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Acyclovir in the treatment of idiopathic sudden sensorineural hearing loss
Acyclovir in the treatment of idiopathic sudden sensorineural hearing loss NECHAMA URI,
MD,
ILANA DOWECK,
MD,
RAANAN COHEN-KEREM,
BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is a vexing problem that continues to pose a diagnostic and therapeutic enigma for the otologist. The aim of the study, adopting the viral theory, was to discover whether patients with ISSNHL would benefit from early treatment with acyclovir and hydrocortisone compared with patients treated by hydrocortisone alone. METHODS: Sixty patients with ISSNHL were treated in a prospective controlled randomized manner. Patients were seen within 7 days of onset and were divided randomly into 2 groups. The study group patients were treated with acyclovir and hydrocortisone, whereas those in the control group were treated with hydrocortisone alone. RESULTS: We compared the 2 groups before and after treatment regarding SRT, mean hearing level at each frequency, speech reception threshold improvement, gender, age, tinnitus, and balance complaints. The overall improvement was 78%. CONCLUSION: We conclude that there probably is no benefit from the addition of acyclovir in the treatment of ISSNHL. (Otolaryngol Head Neck Surg 2003;128:544-9.)
I diopathic
sudden sensorineural hearing loss (ISSNHL) is one of the most controversial issues in the otolaryngology literature regarding etiology and treatment. Contributing to this controversy is the low incidence (4.7 to 15 per 100,000), which makes validation of empirical treatment difficult.1 There are some strong data that support the viral theory. Pathologic specimens of 12 ears of patients with ISSNHL and 10 others2 revealed lesions occurring in known cases of viral cochleitis. Recently, Vasama and Linthicum3 reported histoFrom the Department of Otolaryngology–Head and Neck Surgery, Carmel Medical Center, Haifa, Israel. Reprint requests: Uri Nechama, MD, Department of Otolaryngology–Head and Neck Surgery, Carmel Medical Center, 7 Michal St, Haifa, 34362 Israel; e-mail, druri@ netvision.net.il. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/mhn.2003.109 544
MD,
and ELHANAN GREENBERG,
MD,
Haifa, Israel
logic changes in temporal bones obtained from patients with ISSNHL that suggest a viral etiology. Earlier, Wackym,4 in a discussion of temporal bone pathology in herpes zoster oticus, detected varicella zoster virus in auditory organs of a patient with sudden hearing loss. On the other hand, there was no increase in antibody titers to cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 in the majority of patients with ISSNHL.5 This led to the conclusion that these viruses, which are highly prevalent in the adult population,6 are not the direct cause of ISSNHL in most of the patients. Spontaneous recovery ranging from 40% to 65%7,8 is the natural outcome of ISSNHL. Known suggested therapy includes vasodilators, diuretics, anticoagulants, plasma expanders, CO2, and others. All of these treatment modalities lack proper evaluation or are ineffective.9 Steroid therapy has been shown to improve prognosis to some extent.10 The unknown pathophysiology, the spontaneous recovery, and the low incidence make the selection of treatment options difficult. Adopting the viral theory, Stokroos et al,11 in an experimental study, elicited sudden hearing loss in guinea pigs by inducing herpes simplex virus (HSV)-1 labyrinthitis and found the cochlear histopathology to resemble that in ISSNHL. The treatment in their study consisted of a combination of steroids and acyclovir, resulting in earlier hearing recovery and less extensive cochlear destruction compared with treatment with steroids or acyclovir as monotherapy. The purpose of this study was to define whether patients with ISSNHL will benefit from early treatment with steroids and acyclovir compared with patients treated with steroids alone. METHODS The design of the study was a prospective randomized trial. Between 1991 and 1999, 60 patients with ISSNHL were treated for ISSNHL in the Department of Otolaryngology–Head and Neck
