- Email: [email protected]
Audiological findings in Infantile Refsum disease
G Model
PEDOT-7599; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case Report
Audiological findings in Infantile Refsum disease V.P. Vandana a, Parayil Sankaran Bindu b,*, Madhu Nagappa b, Sanjib Sinha b, Arun B. Taly b a b
Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 March 2015 Received in revised form 13 May 2015 Accepted 16 May 2015 Available online xxx
Audiological manifestations in a four-year-old child with Infantile Refsum disease are reported. He was born to non-consanguineous parents and had normal birth history and mildly delayed milestones prior to presentation. Clinical features were characterized by neuroregression, retinitis pigmentosa, hearing loss, peripheral neuropathy and white matter signal changes on magnetic resonance imaging. Biochemical evaluation showed elevated serum levels of long chain fatty acid and phytanic acid confirming the diagnosis. The audiological profile was characterized by absent auditory brainstem responses with robust otocoustic emissions, which indicated auditory neuropathy as the possible cause of hearing loss. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Infantile Refsum disease Audiological findings Peroxisomal biogenesis disorder
1. Introduction
2. Case report
Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD) [1]. The clinical manifestations include hearing loss of the sensorineural type, retinitis pigmentosa, facial dysmorphism, mental and growth retardation, peripheral neuropathy, cerebellar ataxia, mild tremors, seizures and failure to thrive [2,3]. Progressive deafness has been reported in approximately 80% of patients with classical Refsum disease [4,5]. Compared to the adult Refsum disease, reports on the audiological manifestations in infantile Refsum disease are limited [6]. The condition is often slowly progressive with hearing and vision worsening with time. Children who survive the first year and who have a non-progressive course have a high probability of reaching school age [7]. The improved longevity necessitates attention to the factors that will improve the quality of life – an important factor being with reference to hearing. The present study reports the audiological findings in a child with biochemically proven infantile Refsum disease. The site of lesion associated with hearing loss, was determined using an audiological test battery comprising of puretone audiometry, tympanometry, acoustic reflexes and brainstem auditory evoked potentials.
A 4 year 3 month old boy from the South Indian state of Kerala presented with a history of loss of acquired mile stones at the age of 9 months. Parents were non consanguineous. He was born by lower segment cesarean section for fetal distress and had a birth weight of 2.75 kg. He developed jaundice during the neonatal period for which he received phototherapy. He had mildly delayed milestones prior to the onset of regression. At 9 months of age he could sit without support for few minutes, play peek a boo, hold and transfer objects in hands and could speak bisyllables. On examination, the child had morphological abnormalities in the form of a dolichocephalic head with frontal and parietal bossing, mild downward slanting of eyes, upturned nose and sparse hypopigmented hair. Neurological examination revealed, nystagmus, generalized hypotonia, wasting of the extremities, and reduced reflexes. Tremulousness of the limbs was noted while reaching out for objects. Opthalmological examination revealed retinitis pigmentosa. Based on the findings of neuroregression, retinitis pigmentosa and peripheral neuropathy, the differential diagnosis considered included a mitochondrial disease and infantile refsum disease. Evaluation included routine biochemical and hematological parameters, serum ammonia, serum lactate, serum creatine kinase which revealed normal results. S. Aryl Sulphatase and S. Hexosaminidase levels were normal. His MRI revealed bilateral symmetrical signal changes in the cerebellar and dentate white matter. Very long chain fatty acids estimation revealed elevated C26:0 (1.960 mg/dL, normal 0.23 0.09), S. Phytanic acid (10.42 mg/dL, normal < 3 mg/dL) and pristanic acid
