Auris Nasus Larynx 42 (2015) 249–253
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Steroid-dependent sensorineural hearing loss in a patient with Charcot-Marie-Tooth disease showing auditory neuropathy Yukihide Maeda a,*, Yuko Kataoka a, Akiko Sugaya a, Shin Kariya a, Katsuhiro Kobayashi b, Kazunori Nishizaki a a Department of Otolaryngology-, Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan b Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 August 2014 Accepted 7 November 2014 Available online 28 November 2014
Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary sensorimotor neuropathy and sometimes involves disorders of the peripheral auditory system. We present a case of steroiddependent auditory neuropathy associated with CMT, in which the patient experienced 3 episodes of acute exacerbation of hearing loss and successful rescue of hearing by prednisolone. An 8-year-old boy was referred to the otolaryngology department at the University Hospital. He had been diagnosed with CMT type 1 (demyelinating type) at the Child Neurology Department and was suffering from mild hearing loss due to auditory neuropathy. An audiological diagnosis of auditory neuropathy was confirmed by auditory brainstem response and distortion-product otoacoustic emissions. At 9 years and 0 months old, 9 years and 2 months old, and 10 years and 0 months old, he had experienced acute exacerbations of hearing loss, each of which was successfully rescued by intravenous or oral prednisolone within 2 weeks. Steroid-responsive cases of CMT have been reported, but this is the first case report of steroid-responsive sensorineural hearing loss in CMT. The present case may have implications for the mechanisms of action of glucocorticoids in the treatment of sensorineural hearing loss. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Audiology Sensorineural hearing loss Steroid therapy Auditory neuropathy Hereditary sensorimotor neuropathy
1. Introduction Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary peripheral neuropathy, affecting 1 in 2500 people. CMT typically presents with chronic muscle weakness, atrophy and sensory disturbance in the limbs. CMT can be subtyped as demyelinating (type 1) or axonal-type (type 2) peripheral neuropathy and manifests as X-linked, autosomal-dominant and autosomal-recessive forms. Pathologic mutations of over 20 genes, such as myelin protein zero (MPZ), peripheral myelin protein 22 kD (PMP22), connexin 32 (Cx32), and vanilloid-4 cation channel (TRPV4) have been identified in pedigrees with CMT [1]. Mild hearing loss is sometimes associated with X-linked, autosomal-dominant, and recessive forms of CMT [2]. Hearing loss in CMT represents an auditory neuropathy of the peripheral auditory system. Temporal bone histopathology of a CMT patient revealed marked loss of spiral neurons and peripheral and central
* Corresponding author. Tel.: +81 86 235 7307; fax: +81 86 235 7308. E-mail address: [email protected] (Y. Maeda). http://dx.doi.org/10.1016/j.anl.2014.11.002 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.