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Surgery at Carmel Medical Center in Haifa, Israel. Hearing loss was defined as a sensory hearing impairment of at least 20 dB in at least 3 frequencies. Patients younger than 18 years or older than 60 years were excluded from the study. We also excluded patients with onset of hearing loss more than 7 days before admission. Patients with hypertension, diabetes, autoimmune, collagen and renal diseases, previous ear disease, or known hearing loss were also excluded. Parameters regarding gender, age, accompanying dizziness, vertigo, or tinnitus were obtained. Audiograms were performed before admission and 1 and 3 months and 1 year after treatment. Audiometry testing included pure tone, speech reception threshold (SRT), discrimination, stapedial reflex, tympanometry, and tone decay. A blood sample for complete blood cell count, glucose, creatinine, electrolytes, cholesterol, and triglycerides was obtained. Computed tomography or magnetic resonance imaging of the cerebellopontine angle was performed to exclude an acoustic neuroma. Patients were randomly assigned into 2 groups. Group A, the study group, included 29 patients put on bed rest and treated with intravenous acyclovir 15 mg/kg/d and hydrocortisone 100 mg tid for 7 days. Group H, the control group, consisted of 31 patients put on bed rest and treated with intravenous hydrocortisone 100 mg tid. After intravenous treatment, the patients were put on a taper regimen of prednisone for 7 days. During treatment, blood pressure was taken and body weight was measured daily. An improvement of 15 dB in the involved frequency average or in SRT was considered significant. Statistical analysis was made using SPSS statistical software (SPSS Inc, Chicago, IL). The following tests were performed to compare parameters before and after treatment: analysis of variance for the hearing levels in each frequency, t test for the mean hearing level (250 Hz to 8 kHz), and SRT. We also examined the success rate according to SRT improvement using 2 test (improvement of ⱖ15 dB was considered a success); logistic regression was used to evaluate the correlation of treatment group, day of treatment initiation, gender, age, tinnitus, and dizziness with hearing im-
URI et al 545
provement. The level of significance for all tests was P ⬍ 0.05. RESULTS Sixty patients were included in the study (33 men and 27 women; mean age, 45.8 years; age range, 18 to 60 years; median age, 48 years). Tinnitus was observed in 73% and dizziness in 30% of the patients. None of the patients had spontaneous or positional nystagmus on physical examination throughout hospitalization. The right ear was more often affected than the left (63.3% and 36.7%, respectively). Forty patients were symptomatic 1 to 4 days and 20 patients were symptomatic 5 to 7 days before admission. Twenty-nine patients were on acyclovir and hydrocortisone treatment (group A), and 31 patients were given hydrocortisone alone (group H). There was no significant difference in gender, age, day of treatment, and presence of tinnitus or dizziness between the groups. Overall improvement of both groups, considering the impaired frequencies, was 78% (78.6% in group A and 77.4% in group H). The mean puretone audiograms of the impaired ear before treatment in both groups are shown (Fig 1A). No significant difference was found in the homogeneity of the groups in comparing the SRT and puretone frequencies at 250 Hz to 8 kHz (t test). The average audiogram of the 2 groups 1 year after treatment and the change (⌬) in mean hearing improvement are shown (Figs 1B and 2, respectively), with no significant difference being observed (SRT, P ⫽ 0.922; pure-tone average [PTA], P ⫽ 0.700). During follow-up, no fluctuations in hearing were observed, nor were there reports of any episodes of dizziness or vertigo. Patients who were treated early in the course of their disease (days 1 to 4) tended to do better than patients whose treatment was started after an extended period of symptoms (days 5 to 7), although no statistical difference was noticed (PTA: group H, P ⫽ 0.146; group A, P ⫽ 0.184). However, significant differences were found only in the group treated with hydrocortisone (group H) at 2 kHz (P ⫽ 0.022) (Table 1). Borderline differences were noticed in the group treated with acyclovir and hydrocortisone (group A) at 500 Hz (P ⫽ 0.055) (Table 1, Fig 3).
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Fig 1. A, Audiogram of the mean pure-tone in the hydrocortisone group and the acyclovir group prior to treatment. Both groups had a similar average sensory neural hearing loss. B, Audiogram of the mean pure-tone of both groups after treatment. No significance differences were found in mean pure tone at the different frequencies, between the groups.
Fig 2. The change in hearing improvement after treatment in each group (improvement in each frequency is given in decibels).
