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\begin{document}

\title{Intratympanic gentamicin injection in M\selectlanguage{ngerman}énière's disease: our experience
and outcomes\selectlanguage{english}}



\author[1]{Barbara Filosa}%
\author[2]{Antonio Trusio}%
\author[1]{Giuseppe Malafronte}%
\affil[1]{National Speciality Hospital San Giuseppe Moscati}%
\affil[2]{Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialita San Giuseppe Moscati}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Title: Intratympanic gentamicin injection in M\selectlanguage{ngerman}énière's disease: our
twelve years' experience and outcomes. Objective: The aim of our study
is to evaluate the effectiveness of intratympanic gentamicin
injection(ITG) on vertigo control with reduced doses and its hearing
effects. Study design: Retrospective study Materials and Method: The
study was conducted at our Otolaryngology Department of AORN ``S.G.
Moscati'' between January 2005 and January 2015 on 72 patients with
disabling unilateral Meniere's disease treated with ITG. We use 0.2-0.3
mL of gentamicin sulfate at a concentration of 40mg/ml, injected into
the affected ear through the posterior-inferior quadrant of the tympanic
membrane. The procedure was carried out for three following days. Main
outcome measures: vertigo control and hearing threshold changes after
ITG treatment. Results: In the 98.6\% of the patients (n=71) the ITG
produced the full remission of the vertiginous symptoms. In the 91.6\%
of cases(n=66) a single treatment (three consequent injections) was
sufficient to control vertigo, in the 5.5\% of cases (n=4) two
treatments were necessary to control vertigo and in the 1.3\% of
patients(n=1) three treatments were necessary to control vertigo. In no
case we have had hearing loss after ITG procedure. The pre-treatment
pure tone average was 48 db. The post-treatment pure tone average was
49.2 db. This difference was no statistical difference. Conclusion: In
this study we reported high vertigo control, long follow-up and no case
of significant hearing worsening. We consider the three injections in
the following three days with low doses of gentamicin a safe and valid
treatment for Meniere's disease. Keyword : Meniere's disease,
intratympanic gentamicin injection, vertigo control, hearing worsening,
aminoglycoside ototoxicity.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Meniere's disease(MD) is an idiopathic inner ear disorder characterized
by episodic attacks of vertigo, fluctuating hearing loss, tinnitus, and
aural fullness. MD exhibits a relapsing-remitting pattern, with episodic
attacks terminated by periods of restitution to normal auditory and
vestibular function. Additionally, auditory and vestibular function
decline over time.Although the pathophysiologic mechanism of MD is well
accepted, the underlying causes remains uncertain\textsuperscript{1}. MD
treatment is still objective of controversies in literature and it must
be first based on a trustable diagnosis, as recommended by guidelines
and classification of the AAO-HSN published in
1995\textsuperscript{2}and reviewed by the Equilibrium Committee in
2015\textsuperscript{3}. MD has a considerable negative effect on
patient's quality of life so current therapies are directed to prevent
or reduce the frequency and severity of vertigo
crises\textsuperscript{4}. Intratympanic injection of gentamicin(ITG) is
considered the treatment of choice in patients with refractory
disease\textsuperscript{1,4}. However due to its possible hearing side
effects there is still no general consensus on dose and timing of
ITG\textsuperscript{4}.

The aim of our study is to evaluate the effectiveness of intratympanic
injection of gentamicin on vertigo control with close doses and its
hearing effects.

