Keywords
Multiple Sclerosis - Hearing - Electrophysiology - Evoked Potentials, Auditory - Central
Nervous System
Palavras-chave
Esclerose Múltipla - Audição - Eletrofisiologia - Potenciais Evocados Auditivos -
Sistema Nervoso Central
INTRODUCTION
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system
– where inflammation, demyelination, and axonal loss occur as early as the initial
stages of the disease. It is one of the most frequent causes of neurological disability
in young individuals.[1]
[2]
MS affects mainly young adults, mostly women 20 to 40 years old. However, an estimated
30,000 children and adolescents worldwide are believed to be affected by it, totaling
2% to 5% of all cases.[3]
MS manifests as an inflammatory disease among children and youth, causing more seizures
and evidence of brain atrophy, axonal damage, and accumulated lesions identified in
magnetic resonance imaging (MRI) than in disease onset at adulthood.[4]
Considering these individuals' neuronal impairment, it has been recommended to use
evoked potentials in batteries to diagnose MS, assess the progress of the disease,
and monitor the benefits and limitations of various treatments.[4]
[5]
[6]
[7]
[8] These potentials can measure the physiology of neurological changes, helping identify
the disease locus and lesion severity,[7] though undetectable with MRI.[8] Studies have pointed out that assessments with auditory evoked potentials can locate
lesions throughout the auditory pathways at a rate almost similar to that of MRI[6]–which is greatly important, as it is a noninvasive and low-cost procedure.
Auditory evoked potentials assess the neuroelectric activity in the auditory pathway
from the auditory nerve to the cerebral cortex, evoked with acoustic stimuli. The
brainstem auditory evoked potentials (BAEP) are one of the most used resources in
clinical practice; their main objectives are to identify changes from the auditory
nerve to the brainstem and estimate the electrophysiological hearing threshold.[9] In their turn, the long-latency auditory evoked potentials (LLAEP) reflect the neuroelectric
activity of the auditory pathway in the thalamus and auditory cortex – which are structures
that involve functions of discrimination, integration, and attention, providing information
on the functioning of the central auditory nervous system.[10]
[11]
Various studies have assessed electrophysiological measures in adult MS patients.[5]
[6]
[8]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30] Despite the vast literature on the topic, studies investigating impairments in the
central auditory nervous system of children and youth are scarce. Hence, this study
aimed to assess the central auditory pathway with BAEP and LLAEP in children and adolescents
with MS.
METHODS
The study group (SG) comprised 17 individuals who attended the Children's Institute
of the Medical School Clinics Hospital at the University of Sao Paulo (HCFMUSP), diagnosed
with MS (according to criteria of the International Pediatric Multiple Sclerosis Study
Group for pediatric MS), of both sexes (nine females and eight males), aged 9 to 18
years (13.71 ± 3.01). The age of symptom onset ranged from 4 to 16 years (11.71 ± 3.51),
and the diagnosis was confirmed by 6 to 17 years old (12.29 ± 3.45).
The control group (CG) comprised a convenience sample of 17 healthy volunteers, matched
with SG for age and sex, without developmental impairments or neurological or psychiatric
complaints, recruited from local schools.
None of the participants had obstructions in the external auditory meatus or conductive
impairments – they had type-A tympanograms –, and all of them had normal hearing (hearing
thresholds below 15 dB HL at 500 to 4000 Hz).
The research was approved by the institution's Research Ethics Committee under number
1.784.31. All parents/guardians and participants respectively signed informed consent
and assent forms before the study.
After the complete audiological assessment, the auditory evoked potentials were obtained
using the Smart EP equipment manufactured by Intelligent Hearing System and ER 3-A
insert earphones. During the assessment, subjects remained seated in a reclining chair,
in an acoustically and electrically treated room. The skin surface of the forehead,
mastoids, and scalp was cleaned with abrasive paste, and Ag-AgCl electrodes were then
positioned with electrolytic paste and micropore tape, following the international
10-20 system (International Electrode System). Electrode impedance was maintained
below 3 kOhms in all trials.
Two BAEP channels were applied using an electrode montage of Fz (active electrode),
Fpz (ground), and M1 and M2 (reference electrodes). This potential was evoked monaurally
through rarefaction click, at a presentation rate of 19.1 clicks per second, at 80 dBnHL,
using a 100 Hz high-pass filter, 1500 Hz low-pass filter, and 12 ms recording window.
Dual trials were performed with 2,048 sweeps each to check reproducibility.
