Keywords presbyacusis - glutathione - sensorineural hearing loss - free radicals
Introduction
The cumulative effect of oxidative stress and mitochondrial damage by free radicals
results in accumulation of mutated deoxyribonucleic acid (DNA). Mutation/deletions
causes decline in mitochondrial function that plays an important role in inducing
apoptosis of the cochlear cells.[1 ] Other risk factors include noise exposure, genetic predisposition, health comorbidities
such as atherosclerosis, diabetes, high blood pressure and smoking. Exposure to ototoxic
drugs, infection and immune-induced inflammation of auditory cells can also cause
cochlear cell damage.[2 ]
The glutathione-S transferase (GSTS) is an antioxidant that scavenges enzyme. Decreased
glutathione and GSTS activity levels cause an increase in susceptibility of hair-cell
damage leading to sensorineural hearing loss.[3 ] The role of oxidative stress, free radicals, inflammation of cells of the cochlea,
mitochondrial damage and reduction in glutathione enzyme in the development of sensorineural
loss are well documented. Hearing loss may lead to depression, decreased quality of
life, reduced functional status, and social isolation.[4 ]
[5 ]
Anatomy
The inner ear is divided into bony and membrane labyrinth, which lies within the petrous
portion of the temporal bone. Bony labyrinth consists of a vestibule, semicircular
canal, and cochlea. The cochlea is cone shaped with 2 ¾ turn's and its base lies against
the vestibule. Membrane labyrinth has vestibule (saccule, utricle), semicircular canals
cochlea and endolymphatic sac. The cochlea is divided into scala tympani, scala media,
and scala vestibuli. Scalamedia in membrane labyrinth have the following components:
vestibular membrane, stria-vascularis, and Organ of Corti. The Organ of Corti contains
basilar membrane, sensory receptors nearly 23,500 cells overlaid by a gelatinous tectorial
membrane. Membrane labyrinth contains endolymph and bony labyrinth contains perilymph.[6 ]
The labyrinthine artery is a branch of the anterior–inferior cerebellar artery which
is a branch of the basilar artery. The basilar membrane is wider and elastic at the
apex, vibrates for higher frequency; it is smaller and rigid at the base and vibrates
for lower frequency. The cochlea has a tontopic distribution.[6 ]
The central process of first-order neurons enters the pons at cerebellopontine angle
and synapses with second-order neuron dorsal and ventral cochlear nuclei. These second-order
neurons cross the pons as trapezoid body intermingled with medial lemniscus and synapses
with third-order neuron bodies—medial geniculate body. From there, third-order neurons
ascend through the posterior limb of the internal capsule to the temporal lobe. Thus,
the potential electrical impulses are coded and relayed to the brain through above
nerve root and analyzed in the temporal lobe[6 ] ([Fig. 1 ]).
Fig. 1 Auditory pathway schematic representation.
Physiology
The auditory system acts as a channel and transducer that converts sound pressure
waves into electrophysiologic signals that can be interpreted by the higher cortical
center of the brain. The cochlea is the site of second transduction. The vibration
of the oval window (stapes footplate) causes the vibration of perilymph and basilar
membrane of the cochlea. This, in turn, causes movement of the stereocilia of the
hair cells resulting in increased permeability of the hair cells to potassium and
causing depolarization of the hair cells.[7 ]
The depolarization results in the secretion of neurotransmitter (glutamate) on to
the afferent endings of the cochlear nerve and sensitizing the N-methyl-D-aspartate
(glutamate receptors) with resulting electrophysiological neuronal signal. These neuronal
signals are analyzed by the cognitive center of the brain. There may be reduction
in the numbers of neurons in cochlear nuclei and auditory center of the brain and
also reduction in the size of cells and changes in neurochemical makeup. This leads
to an inability of the central auditory system to process the sound.[7 ]
Classification of Sensorineural Loss
Classification of Sensorineural Loss
Schuknecht and Gacek[8 ]
[9 ](1964) proposed four types of sensorineural hearing loss ([Fig. 2 ]):
Fig. 2 (A–C ) Pattern of hearing loss.
Sensory—a high frequency hearing loss within speech frequency caused by missing outer
hair cells.
Neural—loss of cochlear neurons causing progressive loss of speech discrimination
in the presence of stable pure tone threshold.
Strial—metabolic and vascular degeneration in stria vascularis. Slow progressive hearing
loss with up and down curve of audiogram and good speech discrimination.
