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Auditory neuropathy spectrum disorder in hypomyelinating leukodystrophy—A case study
International Journal of Pediatric Otorhinolaryngology 79 (2015) 2479–2483
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case Report, Case Reports
Auditory neuropathy spectrum disorder in hypomyelinating leukodystrophy—A case study Pradeep Yuvaraj a, M. Jayaram a,*, Rahina Abubacker a, P.S. Bindu b a b
Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences, Bangalore 560029, Karnataka, India Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, Karnataka, India
A R T I C L E I N F O
Article history: Received 14 September 2015 Received in revised form 26 October 2015 Accepted 29 October 2015 Available online 9 November 2015 Keywords: Leukodystrophy Hypomyelination Auditory neuropathy spectrum disorder Otoacoustic emissions Brainstem auditory evoked responses Cochlear microphonics
1. Introduction Leukodystrophy is one of a group of disorders characterized by degeneration of white matter in the brain. The basic defect in this disorder is directly related to the synthesis and maintenance of myelin membranes. When damage occurs to white matter, immune responses may lead to inflammation in the central nervous system along with loss of myelin. Characteristics of leukodystrophy include decreased motor function, spasticity, muscle rigidity, and eventual degeneration of the senses of vision and hearing. The majority of the leukodystrophies involve the inheritance of a recessive, dominant, or X-linked trait while some are the result of spontaneous mutation rather than genetic inheritance (although involving a defective gene). Though the degeneration of white matter can be seen on an MRI, identification of leukodystrophy remains a challenge. Hypo myelinating leukodystrophies (HLD) are identified by a paucity of myelin development. MRI typically shows variable signal (that is, hyper-, hypo-, or isointense) on T1-weighted imaging and mild
* Corresponding author. Tel.: +91 9449264716. E-mail addresses: [email protected] (P. Yuvaraj), [email protected] (M. Jayaram), [email protected] (R. Abubacker), [email protected] (P.S. Bindu). http://dx.doi.org/10.1016/j.ijporl.2015.10.053 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
hyper intensity on T2-weighted imaging of the white matter compared to gray matter signal. This is distinct from other leukodystrophies in which more hypo intense T1-weighted and more severe hyper intense T2-weighted white matter imaging signals are seen, usually in a more geographic or localized distribution [1]. Kohlschu¨tter and Eichler [2] reported that boys with X-ALD may have normal brainstem auditory evoked responses (BAER) in the first decade of life, but BAERs later become abnormal in the course of the disease when demyelinating lesions extend to the brainstem and spinal cord. Even patients with a normal MRI may have an abnormal neurophysiologic pattern identical to that seen in adrenomyeloneuropathy patients (evidently milder in terms of abnormalities); in such cases, usually BAERs are first to be abnormal [3]. Feldman et al. [4] also suggested that abnormal BAERs can be of help in the early diagnosis of the disorder. Dramatically improving BAERs over a 10-year period have been reported in persons affected with HLD [5]. Hypomyelinating disorders like Pelizaeus–Merzbacher disease (PMD) may show normal wave I without subsequent waves and thus BAERs are of particular value in the early diagnosis of the disorder [6,7]. BAERs are typically absent in PMD [1]. Therefore, Pouwels et al. [1] believe that BAERs can serve as an objective marker for identification of PMD. However, the validity of this observation needs to be established.
