Idiopathic Sudden Sensorineural Hearing Loss

Linköping University Medical dissertation
No. 1229
Idiopathic Sudden Sensorineural Hearing Loss
Corticosteroid Treatment, the Diagnostic Protocol and Outcome
Ramesh Nosrati-Zarenoe
__________________________________________________
Department of Clinical and Experimental Medicine
Division of Oto-Rhino-Laryngology
Faculty of Health Science,
Linköping University
SE-58185 Linköping, Sweden
2011
© Ramesh Nosrati-Zarenoe, 2011
Cover picture: Ramin Nosrati
Published articles have been reprinted with the permission of the copyright holders.
Printed in Sweden by Liu-Tryck, Linköping, Sweden, 2011
ISBN 978-91-7393-220-2
ISSN 0345-0082
To my beloved family
Reza,
Alma and Arvid
CONTENTS
ABSTRACT................................................................................................................... 7
LIST OF ORIGINAL PAPERS................................................................................... 9
ABBREVIATIONS ..................................................................................................... 10
INTRODUCTION....................................................................................................... 11
BACKGROUND ......................................................................................................... 13
AIMS ............................................................................................................................ 19
METHODS .................................................................................................................. 21
STATISTICAL METHODS ...................................................................................... 25
ETHICAL CONSIDERATIONS............................................................................... 27
MATERIAL................................................................................................................. 29
RESULTS .................................................................................................................... 33
DISCUSSION .............................................................................................................. 45
Radiological and laboratory examination.......................................................... 45
Treatment ........................................................................................................... 47
Prognostic factors .............................................................................................. 48
Suggestion for further research.......................................................................... 50
CONCLUSIONS ......................................................................................................... 51
ACKNOWLEDGMENTS .......................................................................................... 53
SVENSK SAMMANFATTNING.............................................................................. 55
APPENDIX.................................................................................................................. 67
REFERENCES............................................................................................................ 71
Abstract
7
ABSTRACT
Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) is a rapid loss of hearing
caused by damage to the cochlea (inner ear) or auditory nerve. Spontaneous recovery
has been seen in 32%–81%. The incidence of the ISSNHL has been estimated to be
between 5 and 20 per 100,000 per year. Different theories (vascular catastrophes,
immunologic damage, infections or intracochlear membrane break) about the etiology
have resulted in different treatment policies. The effect of therapy is difficult to
evaluate for a single physician who sees just a few patients annually.
The aim of the present thesis was: 1) to investigate the current management and
treatment of ISSNHL patients in Sweden with regard to outcome, 2) to evaluate
whether, in comparison to placebo, the most common drug given in the treatment of
ISSNHL in any way influences the outcome, and 3) to analyze which variables such as
background data, concomitant disease, audiogram shape and laboratory tests, best can
predict the outcome of ISSNHL.
A national database was developed with half of all ENT clinics in Sweden
participating by submitting a questionnaire for each patient with SSNHL. The
questionnaire covered the patient’s background, current disorder, past and family
history of different diseases, examinations, and treatment. Audiograms at the onset of
SSNHL and after three months were requested.
A randomized placebo controlled multicenter trial (RCT) was performed using a
modified version of the questionnaire used in the national database. Prednisolone in
high tapering dosage, or placebo was given with a total treatment period of eight days.
If recovery was complete, treatment stopped, otherwise medication was continued at
10 mg daily to a total of 30 days from beginning. After an initial pure tone audiogram,
new audiograms were taken at three follow-up visits: day eight of treatment, after one
month, and after three months.
Results from the national database showed that out of 400 patients included in the
study with ISSNHL, almost 60% were medically treated, of which nearly 90% were
given corticosteroids. Hearing improvement was not statistically associated with
receipt of medication. 40% of all patients had an MRI or CT, where 3–4% had
acoustic neuroma. 24% of the patients with ISSNHL who had hematological tests
taken, had one or more pathological findings. Blood screening varied from simple
routine tests to a complete analysis with such tests as HSP70, Anti-Neutrophilic
Cytoplasmic Antibodies (ANCA) and Borrelia tests
In the RCT, 47 patients were randomized to Prednisolone and 46 to placebo. No
significant difference of hearing recovery was observed between the Prednisolone
group and placebo group at either first or final follow-up regarding the effect of
treatment. Presence of vertigo had significant negative effect on hearing improvement
in both groups. Inflammatory signs in laboratory work-up had a positive prognostic
effect, irrespective of treatment.
Conclusion: There is no standard program for management or treatment of ISSNHL in
Sweden. The diagnostic protocol varies. MRI is an underused resource to get specific
8
Abstract
diagnoses for the condition especially acoustic neuromas. Regardless of pathological
findings, treatment is mainly limited to corticosteroids or no medication.
Prednisolone in customary dosage does not influence recovery of Idiopathic Sudden
Sensorineural Hearing Loss. Whenever a drug or a substance is proven not to work for
a specific condition, it should be withdrawn from use and the focus for research within
the field turned in a new direction.
List of original papers
9
LIST OF ORIGINAL PAPERS
This thesis is based on the following papers, which will be referred to in the text by
their roman numbers I - IV:
I.
Nosrati-Zarenoe R, Arlinger S, Hultcrantz E. Idiopathic sudden sensorineural
hearing loss: results drawn from the Swedish national database.
Acta Otolaryngol. 2007 Nov;127(11):1168-75.
II.
Nosrati-Zarenoe R, Hansson M, Hultcrantz E. Assessment of diagnostic
approaches to idiopathic sudden sensorineural hearing loss and their influence
on treatment and outcome. Acta Otolaryngol. 2010; 130:384-91.
III.
Nosrati-Zarenoe R, Hultcrantz E. Corticosteroid treatment of idiopathic
sudden sensorineural hearing loss. Part 1: a randomized triple-blinded placebo
controlled trial. Submitted for publication.
IV.
Hultcrantz E, Nosrati-Zarenoe R. Corticosteroid treatment of idiopathic
sudden sensorineural hearing loss. Part 2: a meta-analysis of a RCT and the
Swedish national database. Submitted for publication.
Reprints were made with the kind permission of copyright holder.
10____________________________________________________________________ Abbreviations
ABBREVIATIONS
ABR
Auditory brainstem responses
AICA
Anterior inferior cerebellar arteries
ANA
Anti-nuclear antibodies
ANCA
Anti-neutrophilic cytoplasmic antibodies
CI
Confidence intervals
CRP
C-reactive protein
CSF
Cerebrospinal fluid
CT
Computed tomography
dB HL
dB hearing level
ENT
Ear, nose and throat
Hb
Hemoglobin
HDL
High-density lipoprotein
HSP-70
Heat-shock protein 70
IgG antibodies
Immunoglobulin G antibodies
IgM antibodies
Immunoglobulin M antibodies
ISSNHL
Idiopathic Sudden Sensorineural Hearing Loss
kHz
kilohertz
LDL
Low density lipoprotein
MRI
Magnetic resonance imaging
OAE
Otoacoustic emission
OR
Odds ratio
PTA
Pure tone average
RCT
Randomized controlled trial
SD
Standard deviation
SLE
Systemic lupus erythematosus
SSNHL
Sudden Sensorineural Hearing Loss
Introduction______________________________________________________________________11
INTRODUCTION
Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) involves a rapid loss of
hearing that is caused by damage to the cochlea (inner ear) or auditory nerve. This
hearing loss can be accompanied by tinnitus and/or vertigo.
A standard definition of ISSNHL does not exist, nor is there a standard method for
reporting recovery. However, agreement has been reached with regard to the
requirement for a 30 dB HL or more hearing loss in at least three contiguous
frequencies1-5. The definition of “sudden” can vary from 24 hour to 72 hours in
different studies 2,6,7.
No standard method exists for audiological assessment with respect to the
configuration of hearing loss and hearing recovery. Hearing recovery has been
reported in different categories, such as “complete recovery”, “good recovery” and
“fair recovery”, but there is no agreement regarding to the actual degree of
improvement indicated by each of these categories. The pattern of hearing loss has
often been mixed with the degree of hearing loss8,9.
Independent of what treatment is given, spontaneous recovery can occur within a few
hours to few days after onset. Complete and partial recovery is often combined when
reporting spontaneous recovery, which is seen in 32%–81% of the cases2,6,10,11. A
higher recovery rate has been reported for patients with hearing loss in the low
frequencies than for those with loss in the high frequencies10.
Due to high rate of spontaneous recovery, not every potential patient ends up seeking
help so that the incidence of ISSNHL is difficult to estimate. In 1944, De Kleyn
reported an increase of ISSNHL between the years 1936 and 1942 in Amsterdam12.
Since 1958, the overall incidence has been reported to be 5–20 per 100,000 per year13.
Recently, there have been two epidemiological studies that have shown that the
prevalence of patients seeking help has increased. One study showed an increase in
Japan from 3.9 to 27.5 per 100,000 persons annually14, and another study in Germany
showed a prevalence of 160 per 100,000 persons per year in the city of Dresden15.
Since the etiology of ISSNHL still remains unknown, a standardized treatment does
not exist. Different theories with regard to its etiology have resulted in different
treatment policies over the years in Sweden and in many other countries16-19. These
treatments have included anti-stress treatment with bed rest and blockage of the
ganglion stellatum in the 1950’s20, treatment with dextran 40 and other hyperosmolar
hemodiluting drugs in the 1970’s21 and corticosteroid treatment since the 1980’s2.
The randomized placebo controlled trial by Wilson et al. 1980 has been the foundation
for a therapy tradition, which over many years, has become internationally the most
common treatment for ISSNHL. Corticosteroid dosage has been successively
increased without any evidence of better effect22. Several later investigations with
corticosteroids have not been able to demonstrate any specific effect even if
administered through the round window23. Moreover, the Wilson study has later been
criticized by Cochrane reports 2006 and 2009 as not fulfilling modern standards for
RCT24,25.
12
Introduction
Due to its low incidence, its rate of spontaneous recovery and its unknown etiology,
the effect of therapy is difficult to evaluate for a single physician who sees just a few
patients annually. By compiling the data from a large number of patients, it was
possible to identify prognostic factors and the impact of the various treatments used in
Sweden. The most common treatment for ISSNHL used in Sweden was then compared
to placebo with regard to treatments influence on outcome.
13
Background
BACKGROUND
The auditory system
The auditory system is described as the peripheral and central auditory system. The
peripheral auditory system is comprised of three components, which are the outer,
middle and inner ear. The central auditory system includes the auditory pathways and
auditory cortex26.
Fig. I. The peripheral auditory system.
The outer ear
The outer ear consists of the pinna/auricle and the ear canal/external auditory meatus.
The pinna/auricle collects and directs sound waves that are traveling through the air
into the ear canal/external auditory meatus, which, in turn, transmits the sound waves
to the tympanic membrane (eardrum). The ear canal forms a resonance channel that
amplifies the sound pressure up to 15–25 dB in 2–5 kHz.
The middle ear
The middle ear is an air-filled cavity that includes the tympanic membrane (eardrum)
and the ossicular chain. The ossicular chain consists of three interconnected bones,
which are the malleus27, incus (anvil) and stapes (stirrup). The malleus is attached to
the tympanic membrane, and the footplate of the stapes inserts into the oval window of
the inner ear. The incus is located between the malleus and the stapes. Thus, the
movements of the tympanic membrane (eardrum) will set the malleus, incus and stapes
into motion. Attached to the ossicular chain are the stapedius and tensor tympani
muscles. The sound is not amplified evenly across the ossicular chain, and contractions
of these muscles protect the inner ear by reducing the intensity of sound transmission
to the inner ear.
14
Background
The inner ear
The inner ear consists of two systems that function independently. These include the
sensory organ of hearing, which is called the cochlea, and the organ of balance, which
is the vestibular system.
The cochlea is spiral-shaped and contains fluid-filled chambers. The two outer
chambers, which are the scala vestibuli and scala tympani, are a part of the bony
labyrinth and are filled with perilymph. The middle chamber, which is the scala media
and is also called the cochlear duct, is filled with endolymph. Both perilymph and
endolymph are clear solutions that contain electrolytes and proteins, and they are
chemically quite different from each other. The perilymph is rich in sodium salts,
whereas the endolymph is rich in potassium salts. The cochlear duct separates the two
chambers from each other by the Reissner's membrane and the basilar membrane, on
which the organ of Corti lies. The third partition consists of the stria vascularis, which
is a rich bed of capillaries and secretory cells that are responsible for the production of
endolymph. The scala vestibuli ends at the oval window, where the footplate of the
stapes sits, and the scala tympani ends at the round window. A vibration coming from
the stapes into the inner ear via the oval window moves the perilymph in the scala
vestibule, which, in turn, vibrates the endolymph in the scala media, the perilymph in
the scala tympani, the basilar membrane and the hair bundles of the hair cells in the
organ of Corti.
The organ of Corti consists
of approximately 3500 inner
hair cells and 15,000 outer
hair cells. The hair cells lie
on the basilar membrane and
are covered by the tectorial
membrane. The basal parts
of the organ of Corti are
responsible for detecting the
highest frequencies that we
can perceive, and the
frequencies that can be
detected gradually decrease
as they move towards the
apical parts. The inner hair
Fig. 2. Cross section of Cochlea.
cells transform the sound
vibrations in the fluids of the
cochlea into electrical signals. The outer hair cells amplify the low-level sounds by
mechanically enhancing the motion of the tectorial membrane in order to increase the
stimulation of the inner hair cells. They also add to the frequency resolution.
Both the outer and inner hair cells are associated with afferent and efferent neurons.
The afferent neurons, which carry information to the brain, contact mainly the inner
hair cells, and the efferent neurons, which carry information back to the hair cells,
connect mostly to the outer hair cells.
Background
15
The labyrinth artery is an end artery and is the sole blood vessel supplying the inner
ear. The artery divides into the cochlear artery and the anterior vestibular artery. The
cochlear artery further divides into the main cochlear artery and the vestibulocochlear
artery. The main cochlear artery lies below the organ of Corti and has more capillaries
in the apical portion of the cochlea then in the basal part. The distance between the vas
spirale and the spiral border near the inner hair cells is shorter in the apical part than in
the basal part28.
