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Olfactory bulb and olfactory sulcus depths are associated with disease duration and attack frequency in multiple sclerosis patients
Journal of the Neurological Sciences, Volume 358, Issues 1–2, 15 November 2015, Pages 304–307
Background and purpose: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease that progresses to axonal loss and demyelinization. Olfactory dysfunction in patients with MS has been reported frequently. We were interested in the associations of olfactory bulb (OB) and olfactory sulcus depth (OSD) with disease duration and attack frequency.
Methods: We included 25 patients with MS and 30 age- and sex-matched controls in this study. The Expanded Disability Status Scale, Beck Depression Inventory, and Mini Mental State Examination were applied. OB, OSD, and magnetic resonance imaging plaque numbers were calculated.
Results: OB volume and OSD in patients with MS were significantly lower than those in the control group (right and left OB: p < 0.001; right OSD: p = 0.001; and left OSD: p = 0.039). Disease duration was negatively correlated with right and left OB volume (right OB: r = − 0.434, p = 0.030 and left OB: r = − 0.518, p = 0.008). Attack frequency was negatively correlated with left OB volume and left OSD (left OB: r = − 0.428, p = 0.033 and left OSD: r = − 0.431, p = 0.032).
Conclusions: The OB and OSD were atrophied significantly in patients with MS, and this was correlated with disease duration and attack frequency. The left side tended to be dominant.
- The olfactory bulb (OB) and olfactory sulcus depth (OSD) were significantly atrophic in patients with MS.
- Olfactory bulb (OB) atrophy is proportional to disease duration.
- Attack frequency was negatively correlated with left olfactory bulb (OB) volume and left olfactory sulcus depth (OSD).
Keywords: Multiple sclerosis, Olfactory bulb, Olfactory sulcus depth, Disease duration, Attack frequency, Neuroimaging.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that progresses to axonal loss and demyelinization. Olfactory dysfunction has been described recently in 15–38.5% of patients with MS using odor tests , , and ; however, the mechanisms remain obscure  and . Loss of odor detection in patients with MS may be an early sign of the disease  and . The mechanisms are still obscure.
Smelling is a complex process. Volumetric measurements of the olfactory bulb (OB) have been used in patients with different diseases to show olfactory dysfunction , , and . These studies investigated the correlations between OB volume and the results of psychophysical tests, such as odor threshold, odor discrimination, and odor identification. The results showed that OB volume is a good indicator of olfactory function. Olfactory bulb volume was measured in neurodegenerative diseases such as Alzheimer and Parkinson diseases  and .
This is the first study to measure the olfactory sulcus depth (OSD) in patients with MS and to show correlations of OB and OSD with disease duration and attack frequency.
This study included 25 patients with relapsing remitting MS diagnosed according to the revised McDonald criteria  and 30 age- and sex-matched healthy controls. Patients < 18 years and > 65 years were excluded. Subjects who were pregnant or had rhinitis, diabetes, hypertension, paranasal sinusitis, major neurological disorders, psychiatric disorders, Alzheimer's disease, or Parkinson's disease were excluded. The Expanded Disability Status Scale (EDSS) was applied to assess disease severity. The Mini Mental State Examination (MMSE) and the Beck Depression Inventory (BDI) were also administered, as dementia and depression can affect olfactory function , , and . Detailed anamnesis was obtained, and MS and neurological examinations were performed. The Bozok University School of Medicine Ethics Committee approved this study protocol. Written informed consent was obtained from all participants.
Physical examinations were performed by a neurologist who was aware of the detailed neurologic history of the patients. Eight functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and others) were evaluated.
Patients were given the MMSE to evaluate their cognitive function, and those with MMSE scores ≥ 24 were included in the study.
Beck Depression Inventory (BDI) was developed to measure risk of depression and level of depressive symptoms. This BDI is a self-assessment scale consisting of 21 items related to depressive symptoms. The BDI has been recommended to screen for depression in patients with MS, as it is short and exclusive of MS symptoms . Patients with BDI scores < 30 were included in the study.
