Audiological evaluation in spinocerebellar ataxia

Purpose: To describe the audiological and electrophysiological results in patients with spinocerebellar ataxia (SCA). Methods: Retrospective and cross-sectional studies were performed. Forty-three patients were assessed using the following procedures: anamnesis and otolaryngologic exam, pure tone audiometry, acoustic immittance measures and brainstem auditory evoked potential (BAEP). Results: Patients showed gait abnormality (83.7%), speech disorder (48.8%), dizziness (41.8%) and dysphagia (39.5%). Hearing loss was referred in 27.9% of the cases; in the audiometric exams, 14 patients (32.5%) presented disorders; in SCA 3, 33.3%; in SCA 2, 12.5%; in SCA 4, 100.0%; in SCA 6, 100.0%; in SCA 7, 100.0%; in SCA 10, 50.0%; and in undetermined SCA, 21.4%. In BAEP, 20 patients (46.5%) were abnormal, being 58.3% in SCA 3, 62.5% in SCA 2, 100.0% in SCA 6, 100.0% in SCA 7, 66.7% in SCA 10 and 14.2% in undetermined SCA. While in acoustic immittance, 19 patients (44.1%) presented disorders, being 50.0% in SCA 3, 50.0% in SCA 2, 100.0% in SCA 4, 100.0% in SCA 6, 100.0% in SCA 7, 33.3% in SCA 10 and 28.5% in undetermined SCA. Conclusion: The most evident abnormalities in the audiological evaluation were the predominance of the down-sloping audiometric configuration beginning at 4 kHz bilaterally and the bilateral absence of acoustic reflex at the frequencies of 3 and 4 kHz. In the electrophysiological evaluation, 50% of the patients showed abnormalities with prevalence of an increase of the latency of waves I, II and V and of the interval in the interpeaks I-III, I-V and III-V.


INTRODUCTION
Spinocerebellar ataxia (SCA) is a disease that belongs to a heterogeneous group of neurodegenerative disorders that are characterized by the presence of progressive cerebellar ataxia (1) .It can be classified as sensitive, frontal, vestibular, and cerebellar, with the latter being the object of this study (1) .Out of the 30 types of identified SCAs, Types 2 and 3 are among the most prevalent (1,2) .
SCAs can be divided according to genetic inheritance: (a) autosomal recessive hereditary ataxia, (b) autosomal dominant hereditary ataxia, (c) hereditary ataxia related to the x chromosome, and (d) mitochondrial hereditary ataxia (6) .
Studies describe differences in the severity of clinical manifestations and the age of onset of symptoms, depending on which parent the expanded gene is inherited from.In the case of SCAs transmitted from the father, an increasing trend was observed in the number of repetitions in children, which is different when SCAs are transmitted from the mother.Therefore, when an SCA is transmitted from the father, it means more severe clinical manifestations in the children, who can even present the first symptoms of ataxia before the father (7) .
In Brazil, especially in the South region, a great number of families have been detected to carry SCAs (3,6) .The Machado-Joseph disease (MJD), also known as SCA 3, is the most common form of autosomal dominant hereditary ataxia found in a number of epidemiological studies (3,(6)(7)(8) .
The exploration of peripheral and central auditory system is conducted by using behavioral, electroacoustic, and electrophysiological assessment methods.
Many authors (9)(10)(11) report that in neurodegenerative diseases, the most common auditory dysfunctions are observed in the brainstem auditory-evoked potential (BAEP) test and occur in the inferior colliculus, lateral lemniscus, and cochlear nuclei.
SCAs are part of a group of diseases that present important changes in the speech-language field.Such research is a key contributor in building knowledge as a substitute for cumbersome and elongated assessment and therapeutic procedures focusing on this disease.
The objective of this study was to assess the results of audiological and electrophysiological evaluations in SCA patients.