Comparing the mean improvement between the groups, when treatment was started within days 1 to 4, it was obvious that all patients improved similarly (P ⫽ 0.574), regardless of the type of treatment. The same results concerning the mean improvement were observed when treatment was started within days 5 to 7 (P ⫽ 0.754). Concerning the improvement in SRT, no difference was observed according to the 2 test be-
tween the 2 study groups (P ⫽ 0.162). Using a logistic regression, it was apparent that the treatment protocol, day of treatment from the onset of symptoms, age, and gender had no effect on SRT improvement. Hearing improvement was significantly better when tinnitus was present (P ⫽ 0.032) and poorer when dizziness existed (P ⫽ 0.047). Reported side effects of acyclovir (central nervous
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URI et al 547
Table 1. Hearing improvement in dB as a function of treatment initiation. Significant improvement was found in 2kHz in group H and a trend of significance in 500Hz in group A when early treatment was provided Hydrocortisone group (H)
Acyclovir & Hydrocortisone group (A)
Frequency
Days 1–4
Days 5–7
Days 1–4
Days 5–7
250Hz 500Hz 1kHz 2kHz 4kHz 8kHz
24.2 25.3 25.2 *26.7 23.5 15.2
12.3 13.2 11.8 6.8 13.2 10.0
18.2 **27.6 25.5 19.2 12.9 11.3
5.6 8.9 12.0 12.8 10.0 6.1
*p ⫽ 0.022; **p ⫽ 0.055.
system, renal, or hepatic) were not observed during treatment. DISCUSSION Many items regarding sudden hearing loss remain an enigma. The etiology is unknown, the audiometric definitions for improvement are not uniform, and the mode of treatment varies from “shotgun” treatment to no treatment at all. Wilkins et al12 treated 109 ISSNHL patients with such a “shotgun” regimen consisting of dextran, histamine, Hypaque meglumine (diatrizoate), diuretics, steroids, vasodilators, and Carbogen inhalation. They concluded that there is no difference between the “shotgun” therapy and spontaneous recovery. Probst et al,13 in a prospective randomized doubleblind study, found no difference between patients treated with dextran and pentoxifylline and those who received placebo. Kronenberg et al14 found no difference in hearing improvement between patients treated with intravenous procaine and low molecular dextran versus those treated with placebo. Redleaf et al15 demonstrated, in a retrospective study, a tendency for better hearing recovery using intravenous contrast. Byl,7 in a prospective study on 225 patients, found no evidence that any treatment has a better result than spontaneous recovery but states that, “Steroids are probably the standard of care in the treatment of SHL” based on studies supporting the steroid therapy.9,10,16
In experimental herpes viral labyrinthitis in the guinea pig inner ear, Stokroos et al11 found a synergistic effect of acyclovir and prednisolone treatment on hearing recovery and cochlear histopathology. In a clinical trial, 44 patients with ISSNHL were treated with acyclovir and prednisolone, but no beneficial effect was achieved by using this protocol.17 Because the experimental state differs from clinical practice in the elimination of treatment delay, they proposed that treatment in ISSNHL would be divided into 2 phases. At a very early phase after hearing loss, treatment will be directed toward the possible provoking pathogen by adding acyclovir to the prednisolone. The second phase treatment will consist of only prednisolone. Adour,18 in a prospective placebo-controlled randomized study of Bell’s palsy patients, found significant improvement with acyclovir combined with prednisone compared with prednisone combined with placebo. In 1996, Murakami et al19 detected herpes simplex virus genome in specimens of 11 of 14 (79%) patients with Bell’s palsy. By making an analogy from Bell’s palsy to ISSNHL and based on the previous data, we adopted the viral etiology. Our purpose was to find out whether treatment with acyclovir has a therapeutic advantage over treatment with hydrocortisone, which we believe to be helpful, thus making it unethical to create a placebo group. The overall hearing improvement rate in the current study was found to be 78%. Although no placebo group was examined, this improvement was better than what is known in the literature as spontaneous recovery.7,8 The definition of recovery varies among authors. Byl’s7 definition for complete recovery is an improvement of 25 dB or more in PTA or return to preloss levels. Partial recovery is an improvement of 10 to 24 dB PTA, and no recovery is when improvement is less than 10 dB. Stokroos et al17 considered improvement as more than 10 dB, and Kronenberg et al14 defined recovery as a minimal increase of 15 dB by the end of treatment and a simultaneous hearing level of more than 40 dB. An alternative option is to measure improvement in the affected frequencies only. In the current study, we considered a 15-dB increase in the involved frequencies as a significant improve-
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Fig 3. A, Hearing improvement in both groups when treatment was started 1 to 4 days from onset of symptoms. Improvement was similar, with no statistical significance in either group. B, Hearing improvement in both groups when treatment initiation was on days 5 to 7. Improvement was similar, with no statistical significance in either group.
