Introduction
Auditory neuropathy spectrum disorder is diagnosed based on the presence of cochlear microphonics and otoacoustic emissions indicating preserved outer hair cells’ functioning and absence of acoustic reflex as well as brainstem-evoked auditory response, suggesting asynchronous firing of cochleovestibular nerve.Reference Sheykholeslami, Kaga, Murofushi and Hughes1–Reference Zeng and Liu5 It has been reported that 1 in every 200 children with sensorineural hearing loss are susceptible to auditory neuropathy spectrum disorders.Reference Davis and Hirsh6 The prevalence of auditory neuropathy spectrum disorders in infants admitted to neonatal intensive care units has been reported to be 0.02 per cent.Reference Sininger and Starr2 Kumar and JayaramReference Kumar and Jayaram7 reported that 1 in every 183 individuals with sensorineural hearing loss have auditory neuropathy spectrum disorders.
The auditory-vestibular nerve consists of auditory and vestibular receptors (first-order neurons), which are intrinsically coupled in a common pathway. Therefore, if the auditory nerve is affected, there is a higher chance that the vestibular nerve will also be involved in individuals with auditory neuropathy spectrum disorders.Reference Buetti and Luxon8 There is immense literature on various auditory deficits in individuals with auditory neuropathy spectrum disorders.Reference Sheykholeslami, Kaga, Murofushi and Hughes1,Reference Starr, Picton, Sininger, Hood and Berlin4,Reference Davis and Hirsh6–Reference Tang, McPherson, Yuen, Wong and Lee12 However, only a few studies have described vestibular pathophysiology in individuals with auditory neuropathy spectrum disorders.Reference Sheykholeslami, Kaga, Murofushi and Hughes1,Reference Starr, Picton, Sininger, Hood and Berlin4,Reference Fujikawa and Starr13,Reference Kumar, Sinha, Singh, Bharti and Barman14 The less-researched vestibular signs and symptoms in individuals with auditory neuropathy spectrum disorders could be due to the slow progression of the disease and compensation from the central nervous system.Reference Sinha, Barman, Singh, Rajeshwari and Sharanya15,Reference Sujeet, Niraj, Animesh, Rajeshwari and Sharanya16
The prevalence reports on vestibular impairment in individuals with auditory neuropathy spectrum disorders are highly variable. Samaha and KatsakasReference Samaha and Katsarkas17 reported hypoactive caloric responses in 53 per cent of individuals with auditory neuropathy spectrum disorders. Fujikawa and StarrReference Fujikawa and Starr13 reported abnormal caloric responses in 64 per cent of the individuals with auditory neuropathy spectrum disorders. The cervical and ocular vestibular-evoked myogenic potentials have also been reported to be abnormal or absent in patients with auditory neuropathy spectrum disorders.Reference Sinha, Barman, Singh, Rajeshwari and Sharanya15,Reference Sujeet, Niraj, Animesh, Rajeshwari and Sharanya16,Reference Singh, Sinha and Barman18 The abnormality of the caloric responses and the responses of vestibular-evoked myogenic potentials indicate an abnormality of both the superior and the inferior vestibular nerve. Further, abnormal Romberg, Mann, and Fukuda stepping tests correlate with the other vestibular test findings, such as caloric and vestibular-evoked myogenic potentials, suggesting the involvement of neuropathologic conditions at the vestibular branch of the 8th cranial nerve.Reference Sheykholeslami, Megerian, Arnold and Kaga19
Video head impulse tests have been reliably recorded with good sensitivity and specificity in various vestibular diseases such as Ménière's disease,Reference McCaslin, Jacobson, Bennett, Gruenwald and Green20 vestibular neuritis,Reference Bartolomeo, Biboulet, Pierre, Mondain, Uziel and Venail21 vestibular migraine,Reference McGarvie, MacDougall, Halmagyi, Burgess, Weber and Curthoys22 and benign paroxysmal positional vertigoReference Blödow, Heinze, Bloching, von Brevern, Radtke and Lempert23. However, many studies have reported a disagreement between the caloric and video head impulse tests in various peripheral vestibular disorders. Most individuals with canal paresis indicated by the caloric test may have variable horizontal vestibulo-ocular reflex gain.Reference Bell, Barker, Heselton, MacKenzie, Dewhurst and Sanderson24
The relation between the caloric test and the video head impulse test may help us understand the sensitivity and specificity of the video head impulse and caloric tests to predict the range of deficiencies in individuals with auditory neuropathy spectrum disorders. Even though, in the condition where the caloric test reveals hypoactive responses in individuals with auditory neuropathy spectrum disorders, the different vestibulo-ocular reflex gain values might suggest the range of damage to the peripheral vestibular apparatus. Therefore, the present study aimed to measure the vestibulo-ocular reflex gain, refixation saccades, and caloric test results in individuals with auditory neuropathy spectrum disorders.
