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Cochlear origin of hearing loss in MELAS syndrome.

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Cochlear Origin of Hearing Loss
in MELAS Syndrome
C. M. Sue, PhD, FRAU,* L. J. Lipsett, MBBS, FRACS,t D. S. Crimmins, MBBS, FRACP,*
C. S. Tsang, DipAud,$ S. C. Boyages, PhD, FRACP,$ C. M. Presgrave, BMed, FRACP,"
W. P. R. Gibson, MD, FRACS,? E. Byrne, DSc, FRACP,II and J. G. L. Morris, DM(Oxon), FRACP*
There have been few studies investigating the mechanism and nature of the hearing loss that occurs in the mitochondrial disorders. We studied 18 patients with the MELAS A3243G point mutation from four different kindreds. Pure
tone audiometry, speech discrimination testing, acoustic reflexes, tympanometry, and brain stem auditory evoked
responses were performed to localize the site of pathology in the auditory pathways. In 12 patients, we performed
electrocochleography and otoacoustic emissions to assess cochlear involvement. Neuroimaging and promontory nerve
stimulation were performed to exclude retrocochlear pathology. Audiological testing confirmed sensorineural hearing
loss in 14 of the 18 patients studied; hearing loss was usually gradual in onset, was symmetrical, and initially affected
the higher frequencies. In some patients, there were features that distinguished the hearing loss from presbyacusis,
including a young age at onset, asymmetrical involvement, stepwise progression, and partial recovery. We treated one
patient who had profound bilateral hearing loss with cochlear implantation; this restored good functional hearing.
Hearing loss in MELAS syndrome appears to be due to dysfunction of the cochlea, probably resulting from metabolic
failure of the stria vascularis and outer hair cells. Cochlear implantation is a therapeutic option worth considering in
those patients who become deaf.
Sue CM, Lipsett LJ, Crimmins DS, Tsang CS, Boyages SC, Presgrave CM, Gibson WPR, Byrne E, Morris JGL.
Cochlear origin of hearing loss in M E U S syndrome. Ann Neurol 1998;43:350-359
Hearing loss is common in mitochondrial disorders,'
but few studies have attempted to characterize its clinical features. In their original description, Pavlakis and
colleagues' reported that 3 of 11 patients with MELAS
syndrome had sensorineural deafness. A number of
workers have reported large kindreds with hearing loss,
usually in combination with diabetes, associated with
large-scale (10.4-kB) mitochondrial gene deletions3 or
the MELAS A3243G point
Hearing loss
has also been described in Kearns-Sayre syndrome' and
M E W syndrome.'
Recently, we reported that hearing loss was present
in a high proportion of patients with clinical features
of MELAS
The purpose of the present
study was to characterize the nature of the auditory
deficit by applying detailed neuro-otological investigations in a large series of patients, in an attempt to define the site of pathology associated with hearing loss
and the MELAS A3243G point mutation.
From the 'Department of Neurology, University of Sydney and
Westmead Hospital, Australia, the ?Department of Surgery, University of Sydney, Australia, *Hearing and Balance Unit, Royal Prince
Alfred Hospital, Sydney, Australia, the %Department of Endocrinology and Diabetes, Westmead Hospital, Sydney, Australia, the "Neuromuscular Research Centre, University of Melbourne, Melbourne,
Australia.
350
Patients and Methods
Patient Selection and Assessment
Four probands presented to hospital with symptoms suggestive of MELAS syndrome: 2 (1.1V.3 and 3.1.1) with strokelike episodes; 1 with isolated status epilepticus (2.IV.3), and
1 with severe hearing loss, diabetes, and muscle weakness
(4.11.3). All probands were found to have the MELAS
A3243G point mutation (see later). Sixty-two maternally related family members from these four kindreds were subsequently recruited for study (Fig 1). Two of the kindreds have
been described el~ewhere.~~'"
Thirty-six of the 62 maternally related members within
the four kindreds were alive, and 29 were able to participate
in this study. Twenty-four of the 29 patients (83%) had the
MELAS A3243G point mutation identified in muscle, hair
follicles, and/or peripheral white blood cells (see Fig 1). Only
patients with the M E U S A3243G point mutation underwent the electrophysiological aspects of this study. There
were 18 patients; 2 declined to have further studies and 4
patients were unable to participate owing to geographical dif-
Received Jun 12, 1997, and in revised form Ocr 20. Accepted for
publication Oct 23, 1997.