ment. No significant difference was found between the 2 study groups in PT measurements or between the 2 groups in the SRT measurements, probably due to the fact that the speech frequencies were not necessarily involved. The type of treatment, gender, and age had no effect on hearing improvement. The only variable that had an effect on hearing improvement was the proximity of treatment to the patient’s hearing loss. Our data suggest that the sooner treatment is started, the better is the chance for recovery. The overall improvement in pure tone in each frequency is higher when treatment was started early
during the course of the disease (days 1 to 4) compared with late treatment (days 5 to 7 from onset of treatment). However, the findings are significant only in one of the frequencies in each group. The lack of significance may be related to the wide standard deviation in each frequency, which may reflect the variety in the type of hearing loss in our study. The interval between the onset of the hearing loss and the beginning of treatment is known as a prognostic factor.7,20 The wide standard deviation in the different frequencies suggests that not all frequencies were equally involved. The patients could have been divided according to their audiogram shape (ris-
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ing, flat, sloping, or complete deafness). As a result, the groups would have been too small for statistical analysis. Our clinical impression is that prognosis is unfavorable in cases of profound hearing loss, regardless of the treatment or the day of arrival. Seventy-three percent of our patients had tinnitus and, contrary to the finding of Stokroos et al,17 had a better prognosis. Thirty percent of the patients in both groups experienced vestibular disturbances (dizziness), and those patients had an unfavorable prognosis regardless of acyclovir use. These findings are supported by Byl,7 who found vertigo to be a poor prognostic factor. On the other hand, Stokroos et al17 found a better prognosis with vestibular involvement. We assume that hearing loss that is accompanied by vestibular symptoms indicates more extensive inner ear disease with a poorer prognosis. The main question remains of why disease with a probable viral etiology shows no improvement after acyclovir treatment. It may be related to other viral pathogens that are not of the herpes group and, hence, not responsive to acyclovir. Another possible explanation may be that the working hypothesis is multifactorial, and the viral pathogen is a part of it. CONCLUSION Our data suggest that acyclovir added to hydrocortisone has no additive effect on the recovery of patients with ISSNHL. Further study is needed to prove the viral etiology in ISSNHL and to identify the population who may have it. Other antiviral agents may be examined as well to solve this frustrating problem. REFERENCES
1. Stokroos RJ, Albers FWJ, Van Cauwenberg P. Diagnosis and treatment of idiopathic sudden sensorineural hearing loss (ISSNHL). A survey in The Netherlands and Flanders. Acta Otolaryngol Belg 1996;50:237-45. 2. Schuknecht HF, Donovan ED. The pathology of idiopathic sudden sensorineural hearing loss. Arch Otorhinolaryngol 1986;243:1-15. 3. Vasama JP, Linthicum FH. Idiopathic sudden sensorineural hearing loss: temporal bone histopathologic study. Ann Otol Rhinol Laryngol 2000;109:527-32.