Glucocorticoids are one of five groups of steroid hormones that are released by the
adrenal glands in response to stress. Receptors that steroid hormones bind to are
ligand-activated proteins and are found in the cytosol and the nucleus. The effect of
glucocorticoid is grouped into two categories namely metabolic and immunological.
Cortisol is the term for glucocorticoids in humans and its metabolic effect is to
increase and maintain normal concentrations of glucose in blood. By interaction with
the glucocorticoid receptor, glucocorticoids can either up-regulate the expression of
anti-inflammatory protein or down-regulate the expression of pro-inflammatory
protein. The density of Glucocorticoid receptors varies in different tissues29. In
cochlea, the spiral ganglion neurons and spiral ligament have the highest expression.
The hair cells and stria vascularis have lower expression30-34.
The central auditory system
A vibration that comes from the middle ear is transmuted into a neural signal in the
cochlea. The neural signal transfers from the hair cells to the spiral ganglion, which is
found in the spiral bony structure located centrally in the cochlea (modiolus). Axons
from the ganglion cells are bundled together to form the auditory portion of the eighth
cranial nerve. The auditory nerve carries the signal into the brainstem and synapses in
the cochlear nucleus. From the cochlear nucleus, auditory information is split into at
least two streams, which include the ventral cochlear nucleus and the dorsal cochlear
nucleus. The ventral cochlear nuclear cells project to a collection of nuclei called the
superior olive, which helps to determine the direction of the sound. The dorsal
cochlear nucleus analyzes the quality of sound. Both streams of information proceed to
the sensory thalamus and from there to the auditory cortex that is located in the
temporal lobes.
Hearing impairment
Hearing loss can be classified into four categories35.
Conductive hearing loss is caused by difficulties in the transmission of sound into the
inner ear. A diagnosis can be made via observation of an air-bone gap on audiometry,
which indicates that hearing is better when sound is transmitted in such a way that it
bypasses the middle ear ossicular chain. The air-bone gap should be more than 10 dB
HL.
Sensorineural hearing loss occurs without an air-bone gap, since air conduction is
equal to bone conduction. A diagnosis is made through audiometry. Patients with
cochlear damage have no Otoacoustic Emissions-testing (OAE), and those with
auditory nerve damage fail the Brainstem Auditory Evoked Responses-testing (ABR).
16
Background
Mixed hearing loss is a combination of sensorineural hearing loss and conductive
hearing loss.
Central hearing loss is caused by damage to the central pathways. The diagnosis
cannot be made by pure tone audiometry, since that is often normal in affected
individuals. A patient with central hearing loss usually has poor scores on their speech
reception threshold or word recognition scores.
Etiologic hypotheses for ISSNHL
Idiopathic diseases are ‘idiopathic’ as long as the causative agent is not known. A
cause for SSNHL can be found in 10% of all cases36,37. An acute hearing loss can be a
symptom caused by a multitude of known diseases within the vascular system or by
different traumas and tumors within the hearing tracts38,39. Hallberg (1956) stated that
”Sudden unilateral or bilateral impairment of hearing is a symptom, not a disease.”40.
Thus far, diagnosis has been based on the patient's audiogram, medical history, and
physical examination, while identification of a specific cause for the sudden hearing
loss is rather unusual.
Vascular theory
In 1949, Rasmussen suggested vascular occlusion or ischemia as a mechanism for
ISSNHL41. Vascular or hematological diseases that are associated with SSNHL, such
as Buerger’s disease42, leukemia43 and sickle cell anemia44 have also been reported.
The labyrinth artery is an end artery that solely carries red blood cells and oxygen into
the inner ear28. Tissue injury that results from oxygen deprivation and ischemia can
occur in the cochlea within 60 seconds6. A total but temporary blood circulation
blockage, can cause damage to the hair cells, the ganglion cells and the spiral ligament
and can also cause neuronal loss and an alteration of the tectorial membrane after
30 minutes. This damage is irreversible even after the blood flow is restored45. The
labyrinth artery is extremely vulnerable to blood pressure oscillation and abnormalities
in blood flow46. Blood flow has an inverse relationship with blood viscosity47. Low
blood flow causes anoxia due to hyperviscosity, which results in cochlear
hypofunction and the inability to maintain cochlear metabolism48. A correlation
between ISSNHL and blood viscosity has been shown49-51.
Different treatments regimes for ISSNHL, such as fibrinogen apheresis52,
Rheopheresis53, dextran infusion54, hyperbaric oxygen55 and pentoxifylline56, have
been developed in response to this vascular theory. There is evidence both to support
and refute such treatment54-58.
Immunologic theory
McCabe (1979) was the first to suggest autoimmunity as a cause of SSNHL, based
upon clinical data, pathological findings in autoimmune tests and positive response to
steroid therapy59. Hearing loss may be a consequence of local autoimmune processes
within the inner ear60,61 or of systemic autoimmune diseases, such as Cogan’s
syndrome62, Wegener’s granulomatosis63 and systemic lupus erythematosus (SLE)64.
Background
17
Although the inner ear was initially considered as an immunologically privileged
organ, it is capable of producing a strong immune response. The presence of
antibodies against antigens in the inner ear and the formation of immune complexes in
the stria vascularis, endolymphatic sac and ducts support the immunologic theory65-67.
Autoimmunity can cause damage to the cellular components of the organ of Corti and
affect the stria vascularis and spiral ligament. Autoimmunity can also cause
dysfunction of the endothelial cells and fibrocytes II, which leads to the impaired
diffusion of K+ through marginal cells to the endolymph fluid. This in turn can affect
the supporting cells of the organ of Corti, which precedes a late effect upon the hair
cells68. The existence of glucocorticoid receptors in the stria vascularis and supporting
cells also suggests their role as immune targets in the inner ear69.
Treatment of ISSNHL with corticosteroids was the result of this immune theory.
Since this therapy was first used in the 1980’s, there have been many studies on the
impact of corticosteroids on SSNHL2,10,70-73. However, the only two randomized,
double-blinded, placebo-controlled studies (19802, 200110) with low power showed
contradictory results.
Infectious theory
Herpes zoster that causes sensorineural hearing loss was first reported by Hunt in
190774. SSNHL has also been reported to be caused by known infectious diseases, of
both bacterial and viral origins, such as by Borrelia and Syphilis75,76, the mumps77,78
and rubella79,80.
Both an acute and latent viral attack may damage the inner ear and cause hearing
loss81. Upper respiratory infection82, as an example of an acute viral infection, and
members of the herpes virus family83, as an example of latent infections, have been
proposed to cause SSNHL. Virus infection can damage the organ of Corti, the
ganglion cells, the nervous fibers, the tectorial membrane and the stria vascularis84.
Two antiviral drugs, acyclovir and valacyclovir, are used to treat SSNHL as a result of
this theory4,85. However, the four published randomized, placebo-controlled clinical
studies that used acyclovir and valacyclovir did not show any benefit for the treatment
of ISSNHL3-5,86.
Membrane breaks
Rupture of the oval or round window can cause loss of the perilymph and result in
pressure alteration between the chambers that contain perilymph and endolymph87,88.
There have been studies on the temporal bones that support this theory89,90. The
membrane break does not happen spontaneously, but rather occurs after a sudden
pressure alteration in the middle ear that can be caused by head injuries, barotraumas
or intense physical exercise40,91. The fact that many of these patients report hearing
loss upon awaking6 and that not all individuals with high intracranial and intraabdominal pressure, such as women in childbirth or weight lifters, experience SSNHL
argues against this theory. In addition, not all of the temporal bones studies found
evidence of active or healed ruptures of the oval or round window, basilar membrane
or Reissner’s membrane81,84,92.
18
Background
Surgery with the intention to repair oval or round window perilymph fistulae
combined with strict bed rest has been used in cases of ISSNHL with a history of
recent trauma or barotrauma93,94.
Genetic Theory
Hearing loss can be inherited. Wilde (1853) was the first to report the genetic cause of
congenital deafness95. Epidemiological data about postlingual hereditary hearing loss
are still unknown. Genetic hearing loss divides into two categories, Syndromic hearing
loss and Nonsyndromic hearing loss. Two-thirds of all genetic hearing losses are
nonsyndromic hearing loss meaning “without other clinical findings”. Seventy percent
of all genetic hearing losses are recessive hearing loss, fifteen percent are dominant
and the remaining fifteen percent are other form of inheritance96,97.
Many genes whose mutation causes nonsyndromic hearing loss have been identified
within the last few years. WFS1exon 8, connexin 26, 30 and 31 are genes which have
been identified in stria vascularis, basal membrane, spiral limbus and spiral
ligament98,99.
Very few studies are done about the heredity of ISSNHL. Two papers were published
2010 on the subject100,101. Gäckler et al., found more individuals with family history of
SSNHL among those who themselves had experienced SSNHL100. In the second
paper, the researchers were looking for a difference in gene mutation between SSNHL
patients and healthy volunteers, but found none101.
Aims
19
AIMS
The general objectives of this thesis were to find predictive factors for hearing
recovery, to investigate the treatment policy of ISSNHL in Sweden and to evaluate the
efficacy of these treatments on hearing recovery in comparison to placebo.
Paper I
 To analyze which variables, such as background data, concomitant disease,
audiogram shape and laboratory tests, can best predict the outcome of ISSNHL.
 To investigate the treatment policy of ISSNHL in Sweden.
 To evaluate the effects of treatments on outcomes.
Paper II
 To explore the different diagnostic test batteries for ISSNHL, that are currently
used in Sweden.
 To evaluate if and how, positive diagnostic findings result in treatment
modifications.
 To investigate whether such treatment modifications influence the outcome of
ISSNHL.
Paper III
 To evaluate whether, in comparison to placebo, corticosteroids (Prednisolone)
used in high tapering dosage in any way influence the outcome of ISSNHL.
Paper IV
 To analyze a larger patient group by meta-analysis of data from the RCT
together with corresponding material drawn from the Swedish national database
for ISSNHL.
Methods
21
METHODS
Paper I and II
The first two publications (I, II) in this thesis are based on data from a national
database in Sweden for sudden sensorineural hearing loss.
Swedish national database for SSNHL
The database began gathering data from patients with SSNHL in winter 2002–2003.
Approximately half of all ENT clinics in Sweden have been contributing data to the
database.
To build the database, a questionnaire was developed that covered the patient’s past
medical history, potential precipitating events that preceded the SSNHL, traumas,
family history of different diseases, especially hearing loss, the current disease, the
diagnostic protocol including laboratory, radiological and further audiological
examinations and all other treatments. The time course of the hearing loss’s onset and
associated symptoms, such as tinnitus and vertigo, were also requested. The
questionnaire included the results of an ENT examination. Information on radiological
investigations (MRI or CT), laboratory work-ups and the use of BRA or a vestibular
work-up were requested. This information request was phrased in general terms so as
not to influence the doctor's own diagnostic practices on their decision-making
process. The questions with regard to treatment included the use of corticosteroids,
antiviral therapy, rheological treatment or “other” drugs, and prescription of rest or
surgery of a suspected fistula. In the case that pathological test results were
performed, the complete lab-sheet for that patient was requested. See Appendix I.
For each patient, after informed consent, a questionnaire was completed by the
otorhinolaryngologist, and two audiograms were requested—one to have been taken
during the first visit to the ENT clinic due to the symptoms of SSNHL and the other
taken after three months. When available, a pure tone audiogram was requested for
patients known to have a prior diagnosed hearing loss before onset of SSNHL.
Paper III
A randomized triple-blind 1 placebo-controlled multicenter trial on the effect of
corticosteroids on ISSNHL was performed between January 2006 and September
2010. Fourteen public otorhinolaryngological centers in Sweden were successively
enrolled and each center contributed for 1 to 4.8 years.
Patients asked to participate were those aged 18–80 years, presenting with sudden
onset of hearing loss developing within 24 hours, and without any known etiology
(no earlier or present ear disease). The pure tone average in the affected ear of the
three contiguous frequencies most affected should be ≥30 dB HL. Enrollment and
treatment was to be started within 7 days from onset. Exclusion criteria were the
1
Triple-blind trial is a trial in which neither the subject, the person administering the treatment nor the person
evaluating the response to treatment knows which treatment a particular subject is receiving.
22
Methods
common medical reason for not using corticosteroids: pregnancy, diabetes, chronic
infections, peptic ulcer, uncompensated heart disease, recent surgery, or psychiatric
disease. The patients' ordinary medication for concomitant disease was permitted
except vascular, antiviral or corticosteroid treatment.
A case report form (CRF) was collected for each patient. The CRF consisted of a
questionnaire, audiograms, information on radiological investigations (MRI or CT),
laboratory work-ups, brainstem response audiometry (BRA) and vestibular work-up,
according to the praxis at the different clinics, and information on adverse events
and/or serious adverse events. The questionnaire was a modified version of one used
for the Swedish database for ISSNHL (see Sppendix II). After an initial pure tone
audiogram, new audiograms were taken at three follow-up visits: day eight of
treatment, after one month, and three months. In cases where patients were known to
have prior diagnosed hearing loss, a copy of any available previous audiogram was
included in the CRF.
All patients received written information about Sudden Sensorineural Hearing Loss,
the aim of the study and instructions for taking the drugs. Prednisolone as 10 mg
capsules, or placebo was given as a single dose of 60 mg daily for three days; the dose
was then reduced by 10 mg per day, with a total treatment period of eight days. If
recovery was complete (complete recovery=difference between the initial audiogram
and audiogram at the follow-up <10 dB), treatment stopped, otherwise medication was
continued at 10 mg daily to a total of 30 days from beginning. Follow-up visits were
scheduled for day eight ± one day, 1 month and 3 months after randomization. If
recovery was complete at day eight, the next follow-up was at 3 months.
Paper IV
Meta-analysis was used to strengthen and confirm the results from the randomized
triple-blind placebo controlled clinical trial on the effect of corticosteroids on ISSNHL
(Paper III). The material from the RCT (Paper III) was augmented with corresponding
data drawn from the Swedish national database for SSNHL.