* Corresponding author. Tel.: +91 80 26577542/26995150; fax: +91 8026564830. E-mail addresses: [email protected] (V.P. Vandana), [email protected] (P.S. Bindu), [email protected] (M. Nagappa), [email protected] (S. Sinha), [email protected] (A.B. Taly). http://dx.doi.org/10.1016/j.ijporl.2015.05.023 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 2
V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
levels (3.460 mg/dL, normal < .3 mg/dL) indicating a defect in peroxysomal fatty acid oxidation. Nerve conduction studies revealed a sensory motor axonal neuropathy. He was diagnosed to have Infantile Refsum disease based on the combination of neuroregression, retinitis pigmentosa, and peripheral neuropathy, cerebellar and white matter signal changes on MRI along with elevated phytanic acid levels. Family history revealed that the 21 months old younger sibling is delayed in milestones. Evaluation at the age of 21 months showed retinitis pigmentosa and peripheral neuropathy. 2.1. Audiological evaluation History revealed regression in the acquired language milestones at the age of nine months. Premorbidly, the child could use one to two words. After the onset of regression the child had inconsistent responses to sound (both conversational and environmental). He did not acquire any language milestones thereafter. Speech and language skills as per the Receptive Expressive Language Scales (REELS) [8] revealed receptive and expressive language skills to be at eight to nine months level. Audiological evaluation was carried out at the age of four years using a test battery, which included pure tone audiometry, tympanometry and acoustic reflexes, otoacoustic emissions and brainstem auditory evoked potentials (BERA). Pure tone/behavioral observation audiometry could not be carried out, as the child was drowsy and not cooperative. Tympanometry was obtained using MAICO M144 middle ear analyzer, with a 226 Hz tone at 85dBSPL. Tympanogram was considered normal if middle ear pressure was >-150 mmH2O and compliance was more than 0.3cc. Acoustic reflexes were also obtained using MAICO M144 by stimulating each ear at 0.5, 1 and 2 kHz from 70 to 120 dBHL in 5 dB steps ipsilaterally. The presence of reflex was ascertained using the criteria used by Cohen and Prasher [9]. BERA was recorded with Intelligent Health Systems (IHS) Opti Amp 8008. Electrodes were placed on high forehead FPz (noninverting), and on each mastoid (A2 and A3). The nontest mastoid served as the ground and the mastoid ipsilateral to stimulus was inverting electrode. Single polarity click stimuli (one condensation and two rarefaction) were presented at a rate of 11.1/s ipsilaterally via insert earphones, to minimize stimulus artifacts. Electrode impedance was <5 kV. The high pass filter was set at 100 Hz and low pass filter was set at 3000 Hz with an averaging window of 12.8 ms and an artifact rejection feature of 0.0–10.0 ms. The number of sweeps was set at 1024. Waveforms were tracked starting from 90 dBnHL. Analysis of waves I, III and V were made and a response was classified as abnormal if the waveforms were not replicable or absent or if the latencies were >2SD from mean normative data obtained in our department. Presence of a cochlear microphonic component was defined by a 180-degree reversal in the polarity of the response waveform associated with a change in polarity of the stimulus. Distortion Product Otoacoustic emissions (DPOAE’s) were measured using the ILO-V6 Clinical OAE software (Otodynamics Echoport instrument Ltd) for seven frequencies ranging from 1 kHz to 8 kHz. The criteria taken for presence of OAE’s is signal to noise ratio (SNR) more than 3 dB in three consecutive frequencies. Tympanograms were normal bilaterally (‘A’ type) and ipsilateral acoustic reflexes were absent bilaterally. Distortion product otoacoustic emissions were present bilaterally in all the frequencies (Fig. 1). No discernible waveforms could be obtained in the BERA testing at 90 dBnHL. Cochlear microphonics were clearly evident (Fig. 2). The absence of brainstem reflexes and BERA waveforms are indicative of possible retro cochlear involvement. The presence of robust OAE’s and cochlear micro phonics in the absence of discernible BERA waveforms is indicative of auditory neuropathy in this patient.