nerve processes within the cochlea [3]. Mutations in neurofilament light (Nefl) [4] and Mpz [3,5] are associated with CMT and cause sensorineural hearing loss as an auditory neuropathy. The proteins encoded in Nefl and Mpz are major cytoskeletal proteins in the peripheral nervous system. To date, no effective therapeutic reagents have been reported for auditory neuropathy. We present a case of steroid-dependent sensorineural hearing loss in a patient with CMT, in which repeated acute worsening of hearing was improved by prednisolone. 2. Case presentation A boy was referred to our otolaryngology department at 8 years and 11 months old for audiological follow-up. He had been diagnosed with CMT in the child neurology department at the University Hospital and mild right-sided hearing loss had been noted during screening audiometry at his primary school at 6 years old. Onset of neuropathy occurred at 5 years old, with weakness and atrophy of the peroneal muscles and pes calcaneovarus. The patient needed canes to walk. Neuropathy was demonstrated by
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electromyography and sporadic type 1 (demyelinating) CMT was diagnosed. Electromyography showed denervation and motor nerve conduction velocity was diminished in the tibial and median nerve (R tibial 17.1 ms; L tibial 27.2 ms; R median 29.9; L median 31.4; normal ranges are: tibial 48.4 3.2 [mean S.D.], median 58.9 4.0). Diminished nerve conduction velocity means demyelination process, which is compatible with a diagnosis of type1 CMT. Nerve conduction studies also revealed distal sensory disturbances in the lower limbs. Pure tone audiometry (PTA) at his first visit showed bilateral mild sensorineural hearing loss with moderate dips at 4000 Hz (Fig. 1; upper panel). Distortion product otoacoustic emissions (DPOAE) were absent at 4000 Hz, compatible with the dips in PTA and correctly reproduced over repeated examinations (Figs. 1 and 2). DPOAE was intact at the other frequencies, suggesting that hearing loss had been initiated as auditory neuropathy (Fig. 1; lower panels). Forty days after his first visit (at 9 years and 0 months old) to the otolaryngology department, he complained of left-sided tinnitus and revisited our department. Acute exacerbation of sensorineural hearing loss on the left side was identified on PTA (Fig. 2; left). He was hospitalized and intravenous prednisolone was initiated and tapered from 60 mg/day over 10 days; after a few days, PTA levels on the left side improved (Fig. 2; middle). At the time of discharge after 10 days of hospitalization, PTA levels of both the left and right sides had improved to normal hearing levels with the exception of mild bilateral dips at 4000 Hz (Fig. 2; right). Prednisolone was discontinued at the time of discharge. Fifty days after discharge (at 9 years and 2 months old), he experienced left tinnitus and mild hearing loss, more severe on the left side (Fig. 3; upper panel, middle). Oral prednisolone, tapered from 10 mg/day over 12 days, was prescribed and PTA levels normalized level within 2 weeks (Fig. 3; upper panel, right). After 10 months with stable PTA levels and without steroid prescription, a third episode of bilateral tinnitus and mild hearing loss occurred (at 10 years and 0 months old) (Fig. 3; lower panel, middle), and was rescued by oral prednisolone tapered from 10 mg/day over 12 days (Fig. 3; lower panel, right). Since then, prednisolone has occasionally been prescribed for short-term use (tapered from 10 mg/day over 6 days, on 3 occasions within 22 months) when he experiences subjective exacerbation of tinnitus. He usually complains of tinnitus on the left side. Normal otoscopic findings and tympanometry have ruled out any middle ear pathology, such as recurrent serous otitis media. Threshold of stapedial acoustic reflex was bilaterally elevated (right ipsilateral reflex, 100 dB at 2000 Hz, absent at 4000 Hz; left ipsilateral reflex, 100 dB at 500, 1000, 2000, 4000 Hz), consistent with typical findings in auditory neuropathy. Click auditory brainstem response confirmed bilaterally elevated thresholds (Fig. 4, right, 60 dB nHL; left, 50 dB nHL). To rule out the differential diagnosis of autoimmune sensorineural hearing loss, blood ESR, CRP, rheumatoid factor (RF), and anti-nuclear antibody (ANA) were examined during a steroid-free period, but all results were normal. Brain and spinal MRI were normal. As this patient has mild bilateral dips at 4000 Hz and click ABR generally reflects hearing threshold at high-frequencies, the ABR threshold showed elevation even after prednisolone treatment. However, interpeak latencies of I–III waves were shortened after prednisolone treatment, as compared to those before treatment (right, 0.195 ms recovery, left, 0.135 ms). In order to detect subclinical disturbances in the auditory function, open set speech perception was examined under the noise and quiet. A 67-S word list was presented at 65 dB under the noise of +10 dB signal-to-noise ratio or quiet. The speech perception score under the noise and quiet were 90% and 100%. 3. Discussion The present case involved repeated acute exacerbations of hearing loss and tinnitus that were each successfully rescued using prednisolone. DPOAE response remained intact except at 4000 Hz,
Fig. 1. Pure tone audiometry (PTA) and distortion-product otoacoustic emissions (DPOAEs) at the first visit to the otolaryngology department. PTA shows mild, bilateral sensorineural hearing loss with bilateral dips at 4000 Hz. In the figures of DPOAEs, the lower line (green lines) indicates background noise levels and the upper line (red and blue lines) indicates DPOAE response levels. The x-axis is F2 frequency.