\textbf{Material and Methods}

The study was conducted at Otolaryngology Department of
AORN``S.G.Moscati'' between January 2005 and May 2015.We selected 72
consecutive patients(28 males and 44 females, mean age 49.5 years,
range:21-78 years) with disabling unilateral M\selectlanguage{ngerman}énière's disease treated
with ITG. Patients included in the study were not responsive to
conservative therapies(lifestyle change, diuretics, salt-restricted
diet, steroid or betahistine). Inclusion criteria for this study were:
definite diagnosis of MD based on criteria of the 1995 Equilibrium
Committee\textsuperscript{2}, lack of response to medical therapy for
six months with invalidating vertigo attacks, unilateral MD,
satisfactory hearing in the contralateral ear, no previous treatment
with surgical conservative procedures or intratympanic steroid
injections, absence of hypersensitivity to aminoglycosides. All patients
included in the study met the inclusion criteria. After a detailed
explanation of the procedure, a written consent was obtained. To exclude
other inner ear diseases, all patients were submitted to magnetic
resonance with contrast. Before intratympanic treatment all patients
underwent a neuro-otological examination, including evaluation of
spontaneous, positional and positioning nystagmus, head shaking test,
subjective visual vertical test, Romberg and stepping test. A caloric
test was used to evaluate the vestibular semicircular canal
excitability. Otomicroscopic examination was performed to evaluate
tympanic membrane. All patients underwent to tympanometry and pure tone
audiometry. Pure tone average(PTA) was calculated on air conduction
thresholds at 500, 1000, 2000 and 3000dB. Before treatment all patients
filled out a questionnaire about number of vertigo, so to calculate a
monthly rate of vertigo.We use gentamicin sulfate at a concentration of
40mg/ml, the intratympanic injection was performed with a 25G spinal
needle in our ambulatory. Without local anesthesia, 0,2-0,3 mL of
gentamicin was injected into the affected ear through posterior-inferior
quadrant of tympanic membrane. Patient was instructed to maintain a
supine position with the head 30 degree tilted toward the healthy side
avoiding to swallow for at least 30 min. The same procedure was carried
out the following two days. After treatment audiometric revaluation was
performed at 3 and 7 days after the third injection. In absence of
vertigo patients were revaluated after 1-3-6-12 months and then every
year. The follow up ranged from 2 to12 years(mean follow-up 7 years).
The aim of the study was to evaluate hearing threshold changes and
vertigo control after ITG treatment.The t student test was used to
compare outcomes. For quantitative variables, descriptive statistics
were computed as mean and Standard Deviation(SD) or median and
Interquartile Range(IQR 25\textsuperscript{th} to
75\textsuperscript{th}percentiles), if they were not normally
distributed, and as absolute frequency and percentage for qualitative
variables. The reporting guideline followed in this study was STROBE
statement.

\textbf{Results}

During the procedure patients complained of a bearable pain, comparable
to an intramuscular injection. In the 6 months prior to treatment,
patients reported a mean frequency of six vertigo attacks per
month(range 2--12). Pre-treatment median PTA was 48 dB(IQR 44-52) and
median unilateral caloric weakness was 42\% (IQR 32-57). In 98.6\% of
the patients(n=71) the ITG produced full remission of vertiginous
symptoms. In 91.6\% of cases(n=66) a single treatment(three consequent
injections) was sufficient to control vertigo, in 5.5\% of cases(n=4)
two treatments were necessary to control vertigo( in 2 patients 1 year
after first treatment; in 1 patients 2 year after first treatment; in 1
patient 9 year after first treatment) and in 1.3\% of patients(n=1)
three treatments were necessary to control vertigo(4 years and 6 years
after first ITG). Number of gentamicin injections applied to achieve
vertigo control is shown in Fig.1. In the unsuccessful patient we have
repeated ITG treatment five times (1, 3, 6 and 7 years after first ITG)
without full control on the vertigo symptoms and, however, without
significantly hearing impairment( pre-treatment PTA=51.25;
post-treatment PTA=52.5; t-value=0.65; The~\emph{p} -value is 0.26). In
no case we have had hearing loss after ITG procedure. Post-treatment PTA
was 49.2dB(IQR 44-54). The difference between pre and post treatment PTA
was no statistical difference at p\textless{}0.05(t-value=-12.1;
p-value\textless{} .00001). Mean post-treatment unilateral caloric
weakness was 78\%(IQR 48-88). The difference between pre- and
post-treatment value was statistically significant at
p\textless{}0.05(t-value=0.40; p-value=0.34). In all cases the same
procedure was performed (three following daily ITG of 40 mg/ml
concentration). All patients of the study group complained imbalance
after gentamicin procedure which resolved 1 to 2 months after the IGT
without a specific vestibular rehabilitation, rather we recommend
patients to practice light physical activity (such as walking) as soon
as possible.

\textbf{Discussion}

Nowadays there is an international consensus on diagnosis of MD while
there is still no general consensus on the most appropriate treatment to
be adopted\textsuperscript{1,4}.Although treatment of medical refractory
unilateral MD with IT aminoglycoside injections has nowadays a standard
therapy, there is still no consensus on the doses and timing of
administration\textsuperscript{4,5}. The IT aminoglycoside injections
was first introduced by Schuknecht using streptomycin and then by Lange
using gentamicin. Gentamicin has now become the most widely used
aminoglycoside for treatment of vestibular symptoms associated with MD.
It's a relative selective vestibulotoxic aminoglycoside antibiotic that
is preferentially taken up by type I hair cells of the vestibular
neuroepithelium\textsuperscript{6}.The ITG treatment was initially
conceived as an ablative method with complete vestibular ablation to
control vertigo\textsuperscript{1}. However, with this approach there
were serious cochleotoxic effects with great hearing loss
risk\textsuperscript{1}.Parnes reported 41,7\% hearing worsening using
high doses of gentamycin(3 daily injections for 4
days)\textsuperscript{7}. Similar results were reported by Cortsen who
performed 3 times daily ITG for 3 days\textsuperscript{8}. It is likely
that the initial reversible effect of gentamicin on both the vestibule
and cochlea turns eventually to an irreversible stage due to the
accumulation of consecutive doses in the inner ear because of slow
clearance of gentamicin\textsuperscript{9}.It has been demonstrated that
gentamicin is eliminated slowly from the inner ear and ototoxic effects
of ITG were delayed 2-3 days after the last
installation\textsuperscript{10,11}.Low-dose treatment may produce
sufficient loss of vestibular function to provide relief from vertigo,
and with less risk of affecting the hearing level. Even though over the
last decade there has been a general trend to conserve vestibular and
consequently cochlear function in order to obtain vertigo control with a
very low hearing risks, some physicians are still concerned about
hearing loss.