Method
Two groups of individuals participated in the study. The first group consisted of 20 participants (9 males and 11 females), 17–38 years old (mean age 29.25 years) diagnosed with auditory neuropathy spectrum disorders. These participants were diagnosed as bilateral auditory neuropathy spectrum disorders based on poor hearing sensitivity, absence of ipsilateral and contralateral acoustic reflexes, presence of otoacoustic emissions and absence of auditory brainstem responses. They all had “A” type tympanogram with no history or presence of middle-ear pathology. The patients with auditory neuropathy spectrum disorders reported to the audiology clinic with complaints of reduced hearing sensitivity and poor speech comprehension abilities in both ears. Neurological examination excluded any space-occupying lesions, other inner-ear, or 8th nerve-related anomalies in all auditory neuropathy spectrum disorder individuals. The study was conducted as per the institute's ethical committee guidelines.
The second group consisted of 20 participants with normal hearing sensitivity. The second group of participants had no history or presence of any middle-ear pathology or neurological problems. None of the participants had taken any vestibulotoxic medication or complained of any other illness before the testing. All the individuals from both groups underwent caloric and video head impulse tests.
Procedure
Pure tone audiometry, tympanometry, otoacoustic emissions and auditory brainstem responses were recorded for all the participants in both groups.
Caloric test
A Biomed Genna videonystagmography instrument was used to record the caloric test. The videonystagmography goggles were placed, and the internment was calibrated for all the individuals separately. For the caloric test, individuals were made to lie down on a bed with their heads ventroflexed by 30°. Caloric stimulation was provided through monaural open-loop water irrigation of the external ear canal at temperatures of 30°C and 44°C for 30 seconds per incident; 200 ml of fluid was irrigated for 30 seconds. The irrigation order was right warm, left warm, right cold, and left cold. Approximately seven minutes of gap between the two irrigations was given (British Society of Audiology, 2010, recommendations). Cumulative frequency was chosen as the parameter to be analysed. The recorded videonystagmography tracings were classified as hypoactive, hyperactive, and normal based on previous studies.Reference Sujeet, Niraj, Animesh, Rajeshwari and Sharanya16,Reference Claussen and von Schlachta25,Reference Kirtane, Merchant and Medikeri26
Video head impulse test
To avoid goggle slippage, the video head impulse goggles were fastened appropriately for the video head impulse test. The video head impulse instrument has two laser pointers projected onto the wall, placed at a distance of 1 meter from participants. The participants’ seats were adjusted for calibration of the equipment. The device was calibrated separately for each participant. Once calibrated, the participants were instructed to fix their gaze at a target in the front. The target was placed on the wall. The eye movements for all the participants was measured with the help of a high-speed digital infrared camera attached to the instrument. Twenty head impulses were given to each of the participants in each of the lateral semicircular canal plane. Video head impulse response was analysed. Vestibulo-ocular reflex gain and the refixation saccades (overt or covert saccades) were analysed for participants of both groups. Video head impulse test was done for the lateral canals only.
Statistical analysis
Descriptive statistics were used to calculate the mean and standard deviation of vestibulo-ocular reflex gain for the auditory neuropathy spectrum disorders group and individuals with normal hearing. In addition, an independent sample t-test was done to see the differences in vestibulo-ocular reflex gain between auditory neuropathy spectrum disorders and normal hearing individuals.
Results
The present study was conducted to understand the caloric test results, vestibulo-ocular reflex gain values of video head impulse test and refixation saccades in individuals with auditory neuropathy spectrum disorders. The demographic details and the audiological test results of auditory neuropathy spectrum disorders individuals are given in Table 1.