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A number of researchers have reported hearing and speech related problems in persons with HLD; absence of language acquisition and evidence of brainstem dysfunction on auditory testing [8]; deafness in 1–3 year old children with leukodystrophy [9]; and learning disability and variable delay in auditory evoked potentials in 7 unrelated patients with leukodystrophy [10]. Van Der Knaap et al. [10] also reported very poor speech development and decreased hearing (not a consistent feature) in another series of 11 unrelated patients with leukodystrophy. Simons et al. [11] reported that 10 out of their 11 patients with HLD had some sort of speech delay and dysarthria. In a retrospective comparative study of neurophysiologic results from 10 patients with PMD-like disease (PMLD1; 608804) and 8 with classic PMD, Henneke et al. [12] found that BAERs were significantly worse in patients with classic PMD. Waves III–V which are generated in the pons and midbrain were absent in all patients with PMD, but were clearly recordable in patients with PMLD1. Investigations of auditory acuity were not available. Henneke et al. [12] concluded that BAER is a helpful tool to differentiate between PMLD1 and PMD. The clinical onset of HLD is frequently insidious, and the symptoms then slowly progress. It can be seen from the above review that many investigators have reported abnormalities of speech and hearing in children with HLD. Most of the investigators have talked of either abnormalities of BAERs or sensorineural hearing loss (general observation only). However, the specific nature of the hearing defect in this clinical population has not been described. We report here a patient with HLD in whom a diagnosis of auditory neuropathy spectrum disorder (ANSD) was made based on detailed audiological investigations. 2. Report of a case A 26-months old girl NM was brought to the outpatient clinic of the Department of Neurology with the complaints of abnormal movements of eye and head since birth, and delayed developmental milestones. She was the second child born to third degree consanguineous parents. She was born at term after an uneventful
pregnancy and delivery (birth weight of 3 Kg). Birth cry was delayed and therefore, the baby was kept in neonatal ICU for a day. Then the parents were counselled and discharged. At one year, mother noticed that the child was not able to hold her neck. The doctors at the local hospital advised the parents to carryout physiotherapy. Parents did not suspect any problem relating to speech-language or hearing in their child. Examination at the Neurology outpatient clinic of the National Institute of Mental Health & Neurosciences showed an active playful child. All anthropometric measurements were below the third centile for age. Neurological examination revealed roving eye movements in the primary position which became exaggerated on horizontal and vertical gaze. Extra ocular movements were full. She could fix and follow light. Ophthalmological examination revealed normal optic disc and retina. Motor system examination showed bilateral pyramidal signs in the form of spasticity, brisk reflexes and extensor plantar response. Tremulousness of bilateral upper limbs on reaching out for objects was noted. Titubation of the head was present at rest. She was evaluated for routine hematological and biochemical studies which revealed normal results. Tandem mass spectrometry revealed normal amino acids and acyl carnitine profiles. Urine was negative for abnormal metabolites. She had a normal thyroid function, and normal levels of S. Homocysteine, Vitamin B12, uric acid, serum ammonia, and serum lactate. Nerve conduction studies showed normal compound muscle action potentials from median, ulnar and common peroneal nerves and sensory nerve action potential from sural and median nerves. The child could stand with support, transfer objects from one hand to another, babble a little and respond to sound though inconsistently. Review of the MRI of the brain done at 22 months of age (Fig. 1) showed presence of myelination confined to the posterior limbs of the internal capsule, pericentral area, brain stem, genu and splenium of the corpus callosum on both T1 weighted and T2 weighted images. There was no evidence of myelination in lobar white matter. Basal ganglia and thalamus showed hypo intensity on T2 weighted images. The findings were suggestive of hypo myelination. Based on the results of clinical, MRI and metabolic
Fig. 1. MRI brain at the age of 22 months: T1 weighted image (A) demonstrating hyper intensity only in the anterior and posterior limb of internal capsule, genu and splenium of the corpus callosum. T2 weighted image (B) demonstrates diffuse hyper intensity of the white matter suggesting hypomyelination.