The patients included in the analysis had been treated with Prednisolone, treated with
placebo or received no treatment. The patients from the database were selected if they
had received the same or equivalent treatment as in the RCT, which was Prednisolone
as 10 mg capsules as a single dose of 60 mg daily for three days, thereafter reduced by
10 mg per day, with a total treatment time of at least eight days. The control group
from the RCT was the placebo treated patients, with audiograms at the start and after
3 months. The control group from the database was those who had not received
Prednisolone or other specific treatment, but been examined with audiograms at the
initial visit and after 3 months.
Assessment of hearing loss and hearing recovery
Sudden Sensorineural Hearing Loss was defined as a hearing loss of at least three
contiguous frequencies between 0.125 kHz to 6 kHz, with a mean of 30 dB HL or
more and that occurred within 24 hours.
Methods
23
The hearing loss was characterized by a comparison of the audiogram taken at the first
visit after onset of SSNHL to an audiogram that was taken not more than two years
before the acute hearing loss. If no previous audiogram was available, hearing was
compared to the non-affected ear in its present state.
Four frequency regions were created to describe the hearing loss:
Low frequency region:
 Pure-tone average (PTA) of low frequencies (125, 250, 500 Hz) > PTA of mid
frequencies (1000, 1500, 2000 Hz) and high frequencies (3000, 4000, 6000 Hz)
by at least 10 dB.
 Hearing loss in the low and mid frequencies – PTA of low frequencies > PTA
of mid frequencies with a difference less than 10 dB.
Mid frequency region:
 PTA of mid frequencies > PTA of low- and high frequencies by at least 10 dB.
 Hearing loss in the low and mid frequencies – PTA of mid frequencies > PTA
of low frequencies with a difference less than 10 dB.
High frequency region:
 PTA of high frequencies > PTA of low- and mid-frequencies by at least 10 dB.
 Hearing loss in the mid and high frequencies – PTA of high frequencies > PTA
of mid frequencies with a difference less than 10 dB.
Flat loss:
 The differences between the PTA for all three frequency regions were less than
10 dB.
The audiogram taken at the first visit and the audiogram obtained three months after
the onset of SSNHL were compared with respect to the PTA, characterizing the loss to
determine the degree of hearing recovery and remaining hearing loss (Table I).
24
Methods
Table I. Hearing improvement and remaining hearing loss after recovery.
Improvement
Large improvement
Moderate improvement
No improvement
Worsening
>30 dB
10 – 30 dB
± 10 dB
>-10 dB
Hearing loss after recovery
No remaining hearing loss
Partial recovery
No regress
Difference between initial audiogram and
audiogram at the follow-up <10 dB
The difference ≥10 dB and
the improvement ≥10 dB
The difference ≥10 dB and
the improvement <10 dB
Categorization of laboratory tests
The pathological results of laboratory tests were categorized by one or more
pathological values prior to analysis.
 “Arteriosclerosis associated variables”:
LDL-cholesterol/HDL-cholesterol ratio>3, Total cholesterol >5 mmol/L and
C-reactive protein (CRP) >3 mg/L in patients with or without earlier known
cardiovascular disease.
 “Inflammation/infection”:
CRP >10 mg /L, Erythrocyte sedimentation rate >20 mm,
Leukocyte count >10 x 109 ml/L, Hemoglobin count (Hb) <120 g/L,
Thrombocyte count >150 x 109 ml/L and Borrelia tests “positive” (IgG
antibodies and IgM antibodies) in patients with or without ongoing clinical
infection.
 “Autoimmune variables”:
HSP-70, Cardiolipin, Antiphospholipid, Anti-Neutrophilic Cytoplasmic
Antibodies (ANCA) and Antinuclear antibodies (ANA) “positive”.
Statistical methods
25
STATISTICAL METHODS
Statistical analysis was performed using Minitab software, version 13.32 for Windows,
for Paper I, version 15 for Windows, for Paper II and version 16 for Windows, for
Paper III and IV.
Descriptive statistics were used in all four papers to show the characteristics of the
subjects. The data was expressed as the number of cases and percentage. Parametric
data was expressed as mean ± standard deviation65.
Paper I and II
Ordinal/Ordered logistic regression was used for all analyses with regard to hearing
recovery. This method performs a logistic regression on an ordinal response variable
(categorical variables that have three or more possible levels with a natural ordering)
with the help of both continuous and categorical predictors.
The estimated probability for hearing improvement and no remaining hearing loss in
relation to the prognostic factor, the frequency regions (low, mid, high and “flat loss”)
and the frequency regions (low, mid and high) in relation to the number of days from
the onset of ISSNHL was expressed as an odds ratio (OR) and 95% confidence
intervals (CI).
Seasonal variance and gender differences with regard to age distribution, the presence
of tinnitus and/or vertigo, the comparison between treatment options and laboratory
tests, the interval between the onset of hearing loss and the first visit to the ENT clinic
and the pure-tone average between different frequency regions were performed using
χ2-test. The level of significance was set at p<0.05.
Paper III and IV
The analyses of primary and secondary endpoints were performed according to
modified Intention-To Treat (modified ITT) and Per Protocol (PP) with comparisons
of pure tone audiograms.
Multiple regression was used with selected variables (age, heredity for hearing loss,
vertigo, tinnitus, time from onset of SSNHL to first ENT visit, prescribed rest or sick
leave, affected frequency regions) which were forced into the model together with
Prednisolone and placebo. The first step in the multiple regression analysis was to
study interactions between treatment and some selected variables The interactions
studied were between treatment & age, treatment & time from onset of SSNHL to first
ENT-visit, treatment & affected frequency regions, treatment & baseline pure tone
average for the affected frequencies. The goal was to see if any of the selected
interactions had a significant covariance with recovery. Interactions, that were not
significant, were thereby removed from further analyses.
The second step in the multiple regression analyses was to include variables with
stepwise forward method if p<0.05 to see if any single variable had a significant
covariance with recovery. Three dummy variables were created out of the four
categories of frequency regions and used to indicate the absence or presence of some
26
Statistical methods
categorical effect that might be expected to shift the outcome. These three dummy
variables were not tested individually in the stepwise forward process; the choice was
between including none or all (partial F-test).
A single-sided null-hypothesis was used in testing the effect of Prednisolone and
placebo, since a deterioration in hearing due to corticosteroids was not expected:
H0 = the efficacy of Prednisolone on recovery ≤10 dB
H1 = the efficacy of Prednisolone on recovery >10 dB
For the other variables, double-sided null-hypothesis was tested that the variable had
no effect on recovery.
A value of p<0.05 was used for all tests to indicate statistical significance.
Ethical considerations
27
ETHICAL CONSIDERATIONS
Paper I and II
The Medical Research Ethic Committee of Linkoping’s University, Sweden
(registrations number 02-337) approved the database. Participants were given oral
information about the database by their local ENT doctors. A written informed consent
was not requested, as there was no intervention that was performed and as the
participant’s identity (security number) was not reported in the database.
The data were handled confidentially. No more than the participant’s birth date and
gender were provided on the questionnaires, audiograms and requested lab-sheets.
Paper III
The study, EudraCT 2005-001487-32 was approved by the regional ethics review
board and Swedish Medical Products Agency in accordance with the Declaration of
Helsinki and good clinical practice guidelines.
All patients received written information about Sudden Sensorineural Hearing Loss,
the aim of the study and instructions for taking the drugs.
A case report form (CRF) was collected for each patient. The data were handled
confidentially. The CRFs were coded with the number of study drug bottle, the
participant’s birth date, gender and the name of the clinic.
29
Material
MATERIAL
Paper I
Three hundred patients with acute hearing loss who had initially received the diagnosis
of “Sudden deafness/Sudden Sensorineural Hearing Loss” by their ENT-doctor, were
included in the Swedish national database for SSNHL.
Of the three hundred patients in the database, ninety-two either had conductive hearing
loss, Mb Ménière, other known disorders of the inner or middle ear, a hearing loss less
than a 30 dB HL, less than three contiguous frequencies involved or a hearing loss that
occurred over more than a 24-hour period. These ninety-two individuals were
excluded from analysis. See Table II.
Paper II
Four hundred patients (three hundred from Paper I and one hundred additional
patients) who were initially diagnosed with SSNHL and, thereby, reported to the
database for SSNHL were evaluated.
Table II. Final diagnosis after examination for patients initially reported
as SSNHL (n=92).
Diagnoses
Number
Acoustic neuromas
Trauma
5
acoustic trauma
head trauma
trauma after water irrigation of
the ear
barotraumas
2
2
2
3
Subdural hematoma
1
Myeloma
1
Mb Ménière
5
Hydrops
1
Progressive hearing loss
Bleeding in Pons
(infarct at the root entry zone)
1
1
Transient ischemic attacks
1
Coronary disease
3
Did not fulfill the criteria
for SSNHL
Hearing loss less than 30 dB HL
Hearing loss did not occur
within 24 hours
44
20
30
Material
Paper III
One hundred and three patients with ISSNHL were included randomized evenly to
treatment with either Prednisolone or placebo. Ten patients were excluded from the
analyses, four of them in the treatment group and six in the placebo group. See Fig. III.
Ninety-three patients were analyzed by modified Intention-To Treat (modified ITT)
forty-seven received Prednisolone and forty-six placebo. For eight of ninety-three
patients, the hearing loss was evaluated by comparison of an audiogram taken within
two years before the ISSNHL. Six of these had been treated with placebo.
Eighty-seven out of ninety-three patients who took the study drug according to the
protocol under the first eight days of the treatment period were analyzed by PP; fortyfive belonged to the treatment group and forty-two placebo. Fourteen of those eightyseven patients either should have continued taking the study drug up to 30 days or did
continue, but not in accordance with the protocol.
Seventy-three out of ninety-three patients who did take the study drug according to the
protocol were analyzed as Total Per Protocol (total PP); thirty-eight belonged to the
treatment group and thirty-five placebo.
Paper IV
A total of one hundred ninety-two patients were analyzed, eighty-seven from the RCT
and one hundred and five from the Swedish national database.
Ninety-nine of the total one hundred ninety-two had received Prednisolone and ninetythree placebo or no treatment.
The hearing of each patient was evaluated at the first visit at the ENT clinics and after
three months.
At the final follow-up, audiograms were missing for two patients in Prednisolone
group (RCT), one patient in corticosteroid group (the Swedish national database) and
two patients in the no treatment group (the Swedish national national database).
Fig. III. Trial profile.
FIG. III. TRIAL PROFIL
Material
31
33
Results
RESULTS
Paper I
The aim of Paper I was to analyze which variables best can predict the outcome of
ISSNHL, to investigate the treatment policy of ISSNHL in Sweden and to evaluate the
effect of treatments on outcome.
None of the patients in the Swedish national database were bilaterally affected.
Of three hundred patients reported to the database, two hundred and eight have been
evaluated according to the defined criteria for ISSNHL
Descriptive data for the two hundred and eight patients with ISSNHL (age range
15–87 years, mean 57) are presented in Table III. All two hundred and eight patients
had a physical examination, 68% had laboratory work-up, and 37% had MRI. The time
between onset of ISSNHL and the first visit at the ENT clinics varied, with a mean of
16.4±31.5 days.
Table III. Profiles of the ISSNHL patients (n=208).
Variables
Number (%)
Gender
Female
Male
Age
Mean ± SD (years)
Range (years)
Affected ear
Left
Right
Prevalence of associated
symptoms
Tinnitus
Interval between onset of
hearing loss and first visit at the
ENT clinics
98 (47)
110 (53)
56.1 ± 16
15 - 87
96 (46)
112 (54)
107 (51.4)
Vertigo
With nystagmus
Without nystagmus
No info. about nystagmus
1 (0.48)
7 (3.4)
1 (0.48)
Tinnitus and vertigo
With nystagmus
Without nystagmus
No info. about nystagmus
10 (4.8)
38(18.3)
7 (3.4)
No info about tinnitus or vertigo
No associated symptoms
1 (0.48)
36 (17.3)
Median (days)
Range (days)
5
0 - 212
All variables in the questionnaire (Appendix I) were analyzed using ordinal logistic
regression in order to look for interactions with hearing recovery and remaining
hearing loss as dependent variables.
34
Results
Independent of treatment or no therapy, “Heredity for hearing loss” and older age
were significantly associated with outcome. “Heredity for hearing loss” was
associated with a significantly lower odds for improvement, with an odds ratio of 3.02
(95% CI 1.34–6.80, p=0.008), but was not associated with the remaining hearing loss.
An older age was related to a reduced chance of both improvement of hearing in dB
(OR 1.05, 95% CI 1.03–1.08, p=0.000) and the remaining hearing loss (OR 1.03,
95% CI 1.0–1.05, p=0.008).
Hearing loss in the low frequency region occurred in 42% of all cases, hearing loss in
the mid frequency region in 26%, hearing loss in the high frequency region in 30% and
3% had a “flat loss”. The reported number of patients with “flat loss” was too low for
statistical analysis (n=6); their hearing improved partly or totally irrespective of
treatment (Table IV). Patients with hearing loss in the mid frequency region had a
significantly higher chance for improvement when compared to those with hearing
loss in low (p=0.000) or in high frequency region (p=0.000), if they visited an ENT
clinic the same day as the onset of ISSNHL. The probability for improvement of the
hearing loss decreased with number of days to ENT visit regardless of the frequency
region.
Total or partial recovery for patients with hearing loss in mid frequency region was
significantly more likely when compared to those with hearing loss in low (p=0.002)
or high frequency region (p=0.014), if they visited an ENT clinic the same day as the
onset of ISSNHL. The probability for no remaining hearing loss decreased with
number of days before the first visit regardless of the frequency region.
Table IV. Treatment and outcome for patient with “flat loss” (n=6).