Y. Maeda et al. / Auris Nasus Larynx 42 (2015) 249–253
251
Fig. 2. First episode of acute exacerbation of hearing loss and improvement by intravenous prednisolone. Forty days after his first visit to the otolaryngology department, the patient experienced left tinnitus and acute exacerbation of hearing, which was more severe on the left side (left). Following initiation of intravenous prednisolone, tapered from 60 mg/day over 10 days, hearing was improved at 2 days (middle) and 8 days (right) later.
Fig. 3. Second and third episodes of acute exacerbation of hearing loss and improvement by oral prednisolone. At 9 years and 2 months old (upper), and 10 years and 0 months old (lower), the patient experienced acute exacerbation of hearing (middle audiograms). Following initiation of oral prednisolone (tapered from 10 mg/day over 12 days), hearing was rescued within 2 weeks (right audiograms).
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Fig. 4. Auditory brainstem response (ABR). Thresholds of ABR were bilaterally elevated (right, 60 dB nHL; left, 50 dB nHL). Interpeak latencies to the stimuli of 90 dB nHL were at the upper limits of the normal ranges.
suggesting that hearing loss was initiated as an auditory neuropathy. The absence of DPOAE response at 4000 Hz was reproducible over repeated examinations, implicating outer hair cell dysfunction. ABR thresholds were bilaterally elevated, ruling out the differential diagnosis of functional hearing loss. The latency of wave I was prolonged (right, 1.81 ms; left, 1.73 ms) and this finding implies the involvement of spiral neurons in the pathology of hearing loss. Interpeak latencies of the ABR were at the upper limits of the normal ranges (I–III, right 2.24 ms, left 2.58 ms; I–V, right 4.53 ms, left 4.71 ms) and suggests only minor involvement of the central nervous system. By brain MRI, it is reported that CMT patients sometimes show hypertrophic cranial nerves without contrast enhancement [6]. In the present case, brain and spinal MRI showed no hypertrophic, demyelinating or mass lesions in neither the internal auditory canal nor the brainstem (data not illustrated). These audiological and imaging data confirmed a diagnosis of auditory neuropathy of primarily peripheral origin. Auditory perception is affected in >60% of school-aged children with CMT type 1 [7]. In the present case, the speech perception scores under the noise and quiet were 90% and 100%, and no remarkable disturbance in the speech perception was detected. The preserved speech perception under the noise and quiet is compatible with the present electrophysiological and imaging data that suggest disturbance in the peripheral auditory system, rather than neuropathies in the central nervous system. Rance et al. also described that neural conduction times (waves I–III and I–V interpeak latencies) are longer for the CMT1 group than control group [7]. In our case, interpeak latencies of the ABR were at the upper limits of the normal ranges. Steroid-sensitive cases of hereditary peripheral neuropathy due to CMT have been described previously [8]. To the best of our knowledge, the present description represents the first report of steroid-sensitive sensorineural hearing loss in CMT. Glucocorticoids are widely used as pharmacotherapy for various forms of sensorineural hearing loss, such as idiopathic sudden sensorineural hearing loss (ISSHL), Me´nie`re’s disease, and autoimmune sensorineural hearing loss. The mechanisms of action for glucocorticoids are tentatively regarded to involve