Waves I, III, and V were identified and analyzed regarding absolute latencies, and
I-III, III-V, and I-V interpeak latencies. Based on the equipment's user manual, each
person's BAEP results were classified as either normal or abnormal (when at least
one of the ears was abnormal). Changes were classified as follows: changes in the
low brainstem if there was an increase in the I-III interpeak latency; changes in
the high brainstem if there was an increase in the III-V interpeak latency; or mixed
if both I-III and I-V interpeak intervals had increased latencies.
For LLAEP, the electrode montage was Cz (active electrode), Fpz (ground), and M1 and
M2 (reference electrode). Tone-burst stimuli were presented monaurally in an oddball
paradigm, at 75 dBnHL, with the standard stimulus (85%) at 1000 Hz and the target
stimulus (15%) at 2000 Hz. A total of 300 sweeps were presented at 1.1 sweeps per
second, with high- and low-pass filters between 1 and 30 Hz, and a 500 ms recording
window.
Participants were instructed to pay attention to the target stimuli and count aloud
the number of times they occurred. The trial that corresponded to the target stimuli
was subtracted from the standard stimuli. P1, N1, P2, and N2 components were identified
and analyzed regarding latency and amplitude in the standard trial, whereas P3 was
so in the target trial. P1, N1, P2, N2, and P3 latencies and P1-N1, P2-N2, and N2-P3
amplitudes were analyzed. The normality of absolute latencies followed that proposed
by McPherson[11] for each age group.
Quantitative values were analyzed regarding descriptive analysis, and a no-paired
t-test was used to compare SG and CG. Concerning qualitative data, the proportion
of normal and abnormal results and the types of changes were analyzed with Fisher's
exact test. Statistical significance was set at p-value ≤ 0.05 for all inferential
analyses.
Also, an analysis was carried out in order to verify the association between the main
focus of alteration on MRI (considering bridge, midbrain, cerebellar peduncles/cerebellum,
and IV ventricle) and the results of BAEP and LLAEP, by means of Fisher's exact test.
RESULTS
Absolute and interpeak BAEP latencies and absolute LLAEP latencies and amplitudes
were initially compared between the right and left ears of each group. As none of
the analyzed variables presented significant differences between the ears, the right
and left ears were grouped for the other analyses (comparison between groups).
The comparison between SG and CG revealed statistically significant differences in
BAEP III-V and I-V interpeak latencies, with longer latencies in SG ([Table 1]). It is noteworthy that in BAEP, 70% of the 10 SG individuals with abnormal results
had changes in the high brainstem, whereas 30% had them in the low brainstem.
Table 1
Absolute BAEP waves I, III, and V latencies and I-III, III-V, and I-V interpeak latencies
of both groups
|
Group
|
Mean (ms)
|
SD
|
p-value
|
|
Wave I
|
SG
|
1.54
|
0.13
|
0.172
|
|
CG
|
1.59
|
0.07
|
|
Wave III
|
SG
|
3.70
|
0.20
|
0.276
|
|
CG
|
3.76
|
0.10
|
|
Wave V
|
SG
|
5.69
|
0.22
|
0.123
|
|
CG
|
5.59
|
0.14
|
|
I-III interpeak interval
|
SG
|
2.17
|
0.14
|
0.822
|
|
CG
|
2.18
|
0.11
|
|
III-V interpeak interval
|
SG
|
1.97
|
0.22
|
0.015*
|
|
CG
|
1.82
|
0.09
|
|
I-V interpeak interval
|
SG
|
4.14
|
0.21
|
0.027*
|
|
CG
|
4.00
|
0.13
|
Abbreviations: BAEP, brainstem auditory evoked potentials; SG, study group; CG, control
group; ms, milliseconds; SD, standard deviation. Note: *p-value with a statistically
significant difference.
For LLAEP, the comparison between groups revealed statistically significant differences
in P2-N2 amplitude, which was higher in CG ([Table 2]). Furthermore, P1, P2, and N2 were the most abnormal components, with 66.7% of the
changes.
