDs without ODF (n = 23)


-1.0 (-2.0, -1.2)

-2.0 (-2.0, -1.4)


-1.9 (-2.0, -1.2)

-2.0 (-2.0, -1.5)


-0.2 (-0.8, 0.7)


-0.2 (-1.6, 1.0)


0.7 (-1.6, 6.0)

1.6 (0.4, 6.0)

NMOSDs neuromyelitis optica spectrum disorders, HC healthy controls, ODF olfactory dysfunction, No. number

We did not find a rise in olfactory dysfunction in NMOSDs associated with accumulation of disease burden as reflected by EDSS, disease duration, and annual relapse rate (p [ 0.05). Each of these was similar in patients with and without olfactory dysfunction (p [ 0.05). No significant difference was found in BDI or MMSE scores between groups with and without olfactory dysfunction. MRI manifestation of olfactory structures in patients with NMOSDs The average OB volume in patients with olfactory dysfunction was markedly decreased when compared with the controls or patients without olfactory dysfunction (94.6 ± 14.9 mm3 vs. 117.5 ± 14.4 mm3, p \ 0.01; 94.6 ± 14.9 mm3 vs. 115.2 ± 19.4 mm3, p \ 0.01, respectively). No difference was found between controls and patients without olfactory dysfunction (p = 0.620) (Figs. 1, 2). Detection and recognition thresholds were


negatively correlated with OB volume in NMOSDs (p = 0.018, r = -0.307; p \ 0.01, r = -0.430, respectively). Receiver operating characteristic (ROC) analysis indicated that OB volume under 107 mm3, with a sensitivity of 0.727 and specificity of 0.846, implied olfactory dysfunction (Youden index = 0.573, area = 0.832). Cerebral GMV of the whole brain in patients with NMOSDs with and without olfactory dysfunction was significantly smaller when compared with controls (432.86 ± 40.63 vs. 453.49 ± 23.70 cm3, p = 0.048; 432.2 ± 44.26 vs. 456.66 ± 29.86 cm3, p = 0.048, respectively), but there was no difference between patients with NMOSDs with and without olfactory dysfunction (p = 0.953) (Fig. 3a). Cerebral white matter volume (WMV) of the whole brain was similar among patients with or without olfactory dysfunction and controls (458.14 ± 55.50, 453.65 ± 43.82, and 465.30 ± 38.30 cm3, p = 0.749) (Fig. 3b). Comparing patients with NMOSDs and controls using VBM based on voxel analysis, regional decreases in GMV of high significance were found in

J Neurol Table 3 Characteristics of NMOSDs with and without olfactory dysfunction NMOSDs with ODF (n = 26)

NMOSDs without ODF (n = 23)


Age at onset, years

43.7 (12.7)

37.6 (13.4)


Age at test, years

50.5 (10.8)

44.3 (12.7)


Gender, female/male




Education, year

10.3 (3.8)

12.3 (3.8)


Disease duration, years

6.9 (5.5)

7.3 (8.6)


Annual relapse rate

0.59 (0.39)

0.84 (0.60)


Median EDSS at latest follow-up (range)

3.5 (1.0, 8.5)a

3.5 (0.0, 8.5)


AQP-4 antibody positive, no. (%)

23 (88.5 %)

19 (82.6 %)


Segments of spinal cord lesion

9.1 (4.7)

7.3 (5.1)



16.1 (11.4)

15.2 (11.1)



27.0 (2.4)

27.1 (4.5)


Values are mean (SD) unless otherwise indicated a

One patient with lower limb fracture, so EDSS score was not assessed. Data are presented as mean ± SD; NMOSDs neuromyelitis optica spectrum disorders, ODF olfactory dysfunction, No. number, F/M female/male, EDSS Expanded Disability Status Scale, AQP-4 aquaporin-4, BDI Beck Depression Inventory, MMSE Mini-Mental State Examination, SD standard deviation

Fig. 1 Representative MRI of olfactory bulb from controls and patients with NMOSDs. Arrows indicate OB on each side. OB in NMOSDs with olfactory dysfunction (c) was smaller than that in HC (a) and NMOSDs without olfactory dysfunction (b). OB olfactory bulb, HC healthy controls, NMOSDs neuromyelitis optica spectrum disorders

Fig. 2 Olfactory bulb volume and correlation with olfactory function in patients with NMOSDs. Compared to OB volume in HC and NMOSDs without olfactory dysfunction group, OB volume in NMOSDs with olfactory dysfunction was significantly smaller, and there was no difference between HC and NMOSDs without olfactory dysfunction (a); detection threshold was negatively correlated with

OB volume (b). Recognition threshold was negatively correlated with OB volume (c). NMOSDs neuromyelitis optica spectrum disorders, HC healthy controls, OBV olfactory bulb volume, ODF olfactory dysfunction. Bars represent group mean values; standard deviation of the mean was used