Demographic details and the audiological test findings of individuals with auditory neuropathy spectrum disorders; ABR = auditory brainstem response; OAE = otoacoustic emissions; PTA = pure tone average; P = present response; A = absent response
Video head impulse test results
The vestibulo-ocular reflex gain of one normal-hearing individual and one individual with auditory neuropathy spectrum disorder is shown in Figure 1. The mean and the standard deviation for the vestibulo-ocular reflex gain for both groups are given in Table 2.
Video head impulse waveform for one participant with normal hearing (A) and one with auditory neuropathy spectrum disorder (B) showing vestibulo-ocular reflex gain and presence of refixation saccades (black arrow).
Mean and standard deviation of vestibulo-ocular reflex (VOR) gain values for normal hearing and auditory neuropathy spectrum disorders (ANSD) individuals
Independent sample t-test revealed a significant difference in vestibulo-ocular reflex gain between individuals with auditory neuropathy spectrum disorders and normal-hearing individuals for the right ear t(38) = 6.66, p = 0.00 and for the left ear t(38) = 5.24, p = 0.00. The mean vestibulo-ocular reflex gain was higher for the normal-hearing individuals than for the auditory neuropathy spectrum disorder groups for both ears.
Caloric test results
The cumulative frequency ranges of both groups were calculated. The cumulative frequency range for normal-hearing individuals is given in Table 3. Figure 2 represents the butterfly diagram with the cumulation frequency of one of the normal-hearing individuals and one of the auditory neuropathy spectrum disorder individuals based on the number of nystagmus beats per 30 seconds in each of the four different stimulations.
The cumulative frequency (nystagmus beats/30 seconds) of caloric test in healthy individuals for different irrigations
Butterfly diagram of a normal hearing individual (A) and an individual with auditory neuropathy spectrum disorder (B). The butterfly chart in Figure 2(B) represents hypofunction caloric response in one of the patient with auditory neuropathy.
All patients with auditory neuropathy spectrum disorders had hypoactive caloric response based on the cumulative frequency, indicating vestibular lesion. The caloric test findings in patients with auditory neuropathy spectrum disorders suggest a peripheral vestibular dysfunction.
Vestibulo-ocular reflex gain and presence of refixation saccades
No refixation saccades were present in the video head impulse test for healthy individuals. Figure 3 represents the vestibulo-ocular reflex gains for individual with auditory neuropathy spectrum disorders. The refixation saccades present in individuals with auditory neuropathy spectrum disorders were categorised into three categories. The mean vestibulo-ocular reflex gain was considered normal if it was 0.8 or above.Reference Spoendlin27
Vestibulo-ocular reflex (VOR) gain value for individual patients with auditory neuropathy spectrum disorders.
Individuals with bilateral normal vestibulo-ocular reflex gain and refixation saccades
Seven out of 20 individuals (35 per cent) with auditory neuropathy spectrum disorders were found to have normal vestibulo-ocular reflex gain in all 14 planes. Of these 14 planes, overt saccades were present in two planes, and covert and overt saccades were present in 11 planes. One individual had no refixation saccades for the left plane, while the right showed overt and covert saccades.
Individuals with unilateral reduced vestibulo-ocular reflex gain and refixation saccades
Unilateral reduction of vestibulo-ocular reflex gain was observed in five (25 per cent) individuals. Among them, three had reduced vestibulo-ocular reflex gain for the left plane, whereas two had reduced vestibulo-ocular reflex gain for the right plane. In terms of the findings of refixation saccades in these individuals with unilateral reduced vestibulo-ocular reflex gain, four planes (all with normal vestibulo-ocular reflex gain) had both covert and overt saccades, and six had covert saccades (three in the affected vestibulo-ocular reflex gain plane and three in the unaffected vestibulo-ocular reflex gain plane).
Individuals with bilaterally reduced vestibulo-ocular reflex gain and refixation saccades
Eight out of 20 individuals (40 per cent) with auditory neuropathy spectrum disorders had affected vestibulo-ocular reflex gain with covert saccade in a total of 16 planes. Therefore, the present study showed a dissociation between the results of caloric and video head impulse tests in auditory neuropathy spectrum disorders. Figure 4 shows the video head impulse and caloric test results depicting the dissociation between the two tests.