Patient No. Treatment
Improvement
Hearing loss after recovery
1
Prednisolon 60 mg/day
Large
No remaining hearing loss
1
No medical treatment
Moderate
Partial recovery
1
Prednisolon 60 mg/day
Moderate
Partial recovery
1
Prednisolon 60 mg/day
Moderate
Partial recovery
1
No medical treatment
Large
No remaining hearing loss
1
Prednisolon 80 mg/day
Moderate
Partial recovery
Corticosteroid therapy was used for one hundred and five (50%) of the total two
hundred and eight patients and ninety (44%) received no medical treatment. Of the
remaining eleven patients, three received antiviral therapy and five received
antibiotics. In all, 38% of the patients treated with corticosteroids had a large
improvement (>30 dB) and 34% had moderate improvement (10–30 dB) compared
with 28% with large and 36% with moderate improvement among those who were not
medically treated. The differences were not significant.
The main corticosteroid used was Prednisolone (80%). The dosage, duration of
treatment and tapering schedule varied from 80 mg to 25 mg per day for five days to
four weeks. No significant difference in outcome was seen as regards the dosage
Results
35
given. Among those who were treated with Prednisolone, 68% received high dose
(>50 mg/day) and 32% received low dose (≤50 mg/day). Large improvement (>30 dB)
was noticed among 40% of patients treated with high dose (>50 mg/day) Prednisolone
and moderate improvement (10–30 dB) among 33% compared to 30% showing large
and 37% moderate improvement among those who were treated with low dose
(≤50 mg/day). See Table V. The differences between the groups were not significant.
36
Results
Paper II
The aim of Paper II was to explore the different diagnostic test batteries for ISSNHL
that are currently used in Sweden, to evaluate if and to what extent, positive diagnostic
findings result in treatment modifications and to investigate whether such treatment
modifications influence the outcome of ISSNHL.
Of four hundred patients reported to the database, three hundred were evaluated as
suffering from ISSNHL. Descriptive data on the three hundred patients evaluated as
suffering from ISSNHL are presented in Table VI.
One hundred and fifty-eight (40%) of the four hundred patients with SSNHL had an
MRI or CT, and twenty-two had pathological findings. Out of the twenty-two with
pathological findings, ten patients had accidental findings that were not connected to
the hearing tracts and thereby were defined as ISSNHL. Out of remaining twelve
patients: five had acoustic neuroma, one had subdural hematoma, one had a pons
infarction and five had different vascular abnormalities that might have had a possible
connection to SSNHL. The five individuals who had different vascular abnormalities
had all a low frequency hearing loss (Table VII).
No significant association was found between pathological MRI-findings and either
hearing recovery or remaining hearing loss for the patients with ISSNHL.
Table VI. Profiles of the ISSNHL patients (n=300).
Variables
Number (%)
Gender
Female
Male
Age
Mean ± SD (years)
Range (years)
Affected ear
Left
Right
Prevalence of associated
symptoms
Tinnitus
Interval between onset of
hearing loss and first visit at the
ENT clinics
146 (49)
154 (51)
57.4 ± 16
8 - 87
141 (47)
159 (53)
149 (49.7)
Vertigo
With nystagmus
Without nystagmus
No info. about nystagmus
1 (0.33)
11 (3.7)
1 (0.33)
Tinnitus and vertigo
With nystagmus
Without nystagmus
No info. about nystagmus
16 (5.3)
49 (16.3)
11 (3.7)
No info about tinnitus or vertigo
No associated symptoms
1 (0.33)
61 (20.3)
Median (days)
Range (days)
5
0 - 498
37
Results
Hematological tests were taken in two hundred and fifty-eight (65%) cases of the total
four hundred. The blood screening varied from simple routine tests to a complete
analysis (CRP, Hb, HSP70, ANCA tests, and Borrelia tests), covering most hypotheses
concerning SSNHL (e.g., infections, vascular catastrophes, autoimmune disease or
membrane rupture).
Of the three hundred patients who were classified as having ISSNHL, one hundred
ninety six had one or more laboratory tests taken, and forty-seven (24%) of these had
one or more pathological findings.
The group categorized as having pathological “arteriosclerosis-associated variables”
(n=13) was significantly older than those with normal laboratory tests (n=148),
65 ± 11 years and 56 ± 17 years, respectively, p=0.016. The twenty-seven patients
with ”inflammation markers” were of the same age as those with normal laboratory
tests. Of these, fifteen had positive Borrelia findings. Seven patients were regarded as
having pathological “autoimmune variables”. No age difference was seen between
those with pathological “autoimmune variables” and those with normal laboratory
tests.
There was no association between any of the laboratory tests and either hearing
improvement or remaining hearing loss, even when the tests were evaluated separately
or after the tests were compared to those who had normal laboratory findings.
Table VII. Patients with low frequency loss and vascular changes as possible cause of
ISSNHL shown by MRI (n=5). Treatment and outcome.
Patient
Diagnosis
Treatment
Hearing recovery
1
ISSNHL
Corticosteroids + Antiviral therapy
No improvement
2
ISSNHL
Corticosteroids
No improvement
3
ISSNHL
Corticosteroids
Moderate improvement
4
ISSNHL
Prescribed rest
Moderate improvement
5
Myeloma
Cytostaticum
Moderate improvement
Medical treatment was given to one hundred eighty-two (61%) of three hundred
patients with ISSNHL. Of these, one hundred sixty-six patients were given
corticosteroids either as single treatment or in combination with antiviral therapy,
antibiotics or blood thinning therapy (acetylsalicylic acid). Three patients were only
given antiviral therapy, six others only antibiotics, two were only given acetylsalicylic
acid, and five received various other drugs. Ninety-six patients received no treatment
at all.
Medical treatment had no significant correlation with either hearing improvement or
remaining hearing loss
Seventy-seven of three hundred patients with ISSNHL (26%) were prescribed “to rest”
or “to stay home on sick leave” for up to four weeks; this was the only treatment for
twenty-two of these patients. Patients who had been prescribed rest or been on sick
38
Results
leave during the first period of the disease had higher odds for hearing improvement
(OR 0.46, 95% CI 0.27 – 0.79, p=0.005), regardless of any other treatment.
40% of the patients had their hearing loss in the low frequency region, 28% in the mid
frequency region, 23% in the high frequency region and 9% had a “flat loss”. Patients
with hearing loss in the mid frequency region had significantly higher odds for hearing
improvement compared to those in the groups with a hearing loss in the low frequency
region, the high frequency region or a “flat loss”.
The odds for a residual hearing loss was lower for patients with hearing loss in the mid
frequency region when compared to those with a hearing loss in the low frequency
region (OR 0.45, 95% CI 0.26 – 0.78, p=0.005), the high frequency region (OR 0.31,
95% CI 0.16 – 0.58, p=0.000), or a “flat loss” (OR 0.43, 95% CI 0.18 – 1.01, p=0.05).
All variables in the questionnaire were analyzed using ordinal/ordered logistic
regression looking for interactions with hearing recovery and remaining hearing loss
as dependent variables. Three factors were significantly related to outcome
independent of treatment or no therapy, namely “Heredity for hearing loss”, age, and
presence of vertigo at onset; for details see Table VIII.
Table VIII. Outcome measures after ISSNHL with respect to hearing improvement and
remaining hearing loss using ordinal logistic regression (n=300).
Hearing improvement
Variable
Remaining hearing loss
OR
95% CI
p-value
OR
95% CI
p-value
Increase of age
1.03
1.01 – 1.05
0.000
0.98
0.96 – 0.99
0.001
Vertigo at onset
1.77
1.06 – 2.95
0.03
0.40
0.24 – 0.67
0.000
Heredity for hearing loss
2.08
1.10 – 3.94
0.02
ns
ns
ns
Prescribed to rest
0.46
0.27 – 0.79
0.005
ns
ns
ns
OR=Odds Ratio, CI= Confidential Interval
39
Results
Paper III
The aim of Paper III was to compare treatment with corticosteroids (Prednisolone)
used in high tapering dosage to treatment with placebo with respect to influence on the
outcome of ISSNHL.
Ninety-three patients were analyzed by modified ITT; forty-seven received
Prednisolone and forty-six placebo (Fig. III). Audiograms were missing for four of
them at final follow-up. Those missing were not included in the analysis—two had
gotten Prednisolone. The baseline characteristics data and hearing improvement of
ninety-three patients included in the modified ITT analyses are described in Table IX.
Of the ninety-three patients in modified ITT analysis, fifty had one or more laboratory
tests taken. One or more pathological findings were discovered in seventeen of twentysix patients with laboratory work-up in the Prednisolone group compared with nine of
twenty-four in the placebo group. Almost all of the patients with abnormal findings
had “inflammations markers”.
MRI or CT was done on forty patients in modified ITT analysis. Abnormal findings
were seen in thirteen of twenty-two patients with MRI or CT in the Prednisolone group
compared with ten of eighteen in the placebo group. The majority of the findings were
different vascular abnormalities. Acoustic neuroma was found in one patient.
Table IX. Baseline characteristics and hearing improvement of 93 patients included in a
modified Intention-To Treat analysis.
Prednisolone
Placebo
p-value
Variables
(n=47)
(n=46)
Gender
Female
Male
Age
Mean ± SD (years)
Range (years)
Affected ear
Left
Right
Initial pure tone
Mean ± SD
average for the affected Range
frequencies (dB HL)
Mean ± SD
Improvement at day
eight (dB)
Range
23
24
17
29
0.297
56.8 ± 12.7
26 - 80
53.8 ± 13.5
26 - 79
0.281
25
22
22
24
0.680
66.2 ± 21.2
32 – 110
63.5 ± 16.9
32 – 100
0.507
25.5 ± 27.1
-40 to +87
26.4 ± 26.2
-32 to +75
39 ± 20.1
-5 to +87
35.1 ± 38.3
-17 to +84
Improvement at day
ninety (dB)
Mean ± SD
Range
Affected frequency
regions
Low frequency region
Mid frequency region
High frequency region
“Flat” loss
14
22
10
1
13
24
6
3
0.573
Prevalence of
associated symptoms
Tinnitus
Vertigo
No associated symptoms
30
11
10
38
14
6
0.061
0.490
0.411
3 ± 1.9
3
0-7
3,2 ± 2.3
2
0-7
0.660
Time from onset of
SSNHL to the first at
the ENT clinics
Mean ± SD
Median
Range
40
Results
Effect of treatment at the first and final follow-up (day eight and ninety)
No significant difference of hearing recovery was observed either at day eight or day
90 between the Prednisolone group and placebo group regarding the effect of
treatment.
The estimated treatment efficacy at the first follow-up was –3.1 dB (p=0.563) and
–0.83 dB (p=0.887) at day 90 for the ninety-three patients in modified ITT analysis.
(See Table X)
For PP analysis, the estimated treatment efficacy at the first follow-up was –2.48 dB
(p=0.662) and for the total PP analysis –2.91 dB (p=0.675), meaning those patients
receiving Prednisolone recovered insignificantly less than the placebo group.
The estimated treatment efficacy at the final follow-up for PP analysis was –0.18 dB
(p=0.976) and for the total PP analysis –0.06 dB (p=0.994).
Total recovery occurred in twenty patients after eight days of medication with the
study drugs, eleven of those had received Prednisolone (ns). At the final follow-up
total recovery had been reached for thirty-nine patients, nineteen of those had received
Prednisolone (ns). These thirty-nine patients with total recovery at the final follow-up
had a mean hearing loss of 60.5 dB ± 17.4. Thirteen of them had a hearing loss
<50 dB HL, six treated with Prednisolone and seven placebo. The range of the hearing
loss for the remaining twenty-six patients was 52–90 dB HL.
Table X. Prognostic factors at the first and final follow-up (day eight) on 93 patients in modified Intention-To Treat analysis.
Final follow-up
First follow-up
Coef.
SE Coef
P-value
P-value
Coef.
SE Coef
Predictor
Constant
46.80
21.47
Treatment
-3.114
5.361
0.563*
-0.827
5.807
0.887*
Age
-0.256
0.189
0.180
-0.346
0.203
0.093
Heredity for hearing loss
10.287
6.013
0.091
8.700
6.397
0.178
Vertigo
-15.706
5.749
0.008
-18.526
6.252
0.004
Tinnitus
4.233
5.788
0.467
-1.764
6.163
0.776
Time from onset of SSNHL to the first at the ENT
clinics
0.350
1.218
0.775
1.509
1.326
0.259
Prescribed rest or sick leave
0.166
6.565
0.980
-3.367
7.414
Frequency regions
Abnormal findings of radiological investigations
Abnormal findings of laboratory work-ups
39.22
25.76
0.262 !
-22.462
6.148
0.000
15.178
5.628
0.009
0.651
0.524 !
ns
14.424
* A single-sided null-hypothesis, that there is less than 10 dB difference of treatment efficacy between the Prednisolon and placebo group was used.
! p-value refers to the partial F-test where null hypothesis is that there is no difference between regions.
5.928
0.018
Results
41
Predictive factors at the first and final follow-up (day eight and ninety)
At the first follow-up, three factors were significantly related to outcome regardless of
treatment:
The effect of vertigo was –15.7 dB (p=0.008) in the modified ITT analysis, –13.7 dB
(p=0.032) in the PP analysis and –14.5 dB (p=0.041) in the total PP analysis.
Abnormal radiological findings had an effect of –22.5 dB (p=0.000) in the modified
ITT analysis, –24.3 dB (p=0.001) in the PP analysis and –29.7 dB (p=0.001) in the
total PP analysis.
The effect of abnormal laboratory findings was +15.2 dB (p=0.009) in the modified
ITT analysis, +16.4 dB (p=0.008) in the PP analysis and +17.3 dB (p=0.031) in the
total PP analysis.
At the final follow-up, modified ITT analysis and PP analysis showed slightly different
prognostic factors for recovery than at the first follow-up, eight days after the
treatment:
The effect of vertigo was –18.5 dB (p=0.004) in the modified ITT and –20.0 dB
(p=0.003) in the PP analysis.
The baseline PTA for the affected frequencies had an effect of +0.4 dB (p=0.014) for
in the modified ITT analysis and +0.4 dB (p=0.025) in the PP analysis. Thus after
90 days, the mean hearing gain was 40% of the initial hearing loss.
The effect abnormal findings of laboratory work-up was +14.4 dB (p=0.018) in the
modified ITT analysis and +15.4 dB (p=0.016) in the PP analysis.