J Neurol

Fig. 3 Comparison of brain volume and olfactory-related brain gray matter volume based on voxel-based morphometry evaluation. GMV of the entire brain in 26 HC was greater compared with 49 patients with NMOSDs with and without olfactory dysfunction, while there was no difference between patients with and without olfactory dysfunction (a). There was no obvious difference in WM volume between HC and patients with and without olfactory dysfunction (b). Olfactory-related brain cortex atrophy was found in the bilateral piriform cortex (c), orbitofrontal cortex (d), parahippocampal gyri

(e) between NMOSDs and HC (FDR corrected, p \ 0.05, cluster size [200 voxels). Right orbitofrontal cortex volume difference was found between NMOSDs patients with and without olfactory dysfunction (uncorrected, p = 0.01, cluster size [200 voxels) (f). GMV gray matter volume, VBM voxel-based morphometry, NMOSDs neuromyelitis optica spectrum disorders, WM white matter, HC healthy controls, ODF olfactory dysfunction, FDR false discovery rate. Bars represent the group mean values; standard deviation of the mean was used

the bilateral piriform cortex, orbitofrontal cortex, and parahippocampal gyri (Fig. 3c–e). A difference in the volume of the right orbitofrontal cortex was found between patients with NMOSDs with and without olfactory dysfunction (uncorrected, p = 0.01, cluster size [200 voxels) (Fig. 3f). We found no plaques in olfactory-related regions on conventional T2 sequence in all patients with NMOSDs.

analyze the effect of AQP-4 antibody on olfactory function, we divided our patients into an AQP-4 antibody-positive group and an AQP-4 antibody-negative group. Then we analyzed the difference in olfactory detection threshold, recognition threshold, OB volume, GMV, WMV (Table 4), and VBM in the two groups (Table 3). However, there was no significant difference between the two groups (p [ 0.05).

Effect of AQP-4 antibody on olfactory function in patients with NMOSDs

Discussion Pathogenic AQP-4 antibody is a hallmark for this disease. Detection threshold correlated with the AQP-4 antiboby (FU) determined by FIPA (p = 0.009, r = 0.369); however, the recognition threshold did not have the similar correlation (p = 0.088, r = 0.246) (Fig. 4). To further


Our results demonstrated that 53 % of patients with NMOSDs had olfactory dysfunction, in line with another study [11]. The prevalence of olfactory dysfunction in NMO/NMOSDs appeared to be higher than that reported in

J Neurol

Fig. 4 Correlation of olfactory function and FIPA results for the AQP-4-Ab in NMOSDs. Detection threshold was positively correlated with FIPA results for the AQP-4-Ab (FU) (a). Recognition threshold was not correlated with FIPA results for the AQP-4-Ab Table 4 Olfactory Evaluation and MRI Results between AQP4-Ab Positive and Negative NMOSDs

(FU) (b). FIPA fluorescence immunoprecipitation assay, AQP-4 aquaporin-4, Ab antibody, FU fluorescent units. Correlation statistical analysis used Pearson’s coefficient

AQP-4-Ab (?) (n = 42)

AQP-4-Ab (-) (n = 7)


Median detection threshold (range)

-2.0 (-2.0, -1.2)

-2.0 (-2.0, -1.8)


Median recognition threshold, (range)

0.7 (-1,6, 6.0)

0.7 (-1.6, 2.6)


OBV (mm3)

103.3 (20.0)

110.4 (19.7)


GMV (cm3)

432.6 (43.4)

432.6 (34.2)


WMV (cm3)

457.7 (48.5)

446.0 (60.9)


Values are mean (SD) unless otherwise indicated. Data are presented as mean ± SD; MRI magnetic resonance imaging, NMOSDs neuromyelitis optica spectrum disorders, AQP-4 aquaporin-4, Ab antibody, OBV olfactory bulb volume, GMV gray matter volume, WMV white matter volume

MS, which has been indicated anywhere from 15 to 44.4 % [19–22], and lower than that of Parkinson’s disease, which is over 80 % [23]. Only three of 27 patients with olfactory dysfunction complained of abnormal olfactory ability. Olfactory dysfunction might persist for a long time without being acknowledged, embedding potential danger in daily life. Therefore, we propose that olfactory function should be assessed early in these patients and proper measures should be taken to prevent the potential threat. AQP-4 is expressed in the nasal olfactory mucosa, including the basal cells, supporting cells, and the Bowman glands that are part of the olfactory epithelium, as well as strongly expressed in the glomerulus, the synaptic unit of the OB, suggesting a role for AQP-4 in olfactory function [24]. A case series study about olfactory function in NMO demonstrated that olfactory dysfunction tends to occur in patients with AQP-4 autoantibodies, also revealing that AQP-4 antibodies can strongly bind to the OB in mice and rats [11]. Fortunately, we found that detection threshold positively correlated with the AQP-4 antibody (FU) determined by FIPA, though we did not find difference in olfactory-related indexes between AQP-4 antibody positive and negative NMOSDs, for the AQP-4 antibody negative patients were only 7 (14 %). Including more AQP-4 antibody negative NMO patients might promote finding the difference. Further pathological studies would be useful to