Results of vestibulo-ocular reflex (VOR) gain values and caloric test results. Normal VOR gain and hypoactive caloric response show a dissociation between the two tests in patients with auditory neuropathy spectrum disorders (ANSD).
Discussion
In the present study, video head impulse and caloric tests were carried out to understand the different patterns of vestibular dysfunction in individuals with auditory neuropathy spectrum disorders. The study's results show hypoactive caloric response in all patients with auditory neuropathy spectrum disorders, suggesting peripheral vestibular dysfunction. Previous studies have also reported hypoactive caloric responses in auditory neuropathy spectrum disorders. For example, Starr et al.Reference Starr, Picton, Sininger, Hood and Berlin4 reported absent caloric responses in 2 out of 10 patients with auditory neuropathy. Kaga et al.Reference Kaga, Nakamura, Shinogami, Tsuzuku, Yamada and Shindo28 reported absence of caloric responses in two patients diagnosed with auditory nerve disease. Sheykhloeslami et al.Reference Sheykholeslami, Kaga, Murofushi and Hughes1 found hypoactive caloric responses in three patients with auditory neuropathy. Sinha et al.Reference Sinha, Barman, Singh, Rajeshwari and Sharanya15 reported hypoactive caloric responses in three patients with auditory neuropathy. Sinha et al.Reference Sujeet, Niraj, Animesh, Rajeshwari and Sharanya16 reported hypoactive caloric responses in 45 out of 52 ears of patients with auditory neuropathy. Sinha et al.Reference Sinha SK and Neupane AK29 also found an absence of caloric responses in three patients with auditory neuropathy.
• Patients with auditory neuropathy spectrum disorders may also have neuropathy of the vestibular nerves
• Caloric tests show hypoactive responses in patients with auditory neuropathy spectrum disorders
• Few patients with auditory neuropathy spectrum disorders have normal vestibulo-ocular reflex gain whereas a few others have reduced vestibulo-ocular reflex gain
• There is a dissociation between the caloric and video head impulse test results in patients with auditory neuropathy spectrum disorders
• Vestibular assessment should be made mandatory for patients with auditory neuropathy spectrum disorders
The pathophysiology of auditory nerve disruption has been explored in patients with auditory neuropathy. It has been suggested that a patient with auditory neuropathy can have cochlear inner hair cell dysfunction or loss, problems with inner hair cell ribbon synapse, dysfunction of dendritic nerve terminals, axonal neuropathy, auditory ganglion cell disorders, or demyelination of the auditory nerve.Reference Rance and Starr30 The eighth cranial nerve consists of both the auditory and the vestibular neurons. Hence, there is a high chance that both the vestibular and auditory nerve might be affected in patients with auditory neuropathy.
Neuropathic involvement of the vestibular branch of the eighth nerve has been reported by Starr et al.Reference Starr, Michalewski, Zeng, Fujikawa-Brooks, Linthicum and Kim31 Starr et al.Reference Starr, Michalewski, Zeng, Fujikawa-Brooks, Linthicum and Kim31 reported the vestibular nerve's beaded appearance along with the myelin sheath's fragmentation in patients with auditory neuropathy. Further, there is also a reduction of the vestibular nerve between the peripheral receptors and the vestibular nucleus, suggesting an axonal disorder of the vestibular nerve in patients with auditory neuropathy.Reference Starr, Michalewski, Zeng, Fujikawa-Brooks, Linthicum and Kim31 Such changes in the vestibular neurons might result in the absence of caloric responses and/or hypoactive caloric responses with cold or warm irrigation.
