Introduction
Sjogren’s syndrome (SS) is a chronic inflammatory disorder with an autoimmune component that typically affects middle-aged women (male to female ratio is 1:9).Reference Jaskólska, Chylińska, Masiak, Nowicka-Sauer, Siemiński and Ziętkiewicz1 SS can be primary (pSS), which is an isolated disease, or secondary (sSS), which is in many systemic connective tissue diseases. The prevalence of pSS is estimated at 0.1-1 per cent of the population.Reference Qin, Wang, Yang, Yang, Ma and Huang2 SS is characterised histopathologically by exocrine lymphocytic infiltration leading to the clinical manifestations of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca).Reference Bjordal, Norheim, Rødahl and Jonsson3, Reference Jonsson, Brokstad, Jonsson, Delaleu and Skarstein4 “Dry eye is a multifactorial disease of the ocular surface characterised by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage and neurosensory abnormalities play etiological roles.”Reference Stern and Pflugfelder5
Dry eye (DE) is a growing public health problem that causes pain and visual distress and affects the quality of life, including physical, psychological and social aspects, everyday activities and productivity of individuals.
Several studies have demonstrated that dry eyes cause discomfort and can influence the quality of life by reducing productivity in tasks that demand sustained attention (driving, reading, etc.).Reference BTV, PT, NTB, NTT, PH and Quyet6 The idea that difficulties in daily activities caused by DE could lead to vestibular function deficit was the inspiration for this study. Inner ear diseases such as dizziness, imbalance and tinnitus may contribute to the pathogenesis of DE.Reference Kim, Hwang, Chang and Shin7 Vertigo and imbalance may indicate disorders or inflammation of the inner ear, such as labyrinthitis or vestibular neuritis.Reference Espinosa-Sanchez and Lopez-Escamez8, Reference Thompson and Amedee9 It has been reported that neuroinflammation and neuropathy associated with dizziness play a critical role in DE.Reference Chin, Kviatkovsky and Lomiguen10–Reference McMonnies12 The neutrophil to lymphocyte ratio, a systemic inflammatory marker, is high in both peripheral vertigo and DE.Reference Temirbekov and Sakallı13–Reference Ozbay, Kahraman, HH, Kucur, NK and DP19 Another study concern is whether the visual system, which inter-operates with the vestibular and proprioceptive systems to provide balance function, is adversely affected by the dryness and causes balance problems in these participants.
Although dryness is the most common symptom, many participants with pSS also have systemic and neurological symptoms.Reference Jaskólska, Chylińska, Masiak, Nowicka-Sauer, Siemiński and Ziętkiewicz1, Reference Gøransson, Herigstad, Tjensvoll, Harboe, Mellgren and Omdal20, Reference Harboe, AB, Maroni, LG, OJ and MK21 The peripheral nervous system (PNS) and central nervous system (CNS) can be impaired in participants with SS.Reference Lafitte, Amoura, Cacoub, Pradat-Diehl, Picq and Salachas22, Reference PP, Alexopoulos, ML, Stamboulis, JG and SJ23 Neurological involvement was found in 28 per cent of individuals with pSS, 46 per cent had PNS involvement, 50 per cent had CNS involvement and 4 per cent had both PNS and CNS involvement. CNS involvement in 6–48 per cent of patients with SS and PNS in 2–60 per cent of patients has been identified.Reference Lafitte, Amoura, Cacoub, Pradat-Diehl, Picq and Salachas22, Reference PP, Alexopoulos, ML, Stamboulis, JG and SJ23 The involvement of the cranial nerve is an unusual finding in this disease. Most of the cases reported in the literature include trigeminal nerve, but there are also case reports including the oculomotor nerve.Reference Colaci, Cassone, Manfredi, Sebastiani, Giuggioli and Ferri24
The vestibular nuclei (VN) are considered to have neuronal associations with the different regions of the brain, including the oculomotor nucleus, trochlear nucleus, abducens nucleus, cerebellum, thalamus, cerebral cortex, insula and hypothalamus.Reference Henkel and Martin25–Reference Kirsch, Keeser, Hergenroeder, Erat, Ertl-Wagner and Brandt32 The VN receives and carries various types of sensory inputs, including eye movements, head movements, direction or speed and body orientation in space to control movements.Reference Barmack29, Reference zu Eulenburg, Caspers, Roski and Eickhoff33 An injury of VN can lead to vertigo and sensorimotor dysfunction, including imbalance, impaired body perception and eye movements.Reference Barmack29, Reference Hitier, Besnard and Smith34
As a result, examining vestibulo-ocular and oculomotor functions in patients with pSS can provide information on peripheral and central vestibular systems. Thus, we hypothesied that, due to the above-mentioned ocular and oculomotor symptoms of the disease, vestibulo-ocular reflexes (VORs) and oculomotor reflexes may be affected in patients with SS.