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Fig. 2. Distortion product otoacoustic emissions recorded from the left ear. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
examination, a tentative diagnosis of HLD was made with a recommendation for a second MRI in a years’ time. The child was put on general vitamin supplements and referred to the departments of Child & Adolescent Psychiatry, and Speech Pathology & Audiology for further management. 3. Audiological assessment Auditory behavior: It was observed at the department of Speech Pathology & Audiology that the child responded to both verbal and nonverbal stimuli though inconsistently. Head turning was observed even for soft sounds. The child could differentiate parent’s voice from those of others. A detailed speech-language evaluation was not possible because of time consideration. The child could utter a few monosyllables, but there was no evidence that the child could understand speech-language of others. However, the child could follow some simple instructions presented through the auditory-visual mode (with gestures). Distortion product otoacoustic emissions (OAE) were recorded (Echoport ILO 292-II). Intensity of the tone pairs was 65 and 55 dB SPL for L1 and L2, respectively. Two separate runs for each ear were collected for determining repeatability. Validity and reliability of normal outer hair cell function was determined by analyzing each
distortion product frequency separately. An OAE response was considered valid if the distortion product amplitude (signal to noise ratio) was greater than or equal to 6 dB (Figs. 2 and 3). The results of otoscopic and tympanometric evaluations were typically normal suggesting a normal outer and middle ear. A recording of BAERs (IHS, Miami, Florida) was carried out with the following protocol: Recordings were made between the upper forehead and ipsilateral mastoid, with the opposite mastoid used as ground; bandpass filtering was set between 100 and 3000 Hz, with manual and automatic artifact rejection; rarefaction and condensation polarity click stimuli were presented at 90 dB nHL through insert earphones (ER-3A) at a stimulus rate of 11.1 clicks per second. Electrode impedance was maintained at <5 kOhms. Two recordings for rarefaction and one for condensation stimuli of 2,000 samples each were obtained (Figs. 4 and 5).
4. Audiological test results Blue lines in Figs. 2 and 3 show the OAEs while the red line indicates noise floor. The numbers at the top (in blue) show the absolute amplitude of the emissions (in dB) at each frequency. The responses were robust and the difference between absolute
Fig. 3. Distortion product otoacoustic emissions recorded from the right ear. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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Fig. 4. Absence of BAERs and clear presence of cochlear microphonics in the left ear.
Fig. 5. Absence of BAERs and clear presence of cochlear microphonics in the right ear.
amplitude and noise floor was greater than 6 dB across all tested frequencies in both ears. BAERs were absent in both the ears. Clear ringing CMs were observed as evident on the reversal seen for rarefaction and condensation stimuli (Figs. 4 and 5). Tube clamp1 was done to confirm the presence of cochlear microphonics. 1 Stimulus artifact is seen at the very onset of the waveform while cochlear microphonics (CM) appear after a brief latency of 0.5 to 1 ms. This is because the stimulus has to travel through the sound tube, outer and middle ear. Tube clamping is done to determine whether the components in the response are biologic in origin (CM) or a recording artifact of the electrical input to the earphone or a stimulus artifact. The stimulus artifact will persist and CM will disappear when stimuli are withdrawn by clamping the sound tube.
The results of audiological evaluation are consistent with the audiological findings reported in the literature in persons with ANSD [13] and meet the criteria for a diagnosis of ANSD. According to Starr, Sininger and Pratt [13], ANSD is characterized by presence of OAEs and CM with absent BAERs. BAERs are not present because of dys-synchrony in the firing of the auditory nerve fibers to stimulation. In addition, Starr, Sininger and Pratt [13] report that individuals afflicted with ANSD may show normal to severe hearing loss for pure tones and that their speech identification scores will be disproportionate to the degree of hearing loss. However, we could not conduct either pure tone or speech audiometry as the patient was only 26 months old.