To our patient, we recommended monitoring audiologic status periodically (behavioral observation audiometry results and repeat OAE and BERA) until a pattern of finding emerges. Based on the behavioral observation audiometry results, we would decide whether hearing aid fitting would be appropriate. Once the hearing aid is fitted with low gain, functioning of the outer hair cell would be checked regularly with OAE. Speech-language evaluation and intensive stimulation was also recommended. Total communication approach may not be useful for this child because of reduced visual acuity. Cochlear implant was also recommended, if the child did not benefit from hearing aid trial and auditory training. Other recommendations for the child included speech and language stimulation, safe swallow strategies and oromotor exercises. Speech and language stimulation and intervention was recommended for both siblings as per the ASHA guidelines [10] Dysphagia management included working on rotary chewing, jaw stability, lip closure and control and safe swallow strategies as recommended by Gallender [11]. 3. Discussion This report describes the audiological findings in a patient with infantile Refsum disease. The salient findings included absent brainstem-evoked potentials and absent bilateral ipsilateral reflexes and presence of bilateral DPOAE’s. The findings were suggestive of auditory neuropathy. Sensorineural hearing loss is a recognized finding in classical form of Refsum disease and the onset is usually between 10 and 30 years of age. Eventhough central nervous system involvement is predominant in Refsum disease, several studies have indicated the involvement of the temporal bone and inner ear structures as the underlying cause for hearing loss rather than central nervous system pathology. The mechanisms described include cochleosaccular atrophy [12], degeneration of first order cochlear neuron, and atrophied striavascularis and Organ of Corti [13]. Collapse of Reissner’s membrane, degeneration of striavascularis, Organ of Corti and spiral ganglion atrophy has also been reported in earlier studies [14,15]. In our patient, auditory brainstem responses were absent in the presence of robust DPOAE’s across all the frequencies and the presence of cochlear microphonics, indicative of auditory neuropathy. Although hearing loss is frequently associated with Refsum disease, there are only few studies investigating the possible site of lesion associated with the loss. A cochlear as well as retrocochlear site of lesion have been suggested in earlier studies [5,6,16,17]. In the study by Bamiou et al. [17], there was mild to moderate hearing loss in seven out of the nine patients with classic Refsum disease and six of them had auditory neuropathy. In the single report, which focused on the audiological findings in a patient with infantile Refsum disease, progressive hearing loss was demonstrated using puretone audiogram [6]. The hearing loss was mild at 6 years and profound at 11 years. One of the consistent features they observed was the absence of auditory brainstem responses and the presence of robust otoacoustic emissions, indicative of auditory neuropathy. The findings in our report are also consistent with Oysu et al. [6]. Early identification of auditory neuropathy in Refsum disease may have implications for appropriate management. Early onset auditory neuropathy can compromise the pre- or post-lingual language acquisition in children [18]. Management of auditory neuropathy aims at restoring compromised auditory processing, either through hearing aid fitting, alternative forms of communication like sign language or cued speech orby cochlear implantation [19]. Two reports have mentioned benefit with cochlear implantation in adult patients with Refsum disease [20,21]. In both the studies, patients who underwent cochlear implantation (age
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
3
Fig. 1. Distortion product otoacoustic emission measures for both ears indicate that DPOAEs are present above the noise level in all the frequencies for both the ears.
Fig. 2. The auditory brainstem evoked potentials for the left (blue) and right (red) ear indicating absence of replicable waveforms. Waveforms are obtained for two rarefaction and one condensation waveform for each ear. The recording between 0 and 1 ms for both ears indicate the presence of cochlear microphonics which is a distinctive sign of outer hair cell integrity in patients with auditory neuropathy. (For interpretation of the references to color in this text, the reader is referred to the web version of the article.)
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 4
V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
range: 59–65) showed better audiometric performance and quality of life after implantation. However, details regarding the type of hearing loss were not mentioned in both reports. Early management of hearing loss in Refsum disease, if present, is very important as other senses (sight and smell) may also be affected in these patients. Conservative (mild gain) amplification trial is a justifiable management option depending on the availability of behavioral audiologic findings, prior to initiation of other forms of treatment like cochlear implants. This may also lead to improvement in speech and language development. For children with typical pattern of auditory findings associated with ‘auditory neuropathy’ who will be considered for cochlear implant candidacy, a period of hearing aid use (approximately 3 months) with close monitoring of responsiveness and cochlear status will meet requirements of cochlear implantation in these children. This will also be a daily reminder and assurance to parents regarding the importance of intensive speech and language stimulation. It is also to be kept in mind that benefits of hearing aid or cochlear implantation also depends on the underlying pathophysiology of the illness. In conclusion, this report highlights that auditory neuropathy is the cause for hearing loss in this patient with infantile Refsum disease. An audiological test battery approach encompassing behavioral observation audiometry, puretone audiometry, tympanometry, brainstem reflexometry, OAE and BERA are crucial for accurate diagnosis, management and intervention in these patients. This in turn may improve the quality of life in these children. References [1] S.J. Steinberg, G.V. Raymond, N.E. Braverman, A.B. Moser, Peroxisome biogenesis disorders, zellweger syndrome spectrum, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, S.E. Wallace, A. Amemiya, L.J.H. Bean, et al. (Eds.), Gene Reviews1 [Internet], University of Washington, Seattle, WA, 2003 December, pp. 1993–2015 (updated 2012 May 10) available from: http://www.ncbi.nlm.nih.gov/books/NBK1448/. [2] A.J. Wills, N.J. Manning, M.M. Reilly, Refsum’s disease, QJM 94 (2001) 403–406. [3] G.A. Jansen, R.J.A. Wanders, P.A. Watkins, S.J. Mihalik, Phytanoyl-coenzyme a hydroxylase deficiency: the enzyme defect in Refsum’s disease, N. Engl. J. Med. 337 (1997) 133–134.