The purpose of this study was to assess the functional balance condition of patients with SS as well as their peripheral and central vestibular capabilities. The study aimed to shed light on the functional and clinical follow-up of patients with SS for relevant experts in medicine.
Materials and methods
This prospective study was conducted at Gazi University Otorhinolaryngology and Audiology Department. Twenty-four female patients with pSS (49.77 ± 10.93) and 26 controls (46.70 ± 7.13) were evaluated in this prospective study. The individuals who had a previous history of ear disease, a family history of early-onset hearing loss, any congenital abnormalities of the head and neck, occupational noise exposure, recent head trauma, neurologic disease or a history of previous use of ototoxic agents were excluded. There were no acute vestibular diseases or vestibular complaints in the participants. The diagnosis of SS was made according to the criteria of the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for pSS.Reference CH, SC, Seror, LA, Labetoulle and TM35 The participants with pSS were diagnosed 19.33 ± 4.52 months ago. To avoid the influence of age and gender variables on the results, controls were randomly selected from among women routinely attending the clinic, as all volunteers with SS were females. All tests were performed with the same equipment, during the same period and by the same investigator to rule out any measurement bias. All of the participants agreed to participate in the research study and signed an informed consent form. This study was approved by the Ethics Commission of Gazi University (Decision Number: 562). The examinations were performed in the following order to assess the participants’ peripheral and central vestibular capabilities as well as their functional balance.
Videonystagmography
The calibration was conducted during the calibration phase by following the periodically moving light in the horizontal and vertical planes in the light bar positioned 150 cm in front of the participants.
Spontaneous nystagmus, gaze (up-down, left-right, centre), saccade, tracking, optokinetic functions and positional nystagmus evaluations were conducted via ICS Chartr VNG device (Otometrics, Denmark).
The gaze test measured the patient’s ability to constantly look at a visual target at different angles. Test positions included gaze up, down, centre left and right. The participant was asked to follow the red light on the opposite side and continue to look without moving her head when the red light moved. The test was evaluated for 30 seconds for each direction. The participant was positioned at a distance of 150 cm from the light bar and the light bar is fixed at the eye level of the participant.
The saccade test measured the ability of an individual to focus his/her eyes toward a visual target moving from one point to another in a quick and single pass. The motion paradigm of the visual target was random, and this motion was evaluated in the horizontal plane. The participant was asked to focus the red light on the opposite side and follow the light as fast as possible without moving your head when the light moved. The test was evaluated for 30 seconds. In the saccade test, three parameters were analysed: the time of finding the target in the participant’s eyes (latency), the ability of the participant’s eyes to focus the target without missing (accuracy or precision), the speed of movement of the participant’s eyes from one point to another is recorded (velocity).
The smooth pursuit (tracking) test measured the ability of the patient to follow the visual target in a controlled and correct manner. The participant was asked to follow the red light across with his/her eyes without eyes blinking. The test was evaluated for 40 seconds and gain asymmetry for each direction (left gain and right).
The optokinetic test evaluated the functionality of the participant’s optokinetic reflex. The participants were asked to count the red lights by focusing on a point. The test was applied at two different velocities (20° per second and 40° per second) and in two different directions in the horizontal plane. In the optokinetic test applied to the right and left directions, the slow phase velocity parameter between the directions was evaluated.