2.4. Magnetic resonance imaging (MRI)
MRI was performed using a 1.5 T system (Initial Ingenia model no: 7813–72; Philips Medical Systems, Best, the Netherlands) with a standard quadrature head coil to detect OB anatomy as the plane of the posterior tangent through the eyeballs, as described previously . Coronal slices were positioned perpendicular to a virtual midline through the nasal septum and the cerebral falx. Coronal T2-weighted fast spin echo sequences were obtained using the following parameters: 1000/100 ms (TR/TE); section thickness, 5 mm; matrix, 384 × 239; FOV, 230 × 184 mm; and in-plane pixel resolution, 0.5 × 0.5 mm. The OB was observed as a hypointense structure surrounded by bright cerebrospinal fluid. The OB was measured manually using coronal T2-weighted images. Volumes were expressed in cubic millimeters by calculating the in-plane area and the thickness of the structures .
Depth of the OS was measured in the plane of the posterior tangent through the eyeballs using coronal T2-weighted brain MRI. Gyri recti are separated from the adjacent medial orbital gyri by the OS. MS plaque counts were performed using axial T2 sequences by two experienced radiologists who were double blinded.
2.5. Statistical analysis
The statistical analysis was performed using SPSS v.16.0 (SPSS Inc., Chicago, IL, USA). All data are presented as means ± standard deviations. p < 0.05 was considered to indicate significance. Differences in parameters between groups were analyzed using the independent-sample t-test. Pearson's correlation analysis was used to detect correlations between disease duration and right or left OB volume and between attack frequency and left OB volume or left OSD.
Demographic and clinical data of the control and MS groups are shown in Table 1. No significant differences in age or sex were observed between the groups. Mean disease duration was 6.92 years. The mean EDSS score was 2.60, the mean MMSE score was 28.96, and the mean BDI score was 8.44. The mean attack frequency was 3.88, and mean number of plaques was 13.9.
|Variables||Control (n = 30)||MS (n = 25)||p|
|Age (years)||34.43 ± 7.04||34.36 ± 8.56||0.973|
22 (73.3%)/8 (26.7%)
17 (68%)/8 (32%)
|Disease duration (years)||–||6.92 ± 3.70||–|
|EDSS||–||2.60 ± 1.32||–|
|MMSE||–||28.96 ± 0.88||–|
|BDE||–||8.44 ± 2.58||–|
|Attack frequency||–||3.88 ± 2.99||–|
|Number of plaque||–||13.9 ± 5.56||–|
|R olfactory bulb V||58.34 ± 10.61||31.84 ± 4.44||< 0.001⁎|
|L olfactory bulb V||60.12 ± 14.21||31.43 ± 3.90||< 0.001⁎|
|R depth of olfactory sulcus||8.36 ± 0.59||7.68 ± 0.74||0.001⁎|
|L depth of olfactory sulcus||8.33 ± 0.62||7.88 ± 0.88||0.039⁎|
⁎ All comparisons were considered statistically significant at p < 0.05.
Values are expressed as n (%), mean ± SD median (25th–75th percentiles).
R, right; L, left; V, volume; EDSS, Expanded Disability Status Scale; MMSE, Mini Mental State Examination; BDE, Beck Depression Inventory.
Volumes are in cubic millimeters.
Right and left OB volume and right and left depth decreased significantly in the MS patients compared with the control group (p < 0.001, respectively) (Table 1).
Disease duration was negatively correlated with right OB volume (r = − 0.434; p = 0.030, Spearman's correlation) and left OB volume (r = − 0.518; p = 0.008, Spearman's correlation) (Table 2).
|R olfactory bulb volume||p = 0.030||r = − 0.434|
|L olfactory bulb volume||p = 0.008||r = − 0.518|
R, right; L, left. Volumes are in cubic millimeters.
Attack frequency was negatively correlated with left OB volume (r = − 0.428; p = 0.033, Spearman's correlation) and left OS depth (r = − 0.431; p = 0.032, Spearman's correlation) (Table 3).
|L olfactory bulb volume||p = 0.033||r = − 0.428|
|L depth of olfactory sulcus (mm)||p = 0.032||r = − 0.431|
R, right; L, left. Volumes are in cubic millimeters.
We found three main findings. First, OB volume and OSD in patients with MS were significantly lower than those in the controls. Second, negative correlations were detected between disease duration and right and left OB volume. Third, we found negative correlations between attack frequency and left OB volume or left OSD.