immunosuppressive and anti-inflammatory effects, but animal experiments have suggested beneficial effects of glucocorticoids against sensorineural hearing loss caused by ischemia [9], noise trauma [10,11], aminoglycosides [12], cisplatin [13] and salicylate [14]. Such observations suggest that glucocorticoids may have multiple modes of actions in the cochlea and may not be restricted to anti-inflammatory and immunosuppressive effects. In general, a major drawback to understanding the mechanisms of glucocorticoid action on hearing is that clinical sensorineural hearing loss, such as ISSHL, is presumably caused by heterogeneous pathologies, including ischemic, viral, inflammatory and autoimmune etiologies. The pathophysiology of the present steroid-dependent sensorineural hearing loss was clearly confined to an auditory neuropathy within the cochlea. As autoimmune etiologies were excluded from the present case, the mechanisms of action of glucocorticoid in this case were assumed to be other than antiinflammatory or immunosuppressive effects. In general, glucocorticoids bind to intracellular glucocorticoid receptor (GR) to induce nuclear translocation of GR. GR regulates gene expression through DNA-binding dependent and independent pathways. In the DNA-binding dependent pathway, GR directly interacts with glucocorticoid response elements of the regulatory regions of target genes as a transcription factor. In the DNA-binding independent pathway, GR mediates gene regulation via interaction with other transcription factors. In the experiments of cultured Schwann cells, glucocorticoid activates the promoter region and upregulates transcription of MPZ gene [15]. MPZ mutations are frequent cause of type1-CMT. In the present case, we have screened the coding region of MPZ gene but did not find mutations in his MPZ exons. It is plausible, however, to hypothesize that there are pathogenic variants in the promoter region of his MPZ gene as de novo variants or autosomal-recessive form. It is also expected that the effectiveness of glucocorticoid on sensorineural hearing loss due to CMT differs according to the regulatory mechanisms of each genes associated with CMT. To date, it is not yet clarified glucocorticoids regulates expression of which genes among over 20,000 genes in humans. The present case offers insights into the activities of glucocorticoids in the cochlea.
Y. Maeda et al. / Auris Nasus Larynx 42 (2015) 249–253
Conflict of interest None. References [1] Li J. Inherited neuropathies. Semin Neurol 2012;32:204–14. [2] Pauli RM. Sensorineural deafness and peripheral neuropathy. Clin Genet 1984;26:383–4. [3] Starr A, Michalewski HJ, Zeng FG, Fujikawa-Brooks S, Linthicum F, Kim CS, et al. Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145!Ser). Brain 2003;126:1604–19. [4] Butinar D, Starr A, Zidar J, Koutsou P, Christodoulou K. Auditory nerve is affected in one of two different point mutations of the neurofilament light gene. Clin Neurophysiol 2008;119:367–75. [5] Kabzinska D, Korwin-Piotrowska T, Drechsler H, Drac H, HausmanowaPetrusewicz I, Kochanski A. Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene. Am J Med Genet Part A 2007;143A:2196–9. [6] L’Heureux-Lebeau B, Alzahrani M, Saliba I. Charcot-Marie-Tooth disease as a cause of conductive hearing loss. Otol Neurotol 2013;34:e105–6. [7] Rance G, Ryan MM, Bayliss K, Gill K, O’Sullivan C, Whitechurch M. Auditory function in children with Charcot-Marie-Tooth disease. Brain 2012;135:1412–22.