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4. Wackym PA. Molecular temporal bone pathology: II. Ramsay Hunt syndrome (herpes zoster oticus). Laryngoscope 1997;107:1165-75. 5. Takasaki T, Higashikawa M, Motoyama S, et al. Serum antibodies to human herpes virus 7, human herpesvirus 6 and cytomegalovirus in patients with idiopathic facial nerve palsy or sudden deafness. J Laryngol Otol 1998; 112:617-21. 6. Okuno T, Takahashi K, Balachandra K, et al. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 1989;27:651-3. 7. Byl FM Jr. Sudden hearing loss: eight years’ experience and suggested prognostic table. Laryngoscope 1984;94: 647-61. 8. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:463-80. 9. Stokroos RJ, Albers FW. Therapy of idiopathic sudden sensorineural hearing loss. A review of the literature. Acta Otorhinolaryngol Belg 1996;50:77-84. 10. Moskowitz D, Lee KJ, Smith HW. Steroid use in idiopathic sudden sensorineural hearing loss. Laryngoscope 1984;94:664-6. 11. Stokroos RJ, Albers FW, Schirm J. Therapy of idiopathic sudden sensorineural hearing loss: antiviral treatment of experimental herpes simplex virus infection of the inner ear. Ann Otol Rhinol Laryngol 1999;108:423-8. 12. Wilkins SA, Mattox DE, Lyles A. Evaluation of a “shotgun” regimen for sudden hearing loss. Otolaryngol Head Neck Surg 1987;97:474-80. 13. Probst R, Tschopp K, Ludin E, et al. A randomized, double-blind, placebo-controlled study of dextran/penotxifylline medication in acute acoustic trauma and sudden hearing loss. Acta Otolaryngol (Stockh) 1992;112: 435-43. 14. Kronenberg J, Almagor M, Bendet E, et al. Vasoactive therapy versus placebo in the treatment of sudden hearing loss: a double-blind clinical study. Laryngoscope 1992; 102:65-8. 15. Redleaf MI, Bauer CA, Gantz BJ, et al. Diatrizoate and dextran treatment of sudden sensorineural hearing loss. Am J Otol 1995;16:295-303. 16. Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of idiopathic sudden hearing loss. A double-blind clinical study. Arch Otolaryngol 1980;106:772-6. 17. Stokroos RJ, Albers FW, Tenvergert EM. Antiviral treatment of idiopathic sudden sensorineural hearing loss: a prospective, randomized, double-blind clinical trial. Acta Otolaryngol (Stockh) 1998;118:488-95. 18. Adour KK, Ruboyianes JM, Von-Doersten PG, et al. Bell’s palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol 1996;105:371-8. 19. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bells palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 1996;124:27-30. 20. Wood MJ, Johnson RW, McKendrick MW, et al. Randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994;330:896-900.
MD,
ILANA DOWECK,
MD,
RAANAN COHEN-KEREM,
BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is a vexing problem that continues to pose a diagnostic and therapeutic enigma for the otologist. The aim of the study, adopting the viral theory, was to discover whether patients with ISSNHL would benefit from early treatment with acyclovir and hydrocortisone compared with patients treated by hydrocortisone alone. METHODS: Sixty patients with ISSNHL were treated in a prospective controlled randomized manner. Patients were seen within 7 days of onset and were divided randomly into 2 groups. The study group patients were treated with acyclovir and hydrocortisone, whereas those in the control group were treated with hydrocortisone alone. RESULTS: We compared the 2 groups before and after treatment regarding SRT, mean hearing level at each frequency, speech reception threshold improvement, gender, age, tinnitus, and balance complaints. The overall improvement was 78%. CONCLUSION: We conclude that there probably is no benefit from the addition of acyclovir in the treatment of ISSNHL. (Otolaryngol Head Neck Surg 2003;128:544-9.)
I diopathic
sudden sensorineural hearing loss (ISSNHL) is one of the most controversial issues in the otolaryngology literature regarding etiology and treatment. Contributing to this controversy is the low incidence (4.7 to 15 per 100,000), which makes validation of empirical treatment difficult.1 There are some strong data that support the viral theory. Pathologic specimens of 12 ears of patients with ISSNHL and 10 others2 revealed lesions occurring in known cases of viral cochleitis. Recently, Vasama and Linthicum3 reported histoFrom the Department of Otolaryngology–Head and Neck Surgery, Carmel Medical Center, Haifa, Israel. Reprint requests: Uri Nechama, MD, Department of Otolaryngology–Head and Neck Surgery, Carmel Medical Center, 7 Michal St, Haifa, 34362 Israel; e-mail, druri@ netvision.net.il. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/mhn.2003.109 544
MD,
and ELHANAN GREENBERG,
MD,
Haifa, Israel