Address correspondence to NProf Morris, Department of Neurology, Level A4b, Westmead Hospital, Darcy Rd, Westmead, Sydney,
Australia, 2145.
Copyright 0 1998 by the American Neurological Association
~
Family 2
Family 1
I
II
1
c)
Ia
.I
Family 3
Family 4
History of hmrlng lass
MELAS 3243 point mutationdetected
History oi hearing bss and
M E U S 3243 point mutation detected
I
I
Fig I . Pedigree5 of the four kindred studied and members who had hearing loss and/or the presence of the MELAS A3243G point
mutation. Numbers refer to individual patients within the text, j p r e s , and tables. Families I and 2 are those reported by Crimmins and colLeague? and Sue and associates." Arrow indicates the proband.
ficulties. The project was approved by the Western Sydney
Area Human Ethics committee.
Patients and maternally related family members were assessed by a neurologist (CS or DC) and muscle, hair follicles,
or blood samples were taken for mitochondria1 genetic analysis. A detailed history regarding the age at onset and progression of their hearing loss was obtained. Where possible,
clinical information regarding maternally related deceased
family members was obtained. Thirty-five of the 62 marernally related members within the four kindreds (both living
and deccased) had a history of hearing loss (see Fig 1).
(Model AC/5). The severity of the hearing loss is expressed
as the percentage of loss of hearing (PLH) relative to age-
Patients and relatives were screened for the MELAS A3243G
point mutation by a polymerase chain reaction (PCR)-based
method using primers at nucleotides 2826-2849 and 37053728 and amplified using one cycle of 92°C for 1 minute
and 30 cycles of denaturation (92°C for 1 minute) and combined annealinglextension (65°C for 5 minutes) as described
previously." All probands had the MELAS A3243G point
mutation confirmed by PCR cycle sequencing (Promega fmol
kit according to the manufacturer's instructions) using a
24-mer universal primer for amplification.
and sex-matched control data." Normal hearing and mild,
moderate, severe, and profound hearing loss were defined as
0 to 1.9 PLH, 2 to 30 PLH, 31 to 60 PLH, 61 to 90 PLH,
and more than 90 PLH, respectively. The configuration of
hearing loss was also assessed; high-frequency (HF) loss was
defined as hearing loss affecting only frequencies above 2
kHz (3, 4, 6, and 8 kHz), and a flat (F) pattern of hearing
loss was defined as hearing loss similarly affecting (<15 dB
difference between) all frequencies measured. If the hearing
loss was most severe in the higher frequencies, and the middle and lower frequencies were affected to a lesser degree,
this was defined as a sloping (S) configuration. Where possible, previous audiograms were reviewed.
W e performed additional tests to discriminate between
neural and cochlear causes of hearing loss. Speech discrimination testing was done using AB Wordlists according to the
Australian Hearing Services standard p r o t o ~ o l . 'Acoustic
~
reflexes were measured ipsilateral and/or contralateral to the
stimulated ear, and tympanometry (impedence testing) was
performed using an Interacoustic Tympanometer (Model
AZ7R, Printer AG3).
Neuro-otological Methods
BRAINSTEM AUDITORY EVOKED RESPONSES.
Mitochondria1 DNA Analysis
AUDIOMETRIC TESTS. Pure tone audiometry was performed using air- and bone-conducted signals in an acoustic
booth on an Interacoustic Clinical Computer Audiometer
Brainstem
auditory evoked responses (BAERs) were performed on all
patients (Medelec MS6O) using previously described techn i q u e ~ . 'Rarefaction
~
click stimuli were used; stimulus inten-
Sue et al: Cochlear Hearing Loss in MELAS Syndrome 351
sity was at 65 to 70 dB above hearing thresholds or at maximal stimulator output (110 dB) if the hearing threshold was
above 40 dB. Two averages were recorded, and the reproducible components of each trace were identified.
plant using Spectra Speech Processor) was performed on a
27-year-old woman with profound bilateral hearing loss.
Results
Clinical Features
There were 7 males and 11 females in the study group.
Ages ranged between 12 and 72 years (mean, 40 years).