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[8] Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH. Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 1982;57: 239–46. [9] Morawski KTF, Bohorquez J, Niemczyk K. Preventing hearing damage using topical dexamethasone during reversible cochlear ischemia: an animal model. Otol Neurotol 2009;30:851–7. [10] Tabuchi K, Murashita H, Sakai S, Hoshino T, Uemaetomari I, Hara A. Therapeutic time window of methylprednisolone in acoustic injury. Otol Neurotol 2006;27:1176–9. [11] Takemura K, Komeda M, Yagi M, Himeno C, Izumikawa M, Doi T, et al. Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig. Hear Res 2004;196:58–68. [12] Himeno C, Komeda M, Izumikawa M, Takemura K, Yagi M, Weiping Y, et al. Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig. Hear Res 2002;167:61–70. [13] Daldal A, Odabasi O, Serbetcioglu B. The protective effect of intratympanic dexamethasone on cisplatin-induced ototoxicity in guinea pigs. Otolaryngol Head Neck Surg 2002;137:747–52. [14] Park YS, Jung TT, Choi DJ, Rhee CK. Effect of corticosteroid treatment on salicylate ototoxicity. Ann Otol Rhinol Laryngol 1994;103:896–900. [15] De´sarnaud F, Bidichandani S, Patel PI, Baulieu EE, Schumacher M. Glucocorticosteroids stimulate the activity of the promoters of peripheral myelin protein-22 and protein zero genes in Schwann cells. Brain Res 2000;865: 12–6.
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Steroid-dependent sensorineural hearing loss in a patient with Charcot-Marie-Tooth disease showing auditory neuropathy Yukihide Maeda a,*, Yuko Kataoka a, Akiko Sugaya a, Shin Kariya a, Katsuhiro Kobayashi b, Kazunori Nishizaki a a Department of Otolaryngology-, Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan b Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 August 2014 Accepted 7 November 2014 Available online 28 November 2014
Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary sensorimotor neuropathy and sometimes involves disorders of the peripheral auditory system. We present a case of steroiddependent auditory neuropathy associated with CMT, in which the patient experienced 3 episodes of acute exacerbation of hearing loss and successful rescue of hearing by prednisolone. An 8-year-old boy was referred to the otolaryngology department at the University Hospital. He had been diagnosed with CMT type 1 (demyelinating type) at the Child Neurology Department and was suffering from mild hearing loss due to auditory neuropathy. An audiological diagnosis of auditory neuropathy was confirmed by auditory brainstem response and distortion-product otoacoustic emissions. At 9 years and 0 months old, 9 years and 2 months old, and 10 years and 0 months old, he had experienced acute exacerbations of hearing loss, each of which was successfully rescued by intravenous or oral prednisolone within 2 weeks. Steroid-responsive cases of CMT have been reported, but this is the first case report of steroid-responsive sensorineural hearing loss in CMT. The present case may have implications for the mechanisms of action of glucocorticoids in the treatment of sensorineural hearing loss. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Audiology Sensorineural hearing loss Steroid therapy Auditory neuropathy Hereditary sensorimotor neuropathy
1. Introduction Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary peripheral neuropathy, affecting 1 in 2500 people. CMT typically presents with chronic muscle weakness, atrophy and sensory disturbance in the limbs. CMT can be subtyped as demyelinating (type 1) or axonal-type (type 2) peripheral neuropathy and manifests as X-linked, autosomal-dominant and autosomal-recessive forms. Pathologic mutations of over 20 genes, such as myelin protein zero (MPZ), peripheral myelin protein 22 kD (PMP22), connexin 32 (Cx32), and vanilloid-4 cation channel (TRPV4) have been identified in pedigrees with CMT [1]. Mild hearing loss is sometimes associated with X-linked, autosomal-dominant, and recessive forms of CMT [2]. Hearing loss in CMT represents an auditory neuropathy of the peripheral auditory system. Temporal bone histopathology of a CMT patient revealed marked loss of spiral neurons and peripheral and central
* Corresponding author. Tel.: +81 86 235 7307; fax: +81 86 235 7308. E-mail address: [email protected] (Y. Maeda). http://dx.doi.org/10.1016/j.anl.2014.11.002 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.