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5. Discussion
Conflict of interest statement
ANSD is a hearing disorder in which afferent neural conduction in the auditory pathway is disordered. This form of hearing impairment is variously known as ‘‘auditory neuropathy’’ [14], or auditory dys-synchrony [15], and at present as ANSD [16]. The clinical findings that define ANSD are the presence of outer hair cell activity and CM; and the absence of evoked neural activity at the level of the eighth nerve (absent BAER). The identified/ hypothesized etiologies of ANSD fall into two broad ‘categories: one, neuropathies originating from hereditary or congenital conditions such as Friedreich’s ataxia or Charcot-Marie-Tooth disease and two, acquired conditions such as hyperbilirubinemia or hypoxia [17]. Some of the other pathologies that result in ANSD include specific damage to the cochlear inner hair cells (IHC), abnormality of IHC—auditory nerve synapse [18], spiral ganglion cell disorder [19], depleted neuronal populations in the auditory brainstem [20], and demyelination of the auditory nerve [14]. Other neurological and genetic disorders that have been reported in over one-third of persons with neuropathies include absent 8th nerve [21], Charcot-Marie-Tooth Disease and Mohr–Tranebjaerg syndrome [14,22] and mitochondrial diseases [23–25]. Starr et al. [14] documented evidence that auditory (axonal) degeneration or demyelination may lead to auditory neuropathy. Myelin plays an important role in the rapid conduction of nerve impulses along axons. Demyelination or degeneration causes a conduction block of auditory nerve fibers; therefore, no compound nerve action potentials distal to the conduction block are generated. Demyelination results in a lack of neural synchrony and poor temporal encoding. This theory accounts for the grossly abnormal or absent BAERs and degraded speech perception in patients with ANSD. Histological studies have reported a reduction of eighth nerve fibers in persons with ANSD [26]. Auditory neuropathy encompasses a broad diagnostic label rather than a single neuropathy affecting just the auditory pathway. Many patients have additional multiple neuropathies outside the auditory pathway. The majority of cases reported are of genetic or idiopathic origin [14] though other pathologies can result in ANSD as detailed above. Though the literature suggests that a generalized demyelinating condition could lead to ANSD, specific report of ANSD in leukodystrophy is yet to be reported. The parents of the child in the present report did not suspect any hearing loss in the child and the child was referred for management of delayed speech and language development rather for any evaluation of auditory behavior. The present report is not only a specific documentation of the nature of hearing disorder in some patients with HLD, but also gives an insight into the precipitating factors leading to delayed or absence of speech and language development in the child. Management of patients with auditory neuropathy poses a formidable challenge with most reports suggesting that persons with ANSD do not benefit from hearing aid amplification though they may benefit from cochlear implantation. The findings of the present case report strongly indicate the need for detailed audiological evaluation in children who show any kind of leukodystrophy. Such an examination may help in identifying the underlying hearing loss (if present) so that an audiologist can put in place, as early as possible, a set of management strategies to teach auditory behaviors to such children.