Clinical features of the participating patients are summarized in Table 1.
There was a high prevalence of hearing loss in our
patients; 14 patients (78%) had permanent hearing
loss. Onset of hearing loss was often early, occurring
before 25 years of age in 4 patients and before or at 35
years of age in an additional 4. The severity of hearing
loss varied from transient reversible hearing loss to profound deafness.
The pattern of hearing loss in about two thirds of
the patients was gradual and symmetrical. In the remainder, there were other features, such as asymmetrical involvement, stepwise progression, and partial recovery in varying combinations (Table 2). Five patients
OTOACOUSTIC EMISSIONS. Otoacoustic emissions (oms)
had a history of a “stepwise progression” in hearing
are important in the evaluation of outer hair cell function.”
loss; they complained of a sudden deterioration in
Outer hair cells amplify the signal in the organ of Corti by
hearing affecting one or both ears. Such episodes were
tensing the tectorial membrane. During this process, sound
usually associated with other features, such as a strokeis emitted and can be recorded from the ear canaL2’ OAEs
like episode (Patients 1.11.5, 1.1V.3, and 2.IV.2) or enare absent in patients with cochlear pathology,” their abcephalopathy (Patient 3.1.1), and often followed a metsence suggesting loss of function of the outer hair ~ e l l s . ’ ~ , ~ ~
abolic stress such as acute gastroenteritis (Patient
To further assess outer hair cell function, distortion product
1.1V.3) or viral infection (Patients 1.1V.3 and 2.V.2).
(2F2-F,) OAEs were performed. These were recorded in a
O
n w o occasions, deterioration in hearing loss was, at
quiet room, using an Otoacoustic Distortion Product Analeast, partially reversible (see Cases 2 and 3). In 6 palyser (Otodynamics ILO 92). Stimulus intensity was set at
70 dB SPL (maximal stimulus output). The FJF, was 1.2.
tients there was asymmetrical hearing loss. In 4 of
OAEs were measured at 1, 1.5, 2, 3, 4, and 6 kHz.
these, the asymmetry has persisted to date. In the other
2 patients, hearing loss progressed until they developed
moderate (Patient 2.IV. 3) or profound (Patient 2.IV.2)
PROMONTORY NERVE STIMULATION. Promontory nerve
symmetrical hearing loss. There was a history of vertigo
stimulation measures the function of the auditory nerve by
direct electrical stimulation. Electrical stimulation of the auin 1 patient (4.11.3) but no evidence of endolymphatic
ditory nerve was performed using a Nucleus Promontory
hydrops on electrocochleography. The variability of the
Nerve Stimulator 210012 at stimulation frequencies of 50
clinical features, particularly the stepwise progression,
and 100 Hz. If the patient perceived sound during the stimasymmetrical involvement, and reversibility of the hearulation, the auditory nerve was judged to be functionally ining loss, is illustrated in the following case histories. Case
tact. This procedure was not performed in patients with nor1 illustrates the progressive nature of the hearing loss
mal or mildly impaired hearing because normal hearing
and
its correction by cochlear implantation.
masks the effects of electrical stimulation.
ELECTROCOCHLEOGRAPHY. Electrocochleography
measures the electrical activity of the cochlea as well as first-order
auditory nerve fibers in response to acoustic s t i m ~ l a t i o n . ’ ~
This technique, when using transtympanic recordings, is also
useful in the detection of endolymphatic hydrops.16 The tip
of a transtympanic electrode was placed on the promontory
of the middle ear, just inferior to the round window, and
recordings were taken after click and tone burst stimulation
at 0.25, 0.5, 1, 2, and 8 kHz. Action and summating potentials (AP and SP, respectively) were measured and the summating to action potential ratio (SP/AP) calculated according
to standard laboratory methods.” The SP amplitude was recorded for each tone burst frequency tested. The presence of
endolymphatic hydrops was defined as an increased SP/AP
ratio after click stimulation or an increased negative SP amplitude recorded after tone burst stimulation.’8
’
NEURORADIOLOGY. T o assess the possibility of retrocochlear pathology (eg, auditory nerve tumors), axial cerebral
CT scans with and without contrast medium enhancement
using 10-mm cuts from the base of the skull to the vertex
and 5-mm cuts through the posterior fossa were performed
in all patients. Magnetic resonance imaging using T1- and
T2-weighted axial and T2-weighted sagittal views were performed on 12 patients.