Both neurodegeneration and neuroinflammation occur in MS, but it is unknown which is secondary. Frequently seen olfactory dysfunctions in MS patients couldn't be related to neurodegeneration or neuroinflammation easily , , , and . Many studies have been conducted on olfactory dysfunction in patients with MS. The loss of smell sense in MS patients was thought be related with Human Herpesvirus-6 (HHV-6). It was postulated that MS was triggered with the entrance of virus to the central nervous system via olfactory bulb and tract. The virus was isolated from the nasal cavities of MS patients . Smelling is a complex process, and studies have commonly used three subtests, such as threshold, discrimination, and identification. As results, identification and discrimination were found to be correlated with disease progression and threshold with early stage deterioration [3,25]. It has been speculated that the threshold for neuronal inflammation may disturb detection of neuronal degeneration. Some studies have reported olfactory dysfunction in patients with MS using smelling tests and found that olfactory dysfunction was correlated with EDSS score  and . Smelling dysfunction is also associated with the numbers of active frontal and temporal plaques, as these regions are part of olfaction , , and . Correlations have also been reported between MS lesion load and olfactory function , , and .
Only a few studies have measured OB volume in patients with MS, but OSD has not been measured. These studies show that decreases in OB volume and the number of brain lesions increase brain volume  and . In another study, OB and chemosensory-evoked potentials were measured to evaluate smelling. They found that decreased OB volume increased chemosensory potential latency . There was a positive correlation between OB volume and olfactory function in the study of Goektas et al. composed of 36 MS patients. In their study they observed that in MS patients olfactory bulb volume has significant effect on olfactory dysfunction .
We found OB and OSD atrophy in patients with MS compared with controls. Wang et al. reported significant decreases in OB and OSD in patients with Parkinson's disease compared with those in controls.  We found a correlation between the OB and olfactory function. In another study, depth of the OS was correlated with olfactory function in patients with isolated anosmia . These studies suggest that depth of the OS and olfactory function are related. Atrophy of the OS may contribute to neurodegeneration in diseases such as Parkinson's disease or MS.
Second, OB atrophy is proportional to disease duration. A correlation between disease duration and olfactory event-related potentials was found in a study involving 30 patients with MS .We supported these findings by MRI. One question is why does the OB atrophy according to disease duration? What is the association between MS pathophysiology and the OB?
High levels of nerve growth factor (NGF) receptors and brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF)-like polypeptides , , and , such as neurotrophin and interleukin-2 (IL-2) , have been reported in the OB of rats. NGF promotes myelin biosynthesis in the central nervous system and could be a new option for treating neurodegenerative diseases . BDNF may induce regeneration of axons, protect neurons from degeneration and protect against MS lesions  and . CTNF increases myelin oligodendrocyte glycoprotein expression, stimulates myelinization and may contribute to the pathophysiology of MS  and . The high IL-2 levels found in the OB may be involved in nerve regeneration . Neurotrophins, which are found at high levels in the OB, play very important roles in neuron regeneration and re-myelinization in MS. Atrophy of the OB seems logical when disease duration increases, as neurotrophins important in neuronal restoration are located in the OB.
Our third main finding was the negative correlations between frequency of attacks and both left OB volume and left OSD. Neuroinflammation and neurodegeneration will probably increase when attack frequency increases, and this is an active process. Is this active process related to OB and OSD? According to a study in 44 healthy subjects, depth of the left OS is correlated with olfactory function . The authors speculated that this finding was due to sensorial inputs delivered to the olfactory system that may induce cortical growth in the OS area and that plasticity of the left OS remains active. Some studies suggest that the OB is plastic like depth of the OS. An increase in the peripheral sense of smell and OB volume occurs during recovery from chronic sinusitis, which may be a result of plasticity . Another study showed that neurogenesis occurs in the adult human OB, which was explained by an active neurogenic process . It is thought that OB plasticity may include visual and olfactory perception compensatory mechanisms , because the presence or absence of sensorial inputs may induce structural changes in the central nervous system .
Is OB volume lateralized by peripheral inputs? Hemispheric lateralization is involved in the olfactory process. The right hemisphere is responsible for smell memory, and the left hemisphere is responsible for emotional processing . We speculate that these plasticity findings may be a result of visual and sensorial inputs, and that the left OB and depth of OS may take a more active role in plasticity if plasticity increases with attack frequency.
Patients with MS may be treated using neuroplasticity of the OB and depth of the OS or increases in important molecules with roles in demyelination, remyelinization, and OB volume could increase peripheral sensorial inputs.
The number of patients with MS in our study was small, and lesion load was not measured volumetrically by MRI. We also did not use a smell battery. All of these are limitations of our study.
We concluded that OB and OSD having neuroplasticity may have an important role in neurodegenerative and neuroinflammatory process of patients with MS. However, according to the current data it is not appropriate to decide whether OB and OSD atrophies are the result or cause of this process.
Conflict of interest
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