There is no conflict of interest for any author. This publication was not funded by anybody and in any manner. References [1] P.J.W. Pouwels, A. Vanderver, G. Bernard, N.I. Wolf, S.F. Dreha-Kulczewksi, S.C.L. Deoni, et al., Hypomyelinating leukodystrophies: translational research progress and prospects, Ann. Neurol. 76 (2014) 5–19. [2] A. Kohlschu¨tter, F. Eichler, Childhood leukodystrophies: a clinical perspective, Expert Rev. Neurother. 11 (2011) 1485–1496. [3] P. Aubourg, C. Adamsbaum, M.C. Lavallard-Rousseau, A. Lemaitre, F. Boureau, M. Mayer, et al., Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy, Neurology 42 (1992) 85–91. [4] J.I. Feldman, D.B. Kearns, A.B. Seid, S.M. Pransky, M.C. Jones, The otolaryngologic manifestations of Pelizaeus–Merzbacher disease, Otolaryngology 116 (1990) 613–616. [5] K. Inoue, H. Tanaka, F. Scaglia, A. Araki, L.G. Shaffer, J.R. Lupski, Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement, Ann. Neurol. 50 (2001) 747–754. [6] K. Inoue, PLP1-related inherited dysmyelinating disorders: Pelizaeus–Merzbacher disease and spastic paraplegia type 2, Neurogenetics 6 (2005) 1–16. [7] F.A. Hanefeld, K. Brockmann, P.J.W. Pouwels, B. Wilken, J. Frahm, P. Dechent, Quantitative proton MRS of Pelizaeus–Merzbacher disease: evidence of dys- and hypomyelination, Neurology 65 (2005) 701–706. [8] S. Miyatake, H. Osaka, M. Shiina, M. Sasaki, J.I. Takanashi, K. Haginoya, et al., Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies, Neurology 82 (2014) 2230–2237. [9] V. Leuzzi, A. Rinna, M. Gallucci, M. Di Capua, C. Dionisi-Vici, D. Longo, et al., Ataxia, deafness, leukodystrophy: inherited disorder of the white matter in three related patients, Neurology 54 (2000) 2325–2328. [10] M.S. Van Der Knaap, T. Linnankivi, A. Paetau, A. Feigenbaum, K. Wakusawa, K. Haginoya, et al., Hypomyelination with atrophy of the basal ganglia and cerebellum: follow-up and pathology, Neurology 69 (2007) 166–171. [11] C. Simons, N.I. Wolf, N. McNeil, L. Caldovic, J.M. Devaney, A. Takanohashi, et al., A de novo mutation in the b-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum, Am. J. Hum. Genet. 92 (2013) 767–773. [12] M. Henneke, S. Gegner, A. Hahn, B. Plecko-Startinig, B. Weschke, J. Ga¨rtner, et al., Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus–Merzbacher disease, Neurology 74 (2010) 1785–1789. [13] A. Starr, Y.S. Sininger, H. Pratt, The varieties of auditory neuropathy, J. Basic Clin. Physiol. Pharmacol. 11 (2000) 215–230. [14] A. Starr, T.W. Picton, Y. Sininger, L.J. Hood, C.I. Berlin, Auditory neuropathy, Brain 119 (Pt 3) (1996) 741–753. [15] C.I. Berlin, L.J. Hood, K. Rose, On renaming auditory neuropathy as auditory dyssynchrony, Audiol. Today 13 (2001) 15–17. [16] D. Hayes, Y.S. Sininger, Identification and management of infants and young children with auditory neuropathy spectrum disorder, in: Presented at the Newborn Hearing Systems Conference, 19–21 June, 2008, Lake Como, Italy, 2008. [17] I. Rapin, J. Gravel, Auditory neuropathy: physiologic and pathologic evidence calls for more diagnostic specificity, Int. J. Pediatr. Otorhinolaryngol. 67 (2003) 707–728. [18] D. Khimich, R. Nouvian, R. Pujol, S. Tom Dieck, A. Egner, E.D. Gundelfinger, et al., Hair cell synaptic ribbons are essential for synchronous auditory signalling, Nature 434 (2005) 889–894. [19] M.G. Amatuzzi, C. Northrop, M.C. Liberman, A. Thornton, C. Halpin, B. Herrmann, et al., Selective inner hair cell loss in premature infants and cochlea pathological patterns from neonatal intensive care unit autopsies, Arch. Otolaryngol. Head Neck Surg. 127 (2001) 629–636. [20] M.M. El-Badry, D. Ding, S.L. McFadden, A.C. Eddins, Physiological effects of auditory nerve myelinopathy in chinchillas, Eur. J. Neurosci. 25 (2007) 1437–1446. [21] C.A. Buchman, P.A. Roush, H.F.B. Teagle, C.J. Brown, C.J. Zdanski, J.H. Grose, Auditory neuropathy characteristics in children with cochlear nerve deficiency, Ear Hear. 27 (2006) 399–408. [22] S.N. Merchant, M.J. McKenna, J.B. Nadol, A.G. Kristiansen, A. Tropitzsch, S. Lindal, et al., Temporal bone histopathologic and genetic studies in Mohr–Tranebjaerg syndrome (DFN-1), Otol. Neurotol. 22 (2001) 506–511. [23] B. Ceranic, L.M. Luxon, Progressive auditory neuropathy in patients with Leber’s hereditary optic neuropathy, J Neurol. Neurosurg. Psychiatry 75 (2004) 626–630. [24] V.M. Corley, L.S. Crabbe, Auditory neuropathy and a mitochondrial disorder in a child: case study, J. Am. Acad. Audiol. 10 (1999) 484–488. [25] F. Forli, M. Mancuso, A. Santoro, M.T. Dotti, G. Siciliano, S. Berrettini, Auditory neuropathy in a patient with mitochondrial myopathy and multiple mtDNA deletions, J. Laryngol. Otol. 120 (2006) 888–891. [26] H. Spoendlin, Optic cochleovestibular degenerations in hereditary ataxias. II. Temporal bone pathology in two cases of Friedreich’s ataxia with vestibulocochlear disorders, Brain 97 (1974) 41–48.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case Report, Case Reports