COCHLEAR IMPLANTATION. Cochlear implants bypass the
cochlea but require functionally intact neural components to
function. Cochlear implantation (Cochlear 22-electrode im-
352
Annals of Neurology
Vol 43
No 3 March 1998
Case 1 (Patient l.IV3)
A 14-year-old girl presented with nausea, vomiting,
and headache after an infection in an ingrowing toenail. Soon after admission to hospital she was observed to have a number of seizures. She had had
mild hearing loss for a number of years. Two months
later she was readmitted in coma. O n recovery of
consciousness, she was found to have bilateral cerebellar signs and worsening of her hearing loss. In the
years that followed, she had many admissions to the
hospital with recurrence of headache associated with a
neurological deficit, such as hemianopia or hemiple-
Table 1. Clinical Features of the 18 Patients Studied
~~~
~
Patient
Hearing
ID
Loss"
1.11.1
1.11.5
1.11.7
1.111.1
1.111.2
1.IV.I
1.IV.2
l.IV.3
2.IV.2
2.1V.3
2.1V.5
2.v. 1
2.v.2
2.V.4
2.w. 1
3.1.1
3.11.2
4.11.3
Mild
~
~~~
Tissue
Abdominal MELAS
MigraineDiabetes Strokelike
Enceph- Muscle
like
Short
PseudoA3243G
Mellitus Episodes Epilepsy Ataxia alopathy Weakness Headache Stature obstruction Detectedb
Profound
Mild
Mild
Mild
Mild
Normal
Profound
Profound
Severe
Moderate
Severe
Profound
Normal
Normal
Severe
Normal
Severe
"Hearing loss is graded according to the percentage of hearing loss in the worst ear when compared with standard normative data corrected for
age and sex in an Australian population (see text).
bTissues in which the MELAS A3243G point mutation could be detected are listed: M = muscle; B = blood; H = hair follicle.
+
=
present;
- =
absent.
Table 2. Characteristics of the Patients Studied and Features of Their Hearing Loss
-
Patient
ID
Age at Onset of
Hearing Loss
(yr)
1.II. 1
1.11.5
1JI.7
1.III. 1
NK
65
61
50
1m . 2
1.IV.1
1IV.2
1.1V.3
37
16
<14
2.1v.2
30
2.1V.3
2.1V.5
2.v.1
40
28
15
2.v.2
2.V.4
2.vI.1
3.1.1
3.11.2
4.11.3
-
<12
-
-
35
-
35
Age at
Audiogram
(Yr)
72
63
61
51
63
57
22
20
19
27
44
47
35
40
33
44
35
40
19
12
33
36
15
38
Hearing
Loss" LIR
15.8113.7
42.7194.2
2.210.8
9.8121.9
24.8122.6
4.614.7
011.1
1001100
100198.2
65.9148.4
34144.5
88.9187.7
34.31100
010
010
5.2167.6
010.5
64162.2
Configuration
of Pure T o n e
Audiometry
Asymmetrical
Onset of
Hearing Loss
History of a
Stepwise
Deterioration of
Hearing Loss
SIS
SIS
HFIHF
SIHF
SIS
SIS
HFIHF
NIN
FIF
FIF
FIF
FIF
SIS
SIS
SIS
SIS
FIHF
FIF
NIN
NIN
HFIHF
SIHF
NIN
FIF
"Hearing loss is given as percentage of hearing loss in each ear when compared with standard normative data corrected for age and sex in an
Australian population.
+ = present; - = absent; L = left ear; R = right ear; NK = not known; N = normal; HF = predominant high-frequency loss; F = flat:
hearing loss affecting all frequencies equally; S = sloping configuration: higher frequencies affected more than middle frequencies and much
more than lower frequencies.
Sue et al: Cochlear Hearing Loss in
MELAS Syndrome 353
gia. On one occasion this followed a Campylobacter
jejuni infection causing diarrhea; on another occasion
it occurred after mild heat stroke occasioned by attending a summer carnival. After each illness she
complained of further deterioration in her hearing.
This was documented on serial audiograms (Fig 2).