The Dix Hallpike and Roll tests were used to evaluate positional nystagmus in the TRV chair. TRV chair (Interacoustics, Middelfart, Denmark) was developed by Dr. Richard-Vitton. This tool, which can rotate 360°, is used in the diagnosis and treatment of benign paroxysmal positional vertigo (BPPV).Reference Richard-Vitton, Seidermann, Fraget, Mouillet, Astier and Chays36 The participant was asked to sit on the TRV chair and was secured to the chair by the shoulders, arms, legs, torso and head. Tests were performed in darkness without visual fixation, using video goggles. The eye movements were recorded with video goggles for 2 minutes.
Video head impulse test
The video head impulse test (vHIT) measurements were performed with an ICS Impulse vHIT (GN Otometrics, Denmark) device and evaluated with the OtoSuite interface. The participants were asked to sit on a chair positioned 150 cm away from a white-colored wall. A visual target was placed at equal height with the eye of the participant on the wall. Before starting the test, the goggle was tightened and fixed enough with the help of rubber to prevent the goggle from moving. Then, the pupil was centred on the program screen and stepped to calibration of the lateral semicircular canal (SCC).
Before the calibration step, participants were informed about how to calibrate and were requested not to blink. During the calibration, the laser light appeared with 7.5° angles on the glasses on the right and left of the visual target. The participants were asked to follow these lights with their eyes without moving their heads. During the evaluation of the lateral SCC, while the head position of the participants was tilted flexion by 30° and, impulse head in the directions of right and left. During the test, participants were asked to try to keep their eyes on the point set on the wall, which was at a distance of 1.5 meters from themselves. After recording 20 impulses for each lateral SCC, stepped to the calibration stage which was used to evaluate the vertical channels.
At the calibration stage for the vertical channels, the participants were asked to bring the laser light to the same point on the visual target. Afterward, the head is positioned from 35° to 39.9° and the eye is positioned from 27° to 32.9°. During these tests, the pushing force was applied with angles of 10° to 20°, and 20 impulses were recorded for each vertical channel.
The correct movement of the head could be checked using the OtoSuite interface tool during testing. The peak of head speed should be between 120° per second and 250° per second for lateral channels and between 100° per second and 250° per second for vertical channels. The head acceleration should be between 1200° per second2 and 2500° per second2 evaluating the lateral channels and 1000° per second2 and 2500° per second2 for evaluating the vertical channels. The impulses that are compatible with these values were accepted and recorded.
Sensory organisation test
In the sensory organisation test (SOT), the participants stand on a static platform and are tested in six conditions with different visual, somatosensory and vestibular inputs. In the first three conditions, the participants stand on a stable surface.
In condition 1, the eyes were open; in condition 2, the eyes were closed; and in condition 3, the visual scene moved. The moving visual scene was produced by a visual projection system. Condition 3 provided deceptive visual information about the position of the body in space. In condition 4, participants stand on an unstable surface with eyes open, but in condition 5, their eyes are closed. In condition 6, the visual scene moves, and the surface is unstable. In the former 3 conditions, the somatosensory and proprioceptive information is not absent but becomes restricted for standing in an upright stance by using a stable surface. The SOT was conducted with SPS computerised posturography (Synapsys Posturography Systems, France).
Statistical analyses
Statistical analyses were performed using SPSS version 24 (IBM Corp., Somers, NY, USA). The variables were investigated by using analytical methods (Shapiro–Wilk’s and Kolmogorov–Smirnov tests) and visual methods (probability plots and histograms) to determine whether they were normally distributed. The difference between the sensory equilibrium scores of pSS and controls was analysed using the Mann–Whitney U test. The difference between the VOR gain of pSS and controls was analysed using a Student t-test. A p-value less than 0.05 was considered statistically significant.
Results
Spontaneous and positional nystagmus tests
In spontaneous and positional nystagmus evaluation tests, no abnormal findings were obtained in any participants with pSS and controls (Table 1).
Findings of the smooth pursuit and saccade tests
pSS = participants with primary Sjogren’s syndrome; VNG = videonystagmography.
The term “abnormal” refers to the findings that are not within normal limits in at least one of the subparameters of the smooth pursuit and saccade tests.
Gaze tests
In the gaze tests (up, down, centre, left, right), there was no nystagmus in both participants with pSS and controls (Table 1).