Table 2
Absolute LLAEP waves P1, N1, P2, N2, and P3 latencies and P1-N1, P2-N2, and N2-P3
amplitudes of both groups
|
Group
|
Mean
|
SD
|
p-value
|
|
P1 latency (in ms)
|
SG
|
65.50
|
23.62
|
0.186
|
|
CG
|
56.59
|
13.52
|
|
N1 latency (in ms)
|
SG
|
109.41
|
25.40
|
0.189
|
|
CG
|
99.53
|
16.63
|
|
P2 latency (in ms)
|
SG
|
177.91
|
32.02
|
0.179
|
|
CG
|
165.79
|
17.42
|
|
N2 latency (in ms)
|
SG
|
226.18
|
32.05
|
0.978
|
|
CG
|
225.94
|
17.40
|
|
P3 latency (in ms)
|
SG
|
308.65
|
26.81
|
0.303
|
|
CG
|
318.97
|
30.63
|
|
P1-N1 amplitude (in µV)
|
SG
|
4.76
|
2.87
|
0.598
|
|
CG
|
5.27
|
2.72
|
|
P2-N2 amplitude (in µV)
|
SG
|
3.49
|
2.28
|
0.025*
|
|
CG
|
5.99
|
3.75
|
|
N2-P3 amplitude (in µV)
|
SG
|
10.12
|
5.84
|
0.717
|
|
CG
|
10.82
|
5.34
|
Abbreviations: LLAEP, long-latency auditory evoked potentials; SG, study group; CG,
control group; ms-milliseconds; µV, microVolts; SD, standard deviation. Note: *p-value
with a statistically significant difference.
The comparison of normal and abnormal BAEP and LLAEP results between the groups showed
a higher incidence of changes in SG than in CG, with a statistically significant difference
between them ([Table 3]).
Table 3
Distribution of normal and abnormal BAEP and LLAEP results of both groups
|
Study group
|
Control group
|
p-value
|
|
Sample number
|
Percentage (%)
|
Sample number
|
Percentage (%)
|
|
BAEP
|
Abnormal
|
10
|
58.8%
|
0
|
0.0%
|
<0.001
|
|
Normal
|
7
|
41.2%
|
17
|
100.0%
|
|
LLAEP
|
Abnormal
|
9
|
52.9%
|
0
|
0.0%
|
<0.001
|
|
Normal
|
8
|
47.1%
|
17
|
100.0%
|
|
BAEP + LLAEP
|
Abnormal
|
6
|
60.0%
|
0
|
0.0%
|
0.001
|
|
Normal
|
4
|
40.0%
|
17
|
100.0%
|
Abbreviations: BAEP, brainstem auditory evoked potentials; LLAEP, long-latency auditory
evoked potentials.
Moreover, the combination of BAEP and LLAEP in group comparison indicated that six
individuals had changes in both potentials, four individuals had changed only in BAEP,
and three individuals had changed only in LLAEP ([Table 3]). Only four individuals presented normal results in both BAEP and LLAEP.
No association was observed between MRI results and BAEP and LLAEP results (p-value > 0.05).
DISCUSSION
This study aimed to assess the central auditory pathways in children and adolescents
with MS. This age range is seldom addressed in the literature, probably because the
disease is more prevalent in adults.
BAEP analysis revealed changes in 58.82% of patients. Increased wave V and consequently
in III-V and I-V interpeak intervals indicate decreased neural conduction speed of
the acoustic stimuli in the auditory pathways in the high brainstem, between the cochlear
nucleus and lateral lemniscus.
The scientific literature reports a great variability in the incidence of BAEP changes
in adults with MS, encompassing 20%,[21] 21.9%,[22] 30%,[17] 45%,[16] and 65%[15] of the cases. Such changes included morphology changes, abnormal tracing, increased
absolute and interpeak latencies, and the absence of some waves.[17]
[27] Furthermore, Di Stadio et al.[31] conducted a literature review and concluded that 100% of MS patients had some type
of BAEP change.
Studies in adults reported similar results to those found in the present one, with
increased wave V latency,[19]
[25]
[32] III-V interpeak latency,[21]
[25] and I-V interpeak latency.[8]
[16]
[19]
[21]
[25] In addition, some studies also found increased latencies in waves I[8] and III[8]
[19]
[32] and in interpeak interval I-III.[8]
[19]
[21]
[25]
As for children and youth, a study assessed a small group of 11 children and adolescents
aged 9 to 17 years and found increased III-V and I-V interpeak latencies, suggesting
changes in the high brainstem.[33] However, another study assessed 10 adolescents aged 13 to 17 years and reported
increased latencies in waves III and V and increased interpeak intervals I-III and
I-V, suggesting changes in the low brainstem.[34]
Such results may suggest a gradual impairment of the auditory pathways, progressing
from the most central region of the auditory system to future impairments in more
distal regions of the central nervous system. Nevertheless, the results found in the
literature remain quite variable. Moreover, there is a gap in the characterization
of samples regarding MS locus and the time elapsed from the disease onset to the study.