By the age of 25 years, she was profoundly deaf. Even
with bilateral hearing aids, she was unable to use the
telephone, hear rhe television, or follow conversation
if more than one person was speaking. The family
had to shout for her to hear. Two years later, after a
life-threatening episode of bowel pseudo-obstruction,
she became almost totally deaf and now relied on lip
reading to communicate. She started to learn sign
language. Some months later, a cochlear implant was
inserted with an excellent result. She is now able to
converse in a crowded room and use the telephone
with ease.
Case 2 (Patient 2. V2)
A school girl gradually developed hearing loss in her
right ear. By the age of 18 years, she was completely
deaf in that ear. She did not complain of tinnitus or
vertigo. There was no past history of ear infection or
systemic illness. At the age of 38, she suddenly developed loss of hearing in her left ear. She saw an ENT
surgeon who found no evidence of infection or trauma.
There was no history of sudden noise exposure, prevjous ear surgery, or head trauma. She was treated with a
course of antibiotics but remained deaf for 3 weeks.
The hearing in the left ear gradually improved over the
next few months, but she suffers from residual hearing
loss in that ear (Fig 3). She now uses a hearing aid.
Case 3 (Patient l . I K 2 )
A 20-year-old, previously well man suddenly lost hear-
ing during a loud rock concert. He had no past history
Fig 2. Serial audiograms of patient I.IV3 showing early-onset hearing loss with initial involvement of the higher frequencies before
involvement of the lower frequencies: after an episode of right hemianopia at age 19 (A); after an episode of nonconvulsive status
epilepticus associated with left hemiparesis, dysphasia, and left hemianopia, at age 21 (B); after an episode o f left-sided hemianopia
at age 23 (C); after an episode of intestinal pseudo-obstruction and seizures at age 27 (0).
B
Hearing level
in Decibels
(I.S.O.Stande
125 250 50(
125 250 500
Frequency in Hz
1OOo2ooo 4000
8OOO
Frequency InHz
D
Hearing level
in Decibels
(1.S.O.Standstrd
1
1
1
125 250 500
1OOO2OOO 4000
8000
Frequency in Hz
Right ear
354 Annals of Neurology
Vol 43
No 3
March 1998
125 250 500
1OOo2OOO 4000
Frequency in Hz
8OOO
Speech discrimination tests were performed in 12
patients. Six patients had good results (90% to 100%
correct responses), suggesting good retrocochlear func24
tion. Only patients who had severe to profound hearing loss (nine ears) had reduced or absent speech discrimination on testing. Contralateral acoustic reflexes
were performed in 10 patients. They were present at
normal levels in 2 patients, at reduced suprathreshold
levels in a further 3 (suggesting a cochlear origin to the
hearing loss), and absent in 5 patients with severe to
profound hearing loss. Tympanograms showed a normal pattern of compliance (type A) in all patients.
Audiogram
0
10
20
30
40
50
Hearing level
in Decibels
6o
(1.S.O.Standard) ' O
80
90
100
110
120
125 250 500
1000 2000
4000
8000
Frequency (kHz)
Right Ear
Left Ear
Fig 3. Audiogam of Patient 2.K 5 showing asymmetrical
hearing loss that had begun during childhood.
of tinnitus, ear infection, head trauma, or systemic illness. He remembered that the music at the concert became like a "pulsating noise." He was unable to discern
speech during that evening, and this persisted for 3
days after the concert. His friends, who also attended
the concert, suffered transient hearing loss and tinnitus
during the performance, but they were able to hear
normally almost immediately afterward. The patient's
hearing gradually returned to normal, and he did not
seek medical attention during this time. An audiogram
performed 14 months after this event showed 10 to 20
dB of hearing loss in the high frequencies. He remains
otherwise well.
Audiometry was performed in all patients and confirmed hearing loss in 14 patients (see Table 2). Thresholds to bone conduction were equal to
thresholds for air conduction, consistent with a sensorineural type of hearing loss. Audiograms in 4 patients
demonstrated a drop of 10 to 20 dB or greater in two or
more frequencies after this hearing loss was noticed. Audiograms showed a hearing loss of greater than 15 dB at
two or more audiometric frequencies in 5 of the 18
cases. A severe to profound hearing loss involving all audiometric frequencies was observed in 3 patients. In 6
patients, the onset of hearing loss was asymmetrical.