Conductive—changes in the stiffness and properties of the basilar membrane, an evenly
sloping hearing loss (linear descending pattern of audiogram).
To add to the above types of sensorineural hearing loss:
Mixed—combination of above or mild-to-moderate high frequency loss.
Indeterminate—no pathological correlation flat or abrupt high-frequency hearing loss.
Etiology
Although ageing process causes degeneration of auditory system, other factors are
noise and ototoxic drugs, that is, aminoglycosides (cochlear outer hair cells and
vestibular cells) diuretic, beta-blockers (reversible hearing loss), Meniere's disease,
otosclerosis can affect cochlea.[10 ]
Systemic diseases such as hypertension, plasma viscosity, atherosclerosis, hyperlipidosis,
metabolic bone diseases, diabetic mellitus, hypothyroidism, and Alzheimer's disease[11 ]
[12 ] are contributing factors to hearing loss, leading to free radical damage, mitochondrial
injury, depletion of glutathione and immune inflammatory reactions. Genetic inheritance
in hearing loss by mitochondrial DNA involvement has limited evidence.[13 ]
[14 ]
Glutathione
Glutathione is often referred to as the mother of all antioxidants. Glutathione is
produced and used by every single cell in the human body and has a very wide range
of scientifically proven health effects. Glutathione is a peptide containing three
important amino acids that are glutamate, cysteine and glycine. Cellular glutathione
levels are a great predictor of life expectancy; it prevents damage to important cellular
components by removing oxygen radicals from the body; thus, it protects many different
body systems from diseases and deterioration. It is a defensive agent against the
action of toxic xenobiotic (drugs pollutants, carcinogens).
So, it is essential to prevent glutathione levels from becoming low, glutathione deficiency
manifest in increased susceptibility to oxidative stress. Glutathione reduces the
amount of reactive oxygen species and oxidative stress in the body that would otherwise
cause damage to cell and DNA. It is important for the regeneration of other antioxidants
such as vitamin C. Glutathione inhibits nuclear factor-κB (NF-κB), a transcription
factor, that increases the transcription of various inflammatory genes. By inhibitor
inflammatory cytokines, it may control the inflammation.
The cells of the human brain consume about 20% of oxygen utilized by the body, but
make up 2% of the body weight reactive oxygen species is continuously generated during
oxidative metabolism; therefore, the detoxification of reactive oxygen species as
an essential task within the brain glutathione plays a key role in this process glutathione
that may limit neurodegeneration.
Glutathione depletion is a key event that leads to the activation of apoptosis. S-glutathionylation
is important for protein modulation and apoptotic (cell death) imitation. Cells depleted
of glutathione are susceptible to damage from arachidonic acid. Taking glutathione
with vitamin C may increase its absorption. The changes in the cochlea with other
several interacting processes can cause significant effects in hearing.
Added to this noise-induced cause, nuclear, mitochondrial injury, depletion of glutathione
(endogenous antioxidant) plays a major role in sensorineural loss. Restoring normal
vitamin level can inhibit glutamate release and reduce the oxidative damage and inflammation[15 ] ([Fig. 3 ]).
Fig. 3 Schematic representation of pathophysiology of auditory function damage. NF-κB, Nuclear
Factor-κB; TNFα, tumor necrosis factor-alpha.
Management
Sensorineural hearing loss occurs over a long span of time or sometimes sudden in
nature. Hearing aid use may not overcome all hearing problems. However, patients who
do not tolerate hearing aids, ear implants may provide improvement in sound quality
and clarity. However, the cost is a major limitation for widespread use.
The main therapeutic intervention is to reduce the cochlear damage, inhibit processes
or pathways that lead to the damage of cochlear cells and enhance processes that enhance
cochlear cell survival.
The drugs used in hearing disorders are as follows:
Dextran 40 with betahistine, heparin, pentoxifylline
Systematic steroids
Antiepileptics
Allopurinol
Antidepressants
Rebamipide
Glutamate and N-methyl-D-aspartate (NMDA) receptors antagonists MK-801 ifenprodil,
memantine
Phospholipids
Ginkgo biloba
Nonsteroid anti-inflammatory drugs
Antioxidant micronutrients may neutralize free radicals, reduce inflammation, and
decrease the effect of glutamate toxicity.[16 ]
Selection of proper type of treatment combinations should be done in terms of neuroprotective
effect in hearing disorders as well as restoring normal vitamin levels which can inhibit
glutamate release, reduce oxidative damage and inflammation. Vitamin E, alpha lipoic
acid, n-acetylcysteine, can protect the inner ear more effectively. A broad spectrum
of antioxidants is necessary to address variable free radical induced hearing injury.