[4] G. Bergsmark, G. Djupesland, Heredopathia atactica polyneuritiformis (Refsum’s diseases). An audiological examination of two patients, Eur. Neurol. 1 (2) (1968) 122–130. [5] H. Feldmann, Refsum’s syndrome, heredopathia atactica polyneuritiformis in the view of the otolaryngologist, Laryngol. Rhinol. Otol. (Stuttg.) 60 (5) (1981) 235– 240. [6] C. Oysu, I. Aslan, B. Basaran, N. Baserer, The site of the hearing loss in Refsum’s disease, Int. J. Pediatr. Otorhinolaryngol. 61 (2001) 129–134. [7] B.T. Poll-The, J. Gootjes, M. Duran, J.B. De Klerk, L.J. Wenniger-Prick, R.J. Admiraal, et al., Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients, Am. J. Med. Genet. A 126A (2004) 333–338. [8] K.R. Bzoch, L. Richard, The Bzoch-League receptive-expressive emergent language scale for the measurement of language skills in infancy, in: Assessing Language Skills in Infancy: A Handbook for the Multidimensional Analysis of Emergent Language, 1st ed., The Tree of Life Press, Inc., Gainesville, Florida, 1971, pp. 43–45Language Education Division of Computer Management Corp. [9] M. Cohen, D. Prasher, ABR and ART in neurotological diagnosis, Scand. Audiol. 17 (1988) 153–162. [10] http://www.asha.org/public/speech/development/parent-stim-activities.htm, Activities to encourage Speech and Language development. [11] D. Gallender, Eating Handicaps. Illustrated Techniques for Feeding Disorders, Charles C Thomas Publisher, Springfield, Illinois, USA, 1979. [12] H.F. Schuknecht, Pathology of the ear, Harvard University Press, Cambridge (United Kingdom), 1974, pp. 3–20. [13] J.B. Nadol, Primary Cochlear degeneration, in: Y. Sininger, A. Starr (Eds.), Auditory Neuropathy, Singular, San Diego, 2001. [14] C.S. Hallpike, Observations on the structural basis of two rare varieties of hereditary deafness, in: A.V.S. De Reusch, J. Knight (Eds.), Myatatic, Kinestetic and Vestibular Mechanisms, CIBA-Foundation Symposium, Churchill, London, 1967, p. 285. [15] M. Rake, M. Saunders, Refsum’s disease: a disorder of lipid metabolism, J. Neurol. Neurosurg. Psychiatry 29 (1966) 417–422. [16] G. Djupesland, S. Flottorp, Refsum’s, Phytanic acid storage disease: hearing maintained after 15 years of dietary treatment, Neurology 33 (2) (1983) 237–240. [17] D.E. Bamiou, P.R. Spraggs, F.B. Gibberd, M.C. Sidey, L.M. Luxon, Hearing loss in adult Refsum’s disease, Clin. Otolaryngol. Allied Sci. 28 (2003) 227–230. [18] P.V. Vlastarakos, T.P. Nikolopoulos, T. Evangelia, G. Papacharalambous, S. Korres, Auditory neuropathy: endocochlear lesion or temporal processing impairment? Implications for diagnosis and management, Int. J. Pediatr. Otorhinolaryngol. 72 (2008) 1135–1150. [19] P.G. Trautwein, Y.S. Sininger, R. Nelson, Cochlear implantation of auditory neuropathy, J. Am. Acad. Audiol. 11 (2000) 309–315. [20] C.H. Raine, M.F. Kurukulasuriya, Y. Bajaj, D.R. Strachan, Cochlear implantation in Refsum’s disease, Cochlear. Implants. Int. 9 (2008) 97–102. [21] C. Nogueira, T. Meehan, G. O’Donoghue, Refsum’s disease and cochlear implantation, Ann. Otol. Rhinol. Laryngol. 123 (2014) 425–427.