Saccade tests
While three participants (12.50 per cent) with pSS showed impaired saccadic movement (findings that are not within normal limits in at least one of the latency, accuracy and velocity parameters), all controls demonstrated saccadic movement within normal limits; there was no statistically significant difference (p = 0.063). Only prolonged latency was observed in two participants with pSS, and one participant who observed prolonged latency showed an impaired saccadic accuracy (Table 1).
Smooth pursuit test (tracking)
In the smooth pursuit test, gains were reduced in two participants (8.30 per cent) with pSS, but no control demonstrated reduced tracking gains; the difference was not statistically significant (p = 0.133). Gains were found to be within the normal range in 22 of 24 participants with pSS (Table 1).
Optokinetic test
There were no impaired findings in both participants with pSS and controls (Table 1).
Video head impulse test
The vHIT findings were separated according to the plane of the three SCCs that the test evaluated (lateral, left anterior–right posterior [LARP] and right anterior–left posterior [RALP]) (Table 2). When examining the horizontal plane, there was a significant difference in each horizontal SCC VOR gain between participants with pSS and controls (p < 0.05). In the RALP plane, there was a significant difference in right anterior SCC gain between participants with pSS and controls (p < 0.05). There was no significant difference in left posterior SCC (p > 0.05). In the LARP plane, there was a significant difference in left anterior SCC gain between participants with pSS and controls (p < 0.05). There was no significant difference in right posterior SCC (p > 0.05).
Findings of the video head impulse test
CI = confidence interval; LA = left anterior SCC; LL = left lateral SCC; LP = left posterior SCC; pSS = participants with primary Sjogren’s syndrome; RA = right anterior SCC; RL = right lateral SCC; RP = right posterior SCC; SCC = semicircular canal; SD = standard deviation.
* There is a statistically significant difference.
Sensory organisation test
In the anterior–posterior plane, vestibular and preference scores of the participants with pSS were significantly lower than the controls (p < 0.05) (Table 3). In the somatosensory and visual scores, there was no significant difference between participants with pSS and controls (p > 0.05) (Table 3).
Findings of the sensory organisation test in the anterior–posterior plane
IQR = interquartile range; Pref = preference scores; pSS = participants with primary Sjogren’s syndrome; SD = standard deviation; Som = somatesensory scores; Vest = vestibular scores; Vis = visual scores.
* There is a statistically significant difference.
In the mediolateral plane, vestibular, somatosensory and visual scores of the participants with pSS were significantly lower than the controls (p < 0.05) (Table 4). In the preference scores, there was no significant difference between participants with pSS and controls (p > 0.05) (Table 4).
Findings of the sensory organisation test in the medio-lateral plane
IQR = interquartile range; Pref = preference scores; pSS = participants with primary Sjogren’s syndrome; SD = standard deviation; Som = somatesensory scores; Vest = vestibular scores; Vis = visual scores.
* There is a statistically significant difference.
Discussion
In the current study, the VOR and oculomotor functions were investigated while taking into account the visual and ocular problems of participants with SS, with the ultimate goal of obtaining preliminary information in order to avoid overlooking any vestibular problems in participants with SS.
The sensorineural hearing loss (SNHL) has been documented in participants with SS, one of the autoimmune inner ear diseases.Reference Calzada, Balaker, Ishiyama and Lopez37, Reference Tucci, Quatraro and Silvestris38 There are, however, a few unusual results in the literature concerning central and peripheral vestibular function and balance abilities in participants with SS.Reference McCombe, Sheean, McLaughlin and Pender39, Reference Estiasari, Matsushita, Masaki, Akiyama, Yonekawa and Isobe40
In this study, three sensory input scores that represent balance related to vestibular function were tested as in the clinical routine. In the SOT, which was conducted on two distinct planes, significant decreases were obtained in all sensory input systems. The musculoskeletal system problems were considered to be probable reasons for the decrease in somatosensory inputs in participants with SS.Reference Rozis, Vlamis, Vasiliadis, Mavragani, Pneumaticos and Evangelopoulos41 These musculoskeletal abnormalities, for example, have been noticed in participants with SS and have been documented in the literature.