Rebamipide, N acetylcysteine, and alpha lipoic acid antioxidant combination acts by
reducing cochlear damage and enhancing cochlear cell preservation.
Rebamipide[17 ]
[18 ]
It is mucoprotective agent
Increases the soluble mucus
Increases mucosal blood flow
Inhibitory synthesis of inflammatory cytokines
Free radicals scavenging effect on reactive oxygen species
Thus, it is an effective anti-inflammatory agent, potent free radical scavenges, and
possesses all preservation action.
N-Acetylcysteine[19 ]
[20 ]
Increase levels of glutathione the body antioxidant
Detoxifying, xenobiotic, peroxide compound, and other free radical generating molecules
Ameliorate the inflammation
Profound protective effect on cells
Alpha Lipoic Acid[21 ]
Serves a critical role in mitochondrial energy metabolism
Biological antioxidant a detoxification agent, an important modulator of various inflammatory
signaling pathways
It helps in the synthesis of endogenous antioxidants
-Increases intracellular glutathione.
Rebamipide along with other antioxidants combination alpha lipoic acid and vitamin
E improves the hearing level at all frequency. Alpha lipoic acid and N-acetylcysteine
reduce mitochondrial reactive oxygen species production, thus, reducing high-frequency
threshold elevator and maintaining sensorineural tissue survival.
Cinnarizine and Dimenhydrinate
Cinnarizine and Dimenhydrinate
Calcium channel blocker increases blood flow by vasodilatation and suppresses vestibular
cell stimuli.
Steroids plays role as anti-inflammatory agents.
Study Design
A prospective, noncomparative, metacentric clinical study.
Subjects and Methods
The study was carried out in 30 patients from May 6, 2016 to January 1, 2018. A total
of 30 patients of sensorineural hearing loss were enrolled (17 males, 13 females)
([Fig. 4A ]).
Fig. 4 Statistical analysis of study group data. (A ) Number of patients with age-wise distribution. (B ) Gender wise distribution. (C ) Associated co-morbidity with presentation of hearing loss. (D ) Audiogram pattern suggestive of pathology.
Inclusive Criteria
Healthy males or non-pregnant females of all age group with a diagnosis of sensorineural
hearing loss were considered.
Exclusive Criteria
Subject with other cause of hearing loss such as otitis media, Meniere's disease,
acoustic trauma, acoustic tumor, or otosclerosis.
The subject who is pregnant, nursing, or planning a pregnancy.
Subject with complete hearing loss based on pure tone audiometry.
Patients with a history of schizophrenia, and other psychotic illness.
Subject with drug-induced ototoxicity and hearing loss.
Overall Study Design
The total duration of the study was 8 weeks. There were three visits for each patient.
After recording the study of disease, the patient had undergone physical and audiogram
examination. The patient was administered rebamipide 100 mg + alpha Lipoic Acid 100
mg and acetylcysteine 100 mg capsules twice a day for a total period of 8 weeks.
Wherever giddiness was an added symptom, Cinnarizine 20 mg + Dimenhydrinate 40 mg
twice a day was added up to complete relief of symptoms twice daily thereafter once
a day as maintenance over a period of 8 weeks. Wherever tinnitus was added symptom,
deflazacort 6 mg twice a day added and tapered up to 1 month. If the symptom, tinnitus,
persists, intratympanic steroid is injection given.
The patient had to make a visit on week 4 and week 8. The patient was subjected to
physical examination in these visits. Last visit audiogram examination was repeated
and clinical assessment was done.