nerve processes within the cochlea [3]. Mutations in neurofilament light (Nefl) [4] and Mpz [3,5] are associated with CMT and cause sensorineural hearing loss as an auditory neuropathy. The proteins encoded in Nefl and Mpz are major cytoskeletal proteins in the peripheral nervous system. To date, no effective therapeutic reagents have been reported for auditory neuropathy. We present a case of steroid-dependent sensorineural hearing loss in a patient with CMT, in which repeated acute worsening of hearing was improved by prednisolone. 2. Case presentation A boy was referred to our otolaryngology department at 8 years and 11 months old for audiological follow-up. He had been diagnosed with CMT in the child neurology department at the University Hospital and mild right-sided hearing loss had been noted during screening audiometry at his primary school at 6 years old. Onset of neuropathy occurred at 5 years old, with weakness and atrophy of the peroneal muscles and pes calcaneovarus. The patient needed canes to walk. Neuropathy was demonstrated by
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electromyography and sporadic type 1 (demyelinating) CMT was diagnosed. Electromyography showed denervation and motor nerve conduction velocity was diminished in the tibial and median nerve (R tibial 17.1 ms; L tibial 27.2 ms; R median 29.9; L median 31.4; normal ranges are: tibial 48.4 3.2 [mean S.D.], median 58.9 4.0). Diminished nerve conduction velocity means demyelination process, which is compatible with a diagnosis of type1 CMT. Nerve conduction studies also revealed distal sensory disturbances in the lower limbs. Pure tone audiometry (PTA) at his first visit showed bilateral mild sensorineural hearing loss with moderate dips at 4000 Hz (Fig. 1; upper panel). Distortion product otoacoustic emissions (DPOAE) were absent at 4000 Hz, compatible with the dips in PTA and correctly reproduced over repeated examinations (Figs. 1 and 2). DPOAE was intact at the other frequencies, suggesting that hearing loss had been initiated as auditory neuropathy (Fig. 1; lower panels). Forty days after his first visit (at 9 years and 0 months old) to the otolaryngology department, he complained of left-sided tinnitus and revisited our department. Acute exacerbation of sensorineural hearing loss on the left side was identified on PTA (Fig. 2; left). He was hospitalized and intravenous prednisolone was initiated and tapered from 60 mg/day over 10 days; after a few days, PTA levels on the left side improved (Fig. 2; middle). At the time of discharge after 10 days of hospitalization, PTA levels of both the left and right sides had improved to normal hearing levels with the exception of mild bilateral dips at 4000 Hz (Fig. 2; right). Prednisolone was discontinued at the time of discharge. Fifty days after discharge (at 9 years and 2 months old), he experienced left tinnitus and mild hearing loss, more severe on the left side (Fig. 3; upper panel, middle). Oral prednisolone, tapered from 10 mg/day over 12 days, was prescribed and PTA levels normalized level within 2 weeks (Fig. 3; upper panel, right). After 10 months with stable PTA levels and without steroid prescription, a third episode of bilateral tinnitus and mild hearing loss occurred (at 10 years and 0 months old) (Fig. 3; lower panel, middle), and was rescued by oral prednisolone tapered from 10 mg/day over 12 days (Fig. 3; lower panel, right). Since then, prednisolone has occasionally been prescribed for short-term use (tapered from 10 mg/day over 6 days, on 3 occasions within 22 months) when he experiences subjective exacerbation of tinnitus. He usually complains of tinnitus on the left side. Normal otoscopic findings and tympanometry have ruled out any middle ear pathology, such as recurrent serous otitis media. Threshold of stapedial acoustic reflex was bilaterally elevated (right ipsilateral reflex, 100 dB at 2000 Hz, absent at 4000 Hz; left ipsilateral reflex, 100 dB at 500, 1000, 2000, 4000 Hz), consistent with typical findings in auditory neuropathy. Click auditory brainstem response confirmed bilaterally elevated thresholds (Fig. 4, right, 60 dB nHL; left, 50 dB nHL). To rule out the differential diagnosis of autoimmune sensorineural hearing loss, blood ESR, CRP, rheumatoid factor (RF), and anti-nuclear antibody (ANA) were examined during a steroid-free period, but all results were normal. Brain and spinal MRI were normal. As this patient has mild bilateral dips at 4000 Hz and click ABR generally reflects hearing threshold at high-frequencies, the ABR threshold showed elevation even after prednisolone treatment. However, interpeak latencies of I–III waves were shortened after prednisolone treatment, as compared to those before treatment (right, 0.195 ms recovery, left, 0.135 ms). In order to detect subclinical disturbances in the auditory function, open set speech perception was examined under the noise and quiet. A 67-S word list was presented at 65 dB under the noise of +10 dB signal-to-noise ratio or quiet. The speech perception score under the noise and quiet were 90% and 100%. 3. Discussion The present case involved repeated acute exacerbations of hearing loss and tinnitus that were each successfully rescued using prednisolone. DPOAE response remained intact except at 4000 Hz,
Fig. 1. Pure tone audiometry (PTA) and distortion-product otoacoustic emissions (DPOAEs) at the first visit to the otolaryngology department. PTA shows mild, bilateral sensorineural hearing loss with bilateral dips at 4000 Hz. In the figures of DPOAEs, the lower line (green lines) indicates background noise levels and the upper line (red and blue lines) indicates DPOAE response levels. The x-axis is F2 frequency.