Total PP analysis of seventy-three patients who did take the study drug according to
the protocol showed that the only factor affecting the outcome was presence of vertigo.
The ability to recover dropped with 20.5 dB (p=0.007) for patients with vertigo.
42
Results
Paper IV
The aim of Paper IV was to analyze a larger patient group by meta-analysis of data
from the RCT together with corresponding material drawn from the Swedish national
database for ISSNHL.
A total of one hundred ninety-two patients had been treated according to inclusion,
eighty-seven from the RCT (III) and one hundred and five from the Swedish national
database (II). At final follow-up audiogram was missing for five patients. Ninety-six of
the total one hundred eighty-seven had received Prednisolone, forty-two placebo and
forty-nine no treatment.
Baseline characteristics data for all groups are described in Table XI.
No significant difference in hearing recovery was observed regarding the effect of
treatment between the total Prednisolone group and Placebo group plus the control
group without treatment.
The estimated treatment efficacy was 6.10 dB (p=0.06), meaning that patients
receiving Prednisolone recovered more than the placebo/no treatment group, but not
significantly so.
The recovery with respect to frequency region that was affected by the hearing loss is
presented in Table XII.
Analyzing all patients together, three variables were significantly related to outcome
regardless of treatment: age at initial contact, presence of vertigo at the onset of
hearing loss and abnormal findings of laboratory work-ups.
Age and presence of vertigo at the onset of ISSNHL was associated with less hearing
improvement. The effect of age was –0.35 dB (p=0.003) which means that hearing
improvement was less with increasing age of the patient (0.35 dB per year). The effect
of vertigo was –15.2 dB (p<0.001).
“Abnormal laboratory findings” at the onset of the disease were associated with better
prognosis for hearing improvement. “Abnormal laboratory findings” effect on hearing
improvement was +11.0 dB (p=0.009). Most of these findings were signs of
inflammation/infection.
Comparison between the placebo group and the control group (no medical
treatment)
No significant difference in hearing recovery was observed between the placebo group
and control group without treatment. The estimated placebo efficacy was 5.90 dB
(p=0.208), meaning that patients receiving placebo recovered not significantly more
than those not medically treated.
Results
43
Discussion
45
DISCUSSION
Sudden sensorineural hearing loss is one of the most mysterious and controversial
unsolved entities in otolaryngology. The lack of a standard definition for SSNHL, the
low incidence and the fact that some spontaneous recovery occurs in up to 80% of
cases, make any evaluation of treatment impossible for those ENT doctors who only
see a few patients a year.
The criteria for SSNHL and for the assessment of hearing recovery were developed by
the Sudden Deafness Research Committee of the Ministry of Health and Welfare in
Japan (1973 and 1981, respectively). However, no specific instruction with regard to
how sudden the onset of hearing loss should be, the degree of hearing loss or the
affected frequencies were actually provided. Although many authors have selected a
hearing loss of 30 dB HL in three contiguous frequencies for their studies1-5, the onset
of hearing loss differs from 24 to 72 hours2,6,7. In the studies for this thesis (I–IV),
hearing loss over a period of 24 hours was selected in order to stress the concept of
“sudden” hearing loss and to avoid including patients with Mb Ménière or
endolymphatic hydrops, where the hearing loss usually develops within a few days.
The seemingly low prevalence of ISSNHL in Sweden seen in the present thesis is far
below 5–20 per 100.000 per year presented earlier13. However, in one ENT clinic in
the countryside to which all patients in the region were referred, the prevalence was
estimated to be 8 per 100.000 per year. In city regions, where many patients were
treated in private practice, selection made it impossible to estimate
prevalence/incidence. The number of patients to treat for ISSNHL seemed to decline
over the study period, which could be observed at all fourteen contributing clinics
(III). This may be due to decreasing interest for the study (III). No other reason is
evident for a real decrease of incidence. In Japan, an epidemiological study for the last
30 years showed the opposite: an increasing prevalence of ISSNHL14.
One reason not to be included in the trial was doctor and patient bias. A prerequisite to
perform a RCT is to be unbiased. Many of the ENT doctors treating at the contributing
clinics had already formed opinions about the effect of corticosteroids and therefore
had difficulties in answering patients’ common question: ”How would you treat it if
you got this disease, Doc?” This made it difficult for them to recruit patients to the
study. Patients today have often studied Internet even before the first visit and already
formed a clear opinion about which treatment they wanted; a common reason for
patients to refuse to participate was that they wanted corticosteroids.
Radiological and laboratory examination
An acute hearing loss can be a symptom that can be caused by a multitude of known
diseases within the vascular system or by different traumas and tumors within the
hearing tracts38,42,43,62,63. In most cases of SSNHL, it will not be possible to arrive at a
specific diagnosis. However, the assessments of these possible mechanisms should still
46
Discussion
be performed in order to find the approximately 10% of cases for which one can arrive
at an identifiable, and hopefully treatable, diagnosis37.
Radiological examination
Only around 40% of the patients had had an MRI or CT. The discovery of only 1.6%
to 3.2% acoustic neuromas among these patients (I–III) was a low number when
compared to other studies on sudden sensorineural hearing loss27,102,103.
In the RCT (III), only one patient with acoustic neuroma was discovered and that
patient was treated with Prednisolone and improved. It might be expected that an
acoustic neuroma would react to corticosteroids, thereby improving hearing when the
tumor diminished or ceased pressing upon the blood vessels that feed the cochlea, as
had been discussed in earlier works104.
Since hearing improvement was possible for almost all of the patients with tumors
prior to their final diagnosis, a radiological examination of all patients with ISSNHL
would be valuable in order to identify treatable acoustic neuromas.
Very often different vascular abnormalities or sign of ischemic vascular disease were
found by MRI (I–III) irrespective of age. Most of these patients had a hearing loss in
the low or mid frequency regions. The hearing loss could therefore theoretically be due
to similar disease of blood vessels feeding the damage part of the cochlea.
Unfortunately, these potential occlusions cannot at present be visualized
radiologically. These patients might have benefited if given any specific treatment that
was associated with their vascular abnormality.
The MRI examination in SSNHL is most often performed several weeks after the first
visit to the ENT clinic, which makes it difficult for the physician to take the findings
into consideration while deciding the acute treatment for the hearing loss. If the
SSNHL of some patients were due to vascular accidents, the CT or MRI should be
performed immediately in order for these tests to be of any value for the patients. This
situation is quite similar to cases in which the best treatment of stroke and heart
infarction occurs when patients are examined as soon as possible.
Laboratory examinations
When a test battery is used in SSNHL as part of a blood laboratory examination, the
results are not always easy to evaluate. Pathological tests may not necessarily be
specific for the patient's hearing disorder. Even if the tests are specific, at least two
tests within weeks of each other are often needed. For example, to see the rising titers
of Borrelia antibodies in order to determine whether an infection is ongoing or has
already past.
In study II, serological Borrelia analyses were most often done, with 11% yielding
pathological findings. This is in accordance with earlier studies in which both serum
and CSF analysis had been performed105. A third of the patients with increased
Borrelia titers were primarily treated with antibiotics, but the effect on hearing
outcome were not related to the treatment. This is in agreement with earlier studies
with respect to ISSNHL106 and is similar to the use of antibiotics for the treatment of
Discussion
47
patients with facial palsy and high Borrelia titers. Since neuroborreliosis is a severe
chronic disease that should be treated even if antibiotics do not specifically cure the
hearing loss, high titers at the onset would at least justify a second test to be taken in
order to verify or substantiate an ongoing infection so that treatment could be
commenced or modified. However, very few additional tests had been taken in the
present material.
Patients with pathological results of laboratory tests were categorized into
“arteriosclerotic causes”, “inflammatory/infectious causes” or “autoimmune causes” to
see whether one group or another had different outcomes or had received different
treatment. The results from study II demonstrated that there was no difference in
medical treatment policy among these different categories. The only alternatives were
corticosteroids or nothing, and there was no difference in the outcomes between these
two options. However, in study II in the atherosclerosis group, where a rheological
treatment might theoretically have been appropriate, potential differences may be
hidden by the fact that only a small fraction of the patients had their total cholesterol
and LDL/HDL ratio evaluated. The association between increased CRP levels and
atherosclerosis is obscured by other acute inflammatory reactions and also by the lack
of standardized time intervals between the onset of SSNHL and the blood sampling.
These circumstances may indicate that ordinary CRP is not the ideal marker for
atherosclerosis in this setting. At least high sensitive CRP is needed in cases where no
acute infection is ongoing.
The introduction of corticosteroids for Sudden Deafness during the 70’s was based on
the hypothesis that it would relieve unknown infections/inflammations. However,
neither proven presence of herpes virus or positive Borrelia findings concomitant with
ISSNHL have shown to yield better outcome after treatment with corticosteroids83,106.
It is interesting that patients in the RCT (III) with “inflammatory sign” had a better
prognosis for hearing improvement, independently of Prednisolone or placebo
treatment. This finding requires further research and can also be a reason for apparent
effects of steroids in other non-RCT studies8,22,107.
Treatment
The treatment of idiopathic sudden sensorineural hearing loss has always been based
on one or another underlying hypothesis of the etiology. The vascular theory was the
basis for anti-stress treatment, consisting of bed rest and blockage of ganglion
stellatum, used primarily during the 1950’s20, and for treatment with dextran 40 and
other hyperosmolar hemodilutive drugs during the 1970’s21. The
inflammation/infection theory was the basis for the use of the anti-inflammatory
properties of corticosteroids, which has been a treatment since the 1980’s2. More
recently, the autoimmune theory108 became the basis for an increased dosage of
steroids and additional cytostatic therapy109.
Only 57% of the patients with ISSNHL in study I and 61% of the patients with
ISSNHL in Paper II had received any type of drug therapy with the aim of influencing
the outcome. Eighty-nine percent (Paper I) and ninety-one percent (Paper II) of those
who were medically treated received corticosteroids, even if the underlying etiology
was unknown. The observed outcomes are in accordance with the conclusions from
48
Discussion
the Cochrane reports24,25, that the individuals who had received corticosteroids had the
same odds for recovery as those who did not receive any drugs. The only randomized
double-blinded placebo-controlled study where a positive effect of corticosteroids
have been proposed, actually had too few patients to allow for drawing such a
conclusion2.
Corticosteroids did not influence outcome in the few patients with positive
autoimmune signs in the present thesis (II, III), although an effect on those might have
been expected110. One explanation could be that too low dosage of corticosteroids for
that purpose and no cytostatic drugs were given.
A recent study by Aoki et al., reported that a very high dosage of corticosteroids seems
to give a significantly better recovery rate in patients with ISSNHL at completion of
treatment, but not two months after treatment22. However, this study did not use a
control group without medical treatment. In the present RCT (III) 42% recovered
completely after three months equally in the Prednisolone and the placebo group.
Surprisingly enough, the 26% of patients who had been prescribed to rest had better
odds for recovery (II). Earlier, bed rest and sick leave were standard treatment for
ISSNHL patients, but this has become very uncommon nowadays. No research seems
to have been performed with regard to that specific treatment modality. It is quite
possible that all individuals who are afflicted by ISSNHL would experience some gain
from rest—especially those individuals who in their questionnaire had reported recent
stress before the onset of the disease.
Site of damage in relation to treatment
Many authors are convinced that several different diseases can cause the symptom of
hearing loss and might be included in the diagnosis ISSNHL. That can be a reason
why no single treatment has given clear evidence of effect111. In Germany, an expert
group has suggested that different shapes of the audiogram can tell about where in the
cochlea the damage is and maybe explain the pathogenesis112: A low frequency loss
might regarded as a sign of hydrops, a mid-frequency loss as a sign of vascular
interference, a high frequency hearing loss of up to 40 dB HL should be a possible
dysfunction of outer hair cells and a hearing loss of more than 40 dB HL as a
dysfunction/damage also to the inner hair cells. A flat loss can be considered as an
interference with the vascular stria giving an acute hearing loss due to a preceding
acute ionic balance disturbance. It would be of utmost interest to see if different
treatment policies will develop according to this hypothesis, as thus far only
Corticosteroids and or rheological treatment are suggested112. This theoretical
approach has as its weakness that it does not fit with experience from clinical praxis
and the present study (III) that all types of audiograms seems to have a chance of
spontaneous recovery and that recovery can either go as quickly as the hearing loss
came or more slowly within a couple of months.
Prognostic factors
Prognostic factors for ISSNHL have been studied by many authors. The findings
which demonstrate that the presence of vertigo (II, III, IV) and a higher age (I, II, IV)
Discussion
49
at onset are related to a reduced probability for recovery, are also in accordance with
earlier studies2,54,113,114. The fact that, a higher age is related to lower probability for
recovery may be because older patients in general have more difficulty in recovering
from illnesses. More widespread involvement of the disease in the inner ear could
explain the reduced odds for recovery when ISSNHL is in combination with vertigo.
The presence of tinnitus has been considered to be a positive prognostic factor for
hearing recovery by Cvorović et al., 2008114, but, in the studies of this thesis (I–IV), no
such connection was found. However, “heredity for hearing loss” or a close relative
who was affected by hearing loss as a prognostic factor for SSNHL does not seem to
have been previously discussed. In fact, the only study100 discussing positive family
history of ISSNHL was published 2010. Gäckler et al., reported that 21.4% of
ISSNHL patients had one or more family members affected by ISSNHL. ISSNHL
patients with a positive family history were younger, had experienced more events of
ISSNHL and had poorer hearing improvement under therapeutic treatment100. In the
Papers (I, II) based on the Swedish national database, heredity was clearly related to a
decreased probability of improvement. This might suggest that in some cases, the
ISSNHL is the first sign of a hereditary, progressive hearing loss. However, in the
present thesis the final follow-up was after only three months, thus it is not possible to
evaluate a possible further progression.
Audiometry
Comparing results from studies based on audiometric pattern is difficult since different
classifications are used. One hypothesis about variation in recovery is that different
types of hair cells are involved: If only the outer hair cells are damaged, a central
adaptation might be possible so the remaining, undamaged outer hair cells can
reorganize the cortical pattern and in that way restore hearing115. If however, the inner
hair cells are involved, it is more difficult to visualize reorganization since their
number in the cochlea is so limited and they are strictly tonotropically arranged both in
the cochlea and all along the central pathways.