logic changes in temporal bones obtained from patients with ISSNHL that suggest a viral etiology. Earlier, Wackym,4 in a discussion of temporal bone pathology in herpes zoster oticus, detected varicella zoster virus in auditory organs of a patient with sudden hearing loss. On the other hand, there was no increase in antibody titers to cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 in the majority of patients with ISSNHL.5 This led to the conclusion that these viruses, which are highly prevalent in the adult population,6 are not the direct cause of ISSNHL in most of the patients. Spontaneous recovery ranging from 40% to 65%7,8 is the natural outcome of ISSNHL. Known suggested therapy includes vasodilators, diuretics, anticoagulants, plasma expanders, CO2, and others. All of these treatment modalities lack proper evaluation or are ineffective.9 Steroid therapy has been shown to improve prognosis to some extent.10 The unknown pathophysiology, the spontaneous recovery, and the low incidence make the selection of treatment options difficult. Adopting the viral theory, Stokroos et al,11 in an experimental study, elicited sudden hearing loss in guinea pigs by inducing herpes simplex virus (HSV)-1 labyrinthitis and found the cochlear histopathology to resemble that in ISSNHL. The treatment in their study consisted of a combination of steroids and acyclovir, resulting in earlier hearing recovery and less extensive cochlear destruction compared with treatment with steroids or acyclovir as monotherapy. The purpose of this study was to define whether patients with ISSNHL will benefit from early treatment with steroids and acyclovir compared with patients treated with steroids alone. METHODS The design of the study was a prospective randomized trial. Between 1991 and 1999, 60 patients with ISSNHL were treated for ISSNHL in the Department of Otolaryngology–Head and Neck
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Surgery at Carmel Medical Center in Haifa, Israel. Hearing loss was defined as a sensory hearing impairment of at least 20 dB in at least 3 frequencies. Patients younger than 18 years or older than 60 years were excluded from the study. We also excluded patients with onset of hearing loss more than 7 days before admission. Patients with hypertension, diabetes, autoimmune, collagen and renal diseases, previous ear disease, or known hearing loss were also excluded. Parameters regarding gender, age, accompanying dizziness, vertigo, or tinnitus were obtained. Audiograms were performed before admission and 1 and 3 months and 1 year after treatment. Audiometry testing included pure tone, speech reception threshold (SRT), discrimination, stapedial reflex, tympanometry, and tone decay. A blood sample for complete blood cell count, glucose, creatinine, electrolytes, cholesterol, and triglycerides was obtained. Computed tomography or magnetic resonance imaging of the cerebellopontine angle was performed to exclude an acoustic neuroma. Patients were randomly assigned into 2 groups. Group A, the study group, included 29 patients put on bed rest and treated with intravenous acyclovir 15 mg/kg/d and hydrocortisone 100 mg tid for 7 days. Group H, the control group, consisted of 31 patients put on bed rest and treated with intravenous hydrocortisone 100 mg tid. After intravenous treatment, the patients were put on a taper regimen of prednisone for 7 days. During treatment, blood pressure was taken and body weight was measured daily. An improvement of 15 dB in the involved frequency average or in SRT was considered significant. Statistical analysis was made using SPSS statistical software (SPSS Inc, Chicago, IL). The following tests were performed to compare parameters before and after treatment: analysis of variance for the hearing levels in each frequency, t test for the mean hearing level (250 Hz to 8 kHz), and SRT. We also examined the success rate according to SRT improvement using 2 test (improvement of ⱖ15 dB was considered a success); logistic regression was used to evaluate the correlation of treatment group, day of treatment initiation, gender, age, tinnitus, and dizziness with hearing im-
URI et al 545
provement. The level of significance for all tests was P ⬍ 0.05. RESULTS Sixty patients were included in the study (33 men and 27 women; mean age, 45.8 years; age range, 18 to 60 years; median age, 48 years). Tinnitus was observed in 73% and dizziness in 30% of the patients. None of the patients had spontaneous or positional nystagmus on physical examination throughout hospitalization. The right ear was more often affected than the left (63.3% and 36.7%, respectively). Forty patients were symptomatic 1 to 4 days and 20 patients were symptomatic 5 to 7 days before admission. Twenty-nine patients were on acyclovir and hydrocortisone treatment (group A), and 31 patients were given hydrocortisone alone (group H). There was no significant difference in gender, age, day of treatment, and presence of tinnitus or dizziness between the groups. Overall improvement of both groups, considering the impaired frequencies, was 78% (78.6% in group A and 77.4% in group H). The mean puretone audiograms of the impaired ear before treatment in both groups are shown (Fig 1A). No significant difference was found in the homogeneity of the groups in comparing the SRT and puretone frequencies at 250 Hz to 8 kHz (t test). The average audiogram of the 2 groups 1 year after treatment and the change (⌬) in mean hearing improvement are shown (Figs 1B and 2, respectively), with no significant difference being observed (SRT, P ⫽ 0.922; pure-tone average [PTA], P ⫽ 0.700). During follow-up, no fluctuations in hearing were observed, nor were there reports of any episodes of dizziness or vertigo. Patients who were treated early in the course of their disease (days 1 to 4) tended to do better than patients whose treatment was started after an extended period of symptoms (days 5 to 7), although no statistical difference was noticed (PTA: group H, P ⫽ 0.146; group A, P ⫽ 0.184). However, significant differences were found only in the group treated with hydrocortisone (group H) at 2 kHz (P ⫽ 0.022) (Table 1). Borderline differences were noticed in the group treated with acyclovir and hydrocortisone (group A) at 500 Hz (P ⫽ 0.055) (Table 1, Fig 3).