Results
The auditory system acts as a channel and transducer.[22 ] The sound waves from the external environment are channeled through the external
auditory canal to the tympanic membrane. The external ear acts as an acoustic resonator
to intensify in the range of 2 to 5 kHz; those frequencies that are most important
in speech. At tympanic membrane first transduction takes place, that is, sound waves
convert into vibrative mechanical energy (sound pressure wave) and also amplification
of pressure wave takes place in the middle ear. The cochlea was the site of the conversion
of mechanical energy to electrophysiologic signal vibration of oval window that causes
vibrations of the basilar membrane of the cochlea. This, in turn, causes movement
of the stereocilia of the hair cells lying on the basilar membrane resulting in an
increase in permeability of hair cells to potassium and depolarization of the hair
cells. The depolarization results in the secretion of a neurotransmitter-glutamate
onto the afferent endings of the cochlear nerve causing chemical reaction with the
glutamate receptor-N-methyl-D-aspartate, with resulting electrophysiologic neuronal
signals. The neuronal signals are analyzed by cognitive center of the brain to permit
an understanding of contents in association with memory. The changes in cochlear hair
cells in turn neurochemical makeup cause significant effects on the hearing of person.[23 ]
The sensorineural hearing loss was synonymous with presbyacusis, but in our study
of 30 patients, nearly 8 patients come under the age group of within 30 years and
another 13 patients under 31 to 60 years, and 9 patients above 60 years. This was
a most distressing factor, causing them handicap in their working place ([Fig. 4B ]).
The auditory system is affected by various risk factors such as free radicals damage,
mitochondrial injury, excessive secretion of glutamate, NMDA sensitization, depletion
of glutathione and immune-inflammatory reaction. Although the ageing process causes
degeneration of auditory system other factors such as noise, ototoxic drugs, and infection
can cause decline in hearing.[24 ]
In our study, nearly 27 patients were unable to explain the cause for hard of hearing,
only one patient had exposure to noise and two for infection (enteric fever).
Above etiological factors cause injury to the auditory apparatus including sensory
and vestibular hair cells. Probably free radical damage was a responsible biochemical
factor in the pathogenesis. Levels of the potential toxic glutamate, NMDA receptor,
and multiple free radicals were markedly elevated in patients with tinnitus. Depletion
of glutathione and ageing were contributing factors to this common pathway of damage.
In our study, all 30 patients all had complaints of hard of hearing; nearly 14 patients
had tinnitus and 7 patients had complaints of giddiness. Most distressing factor was
a delay in approaching for medical assistant as nearly 15 patients took 6 months to
approach us for treatment.
Numerous systemic diseases such as hypertension, plasma hyperviscosity, atherosclerosis
metabolic bone disease, diabetic mellitus, hypothyroidism, and Alzheimer's disease
were contributing factors to sensorineural hearing loss.
In our study, seven patients were suffering from diabetic mellitus, four patients
were of hypertensive, two patients from hypothyroidism and all were under treatment,
while one patient computed tomographic scan shows ischemic changes in brain parenchyma.
Nearly 23 patients had involvement of both ear, 4 patients had only left ear involvement,
and 3 of the right ear only ([Fig. 4C ]).
There are different types of audiogram patterns noted such as sloping with abrupt
steep and progressive at high frequency, parabolic, flat, up and down and slopping
to flat, depending on audiogram pattern the disease is classified and the site of
pathology is identified.
Depending on audiogram curve, nearly 25 ears have sensory hair cells involvement,
15 ears nerve ending and neural cells, 2 ear stria vascularis, 11 ears were having
both basilar membrane, hair cells involvement, and 7 ears were of normal in nature.
This needs further extensive study ([Fig. 4D ]).
Evaluation of Hearing after Treatment
Evaluation of Hearing after Treatment
Determination of hearing was based on pure tone hearing levels at 250, 500, 1,000,
2,000, 4,000, and 8000 KHz and was accomplished by comparing the pre-treatment hearing
level with that after 8 weeks of treatment.
The proportion of subjects with improved, unchanged, or worsen on week 8 of treatment
analyzed is as follows:
Improved—Decrease of ≥ 10 decibels (dB) from baseline score was deemed to denote a
clinically significant improvement.
Unchanged—Decrease or an increase in hearing score but not more than 10 dB from baseline
score represents no change.
Worsen—Increase of 10 dB ≥ from baseline score (pre-treatment score) indicates deterioration.
In our study, totally 30 patients participated regularly. Out of 60 ears, 7 ears were
having normal hearing. Out of remaining 53 ears, 5 ears (2+2+1)—of two patients of
both ears had hard of hearing and one patient had pathology in right ear)—were rejected
because of side effects like vomiting in two cases and acne, skin rashes in one case.
So, total 48 ears having hard of hearing were analyzed after 8 weeks of treatment,
that is, 21 patients having both ear pathology, and 6 patients were having single
ear pathology (4 left ears and 2 right ears). Total 22 ear show improvement, that
is, more than 10 dB decrease from baseline score. Total 26 ear show unchanged or minimal
improvement, that is, there was decrease or an increase in hearing score but not more
than 10 dB baseline score. None have worsening of the condition, i.e., increase of
more than 10 dB from baseline score indicating that there were no deteriorated ears
([Fig. 5A–D ]), [Table 1 ]).