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
PEDOT-7599; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case Report
Audiological findings in Infantile Refsum disease V.P. Vandana a, Parayil Sankaran Bindu b,*, Madhu Nagappa b, Sanjib Sinha b, Arun B. Taly b a b
Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 March 2015 Received in revised form 13 May 2015 Accepted 16 May 2015 Available online xxx
Audiological manifestations in a four-year-old child with Infantile Refsum disease are reported. He was born to non-consanguineous parents and had normal birth history and mildly delayed milestones prior to presentation. Clinical features were characterized by neuroregression, retinitis pigmentosa, hearing loss, peripheral neuropathy and white matter signal changes on magnetic resonance imaging. Biochemical evaluation showed elevated serum levels of long chain fatty acid and phytanic acid confirming the diagnosis. The audiological profile was characterized by absent auditory brainstem responses with robust otocoustic emissions, which indicated auditory neuropathy as the possible cause of hearing loss. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Infantile Refsum disease Audiological findings Peroxisomal biogenesis disorder
1. Introduction
2. Case report
Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD) [1]. The clinical manifestations include hearing loss of the sensorineural type, retinitis pigmentosa, facial dysmorphism, mental and growth retardation, peripheral neuropathy, cerebellar ataxia, mild tremors, seizures and failure to thrive [2,3]. Progressive deafness has been reported in approximately 80% of patients with classical Refsum disease [4,5]. Compared to the adult Refsum disease, reports on the audiological manifestations in infantile Refsum disease are limited [6]. The condition is often slowly progressive with hearing and vision worsening with time. Children who survive the first year and who have a non-progressive course have a high probability of reaching school age [7]. The improved longevity necessitates attention to the factors that will improve the quality of life – an important factor being with reference to hearing. The present study reports the audiological findings in a child with biochemically proven infantile Refsum disease. The site of lesion associated with hearing loss, was determined using an audiological test battery comprising of puretone audiometry, tympanometry, acoustic reflexes and brainstem auditory evoked potentials.
A 4 year 3 month old boy from the South Indian state of Kerala presented with a history of loss of acquired mile stones at the age of 9 months. Parents were non consanguineous. He was born by lower segment cesarean section for fetal distress and had a birth weight of 2.75 kg. He developed jaundice during the neonatal period for which he received phototherapy. He had mildly delayed milestones prior to the onset of regression. At 9 months of age he could sit without support for few minutes, play peek a boo, hold and transfer objects in hands and could speak bisyllables. On examination, the child had morphological abnormalities in the form of a dolichocephalic head with frontal and parietal bossing, mild downward slanting of eyes, upturned nose and sparse hypopigmented hair. Neurological examination revealed, nystagmus, generalized hypotonia, wasting of the extremities, and reduced reflexes. Tremulousness of the limbs was noted while reaching out for objects. Opthalmological examination revealed retinitis pigmentosa. Based on the findings of neuroregression, retinitis pigmentosa and peripheral neuropathy, the differential diagnosis considered included a mitochondrial disease and infantile refsum disease. Evaluation included routine biochemical and hematological parameters, serum ammonia, serum lactate, serum creatine kinase which revealed normal results. S. Aryl Sulphatase and S. Hexosaminidase levels were normal. His MRI revealed bilateral symmetrical signal changes in the cerebellar and dentate white matter. Very long chain fatty acids estimation revealed elevated C26:0 (1.960 mg/dL, normal 0.23 0.09), S. Phytanic acid (10.42 mg/dL, normal < 3 mg/dL) and pristanic acid
