Corrected by:
ErratumArq Neuropsiquiatr 2020; 78(04): 244-244
DOI: 10.1590/0004-282x20190139erratum
Keywords:
hearing - electrophysiology - precursor cell lymphoblastic leukemia-lymphoma - drug
therapy - methotrexate - child
Palavras-chave:
audição - eletrofisiologia - leucemia-linfoma linfoblástico de células precursoras
- tratamento farmacológico - metotrexato, criança
Several factors can compromise the auditory pathway, including the drugs used during
chemotherapy.
Both normal cells and cancer cells are destroyed from chemotherapeutic drugs, causing
secondary problems[1] such as ototoxicity and neurotoxicity.
Several chemotherapeutic drugs are used in the treatment of various types of cancer,
such as cisplatin, carboplatin, actinomycin, bleomycin, nitrogen mustards (mustine),
misonidazole, vincristine, vinblastine[2], among others.
Acute lymphoblastic leukemia (ALL) is the most common type of cancer found in young
children, and may occur in adults[3]. In a study that aimed to estimate the prevalence of hearing loss in children and
adolescents with cancer, 30.8% of the 94 patients treated in 2003 and 2004 in a referral
hospital in São Paulo had ALL[4].
The GBTLI-LLA99 (Grupo Brasileiro de Tratamento da Leucemia na Infância [Brazilian Group for Leukemia Treatment in Childhood ALL-99 Brazilian][5]) and BFM95 (developed by the German group Berlin-Frankfurt-Munich)[6] protocols are used in the treatment of individuals with ALL, and both include the
chemotherapeutic drug methotrexate (MTX)[7].
Although several drugs are used in these protocols, MTX is most commonly reported
to cause neurotoxicity after its use[8],[9].
MTX is used in the treatment of malignant tumors, both solid and hematological, and
can be used in high doses of 3 to 8 g/m2 or even higher if necessary. MTX can also be used in low doses (10 to 15 mg) intrathecally
for prophylaxis or treatment of leptomeningeal infiltration. Its main indications
are ALL and non-Hodgkin's lymphomas, including brain lymphomas and sarcomas (adult
and childhood)[10]. The neurotoxicity occasioned by MTX[11],[12],[13] may occur in an acute, subacute, or late form[14] and can be observed after intrathecal or intravenous administration[9],[11].
The mechanism that MTX causes neurotoxicity is not fully understood, and more than
one mechanism may be involved; however, MTX has been observed to have direct toxicity
in brain tissue[9]. The location and degree of toxicity are difficult to determine, and there is no
clear correlation between the results of auxiliary tests (MRI, radionuclide brain
scan, electroencephalography, neuropsychological tests) and the clinical manifestations[9].
Because MTX can impair both central and peripheral nervous system, its potential
neurotoxicity in the central auditory nervous system (CANS) must be considered. Impairment
of this region can impede the understanding of speech and, consequently, the development
of speech and language in children, possibly hindering the social interaction of individuals.
To evaluate the CANS, auditory evoked potentials (AEPs) are used to assess neuroelectric
activity in the auditory pathway from the auditory nerve to the auditory cortex.
Brainstem auditory evoked potential (BAEP) measurement is an objective test that
captures the electrical responses to acoustic stimulation generated in the brainstem.
This potential consists of seven waves with well-defined generators[15],[16].
BAEPs have been used to investigate ototoxicity in cancer patients undergoing chemotherapy[17],[18],[19], but the investigation of neurotoxicity with this test has rarely been explored.
In a study using BAEPs to assess neurotoxicity in children and adolescents after
chemotherapy with cisplatin, an increase was observed in interpeak I-III value that
was associated with normal distortion product otoacoustic emissions (DPOE), suggesting
neurotoxicity in the auditory pathway in the brainstem. The authors reported the need
for further studies to examine neurotoxicity[20].
Therefore, the objective of this study was to investigate the auditory pathway in
the brainstem of children with ALL undergoing chemotherapy (intravenously or intrathecally).
METHODS
The present study was approved by the Ethics Committee of the institution under number
53924116.0.0000.0068/2016, and data collection was performed only after the parents
or guardians signed an informed consent form and the children signed an assent form.