METHODS
This study was approved by the Institutional Ethics Committee (Number: 058/2008) and authorized by the patients who confirmed their acceptance by signing the informed consent form.
A retrospective cross-sectional study was conducted.A total of 43 patients were evaluated (17 female and 26 male) and referred to the clinical department of Hospital das Clínicas, who were also assisted at the otoneurology department of a teaching institution in the same city.The study participants were diagnosed with SCA (twelve with SCA 3, eight with SCA 2, one with SCA 4, one with SCA 6, one with SCA 7, and six with SCA 10).
The diagnosis of ataxia was performed by a genetic test, using the polymerase chain reaction (PCR) (12)(13)(14) .Fourteen patients were genetically analyzed to discover the type of SCA, who were also part of the group of people with undetermined SCA.
The age of patients ranged from 18.0 to 70.0 years (mean age: 41.6 years, SD=13.0 years).Duration of disease was 1.0 to 15.0 years (mean duration: 7.9 years, SD=3.9 years; Table 1).
Patients with alterations that prevented their participation in examinations were excluded from the study.
The following procedures were performed: • Anamnesis: A questionnaire with emphasis on otoneurological signs and symptoms was applied.• Otolaryngologic evaluation: Evaluation was carried out with the objective of excluding any alteration that could interfere with the examination.• Audiological evaluation: Patients were submitted to puretone air conduction audiometry at frequencies ranging from 250 to 8 kHz, bone conduction at frequencies ranging from 500 to 4 kHz, and tests of speech recognition threshold (SRT) as well as the percentage index of speech recognition (PISR).For these tests, the equipment used was Itera Madsen-GN Otometrics, TDH-39 headphones, from GN-ReSound, with thresholds expressed in dBNA and calibrated according to the ISO 8253 standard (15,16) .• BAEP: Two channels with 90-dBnHL click stimuli, polarity alternated with presentation frequency of 21.1 c/s, 15-ms window, 30-to 3-kHz filter, and at least 2,000 stimuli and two reproduction registers were used.Electrodes from Kendall Medtrace 2000 were placed in the right and left mastoid positions as well as in Fz (10-20 system), and the earth electrode was placed on the forehead.Clicks were presented with 3A insert earphones.The latency of Waves I, III, and V and the Interpeak intervals I-III, III-V, and I-V were analyzed.The equipment used was the Bio-logic's Evoked Potential System, and the analysis criterion was proposed by the author (17) .• Acoustic immittance measures: This procedure was performed to assess the integrity of the tympanic ossicles, and the equipment used for this purpose was the Otoflex middleear analyzer, TDH 39P headphones, from Gn-ReSound, and the author's criteria were applied (18) .

Statistical analysis
The difference-in-proportions test was used to compare the results of the audiological exam, the BAEP test, and the Spinocerebellar ataxia CoDAS 2013;25(4):351-7 acoustic immittance measure, by analyzing results indicating normalcy and abnormalcy.Rejection level in the null hypothesis was fixated at 0.05 or 5%.
The application of the difference-in-proportions test proved there was a significant difference between the proportions of normal and abnormal cases -LE (p<0.05) and B (p=0.0063*).
The application of the difference-in-proportions test further proved there was no significant difference between the proportions of normal and abnormal cases -B (p=0.2843).
The results of audiological evaluation, BAEP, and acoustic immittance measure in relation to the proportions of normal and abnormal cases in SCAs 2, 3, and 10 are presented in Table 5.
The application of the difference-in-proportions test proved there was significant difference only in the audiological evaluation and in SCA 2 (p=0.0096*).