* Corresponding author. Tel.: +91 80 26577542/26995150; fax: +91 8026564830. E-mail addresses: [email protected] (V.P. Vandana), [email protected] (P.S. Bindu), [email protected] (M. Nagappa), [email protected] (S. Sinha), [email protected] (A.B. Taly). http://dx.doi.org/10.1016/j.ijporl.2015.05.023 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 2
V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
levels (3.460 mg/dL, normal < .3 mg/dL) indicating a defect in peroxysomal fatty acid oxidation. Nerve conduction studies revealed a sensory motor axonal neuropathy. He was diagnosed to have Infantile Refsum disease based on the combination of neuroregression, retinitis pigmentosa, and peripheral neuropathy, cerebellar and white matter signal changes on MRI along with elevated phytanic acid levels. Family history revealed that the 21 months old younger sibling is delayed in milestones. Evaluation at the age of 21 months showed retinitis pigmentosa and peripheral neuropathy. 2.1. Audiological evaluation History revealed regression in the acquired language milestones at the age of nine months. Premorbidly, the child could use one to two words. After the onset of regression the child had inconsistent responses to sound (both conversational and environmental). He did not acquire any language milestones thereafter. Speech and language skills as per the Receptive Expressive Language Scales (REELS) [8] revealed receptive and expressive language skills to be at eight to nine months level. Audiological evaluation was carried out at the age of four years using a test battery, which included pure tone audiometry, tympanometry and acoustic reflexes, otoacoustic emissions and brainstem auditory evoked potentials (BERA). Pure tone/behavioral observation audiometry could not be carried out, as the child was drowsy and not cooperative. Tympanometry was obtained using MAICO M144 middle ear analyzer, with a 226 Hz tone at 85dBSPL. Tympanogram was considered normal if middle ear pressure was >-150 mmH2O and compliance was more than 0.3cc. Acoustic reflexes were also obtained using MAICO M144 by stimulating each ear at 0.5, 1 and 2 kHz from 70 to 120 dBHL in 5 dB steps ipsilaterally. The presence of reflex was ascertained using the criteria used by Cohen and Prasher [9]. BERA was recorded with Intelligent Health Systems (IHS) Opti Amp 8008. Electrodes were placed on high forehead FPz (noninverting), and on each mastoid (A2 and A3). The nontest mastoid served as the ground and the mastoid ipsilateral to stimulus was inverting electrode. Single polarity click stimuli (one condensation and two rarefaction) were presented at a rate of 11.1/s ipsilaterally via insert earphones, to minimize stimulus artifacts. Electrode impedance was <5 kV. The high pass filter was set at 100 Hz and low pass filter was set at 3000 Hz with an averaging window of 12.8 ms and an artifact rejection feature of 0.0–10.0 ms. The number of sweeps was set at 1024. Waveforms were tracked starting from 90 dBnHL. Analysis of waves I, III and V were made and a response was classified as abnormal if the waveforms were not replicable or absent or if the latencies were >2SD from mean normative data obtained in our department. Presence of a cochlear microphonic component was defined by a 180-degree reversal in the polarity of the response waveform associated with a change in polarity of the stimulus. Distortion Product Otoacoustic emissions (DPOAE’s) were measured using the ILO-V6 Clinical OAE software (Otodynamics Echoport instrument Ltd) for seven frequencies ranging from 1 kHz to 8 kHz. The criteria taken for presence of OAE’s is signal to noise ratio (SNR) more than 3 dB in three consecutive frequencies. Tympanograms were normal bilaterally (‘A’ type) and ipsilateral acoustic reflexes were absent bilaterally. Distortion product otoacoustic emissions were present bilaterally in all the frequencies (Fig. 1). No discernible waveforms could be obtained in the BERA testing at 90 dBnHL. Cochlear microphonics were clearly evident (Fig. 2). The absence of brainstem reflexes and BERA waveforms are indicative of possible retro cochlear involvement. The presence of robust OAE’s and cochlear micro phonics in the absence of discernible BERA waveforms is indicative of auditory neuropathy in this patient.