Y. Maeda et al. / Auris Nasus Larynx 42 (2015) 249–253
251
Fig. 2. First episode of acute exacerbation of hearing loss and improvement by intravenous prednisolone. Forty days after his first visit to the otolaryngology department, the patient experienced left tinnitus and acute exacerbation of hearing, which was more severe on the left side (left). Following initiation of intravenous prednisolone, tapered from 60 mg/day over 10 days, hearing was improved at 2 days (middle) and 8 days (right) later.
Fig. 3. Second and third episodes of acute exacerbation of hearing loss and improvement by oral prednisolone. At 9 years and 2 months old (upper), and 10 years and 0 months old (lower), the patient experienced acute exacerbation of hearing (middle audiograms). Following initiation of oral prednisolone (tapered from 10 mg/day over 12 days), hearing was rescued within 2 weeks (right audiograms).
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Fig. 4. Auditory brainstem response (ABR). Thresholds of ABR were bilaterally elevated (right, 60 dB nHL; left, 50 dB nHL). Interpeak latencies to the stimuli of 90 dB nHL were at the upper limits of the normal ranges.
suggesting that hearing loss was initiated as an auditory neuropathy. The absence of DPOAE response at 4000 Hz was reproducible over repeated examinations, implicating outer hair cell dysfunction. ABR thresholds were bilaterally elevated, ruling out the differential diagnosis of functional hearing loss. The latency of wave I was prolonged (right, 1.81 ms; left, 1.73 ms) and this finding implies the involvement of spiral neurons in the pathology of hearing loss. Interpeak latencies of the ABR were at the upper limits of the normal ranges (I–III, right 2.24 ms, left 2.58 ms; I–V, right 4.53 ms, left 4.71 ms) and suggests only minor involvement of the central nervous system. By brain MRI, it is reported that CMT patients sometimes show hypertrophic cranial nerves without contrast enhancement [6]. In the present case, brain and spinal MRI showed no hypertrophic, demyelinating or mass lesions in neither the internal auditory canal nor the brainstem (data not illustrated). These audiological and imaging data confirmed a diagnosis of auditory neuropathy of primarily peripheral origin. Auditory perception is affected in >60% of school-aged children with CMT type 1 [7]. In the present case, the speech perception scores under the noise and quiet were 90% and 100%, and no remarkable disturbance in the speech perception was detected. The preserved speech perception under the noise and quiet is compatible with the present electrophysiological and imaging data that suggest disturbance in the peripheral auditory system, rather than neuropathies in the central nervous system. Rance et al. also described that neural conduction times (waves I–III and I–V interpeak latencies) are longer for the CMT1 group than control group [7]. In our case, interpeak latencies of the ABR were at the upper limits of the normal ranges. Steroid-sensitive cases of hereditary peripheral neuropathy due to CMT have been described previously [8]. To the best of our knowledge, the present description represents the first report of steroid-sensitive sensorineural hearing loss in CMT. Glucocorticoids are widely used as pharmacotherapy for various forms of sensorineural hearing loss, such as idiopathic sudden sensorineural hearing loss (ISSHL), Me´nie`re’s disease, and autoimmune sensorineural hearing loss. The mechanisms of action for glucocorticoids are tentatively regarded to involve