Current quantitative findings showed that there were no individuals with obvious vestibular problems in either group. Although significantly lower VOR gains were observed in individuals with SS compared to controls in the vHIT test, these findings were still within normal limits. Since the vHIT test was performed by the same clinician and with the same equipment, test error is unlikely. Given these findings, the lower scores compared to those from the control group, although within normal limits, indicated the need for future comprehensive studies to investigate its clinical significance.
To document the decrease in visual and vestibular input scores in more detail, VOR gains and oculomotor functions were analysed. The low VOR gain might be caused by a link between VOR and the oculomotor nerve. The vestibular nucleus connects directly to the oculomotor nucleus in two ways. The direct path travels through the medial longitudinal fasciculus (MLF), providing the connection with the oculomotor and abducens nuclei. The indirect path is a multisynaptic pathway within the reticular formation. Direct route eye movements initiate swiftly, while the indirect pathway relies on multiple feedback circuits to maintain spontaneous eye tone and intricate control of movements.Reference Cullen42 The question that needs consideration here is: “If the eye movement tests were normal, how could there be a motor issue that causes the low VOR gain on head impulse testing?” in the context of the article. The VOR is responsible for stabilising the gaze during rapid head movements. The question prompts an exploration into the discrepancy between seemingly normal eye movement tests and an impaired VOR gain, inviting consideration of alternative explanations, potential complexities in the underlying mechanisms or the need for further diagnostic investigations to reconcile the conflicting observations.
In a previous study which was included 37 healthy participants, probabilistic monitoring was used in the normal human brain to investigate the neural connection of VN with vestibular pathways. The VN demonstrated comprehensive connectivity with brain regions, including the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus and abducens nucleus.Reference Jang, Lee, Yeo and Kwon43
SS is one of several autoimmune diseases implicated in hearing loss. The collection of “autoimmune inner ear disorders” (AIEDs) was first described in 1979 by McCabe.Reference McCabe44 AIED is thought to be associated with immunoreactivity to the components of the inner ear and describes an SNHL syndrome frequently followed by vertigo and tinnitus due to immunosuppressive treatment.Reference Boulassel, Deggouj, Tomasi and Gersdorff45, Reference Stone and Francis46 In a previous study, temporal bone histopathology and immunoglobulin deposition in four participants with SS was investigated.Reference Calzada, Balaker, Ishiyama and Lopez37 This study showed significant loss of intermediate stria vascularis (SV) and immunoglobulin G (IgG) deposition cells on the basilar membrane of SV blood vessels in the inner ear histopathology in three participants with SS and SNHL. These are similar to those of known models for the SS mouse. Neurons of the spiral ganglia were diminishing in two participants, while neurons of the vestibular ganglia were conserved. The one patient with SS and normal hearing showed only mild SV atrophy and mild vertigo. Furthermore, another patient showed disorganised epithelium in both the utricle and cristae, which was similar to the degeneration seen in the organ of Corti. These data can be shown as the second possible cause of our findings. An important point here is to maintain the balance between the treatment of autoimmune disease and the potential side effects of this treatment to ensure the individual’s well-being and health to the fullest extent. Awareness among professionals working in this field and regular assessments of hearing and vestibular skills are crucial.
• It was observed that the videonystagmography findings of individuals with Sjogren’s syndrome (SS) were normal
• It was observed that the sensory organisation and postural control of individuals with SS were weakened in various perturbations of sensory inputs that create balance
• The importance of comprehensive vestibular examination in autoimmune diseases such as SS has been highlighted once again
• The study’s findings have guided relevant professionals in the follow-up of patients with SS toimprove daily life, balancing performance and quality of life
Conclusion
To the authors’ knowledge, the present study is the first to describe the findings of participants with pSS from a vestibular perspective. The importance of comprehensive vestibular examination in autoimmune diseases such as SS has been highlighted once again. The study’s findings have guided relevant professionals in the follow-up of patients with SS to improve patients’ daily life, balancing performance and quality of life. The future studies that include a detailed peripheral vestibular examination will contribute to the existing literature by evaluating utricular and saccular functions.
Competing interests
There are no conflicts of interest.
Funding
No funding was received.