To our patient, we recommended monitoring audiologic status periodically (behavioral observation audiometry results and repeat OAE and BERA) until a pattern of finding emerges. Based on the behavioral observation audiometry results, we would decide whether hearing aid fitting would be appropriate. Once the hearing aid is fitted with low gain, functioning of the outer hair cell would be checked regularly with OAE. Speech-language evaluation and intensive stimulation was also recommended. Total communication approach may not be useful for this child because of reduced visual acuity. Cochlear implant was also recommended, if the child did not benefit from hearing aid trial and auditory training. Other recommendations for the child included speech and language stimulation, safe swallow strategies and oromotor exercises. Speech and language stimulation and intervention was recommended for both siblings as per the ASHA guidelines [10] Dysphagia management included working on rotary chewing, jaw stability, lip closure and control and safe swallow strategies as recommended by Gallender [11]. 3. Discussion This report describes the audiological findings in a patient with infantile Refsum disease. The salient findings included absent brainstem-evoked potentials and absent bilateral ipsilateral reflexes and presence of bilateral DPOAE’s. The findings were suggestive of auditory neuropathy. Sensorineural hearing loss is a recognized finding in classical form of Refsum disease and the onset is usually between 10 and 30 years of age. Eventhough central nervous system involvement is predominant in Refsum disease, several studies have indicated the involvement of the temporal bone and inner ear structures as the underlying cause for hearing loss rather than central nervous system pathology. The mechanisms described include cochleosaccular atrophy [12], degeneration of first order cochlear neuron, and atrophied striavascularis and Organ of Corti [13]. Collapse of Reissner’s membrane, degeneration of striavascularis, Organ of Corti and spiral ganglion atrophy has also been reported in earlier studies [14,15]. In our patient, auditory brainstem responses were absent in the presence of robust DPOAE’s across all the frequencies and the presence of cochlear microphonics, indicative of auditory neuropathy. Although hearing loss is frequently associated with Refsum disease, there are only few studies investigating the possible site of lesion associated with the loss. A cochlear as well as retrocochlear site of lesion have been suggested in earlier studies [5,6,16,17]. In the study by Bamiou et al. [17], there was mild to moderate hearing loss in seven out of the nine patients with classic Refsum disease and six of them had auditory neuropathy. In the single report, which focused on the audiological findings in a patient with infantile Refsum disease, progressive hearing loss was demonstrated using puretone audiogram [6]. The hearing loss was mild at 6 years and profound at 11 years. One of the consistent features they observed was the absence of auditory brainstem responses and the presence of robust otoacoustic emissions, indicative of auditory neuropathy. The findings in our report are also consistent with Oysu et al. [6]. Early identification of auditory neuropathy in Refsum disease may have implications for appropriate management. Early onset auditory neuropathy can compromise the pre- or post-lingual language acquisition in children [18]. Management of auditory neuropathy aims at restoring compromised auditory processing, either through hearing aid fitting, alternative forms of communication like sign language or cued speech orby cochlear implantation [19]. Two reports have mentioned benefit with cochlear implantation in adult patients with Refsum disease [20,21]. In both the studies, patients who underwent cochlear implantation (age
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
3
Fig. 1. Distortion product otoacoustic emission measures for both ears indicate that DPOAEs are present above the noise level in all the frequencies for both the ears.
Fig. 2. The auditory brainstem evoked potentials for the left (blue) and right (red) ear indicating absence of replicable waveforms. Waveforms are obtained for two rarefaction and one condensation waveform for each ear. The recording between 0 and 1 ms for both ears indicate the presence of cochlear microphonics which is a distinctive sign of outer hair cell integrity in patients with auditory neuropathy. (For interpretation of the references to color in this text, the reader is referred to the web version of the article.)
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023
G Model
PEDOT-7599; No. of Pages 4 4
V.P. Vandana et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
range: 59–65) showed better audiometric performance and quality of life after implantation. However, details regarding the type of hearing loss were not mentioned in both reports. Early management of hearing loss in Refsum disease, if present, is very important as other senses (sight and smell) may also be affected in these patients. Conservative (mild gain) amplification trial is a justifiable management option depending on the availability of behavioral audiologic findings, prior to initiation of other forms of treatment like cochlear implants. This may also lead to improvement in speech and language development. For children with typical pattern of auditory findings associated with ‘auditory neuropathy’ who will be considered for cochlear implant candidacy, a period of hearing aid use (approximately 3 months) with close monitoring of responsiveness and cochlear status will meet requirements of cochlear implantation in these children. This will also be a daily reminder and assurance to parents regarding the importance of intensive speech and language stimulation. It is also to be kept in mind that benefits of hearing aid or cochlear implantation also depends on the underlying pathophysiology of the illness. In conclusion, this report highlights that auditory neuropathy is the cause for hearing loss in this patient with infantile Refsum disease. An audiological test battery approach encompassing behavioral observation audiometry, puretone audiometry, tympanometry, brainstem reflexometry, OAE and BERA are crucial for accurate diagnosis, management and intervention in these patients. This in turn may improve the quality of life in these children. References [1] S.J. Steinberg, G.V. Raymond, N.E. Braverman, A.B. Moser, Peroxisome biogenesis disorders, zellweger syndrome spectrum, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, S.E. Wallace, A. Amemiya, L.J.H. Bean, et al. (Eds.), Gene Reviews1 [Internet], University of Washington, Seattle, WA, 2003 December, pp. 1993–2015 (updated 2012 May 10) available from: http://www.ncbi.nlm.nih.gov/books/NBK1448/. [2] A.J. Wills, N.J. Manning, M.M. Reilly, Refsum’s disease, QJM 94 (2001) 403–406. [3] G.A. Jansen, R.J.A. Wanders, P.A. Watkins, S.J. Mihalik, Phytanoyl-coenzyme a hydroxylase deficiency: the enzyme defect in Refsum’s disease, N. Engl. J. Med. 337 (1997) 133–134.