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Fig 1. A, Audiogram of the mean pure-tone in the hydrocortisone group and the acyclovir group prior to treatment. Both groups had a similar average sensory neural hearing loss. B, Audiogram of the mean pure-tone of both groups after treatment. No significance differences were found in mean pure tone at the different frequencies, between the groups.
Fig 2. The change in hearing improvement after treatment in each group (improvement in each frequency is given in decibels).
Comparing the mean improvement between the groups, when treatment was started within days 1 to 4, it was obvious that all patients improved similarly (P ⫽ 0.574), regardless of the type of treatment. The same results concerning the mean improvement were observed when treatment was started within days 5 to 7 (P ⫽ 0.754). Concerning the improvement in SRT, no difference was observed according to the 2 test be-
tween the 2 study groups (P ⫽ 0.162). Using a logistic regression, it was apparent that the treatment protocol, day of treatment from the onset of symptoms, age, and gender had no effect on SRT improvement. Hearing improvement was significantly better when tinnitus was present (P ⫽ 0.032) and poorer when dizziness existed (P ⫽ 0.047). Reported side effects of acyclovir (central nervous
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Table 1. Hearing improvement in dB as a function of treatment initiation. Significant improvement was found in 2kHz in group H and a trend of significance in 500Hz in group A when early treatment was provided Hydrocortisone group (H)
Acyclovir & Hydrocortisone group (A)
Frequency
Days 1–4
Days 5–7
Days 1–4
Days 5–7
250Hz 500Hz 1kHz 2kHz 4kHz 8kHz
24.2 25.3 25.2 *26.7 23.5 15.2
12.3 13.2 11.8 6.8 13.2 10.0
18.2 **27.6 25.5 19.2 12.9 11.3
5.6 8.9 12.0 12.8 10.0 6.1
*p ⫽ 0.022; **p ⫽ 0.055.
system, renal, or hepatic) were not observed during treatment. DISCUSSION Many items regarding sudden hearing loss remain an enigma. The etiology is unknown, the audiometric definitions for improvement are not uniform, and the mode of treatment varies from “shotgun” treatment to no treatment at all. Wilkins et al12 treated 109 ISSNHL patients with such a “shotgun” regimen consisting of dextran, histamine, Hypaque meglumine (diatrizoate), diuretics, steroids, vasodilators, and Carbogen inhalation. They concluded that there is no difference between the “shotgun” therapy and spontaneous recovery. Probst et al,13 in a prospective randomized doubleblind study, found no difference between patients treated with dextran and pentoxifylline and those who received placebo. Kronenberg et al14 found no difference in hearing improvement between patients treated with intravenous procaine and low molecular dextran versus those treated with placebo. Redleaf et al15 demonstrated, in a retrospective study, a tendency for better hearing recovery using intravenous contrast. Byl,7 in a prospective study on 225 patients, found no evidence that any treatment has a better result than spontaneous recovery but states that, “Steroids are probably the standard of care in the treatment of SHL” based on studies supporting the steroid therapy.9,10,16
In experimental herpes viral labyrinthitis in the guinea pig inner ear, Stokroos et al11 found a synergistic effect of acyclovir and prednisolone treatment on hearing recovery and cochlear histopathology. In a clinical trial, 44 patients with ISSNHL were treated with acyclovir and prednisolone, but no beneficial effect was achieved by using this protocol.17 Because the experimental state differs from clinical practice in the elimination of treatment delay, they proposed that treatment in ISSNHL would be divided into 2 phases. At a very early phase after hearing loss, treatment will be directed toward the possible provoking pathogen by adding acyclovir to the prednisolone. The second phase treatment will consist of only prednisolone. Adour,18 in a prospective placebo-controlled randomized study of Bell’s palsy patients, found significant improvement with acyclovir combined with prednisone compared with prednisone combined with placebo. In 1996, Murakami et al19 detected herpes simplex virus genome in specimens of 11 of 14 (79%) patients with Bell’s palsy. By making an analogy from Bell’s palsy to ISSNHL and based on the previous data, we adopted the viral etiology. Our purpose was to find