immunosuppressive and anti-inflammatory effects, but animal experiments have suggested beneficial effects of glucocorticoids against sensorineural hearing loss caused by ischemia [9], noise trauma [10,11], aminoglycosides [12], cisplatin [13] and salicylate [14]. Such observations suggest that glucocorticoids may have multiple modes of actions in the cochlea and may not be restricted to anti-inflammatory and immunosuppressive effects. In general, a major drawback to understanding the mechanisms of glucocorticoid action on hearing is that clinical sensorineural hearing loss, such as ISSHL, is presumably caused by heterogeneous pathologies, including ischemic, viral, inflammatory and autoimmune etiologies. The pathophysiology of the present steroid-dependent sensorineural hearing loss was clearly confined to an auditory neuropathy within the cochlea. As autoimmune etiologies were excluded from the present case, the mechanisms of action of glucocorticoid in this case were assumed to be other than antiinflammatory or immunosuppressive effects. In general, glucocorticoids bind to intracellular glucocorticoid receptor (GR) to induce nuclear translocation of GR. GR regulates gene expression through DNA-binding dependent and independent pathways. In the DNA-binding dependent pathway, GR directly interacts with glucocorticoid response elements of the regulatory regions of target genes as a transcription factor. In the DNA-binding independent pathway, GR mediates gene regulation via interaction with other transcription factors. In the experiments of cultured Schwann cells, glucocorticoid activates the promoter region and upregulates transcription of MPZ gene [15]. MPZ mutations are frequent cause of type1-CMT. In the present case, we have screened the coding region of MPZ gene but did not find mutations in his MPZ exons. It is plausible, however, to hypothesize that there are pathogenic variants in the promoter region of his MPZ gene as de novo variants or autosomal-recessive form. It is also expected that the effectiveness of glucocorticoid on sensorineural hearing loss due to CMT differs according to the regulatory mechanisms of each genes associated with CMT. To date, it is not yet clarified glucocorticoids regulates expression of which genes among over 20,000 genes in humans. The present case offers insights into the activities of glucocorticoids in the cochlea.
Y. Maeda et al. / Auris Nasus Larynx 42 (2015) 249–253
Conflict of interest None. References [1] Li J. Inherited neuropathies. Semin Neurol 2012;32:204–14. [2] Pauli RM. Sensorineural deafness and peripheral neuropathy. Clin Genet 1984;26:383–4. [3] Starr A, Michalewski HJ, Zeng FG, Fujikawa-Brooks S, Linthicum F, Kim CS, et al. Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145!Ser). Brain 2003;126:1604–19. [4] Butinar D, Starr A, Zidar J, Koutsou P, Christodoulou K. Auditory nerve is affected in one of two different point mutations of the neurofilament light gene. Clin Neurophysiol 2008;119:367–75. [5] Kabzinska D, Korwin-Piotrowska T, Drechsler H, Drac H, HausmanowaPetrusewicz I, Kochanski A. Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene. Am J Med Genet Part A 2007;143A:2196–9. [6] L’Heureux-Lebeau B, Alzahrani M, Saliba I. Charcot-Marie-Tooth disease as a cause of conductive hearing loss. Otol Neurotol 2013;34:e105–6. [7] Rance G, Ryan MM, Bayliss K, Gill K, O’Sullivan C, Whitechurch M. Auditory function in children with Charcot-Marie-Tooth disease. Brain 2012;135:1412–22.
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