Hence, future studies that control these variables may find more systematic and consistent
results concerning impairments in this population's auditory pathways.
As for the cortical auditory pathways, more than half (52.94%) of MS patients in this
study had LLAEP changes. Even though there were no statistically significant differences
in latency values, SG had longer latencies than the healthy volunteers. Similarly,
there was a decrease in response amplitudes, although a statistically significant
difference was found only in P2-N2.
Barbosa et al.[33] also found a significant decrease only in P2-N2 amplitude in children and adolescents
with MS. On the other hand, regarding adults, there are reports of increased latencies
in N1,[14]
[28] P2,[12]
[14] N2,[12]
[14] and P3,[5]
[12]
[14]
[18]
[26]
[28] as well as increased amplitudes in P2,[14]
[28] N2,[28] and P3.[14]
These results suggest that MS patients may have slowed neural processing and decreased
neural activity in sensory, inattentional,[5] and attentional discrimination of acoustic stimuli, due to demyelination[18]–which slows down conduction, while axonal degeneration attenuates the amplitude
of the potential.[7]
According to Comi et al.,[35] demyelination may cause neural conduction attenuation, high-frequency impulse transmission
failures, blocked conduction, and secondary axonal degeneration. Thus, abnormalities
found in MS patients' evoked potentials may consist of delayed latencies in one or
more components, morphological abnormalities, and an increased refractory period.
None of these anomalies is specific to MS, but changes perceived in long-term follow-up
may indicate the progress of demyelination.
In the present study, no association was observed between the main focus of alteration
detected on MRI and the electrophysiological results. This result may be justified
by the limited sample size, considering that the population is heterogeneous in terms
of the different demyelinating lesion sites found in each patient.
In a larger sample, of 32 patients, abnormal latencies in the potentials have been
related to the locus of demyelinating lesions, agreeing with what was observed in
the MRI.[13] The combined assessment of short-, middle-, and long-latency auditory evoked potentials
have shown an 87% sensitivity, helping detect and confirm MS locus.[15] Hence, evoked potential assessment has proved to be a resource available when MRI
is not. It can be used to monitor treatment and long-term prognosis and to assess
changes that are not yet evident or specific in MRI.[6]
[7]
[8]
[25] Furthermore, LLAEP has been correlated with disease duration[12] and neuropsychological test results.[14]
[24] These data furnish information on the application of LLAEP to assess the degree
of cognitive impairment and investigate the neural origin of the disease.[5]
Changes in temporal resolution and auditory task memory and difficulties discriminating
speech in noisy environments have been described in MS[23]–which may justify the decreased P2-N2 amplitude. Moreover, some cognitive function
impairments may be related to attention, processing speed, working memory, visuospatial
skills, and executive functions.[20]
[36]
[37] Such deficits can interfere with academic and social performance and the self-perceived
capacity to do everyday tasks, therefore, detecting it immediately is essential to
the treatment.
MS impact on cognitive functions is still little known – although changes in cognitive
functions are known to be common in children with MS.[38]
[39] Since this population attends school – a phase when auditory processing complaints
are frequent even in individuals with no other impairments –, special attention must
be paid to ensure adequate treatment and resources to make hearing easier in the classroom
or other settings where listening is difficult, thus favoring learning and better
quality of life.
Various otorhinolaryngological symptoms are also described in MS, including speech
disorders, sleep disorders, vertigo, imbalance, dysphagia, changes in smell, and hearing
loss.[40] These data, along with the present study's findings, make clear the importance of
otorhinolaryngological and speech-language-hearing follow-ups on children and adolescents
with MS.
This study had a larger sample than the previous one that assessed auditory evoked
potentials in same-age MS patients. Nonetheless, the present research had a limited
sample size, which hindered other correlations concerning, for instance, the influence
of age on symptom onset, disease duration, and medications used. Therefore, future
research is expected to have larger samples and characterize them in further detail
to control other variables that might influence electrophysiological responses.
Another limitation of the study, regarding LLAEP analysis, was that it did not obtain
data on the participants' school achievements. Neither was it possible to perform
a behavioral assessment of the central auditory processing or a neuropsychological
assessment battery to correlate with the findings of the electrophysiological assessment.
Thus, future studies with larger samples that complement such data may clarify other
nuances that could not be measured in the present one.