This is a clinical and cross-sectional study that evaluated 14 children (8 females;
6 males) aged 2 to 12 years (mean age, 8 years 4 months) who were diagnosed with ALL,
had no infiltration into the central nervous system as confirmed by examination of
the cerebrospinal fluid, and were undergoing chemotherapy. The volunteers were referred
by a public reference hospital in the city of São Paulo, where they were undergoing
chemotherapy and outpatient follow-up (1 individual in remission - patient 7).
The audiological and electrophysiological evaluation of hearing was performed in a
teaching health center, which required patients to travel, justifying why the sample
size was small.
It is noteworthy that in some cases the first assessment was revalued, since the population
had complications of chemotherapy, and data collection was performed in two sessions
of up to 1h30min when necessary.
The doses of MTX were collected using medical records, and the total dose administered
intravenously and/or intrathecally until the date of BAEP measurement was obtained.
Dosages, frequency, and duration of drug infusion were established according to the
risk group in which the patient was entered.
A Heine® Mini2000™ Otoscope was used to examine the ear canal.
The children were subjected to acoustic immittance evaluations (tympanometry and acoustic
reflex measurements) to assess possible middle ear impairment (GN Otometrics tympanometer,
model Otoflex100). Pure-tone audiometry at frequencies of 500, 1000, 2000, 4000 Hz
(if possible 6000 and 8000 Hz) were used to determine auditory thresholds, and speech
audiometry (speech recognition threshold - SRT - and speech recognition percentage
index - SRPI, the latter performed in older children) (Grason Stadler audiometer,
model GSI-61, ER-3A earphones, sound booth meeting the ANSI S3.1-1991 standard for
the amount of ambient noise).
When obtaining auditory thresholds, the ages of the children were considered, and
conditioned play audiometry or pure-tone audiometry using earphones were performed.
To obtain the BAEP measurements, the skin was initially cleaned with an abrasive paste,
and the electrodes were fixed to the skin of the individual using an electrolyte paste
and adhesive tape (micropore), according to the International Electrode System (IES)
10‒20 standard[21]. The impedance values of the electrodes were checked and were below 5kohms.
BAEPs were measured using a click stimulus with rarefied polarity, monoaurally presented
at 80dBnHL, at a rate of 27.7 stimuli per second, totalizing 2000 stimuli (Universal
Smart Box JrTM Smart EP, Intelligent Hearing System-ER-3A earphone for BAEP and ER-10D earphone
for otoacoustic emissions-OAEs). In cases where it was not possible to perform conventional
pure-tone audiometry or transient otoacoustic emissions (TOAEs), the electrophysiological
threshold was obtained using the BAEP, with a normal electrophysiological threshold
considered to be up to 20 dBnHL[22].
To obtain this potential, it was necessary for the child to remain seated or laying
in a recliner in a comfortable position in a sound and electrically treated room.
After collection, for the acoustic immittance measures, normal results were considered
to include the presence of a type A tympanogram pattern[23] and ipsilateral acoustic reflexes present at frequencies of 500, 1000, and 2000
Hz between 80 and 95 dBHL[24].
Because the higher frequencies of pure-tone audiometry are important in the evaluation
of individuals undergoing chemotherapy, the result was classified as normal when auditory
thresholds less than or equal to 15 dBHL were observed at frequencies of 500, 1000,
2000, and 4000 Hz (children up to 6 years of age) and when auditory thresholds less
than or equal to 20 dBHL were observed at frequencies of 250, 500, 1000, 2000, 4000,
6000, and 8000 Hz (children 7 years old or older).
The speech audiometry result was considered compatible when the SRT showed a response
equal to or up to 10 dB above the mean auditory thresholds obtained in pure-tone audiometry
for the frequencies of 500, 1000, and 2000 Hz[25] and when the SRPI showed a percentage of accuracy between 90 and 100% at an intensity
of 30 dB above the SRT[26].
Regarding the BAEP, the results were classified as normal and altered for each individual
according to whether the absolute latency values of waves I, III, and V, and the interpeak
values of I-III, III-V, and I-V were within two standard deviations, as proposed by
the literature[27].
Subsequently, the types of alterations found in each individual were described: alteration
in the lower brainstem auditory pathway (increase of latency values of waves III and
V and/or the interpeak values of I-III and I-V); alteration in the upper brainstem
auditory pathway (increase of latency values of wave V and/or interpeak values of
III-V and/or I-V); when the two alterations occurred concomitantly in the same individual,
the type of alteration was classified as both.
Results that did not meet the criteria described above were considered altered. For
results to be classified as normal, it was necessary for both ears to present results
within the normal range. Results for which at least one ear was compromised were classified
as altered.
RESULTS
Regarding the results of the behavioral tests, two children (1 and 6) did not have
a conditioned response to the conventional pure-tone audiometry; therefore, the TOAEs
were measured. One of the children (subject 1) did not present a response in the TOAE
test due to the intense internal noise, while the other (subject 6) had responses
at frequencies of 1000, 1500, and 2000 Hz. Both children had electrophysiological
thresholds of 20dBnHL bilaterally in the BAEP measurement.
The other children showed normal results on the behavioral tests.
The BAEP results showed that of the 14 children evaluated, 35.71% (1, 2, 4, 8, 11)
had some type of alteration, and the predominant type was auditory impairment in the
lower brainstem (80%) ([Tables 1], [2] and [3]).
Table 1
Characterization of the sample as the use of methotrexate, BAEP result, cerebrospinal
fluid collection, and the child's age.
Individuals
|
age
|
intravenous MTX cumulative dosage
|
dosage of the last administration of MTX
|
days of last administration
|
intrathecal MTX cumulative dosage
|
dosage of the last administration of MTX
|
days of last administration
|
normal
|
abnormal
|
type of alteration
|
time between cerebrospinal fluid collection and ABR (days)
|
Result Liquor (neoplastic cells)
|
1
|
3a6m
|
7.600 mg
|
3.800 mg
|
54
|
72 mg
|
12 mg
|
22
|
|
x
|
low brainstem
|
7
|
negative
|
2
|
4a3m
|
1.447 mg
|
740 mg
|
6
|
48 mg
|
12 mg
|
1
|
|
x
|
low brainstem
|
11
|
negative
|
3
|
4a4m
|
2.700 mg
|
1.400 mg
|
38
|
36 mg
|
12 mg
|
38
|
X
|
|
|
37
|
negative
|
4
|
4a4m
|
1.600 mg
|
200 mg
|
67
|
36 mg
|
12 mg
|
113
|
|
x
|
low brainstem
|
103
|
negative
|
5
|
5a2m
|
710 mg
|
150 mg
|
31
|
48 mg
|
15 mg
|
54
|
X
|
|
|
19
|
negative
|
6
|
3a3m
|
2.229 mg
|
1.100 mg
|
65
|
64 mg
|
12 mg
|
11
|
X
|
|
|
3
|
negative
|
7
|
6a8m
|
4.390 mg
|
330 mg
|
102
|
60 mg
|
12 mg
|
126
|
X
|
|
|
193
|
negative
|
8
|
10a8m
|
8.000 mg
|
5.000 mg
|
43
|
99 mg
|
12 mg
|
13
|
|
x
|
low brainstem
|
8
|
negative
|
9
|
12a6m
|
5.000 mg
|
5.000 mg
|
6
|
30 mg
|
15 mg
|
21
|
X
|
|
|
1
|
negative
|
10
|
11a
|
2.250 mg
|
250 mg
|
15
|
24 mg
|
12 mg
|
155
|
X
|
|
|
27
|
negative
|
11
|
10a5m
|
1.160 mg
|
920 mg
|
36
|
45 mg
|
15 mg
|
7
|
|
x
|
high brainstem
|
7
|
negative
|
12
|
9a7m
|
2.300 mg
|
200 mg
|
9
|
84 mg
|
12 mg
|
9
|
X
|
|
|
9
|
negative
|
13
|
11a6m
|
4.550 mg
|
25 mg
|
2
|
24 mg
|
12 mg
|
2
|
X
|
|
|
19
|
negative
|
14
|
12a8m
|
2.690 mg
|
30 mg
|
79
|
15 mg
|
15 mg
|
109
|
X
|
|
|
18
|
negative
|
MTX: methotrexate; BAEP: brainstem auditory evoked potential.
Table 2
Distribution of the occurrence of normal and abnormal results and types of alterations
on the BAEP observed in children undergoing chemotherapy with methotrexate.
BAEP
|
n
|
%
|
Normal
|
9
|
64.29
|
Abnormal
|
5
|
35.71
|
Type of alteration
|
Low brainstem
|
High brainstem
|
Both
|
n
|
%
|
n
|
%
|
n
|
%
|
BAEP
|
4
|
80
|
1
|
20
|
0
|
0
|
BAEP: brainstem auditory evoked potential.
Table 3
BAEP latency values obtained in the sample.
|
Latency (ms)
|
Interpeak (ms)
|
I
|
III
|
V
|
I-III
|
III-V
|
I-V
|
Individuals
|
age
|
Right
|
Left
|
Right
|
Left
|
Right
|
Left
|
Right
|
Left
|
Right
|
Left
|
Right
|
Left
|
1
|
3a6m
|
1.75
|
1.45
|
4.20
|
4.15
|
5.90
|
5.90
|
2.45
|
2.70
|
1.70
|
1.75
|
4.15
|
4.45
|
2
|
4a3m
|
1.70
|
1.65
|
3.95
|
4.10
|
5.70
|
5.85
|
2.25
|
2.45
|
1.75
|
1.75
|
4.00
|
4.20
|
3
|
4a4m
|
1.60
|
1.45
|
3.80
|
3.80
|
5.65
|
5.55
|
2.20
|
2.35
|
1.85
|
1.75
|
4.05
|
4.10
|
4
|
4a4m
|
1.65
|
1.55
|
4.05
|
4.00
|
5.85
|
5.70
|
2.40
|
2.45
|
1.80
|
1.70
|
4.20
|
4.15
|
5
|
5a2m
|
1.60
|
1.50
|
3.80
|
3.80
|
5.75
|
5.65
|
2.20
|
2.30
|
1.95
|
1.85
|
4.15
|
4.15
|
6
|
3a3m
|
1.60
|
1.55
|
3.75
|
3.80
|
5.60
|
5.65
|
2.15
|
2.25
|
1.85
|
1.85
|
4.00
|
4.10
|
7
|
6a8m
|
1.85
|
1.70
|
3.70
|
3.85
|
5.70
|
5.75
|
1.85
|
2.15
|
2.00
|
1.90
|
3.85
|
4.05
|
8
|
10a8m
|
1.25
|
1.25
|
3.95
|
3.85
|
5.70
|
5.80
|
2.70
|
2.60
|
1.75
|
1.95
|
4.45
|
4.55
|
9
|
12a6m
|
1.55
|
1.55
|
3.85
|
3.75
|
5.70
|
5.65
|
2.30
|
2.20
|
1.85
|
1.90
|
4.15
|
4.10
|
10
|
11a
|
1.65
|
1.45
|
3.75
|
3.75
|
5.80
|
5.50
|
2.10
|
2.30
|
2.05
|
1.75
|
4.15
|
4.05
|
11
|
10a5m
|
1.75
|
1.75
|
3.90
|
3.90
|
6.00
|
6.00
|
2.15
|
2.15
|
2.10
|
2.10
|
4.25
|
4.25
|
12
|
9a7m
|
1.75
|
1.65
|
3.75
|
3.70
|
5.60
|
5.55
|
2.00
|
2.05
|
1.85
|
1.85
|
3.85
|
3.90
|
13
|
11a6m
|
1.75
|
1.55
|
3.65
|
3.70
|
5.50
|
5.50
|
1.95
|
2.10
|
1.80
|
1.85
|
3.75
|
3.95
|
14
|
12a8m
|
1.75
|
1.75
|
3.85
|
3.85
|
5.70
|
5.75
|
2.10
|
2.10
|
1.85
|
1.90
|
3.95
|
4.00
|
BAEP: brainstem auditory evoked potential.
We also observed that 60% of children (1, 2, 4) who presented altered BAEPs were younger
than 5 years old and that 80% of the children (1, 2, 8, 11) with alterations had received
MTX intrathecally less than 30 days before ([Table 1]).