In the 6 patients in whom longitudinal data were
available, a characteristic progression of hearing loss
was observed. Initially, the hearing loss affected the
higher audiometric frequencies. This then progressed
to involve the middle and, to a lesser extent, the low
frequencies, resulting in a sloping configuration. Eventually, the lower frequencies became equally involved,
producing a "flat" configuration.
AUDIOMETRY.
BRAINSTEM AUDITORY EVOKED RESPONSES. Wave I responses were not recordable or delayed in at least one
ear in 11 of the 18 patients (Table 3 ) . Subsequent
waves were absent in 7 of these patients, but waves I11
and V were preserved in 3 (Fig 4). The action potential
latency recorded from electrocochleography (equivalent
to wave I latency on BAERs) was used to estimate the
wave I through 111 latency in a further two of these
patients. This was within normal limits in both cases.
RESULTS OF THE PATIENTS STUDIED IN FURTHER DETAIL.
A subgroup of 12 patients went on to have further cochlear hnction testing, including electrocochleography
and distortion product OAE testing (Table 4). In this
subgroup there were 6 male and 6 female patients. Nine
of these patients complained of hearing loss, and 3 had
normal hearing at the time of testing. Ages ranged beTable 3. Brainstem Auditory Evoked Response Latencies
in the 18 Patients
Patient
ID
BAER
Wave I LIR
BAER
Wave 111 LIR
BAER
Wave V LIR
1.II. 1
1.11.5
1.II.7
1.III. 1
1m . 2
1.IV.1
1.IV.2
1IV.3"
2.IV.2
2.1V.3
2.1V.5
2.v. 1
2.v.2
2.V.4
2.VI. 1
3.1.1
3.11.2
4.11.3
1.911.8
AbslAbs
1.611.5
2.011.8
1.711.8
1.511.4
1.311.5
2.011.9
AbslAbs
1.9lAbs
AbslAbs
AbslAbs
1.512.0
1.411.4
1.711.7
Absll.7
1.711.7
AbslAbs
Absl4.3
AbslAbs
3.9013.72
4.114.1
3.713.7
3.913.7
3.713.9
Abs13.1
AbslAbs
3.6lAbs
Absl3.7
AbslAbs
3.913.7
3.713.7
4.014.0
4.913.9
33/33
AbslAbs
5.916.0
AbslAbs
5.5815.46
6.216.1
5.715.8
5.515.5
5.715.7
Abs15.7
6.5lAbs
AbslAbs
5.715.7
6.5lAbs
5.7lAbs
5.415.4
5.815.7
6.115.5
5.615.6
AbsIAbs
-
Abnormal responses are in bold type (based on standard laboratory
data and Cl~iappa'~).
"Repeat test 6 months later (2194) showed all absent responses.
L
=
left; R
=
right; Abs
=
absent responses.
Sue et al: Cochlear Hearing Loss in MELAS Syndrome 355
ii
*
Fig 4. Brainstem auditory evoked
response of Patient 2.I F 2 (lefi ear)
showing an unrecordable wave I response but normal wave 111 and
wave V responses. Wave II latency,
2.8 msec; wave III latency, 3.7 msec,
wave IV latency, 4.8 msec; wave V
latency, 5.7 msec.
+
tween 12 and 61 years (mean patient age for OAEs and
electrocochleograms = 37 and 38 years, respectively).
Electrocochleography was
normal in 7 of the 11 patients studied. In 2 patients, there
were no recordable responses (see Table 4). In a further
2 patients, the click-evoked electrocochleogram was
broad; the SPIAP percentage ratio was greater than
50% in 1 patient (one ear), and the amplitudes of the
summating potentials after tone burst stimulation were
abnormally large in both patients, indicating the presence of endolymphatic h y d r ~ p s . ~ ~
ELECTROCOCHLEOGRAPHY.
OTOACOUSTIC EMISSIONS. Distortion product OAEs
were recorded in 11 patients (see Table 4). In 7 patients
who had hearing loss, the OAEs were lost at the audiometric frequencies at which moderate to profound hearing loss was demonstrated (Fig 5). When hearing loss
was less than 40 dB, the OAEs were always present.