The weakness of this theoretical approach regarding the site of damage and the
possibility of recovery is that it does not fit with the clinical observation that patients
with all types of audiograms seem to have a chance to a spontaneous recovery of
varying degrees—or that a hearing improvement can come about as quickly as the
onset of the hearing loss. A more slowly developing recovery over a couple of months
would better fit the theory regarding reorganization115.
The results that patients with an hearing loss in the mid frequency region had the best
recovery rate (II) has been reported earlier in several studies2,6,54 and can be explained
on the basis of a vascular theory for ISSNHL. In the cases when two arteries are
supplying the cochlea, one would theoretically expect a hearing loss in the lower and
mid frequency region with a chance of recovery through collaterals from the second
main artery116. The presence of a second main artery occurs in about 50% of the
cases117. The same reasoning can be adapted to the patients in the present thesis (II)
with vascular aberrations who had none or moderate improvement. They may have
had occlusion of the main auditory artery, but with no collateral supply from a second
artery116.
50
Discussion
Suggestion for further research
Whenever a drug or a substance is proven not to work for a specific condition, it
should be withdrawn from use and the focus for research within the field turned in a
new direction.
Further follow-ups of the patients included in the RCT are urgently needed to clarify
different prognostic patterns.
ISSNHL is probably a symptom of several different disorders. If so, a comprehensive
test battery would be developed to identify underlying diseases for a more adequate
treatment. In such test battery, genetic examination should also be included if the case
history reveals other relatives with same disease.
Further studies concerning chronic and acute stress are also indicated. This stress
studies should include both qualitative research and laboratory examinations.
Conclusions
51
CONCLUSIONS
The following general conclusions can be drawn from the present thesis:
 Regardless of diagnostic protocol, treatment of ISSNHL in Sweden is mainly
limited to corticosteroids (50%) or to no medical treatment.
 Presence of vertigo at the onset of SSNHL is negative prognostically for
hearing recovery independently of treatment.
 Higher age is negative prognostically for hearing recovery independent of
treatment.
 In a randomized placebo-controlled clinical trial no positive effect of
Prednisolone on ISSNHL could be demonstrated.
 A Meta-analysis of patient data from the Swedish national database for SSNHL
and the RCT for ISSNHL demonstrated no effect of Prednisolone on ISSNHL.
Acknowledgments
53
ACKNOWLEDGMENTS
A number of people have contributed, inspired and helped me in preparing this thesis.
I wish to express my sincere gratitude to all of you. I especially want to thank:
Professor emerita Elisabeth Hultcrantz, my main supervisor, for sharing her vast
knowledge in “Sudden Deafness”, guidance in the scientific world, and above all for
providing ideas, excellent teaching, enthusiasm and encouragement. Thank you for
always having time to give advice and support wherever you have been at the moment.
Professor Torbjörn Ledin, my co-supervisor, for clarifying statistical terms for me and
for valuable advice and support.
Professor emeritus Stig Arlinger, my co-supervisor, for sharing his endless knowledge
in audiology, skillful editing and answering my questions so quickly.
Magnus Hansson, my co-author, at the department of Clinical Chemistry of
Karolinska University Hospital, for valuable comments and help with clarification of
laboratory tests.
Ed Paulette, for linguistic guidance and careful editing. For having the time and
patirnce to discuss details.
Olle Eriksson and Karl Wahlin, at the department of Computer and Information
Science, division of Statistics, for help with statistical counseling. In particular, I
would like to express my gratitude to Olle for having patience and answering my
“odd” questions. For his kindness to always make and have time for me.
Magnus Johansson, for help with system development of the database.
All staff at the ENT clinics and Audiological clinics in the hospitals of Bollnäs,
Bäckefors, Enköping, Eskilstuna, Fagersta, Gällivare, Gävle, Helsingborg, Huddinge,
Hudiksvall, Jönköping, Kalmar, Karlskrona, Karlstad, Katrineholm, Kristianstad,
Köping, Lindesberg, Linköping, Lund, Lundby, Malmö, Mora, Mölndal, Norrköping,
Sala, Skövde, Stockholm, Strömstad, Sundsvall, Södertälje, Trollhättan, Uddevalla,
Umeå, Uppsala, Visby, Värnamo, Västerås, Ängelholm, Örebro, Örnsköldsvik and
Östersund, for contributing to the Swedish national database and the RCT.
Susan Barclay Öhman, (The Barclay Consultancy AB) for professional assistance
with structuring of the study.
Anette Lagergren, at the Audiological clinic of Linköping University Hospital, for
support and good help in providing me time for my scientific work.
Gunilla Hydén, Torsten Pettersson, Joakim Blomgren and Lars Andersson, at the
ENT clinic, the Audiological clinic of Linköping University Hospital and the division
of Speech, Language Pathology of Linköping University, for always patiently
answering my computer related questions.
My colleagues, at the Audiological clinic of Linköping University Hospital, Motala
Hospital, the division of Technical Audiology and the division of Speech, Language
Pathology of Linköping University, for providing a nice and friendly working
environment and for the very entertaining coffee break discussions.
54
Acknowledgments
My friends Pia Granath, for letting me chill out in her office between the hard work
and for patiently listening to me babbling about anything possible. I am grateful for
your never-ending support and friendship. Linda Lindström and Elisabeth Ericsson,
for all help and support. Dinners with you have been perfect breaks from work and
have helped me to think of other things than “Sudden Deafness”.
My mother Pari, my late father Qasem and my brothers Ramin and Ramtin for love,
support and for believing in me.
Finally, I have many reasons to be grateful to my beloved husband Reza and our
wonderful children Alma and Arvid.
Reza, for your love, support and patience. You are everything I have ever wished for
with your kindness, concern and selflessness. Alma and Arvid, for being who you are
and bringing me down to the earth again when I feel lost in the mist.
Financial support has gratefully been received from Medical Research Council of
Southeast Sweden (FORSS), the Country Council of South East Sweden, Linköping
University, StingerFonden, Stiftelsen Tysta Skolan and Gunnar Arnbrinks Stifte
Svensk sammanfattning
55
SVENSK SAMMANFATTNING
Idiopatisk Plötslig Sensorineural Hörselnedsättning
Diagnostiskt protokoll och kortikosteroidbehandling i relation till resultat
Bakgrund
Idiopatisk Plötslig Sensorineural Hörselnedsättning (IPSH) är en av de gåtfulla
sjukdomar vilka drabbar innerörat och nerverna som passerar den inre hörselkanalen.
Oavsett behandling återkommer hörseln fullständigt hos ungefär en tredjedel av
patienterna och delvis hos en tredjedel, medan resten får kvarstående betydande
hörselnedsättning ofta i kombination med tinnitus eller obehag av ökad ljudkänslighet.
Sjukdomen har tidigare beräknats drabba 5 – 20 per 100 000 invånare årligen men
incidensen är osäker, då det är svårt att veta hur många som insjuknat pga. högt
spontant tillfrisknande innan något läkarbesök har skett.
Orsaken till sjukdomen är okänd. Detta har lett till att patienter både i Sverige och
globalt genom åren har fått olika behandlingar beroende på vilken hypotes om
sjukdomens orsak läkarna har stött sig på:
Infektionsteorin: Redan 1907 rapporterade Hunt att Herpes zoster kan orsaka plötslig
hörselnedsättning. Andra bakteriella sjukdomar såsom Borrelia och syfilis, och virala
som påssjuka och röda hund är också kända orsaker till plötslig hörselnedsättning. Om
man antar att alla fall av IPSH har denna genes använder man sig av antibiotika eller
antivirala läkemedel, (acyklovir och valacyclovir). De fyra hitintills publicerade
randomiserade, placebo-kontrollerade kliniska studier med acyklovir och valacyclovir
visar emellertid inte någon signifikant effekt av den behandlingen.
Immunologisk teori: McCabe (1979) var först med att föreslå autoimmunitet som
orsak till plötslig hörselnedsättning. Han baserade sin hypotes på kliniska data,
patologiska fynd vid autoimmunologiska tester och förbättrad hörsel av kortikosteroid
terapi. Hörselnedsättningen kan vara en följd av lokala autoimmuna processer som
bryter ned enbart vävnaden i innerörat eller en systemisk autoimmun sjukdom som
t.ex. Cogans syndrom, Wegeners sjukdom och systemisk lupus erythematosus (SLE).
Behandling av IPSH med kortikosteroider är baserat på denna immunologiska teori.
Sedan man började behandla IPSH med kortikosteroider på 1980-talet har det gjorts
många studier om deras effekt, men de enda två som varit randomiserade dubbelblinda
placebokontrollerade från 1980 och 2001 har visat motsägande resultat och haft låg
”power”.
Fistelteorin: Rupturer antingen inom snäckan med jonrubbningar som följd och orsak
till hörselnedsättning, eller av membranen i runda eller ovala fönstret med ett
resulterande perilymfaläckage som symptomorsak är en teori om IPSH. Rupturen
anses inte ske spontant utan uppträder efter plötslig tryckändring i mellanörat i
samband med huvudskador, barotrauma eller intensiv fysisk aktivitet. Kirurgi med
tätning av misstänkta hål i runda fönstermembranet i kombination med ordination av
strikt sängläge är en behandlingsmetod, men inte heller här är man ense om nyttan av
denna terapi.
56
Svensk sammanfattning
Blodkärlteorin: Ett minskat blodflöde i den ändartär som försörjer örat skulle kunna
orsaka plötslig hörselnedsättning. Sjukdomar i blodkärl eller hematologiska åkommor
förknippade med plötslig hörselnedsättning har också rapporterats såsom vid Buergers
sjukdom, leukemi och sickelcellsanemi. Vid IPSH har olika behandlingar såsom
extrakorporeal defibrinogering, Rheomacrodex® och andra hyperosmolara
blodförtunningsmedel använts baserat på denna teori. Det finns vetenskapligt stöd
både för och mot sådan terapi.
På grund av den låga incidensen, det spontana tillfrisknandet i vissa fall och
möjligheter av mer än en orsak till sjukdomen är effekten av behandling av IPSH alltid
svår att bedöma på en enskild klinik där man endast ser ett mindre antal patienter per
år. Genom att samla data från ett stort antal patienter finns möjlighet att identifiera
prognostiska faktorer och olika behandlingar för IPSH i Sverige. Den vanligaste
behandlingen för IPSH kan sedan att jämföras med placebo för att utvärdera av
effekten av behandlingen gällande hörselförbättring.
Syfte
Syftet med denna avhandling var att kartlägga vilken utredning och behandling
patienter med IPSH får i Sverige och sedan utvärdera effekten av den vanligaste
behandlingen vad gäller hörseltillfrisknande i jämförelse med placeboterapi.
Studie I
 Att kartlägga behandlingspolicyn för IPSH i Sverige.
 Att utvärdera behandlingseffekten av terapi med avseende på
hörseltillfrisknande.
 Att kartlägga vilka variabler såsom ålder, tinnitus, yrsel, tidigare sjukdomar och
hörselkurvornas utseende har prognostisk värde vid insjuknandet i IPSH.
Studie II
 Att undersöka vilka olika diagnostiska testbatterier för IPSH som för
närvarande används i Sverige.
 Att utvärdera om patologiska diagnostiska fynd leder till
behandlingsmodifikationer och i så fall hur.
 Att undersöka om behandlingsmodifikationer påverkar tillfrisknandet.
Studie III
 Att utvärdera effekten av kortikosteroider (Prednisolon) i hög nedtrappningsdos
vid behandling av IPSH i jämförelse med placebo.
Studie IV
 Att med metaanalys utvärdera effekten av kortikosteroider (Prednisolon) i
nedtrappningsdos vid behandling av IPSH i jämförelse med placebo eller ingen
Svensk sammanfattning
57
behandling alls. Med ett större antal patienter får man högre säkerhet av sina
resultat.
Metod
De två första publikationerna (I, II) i denna avhandling är baserade på data från en
nationell databas i Sverige för plötslig sensorineural hörselnedsättning.
Den nationella databasen om plötslig sensorineural hörselnedsättning startades sent
2002 i Linköping.
Ett frågeformulär hade tagits fram som fylldes i av den först konsulterade öronläkaren,
när patienten sökte för sin hörselnedsättninh. Frågorna berörde patientens tidigare
sjukdomar, trauma, tinnitus, yrsel, ärftlighet för olika sjukdomar särskilt
hörselnedsättning samt viken utredning och behandling som planerades/gavs av den
aktuella plötsliga hörselnedsättningen. Två audiogram, ett taget vid insjuknandet och
ett vid kontroll efter tre månader skickades tillsammans med frågeformuläret till
databasen. Se appendix.
För bedömning av hörselnedsättningen jämfördes det initiala audiogrammet med ett
audiogram taget innan den akuta hörselnedsättningen. För att kategorisera
nedsättningarna definierades fyra frekvensområden: basområdet: skillnad i
hörtröskelmedelvärde vid 125-250-500 Hz, mellanregistret vid 1000-1500-2000 Hz,
diskantområdet vid 3000-4000-6000 Hz och ”flat loss” om skillnaderna i försämring
mellan de tre frekvensbanden var mindre än 10 dB HL.
I studie II kategoriserades patologiska laboratoriefynd (blodprov) på följande sätt:
 “Arteriosklerosassocierade variabler”: LDL-kolesterol/HDL-kolesterol >3,
Totalkolesterol >5 mmol/L och C-reaktivt protein (CRP) >3 mg/L hos patienter
med eller utan tidigare hjärt-kärl sjukdomar.
 “Inflammation/infektionassocierade variabler”: CRP >10 mg/L,
”Sänka” >20 mm, Vita blodkroppar >10 x 109ml/L, Hemoglobinhalt <120 g/L,
Trombocytantal >150 x 109ml/L och Borrelia test “positiv” (IgG antikroppar
och IgM antikroppar) hos patienter med eller utan kliniska tecken på infektion.