DISCUSSION
Anamnesis revealed the predominance of gait disorders, which was expected in terms of SCA.Changes in speech, dizziness, dysphagia, dysphonia, and hearing loss are the most frequent symptoms as described in many past studies (1)(2)(3)(4) .
Changes in audiological evaluation were present in 30% of the patients with ataxia, especially those in the category of SCA 3 and SCA 10.The authors (19) assessed 18 patients with SCA and observed normal hearing in all of them but found hearing changes using the BAEP test, with a 71% occurrence in Friedreich's ataxia, in which only Wave I was found, and 71% in olivopontocerebellar atrophy, which does not refer to the type of alteration found.The authors pointed out to important abnormalities in the brainstem auditory pathways of patients with this disease.
In this study, 46.5% of patients presented alterations in BAEP, with increased Wave I latency only in SCA 3.An increase in Wave V latency was observed in SCAs 3, 6, 7, 10, and undetermined SCA; an increase in Wave III latency was observed in SCAs 2, 6, and 7; and an increase in Interpeak intervals I-III, I-V, and III-V occurred in SCAs 2, 3, 6, 7, 10, and the undetermined SCA.The authors (19)(20)(21)(22) reported frequent abnormalities in this examination.The prevalence of changes in SCAs 2 and 3 are in accordance with the authors (20,21) , which is due to higher prevalence of these types of SCA.Some studies (21) have evaluated the BAEP test in 36 patients (eight with SCA 1, twelve with SCA 2, and sixteen with SCA 3) and observed results indicating abnormalities in 50% of those with SCA 1, 42% with SCA 2, and 63% with SCA 3. Another group of researchers (23) assessed 30 patients with spinocerebellar degeneration and observed abnormalities in 30% of these patients after the BAEP test, with prolonged latencies and Interpeaks of waves I-III and I-V, which is in accordance with this study.Some authors (24) conducted an anatomopathological investigation of brain in 12 patients with SCA (three with SCA 2, seven with SCA 3, and two with SCA 7), considering tissue cuts of auditory nuclei; they reported substantial damage to the central auditory system.
The study showed neural loss of the dorsal and ventral nuclei of the lateral lemniscus in two patients with SCA 2, in all of those with SCA 3, and in one patient with SCA 7. The superior olivary nucleus proved to be the most severely affected by degeneration, and the loss of myelinated fibers in brainstem pathways restricted to the lateral lemniscus was found in a patient with SCA 2, in five patients with SCA 3, and in all of those with SCA 7. The trapezoid body was altered in a patient with SCA 2 and in two patients with SCAs 3 and 7.The involvement of these structures offered plausible explanations for the hearing damage observed in these patients.
Acoustic immittance measures were altered in 44.1% of these patients, and literature has no reference about this finding, so the results cannot be reconfirmed.It is known that fibers leave from the anterior cochlear nuclei, via trapezoid body, and move toward the nuclei of the contralateral facial nerve and the superior olivary nucleus, which in turn forms synapses with the facial nerve nucleus.There are also homolateral fibers coming from the anterior cochlear nuclei, which establish such communications, and, in addition, axons innervate the stapedius muscle or the stapes.However, when there are multiple neurodegenerative diseases, the anterior cochlear nuclei are affected, which in turn renders impossible the task of making interferences in the acoustic reflex mechanism (25,26) .In the present study, a higher prevalence of alterations observed in the BAEP examination proved there were severe changes in the integrity of the brainstem auditory pathway.This finding is in accordance with many other research works (19)(20)(21)(22)(23)(24) , where the authors have observed alterations in many structures of the central auditory pathway, demonstrating the greater sensitivity of this examination to detect changes in the path of acoustic impulse throughout the central auditory pathway.
The importance of studying the auditory system is emphasized, especially in the context of electrophysiological control, together with clinical and genetic follow-ups.

CONCLUSION
The alterations that mostly appeared in the audiological evaluation include the prevalence of descending audiometric configuration from the 4-kHz frequency, bilaterally, and the absence of acoustic reflex in 3-and 4-kHz frequencies, again bilaterally.
In the electrophysiological evaluation, 50% of the patients presented with changes, especially increased latencies in Waves I, III, and V and Interpeak intervals I-III, I-V, and III-V.*WOA collaborated with data collection and formatting; RSS collaborated with collection and bibliography; DF collaborated with collection and bibliography; HM collaborated with collection and bibliography; JMM collaborated with data analysis; HGAT was in charge of writing and final review; ALI participated in the writing and final review; BSZ was in charge of the project and study design as well as general orientation of the stages of execution and elaboration of the manuscript.

Legend:
RE = right ear; LE = left ear; SCA = spinocerebellar ataxia; Und.= Undetermined.The application of the difference-in-proportions test in the acoustic immittance test proves there was no significant difference between the proportions of normal and abnormal cases: B (p=0.2843).ACKNOWLEDGEMENTNational Council for Scientific and Technological Development (CNPQ), Report n. 309965/2009-8.

Table 2 .
Frequency of symptoms in 43 patients with spinocerebellar ataxia

Table 3 .
Results of audiological and brainstem auditory-evoked potential evaluations in 43 patients with spinocerebellar ataxia

Table 4 .
Results of the immittance test in 43 patients with spinocerebellar ataxia

Table 5 .
Distribution of the results of the audiological, brainstem auditory evoked potential and acoustic immittance evaluations in spinocerebellar ataxias 2, e, and 10 SCA = spinocerebellar ataxias; BAEP = brainstem auditory-evoked potential The application of the difference-in-proportions test proves there was a significant difference only in the audiological evaluation and in SCA 2 (p=0.0096*). Legend: