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Sudden sensorineural hearing loss: Is antiviral treatment really necessary?
AMER IC AN JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D NE CK M E D ICI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Original contribution
Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Gültekin Övet, MD a,⁎, Necat Alataş, MD a , Fatma Nur Kocacan, MD a , Sermin Selver Gürcüoğlu, MD a , Hakan Görgülü, MD a , Fatih Güzelkara, MD a , Habibe Övet, MD b a b
Department of Otorhinolaryngology, Konya Training and Research Hospital, Konya, Turkey Department of Microbiology, Konya Training and Research Hospital, Konya, Turkey
ARTI CLE I NFO
A BS TRACT
Article history:
Objectives: It was aimed to investigate the necessity of antiviral agents in the ISSHL
Received 7 January 2015
treatment. Methods: In this study, the patients, diagnosed with sudden hearing loss and admitted in the first 7 days of hearing loss were divided into two groups; a combination therapy was administered to one of the groups, and famciclovir was administered to the other group as an antiviral treatment in addition to the combined therapy. Both groups were compared in terms of levels of recovery. Results: No statistically significant difference was found in the recovery rates between the two groups (p = 0.7). Conclusion: In this study, the additional antiviral treatment was found to have no effect on the remission rates in patients with ISSHL treated with combined therapy. © 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Idiopathic sudden sensorineural hearing loss (ISSNHL) is one of the most controversial issues of otolaryngology since its etiology and treatment cannot be elucidated fully. Sudden hearing loss is defined as development of more than 30 dB of sensorineural hearing loss at three sequential frequencies in less than three days [1]. Since it was described by De Kleyn in 1944 for the first time, its etiopathogenesis has not been fully clarified. Theories such as viral infection, vascular occlusion, perforation of the labyrinthine membranes, immune-mediated mechanisms and abnormal stress response in the cochlea have been proposed to explain the etiopathogenesis of ISSHL [1].
Although a variety of treatment protocols have been applied in ISSNHL, no consensus has been formed yet [2]. Although vasodilators, diuretics, anticoagulants, plasma expanders, CO2 and various other methods are proposed for treatment, all these treatment modalities are applied empirically in many cases, without revealing the cause clearly. Hence, all these treatment modalities need a proper explanation [2]. Only the steroid therapy has been shown to be effective on good prognosis, albeit to a certain extent [3]. Spontaneous healing rate of ISSNHL has been shown as 32–65% in various studies, and the healing rates in ISSNHL have been reported as 49–89% with the use of steroids [4].
⁎ Corresponding author at: Department of Otorhinolaryngology, Konya Training and Research Hospital, Hacı Şaban Mah. Meram Yeniyol Caddesi No: 97, PK: 42040 Meram, Konya, Turkey. Tel.: + 90 332 444 06 42; fax: + 90 332 323 67 23. E-mail address: [email protected] (G. Övet). http://dx.doi.org/10.1016/j.amjoto.2015.02.011 0196-0709/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
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AMER ICA N JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D N E CK M EDI CI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
The insufficiently understood pathophysiology, spontaneous recovery in the course of the disease, and its low incidence makes it difficult to choose the treatment modalities [5]. In recent studies, viral agents were considered responsible in a significant number of patients with ISSNHL, and antiviral-agent acyclovir has been proposed as an effective treatment option in cases with a viral etiology [5]. After some histopathological studies, many clinicians started to consider viral factors' role in the etiopathogenesis. The results of some of the histopathological studies were interpreted in favor of viral etiology, and antiviral therapy has recently started to be adopted [5]. On the other hand, many clinicians have started to add antiviral therapy to their treatment by considering viral etiology, albeit improvable [1]. However, the efficacy of antiviral therapy could not be demonstrated clearly, and, there is a debate on how and by which ways the viruses cause ISSHL as well. The aim of this study is to determine whether the patients with ISSNHL benefit from early treatment with famciclovir antiviral-agent. Thus, the efficacy of antiviral therapy in patients with ISSHL will be studied. Famciclovir is a drug that is rapidly absorbed orally and metabolized to penciclovir. Its bioavailability is high and plasma concentration reaches its peak in an hour. Routine famciclovir use for sudden hearing loss (ISSNHL) has not been found in the literature. This is the first study in the literature on the use of famciclovir in sudden sensorineural hearing loss.
2.
Materials and methods
The patients admitted within 7 days from the onset of the symptoms were included in this study. Detailed histories of the patients were taken first, and then the systemic ENT and vestibular system examinations were performed. All patients were evaluated for the fasting blood glucose, liver function tests (ALT, AST, GGT, total bilirubin), renal function tests (Na, K, Cl, urea, creatinine clearance), bleeding profiles (aPTT, PTZ), and contrast-enhanced magnetic resonance imaging (MRI) of the cranial. The patients with hypertension, diabetes, autoimmune, collagen and renal diseases and the patients
with a previous history of ear disease or the ones that have a known hearing loss, and the patients diagnosed as fluctuating hearing loss at the follow-up and the patients with cerebellopontine angle tumor were not included in the study. In total, 41 patients were included in the study, according to the inclusion criteria. In this study, the patients that were administered with a combined treatment and the patients administered with famciclovir in addition to the combined therapy were divided into groups according to their hearing loss treatments. The Group 1 patients consisted of the patients administered with a combined therapy, and the Group 2 consisted of the patients administered with the additional famciclovir treatment. The Group 1 patients were administered with steroid (methylprednisolone, 250 mg on the first day, 150 mg on the second day, 100 mg on the third day, and this continued by 20 mg reduction in every three days beginning from the fourth day), rheomarodex (500 cc, as to continue for 8 hours, for 5 days) and piracetam (3 × 2 g ampule for 5 days), lansoprol capsule (1× 1 for stomach protection). Patients in the Group 2 were administered with famciclovir 3 × 250 mg orally, for 7 days, in addition to the combined treatment in the Group 1. During the treatment, the blood pressure and blood glucose levels of all patients were monitored. In order to ensure standardization of the groups, the patients were proportionally divided into the groups in terms of the factors (degree of loss, the shape of the audiogram, presence of vertigo and/or tinnitus, age) that may affect prognosis (Table 1). Before and after the treatment, the patients were evaluated by audiometric examinations on the 7th day, 10th day, 1st month and 6th month. The pure tone audiometry, speech reception thresholds (SRT), discrimination, the stapes reflex and tympanometric examinations were performed on the patients. The differences between pure tone averages taken before the treatment and on the 6th month after treatment were calculated for the two groups and the differences were assessed for a statistical significance. The patients with more than 15 dB gain were considered to have benefited from the treatment. The difference between the two groups evaluated to investigate the therapeutic efficacy of famciclovir in sudden hearing loss.
Table 1 – The degree of hearing loss, audiogram type and concomitant clinical features according to the groups. Group 1
Hearing loss Mild Moderate Moderately severe Severe Tinnitus Vertigo Shape of the audiogram Upwards Flat Downwards
Group 2
n
%
Recovery
n
%
Recovery
2 8 5 5 11 5
10 40 25 25 55 25
2 (100%) 7 (88%) 2 (40%) 2 (40%) 6 (55%) 2 (40%)
3 7 5 6 13 3
14 33 24 29 62 14
3 (100%) 6 (85%) 3 (60%) 3 (50%) 8 (62%) 3 (100%)
9 7 4
45 35 20
6 (66%) 5 (71%) 2 (50%)
8 7 6
38 33 29
6 (75%) 6 (85%) 3 (50%)
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
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AMER IC AN JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D NE CK M E D ICI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
Table 2 – Improvement after treatment. Famciclovir (+) Group 2
Improved No improved
2.1.
Famciclovir (−) Group 1
n
%
n
%
p
15 6 21
71 29 100
13 7 20
65 35 100
p = 0.7
Statistical analysis
Fisher's exact test was used in 2 × 2 tables, and nonparametric Mann-Whitney U test was used for the comparison of binary groups that lack the normal distribution. p < 0.05 was considered as statistically significant. SPSS for Windows 10.0 was used in the statistical analysis.
3.
Results
The ages of the patients ranged from 27 to 58, the mean age was 42 ± 7.85 years. 21 patients were included in the Group 2. 10 of the patients were male and 11 were female. 20 patients were included in the Group 1. Of these, 11 were female and 9 were male. There was no significant difference between the Group 1 and Group 2 in terms of the age and gender distribution. No statistically significant difference was found between the two groups in terms of the level of hearing loss (mild, moderate, moderately severe, severe) (Mann-Whitney U test, p = 0.946). No statistically significant difference was found between the two groups in terms of hearing gain over 15 dB (p = 0.744, Fisher's exact test). No statistically significant difference was found between the presence and lack of remission in the Group 1 patients based on the shape of the audiogram (Mann-Whitney U test, p = 0.701). No statistically significant difference was found between the presence and lack of remission in the Group 1 patients based on the shape of the audiogram (Mann-Whitney U test, p = 0.675). Of all patients (41 patients) in the groups, 24 (58%) had tinnitus, and 8 (20%) had vertigo. The level of right and left ear involvement was at equal rates, whereas there was no bilateral involvement. According to the pure tone audiogram taken in the sixth month, the success rate was 71% in the famciclovir group (Group 2), whereas the success rate of the other group (Group 1) was 65% (Table 2). The difference between two groups was not statistically significant (p = 0.07). Although a recovery was observed in 5 (63%) of the 8 patients with vertigo, 2 patients showed no improvement. All three patients with vertigo in the Group 2 were recovered, whereas only 2 of the 5 patients with vertigo in the Group 1 were healed. Although a healing was observed in 14 (58%) of the 24 patients with tinnitus, 10 patients showed no improvement. 8 of the 13 patients with tinnitus in the Group 2 were recovered, whereas only 6 of the 11 patients with tinnitus in the Group 1 were healed. Looking at the gains, according to the shape of the audiogram, 70% healing was observed with those inclined upwards, healing was 50% with those inclined downwards, and the healing rate was 78% with those having a flat audiogram (Table 1). There were no any side effects of famciclovir in the course of the treatment.
4.
Discussion
In the treatment of sudden hearing loss, several treatment methods have been tried so far, but no any exact method that
presents successful results has been found yet. The medical agents to be administered in the treatment are still subject to debate. Previous studies on viruses have examined temporal bone specimens to seek findings that support viral pathology. Although there are numerous studies conducted to demonstrate viruses as etiological agents, there is not much objective evidence that supports the viral etiology. Measles-mumpsrubella, herpes virus family and many upper respiratory viruses have been implicated in the etiology of ISSHL. However, there are a limited number of clinical and laboratory studies indicating that these viruses were effective in this regard [6–8]. Westmore et al. have isolated the mumps virus from the perilymph of a 26-year-old female patient admitted with a hearing loss following mumps parotid. This is the only study indicating that these viruses were the etiologic agent in ISSHL [9]. Many studies, however, reported that mumps virus was only responsible for a very small fraction of ISSHL cases (less than 10%) [7,8], and, measles and rubella virus has been reported as a rare cause of ISSHL serologically in few cases [7,10]. Indeed, these agents, which were considered in the etiology of ISSHL, are almost eradicated thanks to a worldwide vaccination [11]. Herpes virus family (herpesviridae) is perhaps the most accused virus family in the etiology of ISSHL [12–14]. The herpes virus family consists of herpes simplex types 1 and 2 (HSV type 1, HSV type 2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and human herpes virus 6, 7 and 8 (HHV-6, HHV-7, HHV-8). However, once infected, these viruses remain latent for life. Many adults, which have been infected by these viruses in childhood, have serological antibodies against many of these viruses (they are seropositive). For example, 91% of adults are seropositive for HSV-1, 90% are seropositive for VZV, 70% are seropositive for CMV, 90% are seropositive for EBV, and 95% are seropositive for HHV-6 [15]. That is to say, these viruses do not cause new infections in adults. An ISSHL caused by these viruses in humans can only be explained by latent virus reactivation. Unfortunately, there is no any good serological test that may reveal a reactivation of latent virus. According to anamnesis and serological data of the patient, many respiratory viruses, such as Adeno virus and Arena virus, were thought to be cause in ISSHL [7,16]. On the other hand, tests performed against multiple viruses in some studies showed no increase in antibodies against the viruses [17]. In a study conducted by Pitkäranta and Julkunen, no interferon and interferon-induced gene expression samples were found that can be detected in peripheral blood, which are useful in the diagnosis of systemic viral infections in patients with ISSHL [17]. No specific virus was targeted in this study, but markers that increase in any viral infection were investigated, but these markers were not found to increase.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
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AMER ICA N JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D N E CK M EDI CI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
There are studies that reveal histopathological findings in the temporal bones of patients with ISSHL. No evidence has been found in all these studies on the direct viral invasion or inner ear infection. No virus has been isolated from the labyrinth; typical abnormalities of viral cytopathology have not been shown, and, electron microscopic examination has not revealed any viral particles. In the temporal bone sections, viral nucleic acid samples (especially HSV) have been sought by PCR, however, the result has been found to be negative [18]. There are numerous studies where the pathogenic virus was inoculated into the inner ear directly in animal experiments [19]. In most of these studies, hearing loss was found to be progressive, not sudden, leukocyte infiltration, hemorrhage, and a widespread degeneration in sensory and neuronal structure in the cochlea was observed, and a following fibrosis and new bone formation was histopathologically shown in some cases [20]. In other studies, minimal pathological changes were found in labyrinth due to virus inoculation in the labyrinth [21,22]. In the examination of cochlea of a patient died after a deep sudden hearing loss (80 to 100 dB), no leukocyte invasion, hypervascular regions or hemorrhage were observed, which are likely to be found in a real viral cochleitis [21,22]. In numerous clinical studies, antiviral agents were added in the treatment of patients with ISSHL, however, efficacy of antiviral treatment has not been shown clearly. In a randomized clinical trial conducted by Tucci et al. on two groups with sudden hearing loss, one of the groups was administered with high-dose steroids (80 mg steroid was administered to 44 patients for 4 days, and treatment was continued with lower doses afterwards), whereas the other group was administered with oral valacyclovir (1 g to 55 patients 3 times a day for 10 days) in addition to the high-dose steroids. Looking at the comparison of both groups after treatment, a valacyclovir addition to the high-dose steroid treatment has been shown to have no statistically significant effect (p > 0.05, Fischer exact test) [23]. In a double-blind randomized clinical trial, Westerlaken et al. have administered steroids (1 mg/kg prednisolone, continued for 7 days with decreasing doses) and acyclovir (10 mg/kg intravenously, 3 times per day for 7 days) to 46 patients as treatment, and 45 patients have been administered with steroids and placebo. The patients were followed for a year after the treatment, and no statistically significant difference was found between the groups administered with prednisolone + acyclovir and the group administered with prednisolone + placebo (analyzed by Mann-Whitney and Fisher's exact test, p > 0.05) [24]. Conlin and Parnes have performed a meta-analysis on the benefits of additional antiviral therapy in the oral steroid therapy, and demonstrated that antiviral additions to the steroid therapy have no effect on healing and recovery time in the treatment of hearing [25]. Recently, a guideline was published by the American Academy of Otolaryngology for sudden hearing loss. This guideline provides evidence-based recommendations for the diagnosis, management, and follow-up of patients who present with SHL. The panel made a recommendation against clinicians routinely prescribing antivirals to patients with ISSNHL. In addition, antiviral agent use is not without consequences, and reported side effects include
nausea, vomiting, photosensitivity, and, rarely, reversible neurologic reactions, including mental status changes, dizziness, and seizures [26]. Although there was a 65% success rate in the combined therapy group in our study, and the success rate was 71% in the group additionally administered with famciclovir, the difference was not statistically significant.
5.
Conclusion
ISSNHL etiology is not clarified in full yet. In this study, the additional antiviral treatment was found to have no effect on the remission rates in patients with ISSHL treated with combined therapy. This can be explained by the fact multifactorial etiology. Viruses are perhaps less active than expected in the etiology of the disease. Without a history of a viral infection or a viral infection identified in their history, we believe that patients are not routinely prescribed antiviral agents. With regard to the etiology of the disease, more research that needs to be done is related to the different hypotheses. The hypothesis that states the pathological stress pathways within the cochlea induce circulating ligands (cellular-stress response) should be investigated in a more serious manner.
Conflict of interest None of the authors has any conflict of interest, financial or otherwise.
REFERENCES
[1] De Kleyn A. Sudden complete or partial loss of function of the octavus-system in apparently normal persons. Acta Otolaryngol (Stockh) 1944;32:407–29. [2] Stokroos RJ, Albers FW, Tenverget EM. Antiviral treatment of idiopathic sudden sensorineural hearing loss: a prospective, randomized, double-blind clinical trial. Acta Otolaryngol 1998;118:488–95. [3] Westerlaken BO, Stokroos RJ, Dhooge IJ, et al. Treatment of idiopathic sudden sensorineural hearing loss with antiviral therapy: a retrospective, randomized double-blind clinical trial. Ann Otol Rhinol Laryngol 2003;112:993–1000. [4] Cinamon U, Bendet E, Kronenberg J. Steroids, carbogen or placebo for sudden hearing loss: a prospective double-blind study. Eur Arch Otorhinolaryngol 2001;258:477–80. [5] Rauch SD. Intratympanic steroids for sensorineural hearing loss. Otolaryngol Clin North Am 2004;37:1061–74. [6] Vuori M, Lahikainen EA, Peltonen T. Perceptive deafness in connection with mumps. A study of 298 servicemen suffering from mumps. Acta Otolaryngol 1962;55:231–6. [7] Veltri RW, Wilson WR, Sprinkle PM, et al. The implication of viruses in idiopathic sudden hearing loss: primary infection or reactivation of latent viruses? Otolaryngol Head Neck Surg 1981;89:137–41. [8] Okamoto M, Shitara T, Nakayama M, et al. Sudden deafness accompanied by asymptomatic mumps. Acta Otolaryngol Suppl 1994;514:45–8. [9] Westmore GA, Pickard BH, Stern H. Isolation of mumps virus from the inner ear after sudden deafness. BMJ 1979;1:14–5.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
AMER IC AN JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D NE CK M E D ICI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
[10] Kobayashi H, Suzuki A, Nomura Y. Unilateral hearing loss following rubella infection in an adult. Acta Otolaryngol Suppl 1994;514:49–51. [11] Pitkäranta A, Vasama JP, Julkunen I. Sudden deafness and viral infections. Otorhinolaryngol Nova 1999;9:190–7. [12] Wilson WR. The relationship of the herpes-virus family to sudden hearing loss: a prospective clinical study and literature review. Laryngoscope 1986;96:870–7. [13] Fukuda S, Furuta Y, Takasu T, et al. The significance of herpes viral latency in the spiral ganglia. Acta Otolaryngol Suppl 1994;514:108–10. [14] Takasaki T, Higashikawa M, Motoyama S, et al. Serum antibodies to human herpesvirus 7, human herpesvirus 6 and cytomegalovirus in patients with idiopathic facial nerve palsy or sudden deafness. J Laryngol Otol 1998;112:617–21. [15] Merchant SN, Adams JC, Nadol JB. Pathology and pathophysiology of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2005;26:151–60. [16] Van Dishoeck H, Bierman T. Sudden perceptive deafness and viral infection (report of the first one hundred patients). Ann Otol Rhinol Laryngol 1957;66:963–80. [17] Pitkäranta A, Julkunen I. Sudden deafness: lack of evidence for systemic viral infection. Otolaryngol Head Neck Surg 1998;118:397–9. [18] 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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[19] Schuknecht HF, Donovan ED. The pathology of idiopathic sudden sensorineural hearing loss. Arch Otorhinolaryngol 1986;243:1–15. [20] Khetarpal U, Nadol JB, Glynn RJ. Idiopathic sudden sensorineural hearing loss and postnatal viral labyrinthitis: a statistical comparison of temporal bone findings. Ann Otol Rhinol Laryngol 1990;99:969–76. [21] Stokroos RJ, Albers FWJ, Schirm J. The etiology of idiopathic sudden sensorineural hearing loss: experimental herpes simplex virus infection of the inner ear. Am J Otol 1998;19: 447–52. [22] Karmody CS. Viral labyrinthitis. An experimental study. Ann Otol Rhinol Laryngol 1975;84:179–81. [23] Tucci DL, Farmer JC, Kitch RD, et al. Treatment of sudden sensorineural hearing loss with systemic steroids and valacyclovir. Otol Neurotol 2002;23:301–8. [24] Westerlaken BO, Stokroos RJ, Dhooge IJ, et al. Treatment of idiopathic sudden sensorineural hearing loss with antiviral therapy: a prospective, randomized, double-blind clinical trial. Ann Otol Rhinol Laryngol 2003;112:993–1000. [25] Conlin AE, Parnes LS. Treatment of sudden sensorineural hearing loss: II. A Meta-analysis. Arch Otolaryngol Head Neck Surg 2007;133:582–6. [26] Stachler RJ, Chandrasekhar SS, Archer SM, et al. American Academy of Otolaryngology-Head and Neck Surgery. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg 2012;146:1–35.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Original contribution
Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Gültekin Övet, MD a,⁎, Necat Alataş, MD a , Fatma Nur Kocacan, MD a , Sermin Selver Gürcüoğlu, MD a , Hakan Görgülü, MD a , Fatih Güzelkara, MD a , Habibe Övet, MD b a b
Department of Otorhinolaryngology, Konya Training and Research Hospital, Konya, Turkey Department of Microbiology, Konya Training and Research Hospital, Konya, Turkey
ARTI CLE I NFO
A BS TRACT
Article history:
Objectives: It was aimed to investigate the necessity of antiviral agents in the ISSHL
Received 7 January 2015
treatment. Methods: In this study, the patients, diagnosed with sudden hearing loss and admitted in the first 7 days of hearing loss were divided into two groups; a combination therapy was administered to one of the groups, and famciclovir was administered to the other group as an antiviral treatment in addition to the combined therapy. Both groups were compared in terms of levels of recovery. Results: No statistically significant difference was found in the recovery rates between the two groups (p = 0.7). Conclusion: In this study, the additional antiviral treatment was found to have no effect on the remission rates in patients with ISSHL treated with combined therapy. © 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Idiopathic sudden sensorineural hearing loss (ISSNHL) is one of the most controversial issues of otolaryngology since its etiology and treatment cannot be elucidated fully. Sudden hearing loss is defined as development of more than 30 dB of sensorineural hearing loss at three sequential frequencies in less than three days [1]. Since it was described by De Kleyn in 1944 for the first time, its etiopathogenesis has not been fully clarified. Theories such as viral infection, vascular occlusion, perforation of the labyrinthine membranes, immune-mediated mechanisms and abnormal stress response in the cochlea have been proposed to explain the etiopathogenesis of ISSHL [1].
Although a variety of treatment protocols have been applied in ISSNHL, no consensus has been formed yet [2]. Although vasodilators, diuretics, anticoagulants, plasma expanders, CO2 and various other methods are proposed for treatment, all these treatment modalities are applied empirically in many cases, without revealing the cause clearly. Hence, all these treatment modalities need a proper explanation [2]. Only the steroid therapy has been shown to be effective on good prognosis, albeit to a certain extent [3]. Spontaneous healing rate of ISSNHL has been shown as 32–65% in various studies, and the healing rates in ISSNHL have been reported as 49–89% with the use of steroids [4].
⁎ Corresponding author at: Department of Otorhinolaryngology, Konya Training and Research Hospital, Hacı Şaban Mah. Meram Yeniyol Caddesi No: 97, PK: 42040 Meram, Konya, Turkey. Tel.: + 90 332 444 06 42; fax: + 90 332 323 67 23. E-mail address: [email protected] (G. Övet). http://dx.doi.org/10.1016/j.amjoto.2015.02.011 0196-0709/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
2
AMER ICA N JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D N E CK M EDI CI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
The insufficiently understood pathophysiology, spontaneous recovery in the course of the disease, and its low incidence makes it difficult to choose the treatment modalities [5]. In recent studies, viral agents were considered responsible in a significant number of patients with ISSNHL, and antiviral-agent acyclovir has been proposed as an effective treatment option in cases with a viral etiology [5]. After some histopathological studies, many clinicians started to consider viral factors' role in the etiopathogenesis. The results of some of the histopathological studies were interpreted in favor of viral etiology, and antiviral therapy has recently started to be adopted [5]. On the other hand, many clinicians have started to add antiviral therapy to their treatment by considering viral etiology, albeit improvable [1]. However, the efficacy of antiviral therapy could not be demonstrated clearly, and, there is a debate on how and by which ways the viruses cause ISSHL as well. The aim of this study is to determine whether the patients with ISSNHL benefit from early treatment with famciclovir antiviral-agent. Thus, the efficacy of antiviral therapy in patients with ISSHL will be studied. Famciclovir is a drug that is rapidly absorbed orally and metabolized to penciclovir. Its bioavailability is high and plasma concentration reaches its peak in an hour. Routine famciclovir use for sudden hearing loss (ISSNHL) has not been found in the literature. This is the first study in the literature on the use of famciclovir in sudden sensorineural hearing loss.
2.
Materials and methods
The patients admitted within 7 days from the onset of the symptoms were included in this study. Detailed histories of the patients were taken first, and then the systemic ENT and vestibular system examinations were performed. All patients were evaluated for the fasting blood glucose, liver function tests (ALT, AST, GGT, total bilirubin), renal function tests (Na, K, Cl, urea, creatinine clearance), bleeding profiles (aPTT, PTZ), and contrast-enhanced magnetic resonance imaging (MRI) of the cranial. The patients with hypertension, diabetes, autoimmune, collagen and renal diseases and the patients
with a previous history of ear disease or the ones that have a known hearing loss, and the patients diagnosed as fluctuating hearing loss at the follow-up and the patients with cerebellopontine angle tumor were not included in the study. In total, 41 patients were included in the study, according to the inclusion criteria. In this study, the patients that were administered with a combined treatment and the patients administered with famciclovir in addition to the combined therapy were divided into groups according to their hearing loss treatments. The Group 1 patients consisted of the patients administered with a combined therapy, and the Group 2 consisted of the patients administered with the additional famciclovir treatment. The Group 1 patients were administered with steroid (methylprednisolone, 250 mg on the first day, 150 mg on the second day, 100 mg on the third day, and this continued by 20 mg reduction in every three days beginning from the fourth day), rheomarodex (500 cc, as to continue for 8 hours, for 5 days) and piracetam (3 × 2 g ampule for 5 days), lansoprol capsule (1× 1 for stomach protection). Patients in the Group 2 were administered with famciclovir 3 × 250 mg orally, for 7 days, in addition to the combined treatment in the Group 1. During the treatment, the blood pressure and blood glucose levels of all patients were monitored. In order to ensure standardization of the groups, the patients were proportionally divided into the groups in terms of the factors (degree of loss, the shape of the audiogram, presence of vertigo and/or tinnitus, age) that may affect prognosis (Table 1). Before and after the treatment, the patients were evaluated by audiometric examinations on the 7th day, 10th day, 1st month and 6th month. The pure tone audiometry, speech reception thresholds (SRT), discrimination, the stapes reflex and tympanometric examinations were performed on the patients. The differences between pure tone averages taken before the treatment and on the 6th month after treatment were calculated for the two groups and the differences were assessed for a statistical significance. The patients with more than 15 dB gain were considered to have benefited from the treatment. The difference between the two groups evaluated to investigate the therapeutic efficacy of famciclovir in sudden hearing loss.
Table 1 – The degree of hearing loss, audiogram type and concomitant clinical features according to the groups. Group 1
Hearing loss Mild Moderate Moderately severe Severe Tinnitus Vertigo Shape of the audiogram Upwards Flat Downwards
Group 2
n
%
Recovery
n
%
Recovery
2 8 5 5 11 5
10 40 25 25 55 25
2 (100%) 7 (88%) 2 (40%) 2 (40%) 6 (55%) 2 (40%)
3 7 5 6 13 3
14 33 24 29 62 14
3 (100%) 6 (85%) 3 (60%) 3 (50%) 8 (62%) 3 (100%)
9 7 4
45 35 20
6 (66%) 5 (71%) 2 (50%)
8 7 6
38 33 29
6 (75%) 6 (85%) 3 (50%)
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
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AMER IC AN JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D NE CK M E D ICI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
Table 2 – Improvement after treatment. Famciclovir (+) Group 2
Improved No improved
2.1.
Famciclovir (−) Group 1
n
%
n
%
p
15 6 21
71 29 100
13 7 20
65 35 100
p = 0.7
Statistical analysis
Fisher's exact test was used in 2 × 2 tables, and nonparametric Mann-Whitney U test was used for the comparison of binary groups that lack the normal distribution. p < 0.05 was considered as statistically significant. SPSS for Windows 10.0 was used in the statistical analysis.
3.
Results
The ages of the patients ranged from 27 to 58, the mean age was 42 ± 7.85 years. 21 patients were included in the Group 2. 10 of the patients were male and 11 were female. 20 patients were included in the Group 1. Of these, 11 were female and 9 were male. There was no significant difference between the Group 1 and Group 2 in terms of the age and gender distribution. No statistically significant difference was found between the two groups in terms of the level of hearing loss (mild, moderate, moderately severe, severe) (Mann-Whitney U test, p = 0.946). No statistically significant difference was found between the two groups in terms of hearing gain over 15 dB (p = 0.744, Fisher's exact test). No statistically significant difference was found between the presence and lack of remission in the Group 1 patients based on the shape of the audiogram (Mann-Whitney U test, p = 0.701). No statistically significant difference was found between the presence and lack of remission in the Group 1 patients based on the shape of the audiogram (Mann-Whitney U test, p = 0.675). Of all patients (41 patients) in the groups, 24 (58%) had tinnitus, and 8 (20%) had vertigo. The level of right and left ear involvement was at equal rates, whereas there was no bilateral involvement. According to the pure tone audiogram taken in the sixth month, the success rate was 71% in the famciclovir group (Group 2), whereas the success rate of the other group (Group 1) was 65% (Table 2). The difference between two groups was not statistically significant (p = 0.07). Although a recovery was observed in 5 (63%) of the 8 patients with vertigo, 2 patients showed no improvement. All three patients with vertigo in the Group 2 were recovered, whereas only 2 of the 5 patients with vertigo in the Group 1 were healed. Although a healing was observed in 14 (58%) of the 24 patients with tinnitus, 10 patients showed no improvement. 8 of the 13 patients with tinnitus in the Group 2 were recovered, whereas only 6 of the 11 patients with tinnitus in the Group 1 were healed. Looking at the gains, according to the shape of the audiogram, 70% healing was observed with those inclined upwards, healing was 50% with those inclined downwards, and the healing rate was 78% with those having a flat audiogram (Table 1). There were no any side effects of famciclovir in the course of the treatment.
4.
Discussion
In the treatment of sudden hearing loss, several treatment methods have been tried so far, but no any exact method that
presents successful results has been found yet. The medical agents to be administered in the treatment are still subject to debate. Previous studies on viruses have examined temporal bone specimens to seek findings that support viral pathology. Although there are numerous studies conducted to demonstrate viruses as etiological agents, there is not much objective evidence that supports the viral etiology. Measles-mumpsrubella, herpes virus family and many upper respiratory viruses have been implicated in the etiology of ISSHL. However, there are a limited number of clinical and laboratory studies indicating that these viruses were effective in this regard [6–8]. Westmore et al. have isolated the mumps virus from the perilymph of a 26-year-old female patient admitted with a hearing loss following mumps parotid. This is the only study indicating that these viruses were the etiologic agent in ISSHL [9]. Many studies, however, reported that mumps virus was only responsible for a very small fraction of ISSHL cases (less than 10%) [7,8], and, measles and rubella virus has been reported as a rare cause of ISSHL serologically in few cases [7,10]. Indeed, these agents, which were considered in the etiology of ISSHL, are almost eradicated thanks to a worldwide vaccination [11]. Herpes virus family (herpesviridae) is perhaps the most accused virus family in the etiology of ISSHL [12–14]. The herpes virus family consists of herpes simplex types 1 and 2 (HSV type 1, HSV type 2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and human herpes virus 6, 7 and 8 (HHV-6, HHV-7, HHV-8). However, once infected, these viruses remain latent for life. Many adults, which have been infected by these viruses in childhood, have serological antibodies against many of these viruses (they are seropositive). For example, 91% of adults are seropositive for HSV-1, 90% are seropositive for VZV, 70% are seropositive for CMV, 90% are seropositive for EBV, and 95% are seropositive for HHV-6 [15]. That is to say, these viruses do not cause new infections in adults. An ISSHL caused by these viruses in humans can only be explained by latent virus reactivation. Unfortunately, there is no any good serological test that may reveal a reactivation of latent virus. According to anamnesis and serological data of the patient, many respiratory viruses, such as Adeno virus and Arena virus, were thought to be cause in ISSHL [7,16]. On the other hand, tests performed against multiple viruses in some studies showed no increase in antibodies against the viruses [17]. In a study conducted by Pitkäranta and Julkunen, no interferon and interferon-induced gene expression samples were found that can be detected in peripheral blood, which are useful in the diagnosis of systemic viral infections in patients with ISSHL [17]. No specific virus was targeted in this study, but markers that increase in any viral infection were investigated, but these markers were not found to increase.
Please cite this article as: Övet G, et al, Sudden sensorineural hearing loss: Is antiviral treatment really necessary? Am J Otolaryngol–Head and Neck Med and Surg (2015), http://dx.doi.org/10.1016/j.amjoto.2015.02.011
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AMER ICA N JOURNAL OF OT OLA RYNGOLOGY– H E A D A N D N E CK M EDI CI N E AN D S U RGE RY X X (2 0 1 5) XXX – XXX
There are studies that reveal histopathological findings in the temporal bones of patients with ISSHL. No evidence has been found in all these studies on the direct viral invasion or inner ear infection. No virus has been isolated from the labyrinth; typical abnormalities of viral cytopathology have not been shown, and, electron microscopic examination has not revealed any viral particles. In the temporal bone sections, viral nucleic acid samples (especially HSV) have been sought by PCR, however, the result has been found to be negative [18]. There are numerous studies where the pathogenic virus was inoculated into the inner ear directly in animal experiments [19]. In most of these studies, hearing loss was found to be progressive, not sudden, leukocyte infiltration, hemorrhage, and a widespread degeneration in sensory and neuronal structure in the cochlea was observed, and a following fibrosis and new bone formation was histopathologically shown in some cases [20]. In other studies, minimal pathological changes were found in labyrinth due to virus inoculation in the labyrinth [21,22]. In the examination of cochlea of a patient died after a deep sudden hearing loss (80 to 100 dB), no leukocyte invasion, hypervascular regions or hemorrhage were observed, which are likely to be found in a real viral cochleitis [21,22]. In numerous clinical studies, antiviral agents were added in the treatment of patients with ISSHL, however, efficacy of antiviral treatment has not been shown clearly. In a randomized clinical trial conducted by Tucci et al. on two groups with sudden hearing loss, one of the groups was administered with high-dose steroids (80 mg steroid was administered to 44 patients for 4 days, and treatment was continued with lower doses afterwards), whereas the other group was administered with oral valacyclovir (1 g to 55 patients 3 times a day for 10 days) in addition to the high-dose steroids. Looking at the comparison of both groups after treatment, a valacyclovir addition to the high-dose steroid treatment has been shown to have no statistically significant effect (p > 0.05, Fischer exact test) [23]. In a double-blind randomized clinical trial, Westerlaken et al. have administered steroids (1 mg/kg prednisolone, continued for 7 days with decreasing doses) and acyclovir (10 mg/kg intravenously, 3 times per day for 7 days) to 46 patients as treatment, and 45 patients have been administered with steroids and placebo. The patients were followed for a year after the treatment, and no statistically significant difference was found between the groups administered with prednisolone + acyclovir and the group administered with prednisolone + placebo (analyzed by Mann-Whitney and Fisher's exact test, p > 0.05) [24]. Conlin and Parnes have performed a meta-analysis on the benefits of additional antiviral therapy in the oral steroid therapy, and demonstrated that antiviral additions to the steroid therapy have no effect on healing and recovery time in the treatment of hearing [25]. Recently, a guideline was published by the American Academy of Otolaryngology for sudden hearing loss. This guideline provides evidence-based recommendations for the diagnosis, management, and follow-up of patients who present with SHL. The panel made a recommendation against clinicians routinely prescribing antivirals to patients with ISSNHL. In addition, antiviral agent use is not without consequences, and reported side effects include
nausea, vomiting, photosensitivity, and, rarely, reversible neurologic reactions, including mental status changes, dizziness, and seizures [26]. Although there was a 65% success rate in the combined therapy group in our study, and the success rate was 71% in the group additionally administered with famciclovir, the difference was not statistically significant.
5.
Conclusion
ISSNHL etiology is not clarified in full yet. In this study, the additional antiviral treatment was found to have no effect on the remission rates in patients with ISSHL treated with combined therapy. This can be explained by the fact multifactorial etiology. Viruses are perhaps less active than expected in the etiology of the disease. Without a history of a viral infection or a viral infection identified in their history, we believe that patients are not routinely prescribed antiviral agents. With regard to the etiology of the disease, more research that needs to be done is related to the different hypotheses. The hypothesis that states the pathological stress pathways within the cochlea induce circulating ligands (cellular-stress response) should be investigated in a more serious manner.
Conflict of interest None of the authors has any conflict of interest, financial or otherwise.
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