 “Autoimmuna variabler”: förekomst av patologiska värden av HSP-70,
Kardiolipin, Antifosfolipid, Antineutrofila cytoplasmiska antikroppar (ANCA)
och Antinukleära antikroppar (ANA) “positiv”.
Studie III
En randomiserad trippel-blind, placebo-kontrollerad multicenterstudie om effekten av
kortikosteroid på IPSH genomfördes mellan januari 2006 och september 2010. Fjorton
ÖNH kliniker i Sverige deltog i studien.
Patienter mellan 18 – 80 år med plötslig påkommande sensorineural hörselnedsättning
inom 24 timmar och utan någon känd etiologi tillfrågades om att ingå i studien.
Hörselnedsättningen skulle vara minst 30 dB HL eller mer i tre närliggande frekvenser
och patienterna skulle ha kommit till ÖNH klinikerna inom 7 dagar från insjuknandet.
Exklusionskriterier var graviditeten, diabetes, kroniska infektioner, magsår,
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okompenserad hjärtsjukdom, nylig operation, eller psykisk sjukdom.
Ett registreringsformulär (CRF) samlades in för varje patient. CRF bestod av en enkät,
audiogram, information om radiologiska undersökningar (MRT eller CT),
laboratorietester, hjärnstamsaudiometri (BRA), enligt de olika klinikernas praxis, och
information om biverkningar. Frågeformuläret var en modifierad version av
frågeformuläret som användes för den svenska databasen för IPSH.
Alla patienter fick skriftlig information om sjukdomen plötslig sensorineural
hörselnedsättning och om syftet med studien samt ett nedtrappningsschema för
medicinen. En engångsdos på 60 mg Prednisolon eller placebo gavs dagligen i tre
dagar, sedan minskats dosen med 10 mg per dag, med en total behandlingsperiod på
åtta dagar. Om total hörselåterhämtningen hade skett, avslutade man behandlingen då,
annars fortsatte medicinering med 10mg dagligen till sammanlagt 30 dagar från
början. Uppföljningsbesök var planerad för dag åtta ± en dag, 1 månad och 3 månader
efter randomisering. Om återhämtning var fullständig på dag åtta, skedde nästa
uppföljning vid 3 månader.
Studie IV
För att höja tillförlitligheten av de resultat som framkommit i studie III, ökades
patientmaterialet med motsvarande data från den svenska databasen för PSH.
Patienter från den svenska nationella databasen som hade fått samma eller likvärdig
behandling som patienterna i RCT valdes. Behandlingen hade varit engångsdos på 60
mg Prednisolon dagligen i tre dagar, sedan minskats dosen med 10 mg/dag, med en
total behandlingstid på minst åtta dagar. Kontrollgruppen från RCT var
placebobehandlade patienter, med audiogram vid start och efter 3 månader.
Kontrollgruppen från den svenska nationella databasen var de som inte hade fått
Prednisolon eller annan specifik behandling, men undersökts med audiogram vid det
första besöket och efter 3 månader.
Material
Studie I
Trehundra patienter med plötslig hörselnedsättning som initialt hade diagnostiserats
som ”Plötslig dövhet/plötslig sensorineural hörselnedsättning” av sina lokala
öronläkare och som inkluderats i den svenska nationella databasen. Av dessa trehundra
patienter hade nittiotvå antingen ledningshinder, Mb Ménière, eller andra kända
inneröre- eller mellanöresjukdomar, eller mindre än 30 dB HL hörselförlust, färre än
tre närliggande frekvenser drabbade eller hade insjuknat under mer är 24 timmar. Se
tabell II.
Studie II
Fyrahundra patienter (300 från studie I samt ytterligare 100) vilka initialt hade
diagnostiserats som ”Plötslig dövhet/plötslig sensorineural hörselnedsättning” och
därför rapporterats till databasen.
Svensk sammanfattning
59
Studie III
Etthundratre patienter med IPSH randomiserades jämnt till behandling med antingen
Prednisolon eller placebo. Tio patienter uteslöts från analyserna, fyra av dem i
behandlingsgruppen och sex i placebogruppen. Se fig. III.
Nittiotre patienter analyserades som modifierad intention-to treat, fyrtiosju fick
Prednisolon och fyrtiosex placebo.
Åttiosju patienter (av nittiotre patienter) som tog studieläkemedlet enligt protokollet
under de första åtta dagarna av behandlingsperioden analyserades som” Per Protokoll”,
45 tillhörde behandlingsgruppen och 42 placebo. Fjorton av dessa åttiosju patienter
skulle antingen ha fortsatt att ta studieläkemedlet upp till 30 dagar eller inte men inte
enligt protokollet.
Sjuttiotre patienter (av nittiotvå tre patienter) som tog studieläkemedlet i enlighet med
protokollet analyserades som ”Totalt per protokoll” (totalt PP), trettioåtta tillhörde
behandlingsgruppen och trettiofem placebo.
Studie IV
Totalt 192 patienter ingick i studien, 87 från RCT om IPSH och 105 från den svenska
nationella databasen för PSH.
Nittionio av de totala 192 hade fått Prednisolon, 42 placebo och femtio ingen
behandling alls.
Varje patients hörsel utvärderades dels vid det första besöket på ÖNH-kliniken och
dels efter tre månader.
Vid den slutliga uppföljningen, saknades audiogram för två patienter i Prednisolon
gruppen (RCT), för en patient i kortikosteroidgruppen (den svenska databasen) och för
två patienter i kontrollgruppen (den svenska nationella databasen).
Resultat
Studie I
Ingen av patienterna i den svenska nationella databasen hade bilateralt PSH. Av 300
patienter som rapporterades till databasen, hade 208 patienter bedömts enligt de
definierade kriterierna att ha IPSH.
Alla 208 patienterna hade genomgått en ÖNH undersökning, 68% hade tagit
blodprover och 37% hade undersökts med MRT. Tiden från debut av IPSH till första
besöket på ÖNH-kliniken varierade med ett medianvärde på 5 (Range 0-212).
Oavsett medicinsk behandling eller ingen behandling alls hade ålder och ”ärftlighet för
hörselnedsättning” signifikant samband med lägre odds för hörselförbättring.
Hörselförlust i mellanregistret hade signifikant bättre möjligheter till hörselförbättring
jämfört med basregister-, och diskantförluster.
Etthundrafem patienter (50%) av de totala 208 patienter hade behandlats med
kortikosteroider och 90 (44%) hade inte fått någon medicinsk behandling. Tre
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Svensk sammanfattning
patienter av de återstående elva patienterna fick antiviral terapi och fem fick
antibiotika.
Det fanns ingen signifikant skillnad i hörseltillfrisknande mellan patienter som hade
behandlats med kortikosteroider och de som inte hade behandlats medicinskt.
Studie II
Av fyrahundra patienter som hade rapporterats till databasen, bedömdes trehundra
patienter lida av IPSH.
Ett hundrafemtioåtta (40%) av de fyra hundra patienterna med PSH hade undersökts
med MRT/ CT, tjugutvå hade patologiska fynd. Tio patienter av de tjugotvå
patienterna med patologiska fynd, hade fynd som inte var kopplat till hörseln och
kunde därför definierades som IPSH. Inget signifikant samband påvisades mellan
patologiska MRT-fynd med vare sig hörselförbättring eller kvarvarande
hörselnedsättning för patienter med IPSH.
Hematologiska test togs i tvåhundra åtta (65%) fall av totalt fyra hundra. Av de tre
hundra patienter som ansågs ha IPSH, hade hundra nittiosex en eller flera tester tagna,
och fyrtiosju (24%) av dessa hade en eller flera patologiska fynd. Det fanns inget
samband mellan någon av laboratorietester med vare sig hörselförbättring eller
kvarvarande hörselnedsättning.
Ett hundraåttiotvå patienter (61%) av 300 med IPSH hade behandlats medicinsk. Av
dessa hade 166 fått kortikosteroider antingen som enda behandling eller i kombination
med antiviral behandling, antibiotika eller blodförtunnande behandling
(acetylsalicylsyra). Den medicinska behandlingen hade ingen signifikant korrelation
med vare sig hörselförbättring eller kvarvarande hörselnedsättning.
Patienter som hade ordinerats vila eller varit sjukskrivna under den första perioden av
sjukdomen hade högre odds för hörselförbättring, oberoende av någon annan
behandling.
Hörselförlust i mellanregistret hade signifikant bättre chans till hörselförbättring
jämfört med basregister och diskant.
Tre faktorer var signifikant relaterade till hörselförbättring oavsett medicinsk
behandling eller ingen behandling, nämligen ålder och ”ärftlighet för
hörselnedsättning" samt förekomst av yrsel vid insjuknandet.
Studie III
Nittiotre patienter analyserades med modifierad ITT, fyrtiosju fick Prednisolon och
fyrtiosex placebo.
Ingen signifikant skillnad av hörselförbättring observerades varken på dag åtta eller
dag 90 mellan Prednisolongruppen och placebogruppen gällande effekten av
behandlingen.
Den beräknade behandlingseffekten vid första uppföljningen var -3,1 dB (p=0,563)
och -0,83 dB (p=0,887) vid dag 90 för de nittiotre patienter i modifierade ITTanalysen. D.v.s. terapin hade inte medfört någon förbättring.
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61
Vid PP-analys uppskattades behandlingseffekten vid första uppföljningen till -2,48 dB
(p=0,662)och för den totala PP analysen -2,91 dB (p=0,675), d.v.s. hörseln i
Prednisolongruppen förbättrades mindre än placebogruppen.
Den beräknade behandlingseffekten på den slutliga uppföljningen för PP-analysen var
-0,18 dB (p=0,976) och för den totala PP-analysen -0,06 dB (p=0,994).
Total hörselförbättring hade uppnåtts för tjugo patienter efter åtta dagar av
medicinering, elva av dem hade fått Prednisolon (ns). Vid den slutliga uppföljningen
hade total återhämtning uppnåtts för trettionio patienter, nitton av dem hade fått
Prednisolon (ns).
De faktorer som hade samband med hörselförbättring oavsett medicinsk behandling
eller ingen behandling var yrsel vid insjuknandet, onormala fynd av MRT och
onormala fynd av lab-prover.
Studie IV
Totalt 192 patienter hade behandlats enligt inklusionskriterierna, åttiosju från den
randomiserade kliniska studien (III) och etthundrafem från den svenska nationella
databasen (II). Vid den slutliga uppföljningen saknades audiogram för fem patienter.
Nittiosex patienter av de totalt hundraåttiosju hade fått Prednisolon, fyrtiotvå placebo
och fyrtionio ingen behandling.
Ingen signifikant skillnad i hörselförbättring kunde påvisas med avseende på
behandlingseffekten mellan Prednisolongruppen och placebogruppen plus
kontrollgruppen utan behandling.
Den uppskattade behandlingseffekten var 6,10 dB, vilket innebär att patienter som fått
Prednisolon återhämtade sig mer än de som fått placebo/ingen behandling, men
skillnaden var inte signifikant.
Vid analys av alla 187 patienterna var oavsett behandling tre variabler signifikant
relaterade till hörselförbättring: ålder, förekomst av yrsel vid insjuknandet av PSH och
onormala fynd av lab-prover. Ålder och yrsel hade en negativ inverkan på
tillfrisknandet medan onormala lab-prover av inflammationstyp visade sig ha en
positiv effekt på slutresultatet.
Diskussion
Plötslig sensorineural hörselnedsättning är en av de gåtfulla sjukdomarna som drabbar
innerörat och nerverna som passerar den inre hörselkanalen.
Den låga incidensen av PSH, bristen på en standard definition för PSH, och det faktum
att spontan återhämtning mer eller mindre kan ske i upp till 80 %, har lett till att
behandlingseffekten varit svårt att bedöma på en enskild klinik, där man endast ser ett
mindre antal patienter per år.
Kriterier för PSH och för bedömningen av hörseltillfrisknande utvecklades av ”the
Sudden Deafness Research Committee of the Ministry of Health and Welfare” i Japan
(1973 resp. 1981). Men graden av hörselnedsättning, berörda frekvenser eller hur
plötslig hörselförlusten bör vara har inte tagits upp. Många författare har valt en
hörselförlust på 30 dB i tre närliggande frekvenser för deras studier men hur plötslig
uppkomsten av hörselförlusten har varit är olika (24-72 timmar). I denna avhandling
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Svensk sammanfattning
(I - IV) har hörselförlust under 24 timmar valts för att betona begreppet "plötslig"
hörselnedsättning och för att undvika att inkludera patienter med Mb Ménière eller
hydrops, där hörselnedsättning utvecklas vanligen inom några dagar.
Den låga prevalensen av PSH i Sverige som setts i denna avhandling är långt under
den tidigare presenterade 5-20 per 100 000 per år. Men för en deltagande ÖNH-klinik i
landet som alla patienter i regionen hade remitterats till, kan prevalensen uppskattas
till 8 per 100 000 per år. Att uppskatta prevalens/incidens i storstadsregionerna där
många patienter behandlats hos privatpraktiker är omöjligt. Antalet patienter att
behandla för IPSH verkade minska under studieperioden, vilket kunde observeras vid
alla fjorton bidragande kliniker (III). Detta kan bero på minskande intresse för studien
(III). Ingen annan orsak är uppenbart för en verklig minskning av incidensen. En
epidemiologisk studie för de senaste 30-åren i Japan visade istället en ökad prevalens
av IPSH.
Ett skäl för att inte bli inkluderad i studien var läkare- och patient ”bias”. En
förutsättning för att utföra en randomiserad klinisk prövning är att vara objektiv.
Många av de ÖNH-läkarna på de bidragande kliniker hade redan åsikter om effekten
av kortikosteroider på PSH och därför hade svårt att svara patienternas vanliga fråga:
"Hur skulle du behandla dig om du själv fick den här sjukdomen?" Det gjorde det svårt
för läkarna att rekrytera patienter till studien. Idag har patienter ofta studerat Internet
innan det första besöket och har redan en klar uppfattning om vilken behandling de vill
ha. En vanlig orsak till att patienter inte ville delta i studien var att de ville ha
kortikosteroidbehandling.