[4] G. Bergsmark, G. Djupesland, Heredopathia atactica polyneuritiformis (Refsum’s diseases). An audiological examination of two patients, Eur. Neurol. 1 (2) (1968) 122–130. [5] H. Feldmann, Refsum’s syndrome, heredopathia atactica polyneuritiformis in the view of the otolaryngologist, Laryngol. Rhinol. Otol. (Stuttg.) 60 (5) (1981) 235– 240. [6] C. Oysu, I. Aslan, B. Basaran, N. Baserer, The site of the hearing loss in Refsum’s disease, Int. J. Pediatr. Otorhinolaryngol. 61 (2001) 129–134. [7] B.T. Poll-The, J. Gootjes, M. Duran, J.B. De Klerk, L.J. Wenniger-Prick, R.J. Admiraal, et al., Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients, Am. J. Med. Genet. A 126A (2004) 333–338. [8] K.R. Bzoch, L. Richard, The Bzoch-League receptive-expressive emergent language scale for the measurement of language skills in infancy, in: Assessing Language Skills in Infancy: A Handbook for the Multidimensional Analysis of Emergent Language, 1st ed., The Tree of Life Press, Inc., Gainesville, Florida, 1971, pp. 43–45Language Education Division of Computer Management Corp. [9] M. Cohen, D. Prasher, ABR and ART in neurotological diagnosis, Scand. Audiol. 17 (1988) 153–162. [10] http://www.asha.org/public/speech/development/parent-stim-activities.htm, Activities to encourage Speech and Language development. [11] D. Gallender, Eating Handicaps. Illustrated Techniques for Feeding Disorders, Charles C Thomas Publisher, Springfield, Illinois, USA, 1979. [12] H.F. Schuknecht, Pathology of the ear, Harvard University Press, Cambridge (United Kingdom), 1974, pp. 3–20. [13] J.B. Nadol, Primary Cochlear degeneration, in: Y. Sininger, A. Starr (Eds.), Auditory Neuropathy, Singular, San Diego, 2001. [14] C.S. Hallpike, Observations on the structural basis of two rare varieties of hereditary deafness, in: A.V.S. De Reusch, J. Knight (Eds.), Myatatic, Kinestetic and Vestibular Mechanisms, CIBA-Foundation Symposium, Churchill, London, 1967, p. 285. [15] M. Rake, M. Saunders, Refsum’s disease: a disorder of lipid metabolism, J. Neurol. Neurosurg. Psychiatry 29 (1966) 417–422. [16] G. Djupesland, S. Flottorp, Refsum’s, Phytanic acid storage disease: hearing maintained after 15 years of dietary treatment, Neurology 33 (2) (1983) 237–240. [17] D.E. Bamiou, P.R. Spraggs, F.B. Gibberd, M.C. Sidey, L.M. Luxon, Hearing loss in adult Refsum’s disease, Clin. Otolaryngol. Allied Sci. 28 (2003) 227–230. [18] P.V. Vlastarakos, T.P. Nikolopoulos, T. Evangelia, G. Papacharalambous, S. Korres, Auditory neuropathy: endocochlear lesion or temporal processing impairment? Implications for diagnosis and management, Int. J. Pediatr. Otorhinolaryngol. 72 (2008) 1135–1150. [19] P.G. Trautwein, Y.S. Sininger, R. Nelson, Cochlear implantation of auditory neuropathy, J. Am. Acad. Audiol. 11 (2000) 309–315. [20] C.H. Raine, M.F. Kurukulasuriya, Y. Bajaj, D.R. Strachan, Cochlear implantation in Refsum’s disease, Cochlear. Implants. Int. 9 (2008) 97–102. [21] C. Nogueira, T. Meehan, G. O’Donoghue, Refsum’s disease and cochlear implantation, Ann. Otol. Rhinol. Laryngol. 123 (2014) 425–427.
Please cite this article in press as: V.P. Vandana, et al., Audiological findings in Infantile Refsum disease, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.05.023