Auditory neuropathy spectrum disorder in hypomyelinating leukodystrophy—A case study Pradeep Yuvaraj a, M. Jayaram a,*, Rahina Abubacker a, P.S. Bindu b a b
Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences, Bangalore 560029, Karnataka, India Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, Karnataka, India
A R T I C L E I N F O
Article history: Received 14 September 2015 Received in revised form 26 October 2015 Accepted 29 October 2015 Available online 9 November 2015 Keywords: Leukodystrophy Hypomyelination Auditory neuropathy spectrum disorder Otoacoustic emissions Brainstem auditory evoked responses Cochlear microphonics
1. Introduction Leukodystrophy is one of a group of disorders characterized by degeneration of white matter in the brain. The basic defect in this disorder is directly related to the synthesis and maintenance of myelin membranes. When damage occurs to white matter, immune responses may lead to inflammation in the central nervous system along with loss of myelin. Characteristics of leukodystrophy include decreased motor function, spasticity, muscle rigidity, and eventual degeneration of the senses of vision and hearing. The majority of the leukodystrophies involve the inheritance of a recessive, dominant, or X-linked trait while some are the result of spontaneous mutation rather than genetic inheritance (although involving a defective gene). Though the degeneration of white matter can be seen on an MRI, identification of leukodystrophy remains a challenge. Hypo myelinating leukodystrophies (HLD) are identified by a paucity of myelin development. MRI typically shows variable signal (that is, hyper-, hypo-, or isointense) on T1-weighted imaging and mild
* Corresponding author. Tel.: +91 9449264716. E-mail addresses: [email protected] (P. Yuvaraj), [email protected] (M. Jayaram), [email protected] (R. Abubacker), [email protected] (P.S. Bindu). http://dx.doi.org/10.1016/j.ijporl.2015.10.053 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
hyper intensity on T2-weighted imaging of the white matter compared to gray matter signal. This is distinct from other leukodystrophies in which more hypo intense T1-weighted and more severe hyper intense T2-weighted white matter imaging signals are seen, usually in a more geographic or localized distribution [1]. Kohlschu¨tter and Eichler [2] reported that boys with X-ALD may have normal brainstem auditory evoked responses (BAER) in the first decade of life, but BAERs later become abnormal in the course of the disease when demyelinating lesions extend to the brainstem and spinal cord. Even patients with a normal MRI may have an abnormal neurophysiologic pattern identical to that seen in adrenomyeloneuropathy patients (evidently milder in terms of abnormalities); in such cases, usually BAERs are first to be abnormal [3]. Feldman et al. [4] also suggested that abnormal BAERs can be of help in the early diagnosis of the disorder. Dramatically improving BAERs over a 10-year period have been reported in persons affected with HLD [5]. Hypomyelinating disorders like Pelizaeus–Merzbacher disease (PMD) may show normal wave I without subsequent waves and thus BAERs are of particular value in the early diagnosis of the disorder [6,7]. BAERs are typically absent in PMD [1]. Therefore, Pouwels et al. [1] believe that BAERs can serve as an objective marker for identification of PMD. However, the validity of this observation needs to be established.