Radiologiska och laboratorieundersökning
En akut hörselförlust kan vara ett symptom som kan orsakas av en mängd kända
sjukdomar inom blodkärlsystemet eller av olika trauman och tumörer. I de flesta fall
av PSH, kommer det inte att vara möjligt att komma fram till en specifik diagnos.
Radiologisk undersökning
Endast 40 % av patienterna hade undersökt med MRT eller CT. Upptäckten av endast
1,6 % - 3,2 % akustikusneurinom bland dessa patienter (I - III) var en låg siffra jämfört
med andra studier om plötslig sensorineural hörselnedsättning.
I den randomiserade kliniska prövningen (III), hade enbart en patient
akustikusneurinom och patienten behandlades med Prednisolon och fick sin hörsel
tillbaka fullständigt. Ett akustikusneurinom kan förväntas reagera på kortikosteroider
och när tumören minskat eller upphört att trycka på blodkärlen som ger näring till
snäckan, kan hörseln förbättras.
En radiologisk undersökning (MRT/CT) av alla patienter med IPSH skulle vara
värdefullt för att identifiera behandlingsbara akustikusneurinom. Alla patienter med
akustikusneurinom i denna avhandling (I-III) hade hunnit få en hörselförbättring innan
MRT/CT undersökningen, som hade gjorts flera veckor efter insjuknandet.
Genom MRT (I-III) upptäcktes ofta olika blodkärlförändringar som möjligen kunde
kopplas till IPSH. De flesta av dessa patienter hade en hörselförlust i basen eller
mellanregistret. Den typen av hörselförlust kan teoretiskt bero på sjukdom i det
blodkärl som försörjer det skadade delen av cochlean. Denna potentiella ocklusion kan
Svensk sammanfattning
63
för närvarande inte visualiseras radiologiskt. Dessa patienter kunde ha haft nytta av en
specifik behandling avsett för blodkärlförändringar.
MRT/CT undersökningar av PSH patienter görs ofta flera veckor efter insjuknande
vilket gör det svårt för läkaren att ta hänsyn till resultaten vid beslut om akut
behandling. Om PSH vid vissa fall beror på blodkärlförändringar, borde MRT/CT
utföras omedelbart för att dessa undersökningar skulle kunna vara av något värde för
patienterna. Denna situation är ganska lik de fall där den bästa behandlingen för stroke
och hjärtinfarkt kan sättas in när patienterna undersöks så snart som möjligt.
Laboratorieundersökningar
Hematologiska prover som tas i PSH fall är inte alltid lätta att utvärdera. Patologiska
undersökningar behöver inte nödvändigtvis vara specifika för patientens
hörselsjukdom. Även om proven är specifika behövs det oftast minst två prover inom
några veckor från varandra. Till exempel, för att se stigande titrar av Borrelia
antikroppar för att avgöra om det är en pågående eller tidigare infektion.
I studie II var serologiska Borreliaanalyser oftast gjort, med 11% patologiska fynd.
Detta är i enlighet med tidigare studier där både serum och CSF analys hade utförts.
En tredjedel av patienterna med ökade Borrelia titrar behandlades främst med
antibiotika, men effekten på hörseln var inte relaterat till behandlingen. Detta stämmer
väl överens med tidigare studier gällande IPSH och liknar även användningen av
antibiotika för behandling av patienter med facialispares och höga Borrelia titrar.
Eftersom neuroborreliosis är en svår kronisk sjukdom som bör behandlas. Även om
antibiotika inte specifikt botar hörselskador, skulle höga titrar motivera ett andra test
för att bekräfta en pågående infektion så att behandling kunde sättas in. I det aktuella
materialet hade dock mycket få andra test tagits.
Patienterna med patologiska fynd av laboratorietester hade kategoriserats i
"arteriosklerosassocierade variabler", " inflammation/infektionassocierade variabler "
eller "autoimmuna variabler" för att se huruvida dessa grupper hade fått olika
behandlingar och om detta påverkat resultatet. Resultaten visade ingen skillnad av den
medicinska behandlingen mellan dessa olika kategorier. Det enda alternativet var
kortikosteroider eller ingenting och det förelåg ingen skillnad i tillfrisknande dem
emellan.
Införandet av kortikosteroider för PSH under 70-talet byggde på hypotesen att det
skulle lindra okända infektioner/inflammationer. Men varken förekomst av herpesvirus
eller positiva fynd av Borrelia i kombination med IPSH har visat sig ge bättre resultat
efter behandling med kortikosteroider. Det intressanta är att patienter med "
inflammation/infektionassocierade variabler " i den randomiserade kliniska
prövningen (III) hade en bättre prognos för hörseltillfriskanande, oberoende av
Prednisolon eller placebo. Detta fynd kräver ytterligare forskning och kan också vara
en orsak till synbara effekter av steroider i andra icke-randomiserade studier.
Behandling
Behandling av idiopatisk plötslig sensorineural hörselnedsättning har alltid varit
baserat på en eller annan underliggande hypotes om orsaken. Blodkärlteorin ligger till
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Svensk sammanfattning
grund för anti-stress behandling, bestående av sängliggande och blockering av
ganglion Stellatum, som användes främst under 1950-talet, och för behandling med
dextran 40 och hemodilution under 1970-talet. Inflammation/infektionsteori var
grunden för användningen av antiviral terapi tillsammans med kortikosteroider en
1980-talet. Mer nyligen blev den autoimmuna teorin grunden för en ökad dos av
steroider och cytostatisk behandling.
Endast 57 % av patienterna med IPSH i studie I och 61 % av patienterna i studie II
hade fått någon typ av medicinsk behandling. Åttionio procent (studie I) och nittioen
procent (studie II) av dem som var medicinskt behandlade hade fått kortikosteroider,
även om den underliggande orsaken inte var okänd. Att de som fick kortikosteroider
hade samma odds för tillfrisknande som de som inte fick något alls är helt i enlighet
med slutsatserna från de senaste Cochrane rapporterna om IPSH från 2006 och 2009.
Den enda randomiserade dubbelblind placebokontrollerade studien, där en positiv
effekt av kortikosteroider har påvisats, hade för få patienter för en sådan slutsats.
Kortikosteroider påverkade inte resultatet för de fåtal patienter med autoimmuna fynd i
denna avhandling (II, III), även om en effekt kunde ha förväntats. En förklaring kan
vara att alltför låg dos av kortikosteroider använts för detta ändamål och ingen
cytostatika givits.
Aoki med flera rapporterade nyligen (2006) att en mycket hög dos av kortikosteroider
verkar ge en betydligt större odds för hörselförbättring efter två månader. Men denna
studie har inte använt någon kontrollgrupp som inte har behandlats medicinskt. I den
randomiserade kliniska prövningen (III) hade 42 % av patienterna fått sin hörsel
tillbaka efter tre månader, jämt antal i både Prednisolon- och placebogruppen.
26 % av patienterna som hade ordinerats att vila hade bättre odds för
hörseltillfrisknande (II). Tidigare var sängliggande och sjukledighet
standardbehandling för patienter med IPSH, men detta har numera blivit mycket
ovanligt. Ingen forskning har gjorts kring denna speciella behandlingsmetod. Det är
mycket möjligt att alla individer som drabbas av IPSH skulle uppleva någon
förbättring av vila, särskilt de personer som hade rapporterat stress innan
sjukdomsdebuten.
Skada i olika delar av innerörat i relation till behandling
Många forskare är övertygade om att flera olika sjukdomar kan orsaka
hörselnedsättning och kan ingå i diagnosen IPSH. Det kan vara en anledning till varför
ingen enskild behandling har påvisat en klar effekt på PSH. I Tyskland har en
expertgrupp föreslagit att olika typer av hörselnedsättning kan ge en förklaring till var
i hörselsnäckan skadan kan ligga: hörselförlust i basregistret kan ses som ett tecken på
hydrops och hörselförlust i mellanregistret kan ses som ett tecken på
cirkulationsstörning i en viss del av snäckan. Hörselnedsättning upp till 40 dB HL i
diskanten kan vara skadade yttre hårceller och en hörselnedsättning på mer än 40 dB
HL kan ses som en skada på de inre hårcellerna. ”Flat loss” kan anses som en
påverkan av stria vaskularis vilket kan ge en akut hörselnedsättning på grund av akut
jonbalansstörning. Det skulle vara av stort intresse att se om olika behandlingar
utvecklas av denna hypotes. Detta teoretiska synsätt har sina svagheter då den inte
Svensk sammanfattning
65
överstämmer med klinisk erfarenhet och resultat från den randomiserade kliniska
prövningen (III) som visar att alla typer av hörselnedsättning tycks ha en chans att
spontant tillfrisknande. Återhämtningen kan antingen gå lika snabbt som när
hörselnedsättningen kom eller långsammare inom ett par månader.
Prognostiska faktorer
Prognostiska faktorer för IPSH har studerats av många forskare. Att förekomsten av
yrsel (II, III, IV) och ålder (I, II, IV) vid insjuknandet är relaterade till minskat odds
för hörselförbättring är i enlighet med tidigare studier. Att ålder är relaterad till
minskad sannolikhet för hörselförbättring kan bero på att äldre patienter har i
allmänhet svårare att återhämta sig från sjukdomar. Mer utbrett engagemang av
sjukdomen i innerörat kan förklara det minskade oddsen för återhämtning när yrsel
förekommer vid IPSH. Förekomsten av tinnitus har ansetts vara en positiv prognostisk
faktor för hörselförbättring av Cvorovic med flera, men resultat från denna avhandling
(I - IV) kunde inte påvisa ett sådant samband. Men "ärftlighet för hörselnedsättning"
som en prognostisk faktor för PSH har inte tidigare diskuterats. Den enda studie som
tar upp ”ärftlighet för hörselnedsättning” vid IPSH publicerades 2010. Gäckler med
flera rapporterade att 21,4 % av patienter med IPSH hade en eller flera
familjemedlemmar som tidigare drabbats av IPSH. Patienter med IPSH med ”
ärftlighet för hörselnedsättning” var yngre, hade upplevt fler episoder av PSH och
hade lägre hörselförbättring vid behandling. I studierna (I, II), baserat på den svenska
nationella databasen, var ärftlighet tydligt relaterade till en minskad sannolikhet för
förbättring. Detta kan tyda på att IPSH i vissa fall är det första tecknet på en ärftlig,
progressiv hörselnedsättning. Den sista uppföljningen i denna avhandling var efter tre
månader varför en fortsatt förbättring/försämring är inte möjlig att utvärdera.
Audiometri
En hypotes om variation i hörseltillfrisknandet är att olika typer av hårceller är
inblandade. Om bara de yttre hårcellerna är skadade, kan en central anpassning vara
möjligt så de återstående oskadade yttre hårcellerna kan omorganisera och på det sättet
återställa hörseln. Om däremot de inre hårcellerna är inblandade, är det svårare att
visualisera omorganisation eftersom antalet inre hårceller i snäckan är begränsat och
att de är tonotopiskt organiserade. Svagheten i detta teoretiska förhållningssätt
gällande hörselskadans läge och möjligheten till hörselförbättring är att det inte passar
ihop med den kliniska observationen att alla typer av hörselnedsättning verkar ha en
chans till spontan återhämtning av varierande grad. Samt att hörselförbättringen kan
ske så snabbt som uppkomsten av hörselförlusten. En långsammare utveckling av
återhämtning under ett par månader skulle bättre passa teorin om omorganisation.
Patienter med hörselförlust i mellanregistret hade signifikant bättre chans till
tillfrisknande (II). Detta har kunnat visas i en del tidigare studier och kan förklaras
utifrån blodkärlsteorin. I de fall där det finns två artärer till cochlean, vilket
förekommer i cirka 50% av fallen, och det ena blir blockerat, kan man teoretiskt räkna
med en hörselnedsättning i de lägre och mellersta frekvenserna med chans till
tillfrisknande eftersom det då finns anastomoser. Samma resonemang kan gälla för de
patienter i denna avhandling (II) som hade ingen eller måttlig förbättring :de kan ha
66
Svensk sammanfattning
haft blodkärlförändringar, men ingen andra artär som kunde ge kollateralblodflöde.
Förslag på vidare forskning
När ett läkemedel eller en substans visat sig inte ha effekt på en sjukdom, bör det tas ur
bruk och fokus för forskningen inom området bör vändas i en ny riktning.
Ytterligare uppföljning av de patienter som ingår i den randomiserade kliniska
prövningen behövs för att tydliggöra olika prognostiska mönster.
IPSH är förmodligen ett symptom för flera sjukdomar. Om så är fallet skulle ett
omfattande testbatteri tas fram för att identifiera underliggande sjukdomar för en mer
adekvat behandling. I ett sådant testbatteri bör också genetisk undersökning ingå om
släktingar med samma sjukdom upptäcks i sjukhistorien.
Fler studier om kronisk och akut stress är nödvändiga. Dessa studier kring stress bör
omfatta både kvalitativ forskning och laboratorieundersökningar.
Konklusioner
Följande generella slutsatser kan dras från denna avhandling:
 Oavsett diagnos är behandlingen av IPSH i Sverige huvudsakligen begränsad
till kortikosteroider (50%) eller ingen medicinsk behandling.
 Förekomsten av yrsel vid insjuknandet av PSH har en negativ effekt på
hörselförbättringen oavsett om patienten behandlas eller inte.
 Ålder har en negativ effekt på hörselförbättringen oavsett behandling eller inte.
 I en randomiserad placebokontrollerad klinisk studie kunde ingen positiv effekt
av Prednisolon på IPSH påvisas.
 En metaanalys av patientdata från den svenska nationella databasen för PSH
och den randomiserade kliniska studien för IPSH visade i ett större
patientmaterial ingen effekt av Prednisolon på IPSH
Dessa slutsatser torde medföra att kortikosteroidbehandling vid IPSH inte självklart
bör fortsätta.
Appendix
APPENDIX
Appendix 1. Questionnaire used in the Swedish national database (I, II).
Appendix II. Questionnaire used in the RCT (III).
67
68
APPENDIX I.
Appendix
Appendix
APPENDIX II.
69
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