In our study we used a low dose of gentamycin injected once daily for 3
consecutive days with high vertigo control (98.6\%) and no case of
statistically significant hearing impairment. Similar results were
reported by Quaglieri et al, who achieved 96.5\% of total effective
vertigo control with no cases of statistical hearing
impairment\textsuperscript{11}. We agree with Yetiser who states that
titration methods or multiple injections on a daily basis can be used
only in patients with profound or non-serviceable hearing, since these
methods have significant incidence of hearing loss\textsuperscript{9}.
In our series with a long follow-up, we noticed that the used protocol
(three injections in the following three days) provides effective
vertigo control without risk of anacusia and almost no risk of hearing
impairment. In one case of our series we have repeated the ITG treatment
five times(1,3, 6 and 7 years after the first ITG) without achievement
the full control on the vertigo symptoms but,however, without
significantly hearing impairment. It is likely that if the patient had
no hearing damage on the first treatment he probably does not have a
genetic predisposition for aminoglycoside
ototoxicity\textsuperscript{12}. We are aware that the limit of our work
is that it is a retrospective study. For this reason, at the end of 2015
we have started a new prospected study to check if a further reduction
of the ITG administration times gives the same satisfactory results in
vertigo control.

\textbf{Conclusion}

Taking into account that the great limit of this study is that it is an
observational retrospective study, we reported high vertigo control,
long follow-up and no case of significant hearing improvement. For these
reasons we consider the three injections in the following three days
with low doses of gentamicin as a safe and valid treatment for Meniere's
disease.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Yaz F, Ziylan F, Smeeing DPJ, Thomeer HGXM. Intratympanic Treatment in
  Menière's Disease, Efficacy of Aminoglycosides Versus Corticosteroids
  in Comparison Studies: A Systematic Review. Otol Neurotol. 2020
  Jan;41(1):1-10.
\item
  Committee on hearing equilibrium guidelines for the diagnosis
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  Surg 1995; 113:181-5.
\item
  Lopez-Escamez JA, Carey J, Chung WH, et al. Diagnostic criteria for
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\item
  Basura Gj, Adams ME, Monfared A, et al. Clinical Practice Guideline:
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\item
  Nevoux J, Barbara M, Dornhoffer J, et alt. International consensus
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  Head Neck Dis. 2018 Feb;135(1S):S29-S32.
\item
  Lyford-Pyke S, Vogelheim C, Chu E, et al. Gentamicin is primarily
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\item
  Parnes LS, Riddell D. Irritative spontaneous nystagmus following
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\item
  Corsten M1, Marsan J, Schramm D et alt. Treatment of intractable
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\item
  Yeti\selectlanguage{polish}ş\selectlanguage{english}er S. Intratympanic Gentamicin for Intractable M\selectlanguage{ngerman}énière's Disease
  - A Review and Analysis of Audiovestibular Impact. Int Arch
  Otorhinolaryngol. 2018 Apr;22(2):190-194.
\item
  Magnusson M, Padoan S, Karlberg M, et alt. Delayed onset of ototoxic
  effects of gentamicin in patients with Meniére's disease. Acta
  Otolaryngol Suppl. 1991;485:120-2.
\item
  Quaglieri S, Gatti O, Rebecchi E, et alt. Intratympanic gentamicin
  treatment 'as needed' for Meniere's disease. Long-term analysis using
  the Kaplan-Meier method.Eur Arch Otorhinolaryngol. 2014
  Jun;271(6):1443-9. doi: 10.1007/s00405-013-2597-7
\item
  Higashi K. Unique inheritance of streptomycin-induced deafness. Clin
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\end{enumerate}

\textbf{Data Availability Statement}Data are available on request from
the authors. The data that support the findings of this study are
available from the corresponding author upon request, with the agreement
of our health management department.

\textbf{Figure Legend}

Fig. 1. Number of treatments to achieve vertigo control. Each treatment
consists of one injection per day for 3 consecutive days.\selectlanguage{english}
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