Table 1
Assessment of improvement in hearing after treatment
Mean improvement in the right ear (in decibels)
Percentage of improvement in the right ear hearing loss
250
500
1,000
2,000
4,000
8,000
250
500
1000
2000
4000
8000
Before treatment
41.5
45.625
53.125
58.125
63.125
69.375
6.65
6.85
16.47
15.00
11.88
17.1
After treatment
38.75
42.50
44.375
49.375
55.625
57.500
Difference
2.75 dB
3.125 dB
8.750 dB
8.750 dB
7.50 dB
11.875 dB
In higher frequencies, it is 14.66%
Mean improvement in the left ear (in decibels)
Percentage improvement in the left ear hearing loss
250
500
1,000
2,000
4,000
8,000
250
500
1000
2000
4000
8000Hz
Before treatment
45
48.5
55.5
60
67
77
6.66
9.27
11.71
14.17
16.56
23.37
After treatment
42
44
49
51.5
56
59
Difference
3 dB
4.5 dB
6.5 dB
8.5 dB
11 dB
18 dB
Mean improvement is better in the left ear. Frequency wise, it was better with higher
frequency (10 dB or more)
In higher frequency, it was 18%. So, in our study, better hearing improvement in higher
frequencies was noticed
Fig. 5 Statistical analysis of results of study group. (A ) Ears affected; after application of exclusion factor, 48 ears were included in the
study. (B ) Side of ear involved. (C ) Patients presenting with complaints. (D ) Patient’s hearing status. (E ) Assessment of Improvement in Hearing after treatment.
Other Symptoms
Giddiness had been controlled in all seven patients. Tinnitus improved in eight patients
(in two patients after injecting intratympanic steroids). In six patients, tinnitus
was persisting (in two cases intensity of tinnitus reduced and in four cases no change
was noted).
Discussion
Sensorineural hearing loss affects millions of people is characterized by a decline
of auditory function.[1 ]
The etiology of sensorineural hearing loss is multifactorial, where oxidative stress,
free radicals, inflammation of cells of auditory apparatus, mitochondrial damage,
excessive secretion of glutamate and its toxicity, depletion of glutathione enzyme
have a significant role in the development of sensorineural hearing loss. Other risk
factors are noise exposure ototoxic drugs, and health comorbidities.[2 ]
[3 ]
The most of pathological and biochemical changes occur in the cochlea with several
interacting processes. A meaningful addition to current otology practice should be
based on understanding the synthesis of free radicals in the inner ear and their effect
over mitochondrial function, in turn biological changes that take place in hair cells
and neural cells (excessive secretion of glutamate and its toxic effect over N-methyl-D-aspartate
and decreased glutathione and glutathione-S enzymes in hair cells and neuronal cells).[24 ]
With respect to the above-established mechanisms, a potential treatment strategy that
restores normal antioxidant level, inhibits glutamate release and reduces its toxicity
and reducing oxidative damage, with decrease in free radicals and inflammation, increasing
glutathione levels should be evaluated.
This approach may be also relevant to the patient with tinnitus and giddiness along
with hard of hearing. Rebamipide 100 mg + alpha lipoic acid 100 mg + acetylcysteine
100 mg along with combination of cinnarizine 20 mg, and dimenhydrinate 40 mg and steroids
may be a clinically relevant approach to treat age-related and other sensorineural
hearing loss.
Eight weeks BD dose improves nearly 10 dB loss.
This combination will address both inhibiting cochlear cell damage and enhance cochlear
cell preservation by reducing free radicals—prevent mitochondrial injuries—decrease
glutamate secretion and its toxicity and enhancing glutathione levels in hair cells.
Conclusion
Synthesis of free radicals in the inner ear may play an important part in the pathogenesis
of sensory hearing loss. Our study demonstrated greater improvement in hearing at
higher frequencies with 8 weeks of rebamipide 100 mg + alpha lipoic acid 100 mg +
acetylcysteine 100 mg administration in 30 patients with twice-daily dosing.
Present scientific experience supports above combination therapy as effective prophylaxis
in sensorineural hearing loss. This combination will address both inhibiting the cochlear
cell damage and enhancing cochlear cell preservation.