The mean vestibulo-ocular reflex gain recorded was reduced in patients with auditory neuropathy spectrum disorders compared with healthy individuals. A vestibulo-ocular reflex gain value of 0.8 is considered normal.Reference Patterson, Bassett, Mollak and Honaker32 However, when we investigated individual data, not all the individuals with auditory neuropathy spectrum disorders had reduced vestibulo-ocular reflex gain in the lateral plane. Similar findings have been reported in individuals with auditory neuropathy spectrum disorders.Reference Sinha SK and Neupane AK29,Reference Sinha, Neupane and Gururaj33 Sinha et al.Reference Sinha SK and Neupane AK29,Reference Sinha, Neupane and Gururaj33 also reported normal vestibulo-ocular reflex gain in few patients with auditory neuropathy spectrum disorders. A large variability has been reported in the vestibular findings by various authors. Starr et al.Reference Starr, Picton, Sininger, Hood and Berlin4 reported absence of caloric responses in only 2 out of 10 individuals with auditory neuropathy spectrum disorders. Fujikawa and StarrReference Fujikawa and Starr13 also reported abnormal vestibular findings in 64.28 per cent of the patients with auditory neuropathy spectrum disorders, and Kumar et al.Reference Kumar, Sinha, Singh, Bharti and Barman14 reported abnormal vestibular evoked myogenic potential findings in 80 per cent of the patients with auditory neuropathy spectrum disorders. However, KonrádssonReference Konrádsson34 reported normal caloric responses in 100 per cent of the patients with auditory neuropathy spectrum disorders. Thus, it could be understood that in individuals with auditory neuropathy spectrum disorders, irrespective of the site of the lesion (inner ear and/or vestibular nerve), there is abnormally reduced vestibulo-ocular reflex gain.
Various neuropathic conditions of the vestibular nerve, including fragmentation of the myelin sheath, axonal degeneration, and others, might result in the inability of the neural pathway to produce action potentials required for the appropriate functioning of vestibulo-ocular reflex reflex pathway, therefore resulting in the reduction of the gain.Reference Spoendlin27,Reference Sinha, Neupane and Gururaj33 The normal vestibulo-ocular reflex gain in a few patients with auditory neuropathy spectrum disorders could be because of the slow progression of the disease or an early stage of involvement of the vestibular nerve.
In the present study, we also found the presence of refixation saccades in patients with auditory neuropathy spectrum disorders. The presence of refixation saccades is a good indicator of reduced vestibulo-ocular reflex function. Blödow et al.Reference Blödow, Pannasch and Walther35 suggested that compensatory refixation saccades occur due to reduced vestibulo-ocular reflex gain in individuals with vestibulopathy. The presence of refixation saccade in patients with auditory neuropathy spectrum disorders suggests that they might have difficulty stabilising their gaze on the target. However, we did not do any functional study to check the gaze stability of these patients.
However, we noticed some discrepancies between the caloric and video head impulse test results in patients with auditory neuropathy spectrum disorders. The caloric responses were absent for all the patients with auditory neuropathy spectrum disorders. However, the vestibulo-ocular reflex gain was normal for a few patients with auditory neuropathy spectrum disorders. Such discrepancies have been found for other vestibular diseases such as Ménière's disease, benign paroxysmal positional vertigo, and vestibular neuritis.Reference McCaslin, Jacobson, Bennett, Gruenwald and Green20 The discrepancy could be due to differences in vestibular afferents, which carry the inputs of the caloric and video head impulse. The cochlea–vestibular nerve consists of regular firing neurons and irregular firing neurons.Reference Tranter-Entwistle, Dawes, Darlington, Smith and Cutfield36 The neural inputs for low-frequency stimulation of about 0.003 Hz, as used in caloric tests, is operated through the nerve fibres with regular neural spike timing. However, the high-frequency stimuli up to 5 Hz, like the one used in video head impulse, drive vestibulo-ocular reflex impulses that are carried forward by the fibres with irregular firing rate. It is possible that there can be a selective impairment of nerve fibbers encoding the low- and high-frequency information.Reference Lasker, Hullar and Minor37 It is possible to have an impairment of neural impulse generated by the caloric test with complete sparing of the ones generated by video head impulse, and vice versa, which explains the dissociation of video head impulse and caloric results in individuals with auditory neuropathy spectrum disorders having hypoactive caloric responses.
Conclusion
The outcomes of the present study revealed a discrepancy between video head impulse test results and caloric test results in patients with auditory neuropathy spectrum disorders. The dissociation between the video head impulse and caloric test results suggests the need to include both the video head impulse and caloric tests in the vestibular test battery to understand the various mechanisms of compensation or vestibulo-ocular reflex deficit in individuals with auditory neuropathy spectrum disorders. The study also highlights the importance of administering vestibular testing in patients with auditory neuropathy spectrum disorders.
Conflicts of interest
The authors declare no conflicts of interest.
Funding sources
None to declare.
Acknowledgements
The authors thank Director Aiish for granting permission to conduct the study. The authors thank all the participants for their voluntary participation in the study.