The 40% of children (1 and 8) who had abnormal BAEP results had the highest cumulative
doses of MTX administered intravenously (8.000 mg, subject 1; 7.600 mg, subject 2)
and intrathecally (72 mg, subject 1; 99 mg, subject 2) ([Table 1]).
DISCUSSION
Although data from the literature[4] show that ALL occurs more frequently in males, in the present study, our sample
included mostly females. This may have occurred because the sample number was small.
Conductive impairment was only observed in children younger than 5 years (3 years
7 months), while upper airway impairment was present in both younger and older children.
This hindered the measurement of OAEs; therefore, this procedure was performed only
in children who did not undergo pure-tone audiometry. These findings are consistent
with reports in the literature of individuals undergoing chemotherapy who have both
complaints of otitis and upper airway infection[4].
Chemotherapeutic drugs do not differentiate normal cells from cancer cells; therefore,
several types of normal cells are destroyed, causing secondary problems[1], such as ototoxicity[4]. The results of the behavioral tests obtained in the present study showed that the
peripheral hearing of children at the frequencies conventionally evaluated was not
impaired by chemotherapy because all children had thresholds within the normal range
for their age.
However, analysis of the TOAEs for subject 6 ([Table 1]) showed responses at frequencies of 1000, 1500, and 2000 Hz and no response at frequencies
of 3000 and 4000 Hz (higher frequencies) bilaterally. Due to the absence of response
to the 3000 and 4000 Hz frequencies, the electrophysiological threshold was obtained
using the BAEP, which was 20 dBnHL bilaterally. The medical records showed that this
individual had been undergoing chemotherapy for several months, and one of the drugs
used was vincristine at a dose of 4.400 mg, which, according to the literature, is
considered an ototoxic drug[28]. These findings suggest that alterations occur in the cochlea and are first detected
by the TOAE responses and later by the auditory thresholds obtained in pure-tone audiometry,
which would explain the electrophysiological threshold of 20 dBHL bilaterally. In
a study involving auditory monitoring in patients undergoing chemotherapy, the TOAE
results showed that a response to frequencies of 1000 and 2000 Hz was observed until
the end of treatment, while a progressive increase in the absence of responses to
frequencies of 3000 and 4000 Hz was observed during treatment[29].
In the present study, we found that 5 (35.71%) of the individuals who underwent audiological
and electrophysiological assessment of hearing ([Tables 1] and [2]) showed impairment in the auditory pathway in its most central portion, demonstrating
the importance of peripheral and central auditory assessment in this population.
According to the BAEP results, the five individuals mentioned above had some type
of alteration, and the predominant type was auditory impairment in the lower brainstem
([Tables 1] and [2]). These findings suggest possible impairment by MTX, as the literature emphasizes
that this drug can cause adverse effects, such as neurotoxicity[11],[12],[13]. In addition, studies have reported that neurotoxicity can occur in an acute, subacute,
or chronic form[14] and can be observed after intrathecal or intravenous administration of MTX[9],[11]. In the present study, it was also observed that the majority of children with alterations
had used MTX intrathecally less than 30 days prior.
Other authors have further reported that acute and subacute forms of neurotoxicity
may occur during ALL treatment, generally manifesting as neurological signs. In some
cases, neurotoxicity is transient and benign, and in other cases, it can be severe
and debilitating, leading to permanent neurological deficits[8].
Because BAEP measurement was not performed prior to MTX administration, and follow-up
was not performed, it was not possible to determine when auditory nerve impairment
and/or brainstem impairment occurred or the duration of such impairment. According
to the literature, the mechanism by which MTX causes neurotoxicity is not fully understood,
and more than one mechanism may be involved, but MTX has been shown to have an immediate
effect on nerve tissue[9]. The findings of our study suggest that this effect occurred because children exhibited
impairment of the auditory nerve/brainstem at 1, 7, and 13 days after administration
of MTX.
It was not possible to establish the minimum (or exact) amount of drug likely to impair
the lower brainstem region using the results of this study. However, we found that
40% of children who had abnormal BAEP results received the highest cumulative doses
of MTX intravenously (8.000 mg, subject 1; 7.600 mg, subject 2) and intrathecally
(72 mg, subject 1; 99 mg, subject 2) ([Table 1]), which are doses considered to be high according to the literature[10].