clarify the potential mechanism. The introduction of highfield MRI or double inversion recovery (DIR) MRI sequence was demonstrated to be a promising method for lesion detection in olfactory-related cerebral regions [25, 26]. Neuroimaging studies associated with olfactory dysfunction in NMOSDs had not been reported until now. Previous research has investigated thinning in regions of the visual cortex in NMO patients [27], cognitive deficits with associated cortical atrophy have also been reported in NMO [28], but insufficient attention had been directed to cortices related to olfaction. We found that cerebral GM was reduced in patients with NMOSDs. The region related to olfactory function, as part of GM, was also noticeably decreased in volume. Accordingly, we inferred that atrophy might emerge in olfactory-related cerebral regions, accompanied by other cerebral regions, thereby contributing to olfactory dysfunction. Filippi et al. [29] pointed that retrograde degeneration of neurons secondary to spinal cord and optic nerve lesions or GM lesions might be the reasons of normal-appearing GM damage in patients with NMO, and though no pathological findings supported cortical demyelination in NMOSD [4], Saji et al. [30] concluded that the pathological process of cortical neurodegeneration contributed to cognitive impairment in NMOSDs, in line with the present imaging results. Brain


J Neurol

tissue volume changes accompanying perfusion changes in NMO were pointed by Sa´nchez-Catasu´s et al. [31]. Nevertheless, neuroregeneration and synaptogenesis could also influence the volume changes in central nervous structures. The relation between olfactory-related structures and olfactory function was reported by Hummel et al. and Lemasson et al, they thought the relation was grounded in adult neurogenesis and synaptogenesis [32, 33]; trans-synaptic degeneration has been suggested as a contributor to chronic axon damage, associated with visual cortex atrophy in MS [34], while in NMO the hypothesis of neurogenesis and transsynaptical changes has not been clarified. However, a recent pathology study reported that inflammation and demyelination could present in olfactory structures [10]. Unfortunately, this study lacked olfactory assessment information. As no obvious lesions in the olfactory-related cerebral cortex on conventional MRI were found in our patients with NMOSDs, atrophy of olfactory structures and/or microstructure injury might be the reason for the presence of olfactory dysfunction in these patients. Although patients without olfactory dysfunction showed slight cortical volume changes associated with olfactory structures compared with controls, following up with these patients and trying to determine whether they might present with olfactory dysfunction with aggravation of the atrophy of these cerebral regions would provide further evidence and validate this hypothesis. In addition, OB volume was significantly decreased in patients with olfactory function deterioration. The OB is the first and most critical site for the processing of olfactory information in the brain [35]. Measurement of OB volume is feasible and simple in clinical practice compared with other olfactory-related cerebral regions, and it can provide valuable information for monitoring olfactory function. Yousem et al. and colleagues [36, 37] founded the OB volume measurements using MRI. They valued olfactory bulb and tract together and reported the mean volume in 4th decade was 152.1 mm3 in people with normal sense of smell. Hummel and coworkers [38] demonstrated a correlation between olfactory function and OB volume, while no ROC analysis was performed by them to predict hyposmia and anosmia. However, cut-off value determined by Bauknecht et al. [39] was 80.7 mm3 for olfactory dysfunction (sensitivity 0.95; specificity of 0.9). The ROC analysis in our study showed that an OB volume of 107 mm3 was the cut-off point for olfactory dysfunction. Though this cut-off value of OB volume needs further validation, we suggest the use of manual measurement of OB volume combined with the olfactory threshold test in single patient as an auxiliary means of diagnosis and monitoring olfactory function. Olfactory dysfunction has been studied for many years and demyelination in olfactory-related structures were


confirmed by pathologic studies in MS, while fewer cases and only chronic inactive lesions in olfactory bulb/tract demyelination were found in NMO; besides, aquaporin-4 was absent within NMO lesions compared to MS [10]. Different pathophysiological process between these two diseases might be the reason that there was a little higher olfactory deficit percentage in NMOSD than MS tested by Hawkes et al., Doty et al., Fleiner et al. and so on. Recruitment of more patients with NMOSDs, monitoring olfactory function during the disease course, and application of higher-field MRI are what we need to investigate further. Pathological data are required to elucidate the structural basis for olfactory function impairment in NMOSDs. In spite of these limitations, our data suggested that olfactory function deficits are prevalent in patients with NMOSDs. Reduced OB and olfactory-related cortex volume may be responsible for the olfactory dysfunction in these patients. However, our study raises awareness on olfactory dysfunction in NMOSDs and calls for neurologists’ attention on olfactory disability in these patients. Acknowledgments We thank our patients as well as healthy volunteers for participating in this study and members of the Neuroimmunology Team for critical support; we thank Drs A. Vincent and D. Beeson for providing plasmids for AQP-4 antibody detection. This research was supported in part by the National Natural Science Foundation of China (81171183, 81471221 to L.Y.), the National Basic Research Program of China (2013CB966900 to F. D. S.), and the National Key Clinical Specialty Construction Project of China. Conflicts of interest The authors declare that there is no conflict of interest.

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Olfactory dysfunction in neuromyelitis optica spectrum disorders.

Few data were available for the understanding of olfactory function in neuromyelitis optica spectrum disorders (NMOSDs). The aims of our study were to...
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