When hearing loss was greater than 60 dB, they were
always unrecordable. In the patients who had normal
hearing, the O M Swere preserved at all frequencies.
NERVE
STIMULATION. Promontory
nerve stimulation was performed in the 2 patients who
PROMONTORY
Table 4. Results of Electrocochleography and Otoacoustic Emissions in 12 Patients
Patient
ID
ECochg
SP/AP%
LIR
ECochg
Abnormalities
8-kHz SP
(mV) LIR
2-kHz SP
(mV) LIR
1.11.7
1.111.1
1.IV.2
1AV.3
2.1V.3
2.1V.5
2.v. 1
2.v.2
2.vl.l
3.1.1
3.11.2
4.11.3
37/18
301ND
2415
Absent
35/42
47/62
Absent
3 1/ND
NDIND
1514
17/30
42/28
Nil
Nil
Nil
No APs
ELH
Nil
No APs
ELH
ND
Nil
Nil
Nil
1.114.8
7.81ND
0.911.9
-1-6.1"I1.4
0.91-0.7
-0.81-3.2
-6.91ND
-1.110
-1-
-7"IND
-1-
4.210.2
1.310.4
NDIND
-1-
3.21 -2
-1.01-0.8
-17.8"lND
-1-3.410.3
-2.21-0.1
0.21-0.4
-
1-kHz SP
(mV) LIR
1.21-0.8
-0.41ND
1.211.1
-1-2.210.4
1.511.4
-1-
7.3"IND
500-Hz SP
(mV) LIR
oms
1.413.7
1.71ND
0.810.5
Present
NR
Present
ND
NR
NR
NR
NR
Present
NR
Present
NR
-1-
5*/-0.4
1.41-0.1
-12.5"IND
-1-
-1-
-210.2
1.71-1.3
0.21- 1.4
412.0
3.212.9
0.510.4
LIR
"Abnormal suggestive of endolymphatic hydrops.
L = left; R = right; ECochg = electrocochleography; OAEs = otoacoustic emissions; ND = not done; No APs = no recordable action
potentials; ELH = endolymphatic hydrops; - I - = not measured; NR = OAEs not recordable at audiometric frequencies where there was
moderate to profound hearing loss.
356 Annals of Neurology Vol 43 No 3 March 1998
10
istort
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Audiogram - Right Ear
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.
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0
20
30
40
4
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00
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90
100
110
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Choose p o i n t
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Fig 5. Audiogram and otoacoustic emission (OAE) distortion product recording of Patient 1.III. 1 showing asymmetrical hearing loss
and loss of OAEs at the audiometric frequencies where there is moderate to profound hearing loss. Solid lines show where OAEs
are present, dotted lines indicate where OAEs were not recordable, and shaded regions below the lines indicate background noise.
had unrecordable responses to transtympanic electrocochleography (Patients 1.IV.3 and 2.V.1). Both patients
were able to perceive sound, indicating persisting function of the auditory nerve.
NEUR~RADIOLOGY. Cerebral CT scans were performed in
all patients, and 12 underwent magnetic resonance imaging.
No patient had evidence of lesions that might have caused
hearing impairment.
Discussion
We observed a high prevalence of sensorineural hearing
loss in the four families with MELAS A3243G point
mutation. Hearing loss was sometimes the sole manifestation, but it usually coexisted with other neurological features or other disorders such as diabetes. Distinctive features that were present in some patients
included a young or asymmetrical onset, stepwise pro-
Sue et al: Cochlear Hearing Loss in MELAS Syndrome 357
gression, and/or partial reversibility. The sudden deterioration in hearing loss was reminiscent of the sudden
loss of neurological function that occurs in the strokelike episodes associated with MELAS ~yndrome.~.'
Audiograms showed that hearing loss to air-conducted
sounds was equal to that to bone-conducted sounds, a
feature of sensorineural hearing loss. The relatively late
loss of acoustic reflexes and preservation of speech discrimination suggested that the hearing loss was due to
cochlear rather than neural dysfunction. BAER data
helped to confirm that the central auditory pathways
were intact in some patients. The preservation of responses to promontory nerve stimulation in two patients
also supported the proposition that the hearing loss was
due to cochlear pathology rather than a neural lesion.