In addition, the location and degree of toxicity that MTX causes in the central nervous
system are difficult to establish[9], but in the present study most of the impairment occurred in the lower brainstem.
The only study found in the literature that used BAEPs to evaluate the central auditory
pathway of individuals undergoing chemotherapy showed that these individuals exhibited
an increase in the interpeak I-III value[20]. This result is suggestive of impairment in the lower brainstem auditory pathway.
Studies of BAEP measurement in individuals receiving MTX were not found in the literature;
however, in a study that assessed motor evoked potentials, delayed conduction of the
stimulus in the peripheral motor nerve as well as impairment of the central nervous
system were observed after intrathecal MTX administration[30].
It is known that, ABR waves I, III, and V are the largest and most frequently observed
waves when compared to waves II and IV that may not be present even in normal individuals.
Thus, the present study opted for the analysis of waves I, III, and V and their interpeaks
I-III, III-V, and I-V. Normal wave I latency values were observed in all evaluated
individuals, and the same was not observed for waves III and V and / or interpeaks
I-III, I-V, III-V.
As most children in the present study exhibited alterations in the lower brainstem,
it can be inferred that a deficit in nerve conduction of the acoustic stimulus was
present in the region proximal to the brainstem of the auditory nerve (wave II) (although
the values were not obtained), which is part of the final structure of the peripheral
auditory system[31], that interfered with the latency value of wave III, or there may have been a deficit
in the cochlear nucleus region (wave III) located in the brainstem - the first structure
of the central auditory nervous system[31].
In the present study, another important finding was the observation that children
younger than five years old were the most susceptible to chemotherapy because most
had some type of impairment in the auditory pathway. These findings corroborate a
previous study that showed that children and elderly people undergoing chemotherapy
are most susceptible to auditory alterations[32].
Although MTX is considered neurotoxic, it is important to highlight that there is
interindividual variability, which may be due to genetic susceptibility, having as
participants the following genes involved: megaline, glutathione S-transferase, cross-complementation
group’s excision repair 1 and 2, acylphosphatase 2, and mutations in mitochondrial
genes[33]. Such variability would explain lower dose individuals in the present study with
impairments after drug use (individual 4 intrathecal) and individual with higher dose
without alteration (individual 12 intrathecal).
Considering that all individuals in the present study underwent cerebrospinal fluid
examination with negative results during the investigation of neoplastic cells (suggesting
absence of infiltration into the central nervous system) and that, among the drugs
used in the treatment of ALL, MTX is most often referred to by authors as being the
main drug related to neurotoxicity, we can infer that the findings of brainstem auditory
pathway impairment in the present study might have been caused by the administration
of MTX in this population.
Because the auditory nerve is responsible for the tonotopic organization of frequencies
(low and high)[31] (wave II of the BAEP) and the cochlear nucleus is responsible for listening in noisy
conditions[34] (wave III of the BAEP), impairment in one of these regions, even if temporary, especially
in young children, can compromise the development of speech and language and impair
their social interaction (family, school).
Although this population is difficult to assess due to the complications of chemotherapy,
behavioral assessment of auditory processing would be indicated in individuals with
alterations in BAEP, as well as in those with complaints and normal hearing thresholds,
aiming at a better direction in the therapeutic treatment and stimulation of impaired
auditory skills.
The present study demonstrated that BAEP measurement is a useful tool in the evaluation
of individuals undergoing chemotherapy, which demonstrated the importance of peripheral
and central auditory evaluation in this population, in addition to audiological monitoring
during chemotherapy. Thus, therapeutic strategies can be implemented early to decrease
future impairments in this population who are undergoing acquisition and development
of speech and language.
Further prospective studies with a larger number of individuals and with BAEP measurements
conducted prior to chemotherapy should be performed to better define the auditory
impairment of these patients.
In conclusion, children with ALL undergoing chemotherapy exhibit impairment of the
brainstem auditory pathway, and the main impairment was located in the auditory pathway
in the lower brainstem.