out whether treatment with acyclovir has a therapeutic advantage over treatment with hydrocortisone, which we believe to be helpful, thus making it unethical to create a placebo group. The overall hearing improvement rate in the current study was found to be 78%. Although no placebo group was examined, this improvement was better than what is known in the literature as spontaneous recovery.7,8 The definition of recovery varies among authors. Byl’s7 definition for complete recovery is an improvement of 25 dB or more in PTA or return to preloss levels. Partial recovery is an improvement of 10 to 24 dB PTA, and no recovery is when improvement is less than 10 dB. Stokroos et al17 considered improvement as more than 10 dB, and Kronenberg et al14 defined recovery as a minimal increase of 15 dB by the end of treatment and a simultaneous hearing level of more than 40 dB. An alternative option is to measure improvement in the affected frequencies only. In the current study, we considered a 15-dB increase in the involved frequencies as a significant improve-
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Fig 3. A, Hearing improvement in both groups when treatment was started 1 to 4 days from onset of symptoms. Improvement was similar, with no statistical significance in either group. B, Hearing improvement in both groups when treatment initiation was on days 5 to 7. Improvement was similar, with no statistical significance in either group.
ment. No significant difference was found between the 2 study groups in PT measurements or between the 2 groups in the SRT measurements, probably due to the fact that the speech frequencies were not necessarily involved. The type of treatment, gender, and age had no effect on hearing improvement. The only variable that had an effect on hearing improvement was the proximity of treatment to the patient’s hearing loss. Our data suggest that the sooner treatment is started, the better is the chance for recovery. The overall improvement in pure tone in each frequency is higher when treatment was started early
during the course of the disease (days 1 to 4) compared with late treatment (days 5 to 7 from onset of treatment). However, the findings are significant only in one of the frequencies in each group. The lack of significance may be related to the wide standard deviation in each frequency, which may reflect the variety in the type of hearing loss in our study. The interval between the onset of the hearing loss and the beginning of treatment is known as a prognostic factor.7,20 The wide standard deviation in the different frequencies suggests that not all frequencies were equally involved. The patients could have been divided according to their audiogram shape (ris-
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ing, flat, sloping, or complete deafness). As a result, the groups would have been too small for statistical analysis. Our clinical impression is that prognosis is unfavorable in cases of profound hearing loss, regardless of the treatment or the day of arrival. Seventy-three percent of our patients had tinnitus and, contrary to the finding of Stokroos et al,17 had a better prognosis. Thirty percent of the patients in both groups experienced vestibular disturbances (dizziness), and those patients had an unfavorable prognosis regardless of acyclovir use. These findings are supported by Byl,7 who found vertigo to be a poor prognostic factor. On the other hand, Stokroos et al17 found a better prognosis with vestibular involvement. We assume that hearing loss that is accompanied by vestibular symptoms indicates more extensive inner ear disease with a poorer prognosis. The main question remains of why disease with a probable viral etiology shows no improvement after acyclovir treatment. It may be related to other viral pathogens that are not of the herpes group and, hence, not responsive to acyclovir. Another possible explanation may be that the working hypothesis is multifactorial, and the viral pathogen is a part of it. CONCLUSION Our data suggest that acyclovir added to hydrocortisone has no additive effect on the recovery of patients with ISSNHL. Further study is needed to prove the viral etiology in ISSNHL and to identify the population who may have it. Other antiviral agents may be examined as well to solve this frustrating problem. REFERENCES
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