Cochlear dysfunction was subsequently confirmed
with electrocochleography and OAEs. Electrocochleography in some patients showed either loss of electrical
activity or evidence of endolymphatic hydrops, both
features of cochlear dysfunction. Based on the OAE
data, the hearing loss could also be attributable to involvement of the outer hair cells.2"28
Our results extend the findings of previous workers
who have suggested that the hearing loss associated
with mitochondrial disorders is more likely to involve
cochlear rather than retrocochleat ~ t r u c t u r e s . ~ ' -One
~~
study on a large family with an unspecified type of mitochondrial disorder2' found high-frequency hearing
loss with preserved speech recognition and acoustic reflexes, features suggestive of cochlear (sensory) involvement. They also reported that the brainstem auditory
evoked responses were absent or of increased latency in
patients with poor hearing and postulated that there
was also retrocochlear (neural) pathology in severe
cases. More recently, two small studies involving patients with the MELAS A3243G point mutation suggested that the associated sensorineural hearing loss was
best explained by cochlear dysfunction on the basis of
their audiological findings and absent OAES.~'~~'
Which part of the cochlea fails in MELAS syndrome? Cells that appear to be most at risk in any mitochondrial disorder are those that do not divide32 and
have a high metabolic rate.33 By contrast, actively dividing tissues, such as skin or blood, have the capacity
to reduce their mutation load with time.34 The stria
vascularis is highly metabolically active,35936and its
cells do not divide?' Like neurons and muscle, a
higher proportion of abnormal mitochondria in the
stria may accumulate over time, eventually causing dysfunction at times of increased metabolic demand and
ultimately leading to cell death.
The stria vascularis lines the cochlear duct and has
abundant Na+,K'-ATPase pumps.38 It has two main
functions: the maintenance of endolymphatic osmolaliand the generation of the endocochlear potentia1.4"241Hair cells require a normal endocochlear poten-
g9
358 Annals of Neurology
Vol 43
No 3
March 1998
tial to function well,38 and the outer hair cells are most
sensitive to changes in this potential. A fall in the availability of adenosine triphosphatase due to mitochondrial
dysfunction may result in ionic imbalances in either the
outer hair cells and/or the stria v a s c u l a r i ~ Thus,
. ~ ~ failure
of the cells in the stria vascularis would account for our
findings of both outer hair cell dysfunction and endolymphatic hydrops. In support of this, strial degeneration has been reported43 in a histopathological study of
a patient with Kearns-Sayre syndrome.
The OAE data indicated abnormalities of outer hair
cell function. Whereas stria vascularis abnormalities
could cause outer hair cell d y s f ~ n c t i o n it
, ~is~ also possible that the outer hair cells themselves, which also do
not divide and are highly metabolically active, are directly affected by mitochondrial dysfunction. This
would explain the preferential loss of hearing for higher
frequencies that was observed in our patients and othe r ~ . ~The
'
outer hair cells within the basal coil that
respond to high-frequency sound are the most metabolically active; they would also be the most vulnerable
to strial failure.
Fluctuating hearing loss in this context has only
been reported in one other ~ a t i e n t , ~and
" its mechanism is poorly understood. The transient loss of hearing resulting from loud sound and intercurrent infection observed in the patients in the present report may
have reflected failure of the stria vascularis and/or the
outer hair cells to respond to an increased metabolic
demand. That hearing did not always return to its previous level suggests that some cells perished during this
period of stress. For this reason, we suggest that patients with this disease be advised to minimize their
exposure to loud noise.
Because all the findings pointed to pathology in the
cochlea rather than in the neural pathways, we bypassed the site of pathology with cochlear implantation
in 1 patient with profound bilateral hearing loss. Cochlear implants require functionally active neural components to restore hearing. Although a degree of retrocochlear pathology cannot be excluded from this single
case, the gratifying response to this procedure supports
the proposition that the predominant lesion responsible for hearing loss associated with MELAS syndrome
is within the cochlea. A greater number of patients undergoing cochlear implantation will be required to confirm this observation.
Dr Sue is a National Health and Medical Research Council Postgraduate Research Scholar.
The authors would like to thank M. Cooke, D. Boljevac, C. Ball,
and C. O'Neill for technical assistance and Drs M. Halmalgyi,
R. Patuzzi, and M. da Cruz for helpful discussion.
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