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A number of researchers have reported hearing and speech related problems in persons with HLD; absence of language acquisition and evidence of brainstem dysfunction on auditory testing [8]; deafness in 1–3 year old children with leukodystrophy [9]; and learning disability and variable delay in auditory evoked potentials in 7 unrelated patients with leukodystrophy [10]. Van Der Knaap et al. [10] also reported very poor speech development and decreased hearing (not a consistent feature) in another series of 11 unrelated patients with leukodystrophy. Simons et al. [11] reported that 10 out of their 11 patients with HLD had some sort of speech delay and dysarthria. In a retrospective comparative study of neurophysiologic results from 10 patients with PMD-like disease (PMLD1; 608804) and 8 with classic PMD, Henneke et al. [12] found that BAERs were significantly worse in patients with classic PMD. Waves III–V which are generated in the pons and midbrain were absent in all patients with PMD, but were clearly recordable in patients with PMLD1. Investigations of auditory acuity were not available. Henneke et al. [12] concluded that BAER is a helpful tool to differentiate between PMLD1 and PMD. The clinical onset of HLD is frequently insidious, and the symptoms then slowly progress. It can be seen from the above review that many investigators have reported abnormalities of speech and hearing in children with HLD. Most of the investigators have talked of either abnormalities of BAERs or sensorineural hearing loss (general observation only). However, the specific nature of the hearing defect in this clinical population has not been described. We report here a patient with HLD in whom a diagnosis of auditory neuropathy spectrum disorder (ANSD) was made based on detailed audiological investigations. 2. Report of a case A 26-months old girl NM was brought to the outpatient clinic of the Department of Neurology with the complaints of abnormal movements of eye and head since birth, and delayed developmental milestones. She was the second child born to third degree consanguineous parents. She was born at term after an uneventful
pregnancy and delivery (birth weight of 3 Kg). Birth cry was delayed and therefore, the baby was kept in neonatal ICU for a day. Then the parents were counselled and discharged. At one year, mother noticed that the child was not able to hold her neck. The doctors at the local hospital advised the parents to carryout physiotherapy. Parents did not suspect any problem relating to speech-language or hearing in their child. Examination at the Neurology outpatient clinic of the National Institute of Mental Health & Neurosciences showed an active playful child. All anthropometric measurements were below the third centile for age. Neurological examination revealed roving eye movements in the primary position which became exaggerated on horizontal and vertical gaze. Extra ocular movements were full. She could fix and follow light. Ophthalmological examination revealed normal optic disc and retina. Motor system examination showed bilateral pyramidal signs in the form of spasticity, brisk reflexes and extensor plantar response. Tremulousness of bilateral upper limbs on reaching out for objects was noted. Titubation of the head was present at rest. She was evaluated for routine hematological and biochemical studies which revealed normal results. Tandem mass spectrometry revealed normal amino acids and acyl carnitine profiles. Urine was negative for abnormal metabolites. She had a normal thyroid function, and normal levels of S. Homocysteine, Vitamin B12, uric acid, serum ammonia, and serum lactate. Nerve conduction studies showed normal compound muscle action potentials from median, ulnar and common peroneal nerves and sensory nerve action potential from sural and median nerves. The child could stand with support, transfer objects from one hand to another, babble a little and respond to sound though inconsistently. Review of the MRI of the brain done at 22 months of age (Fig. 1) showed presence of myelination confined to the posterior limbs of the internal capsule, pericentral area, brain stem, genu and splenium of the corpus callosum on both T1 weighted and T2 weighted images. There was no evidence of myelination in lobar white matter. Basal ganglia and thalamus showed hypo intensity on T2 weighted images. The findings were suggestive of hypo myelination. Based on the results of clinical, MRI and metabolic
Fig. 1. MRI brain at the age of 22 months: T1 weighted image (A) demonstrating hyper intensity only in the anterior and posterior limb of internal capsule, genu and splenium of the corpus callosum. T2 weighted image (B) demonstrates diffuse hyper intensity of the white matter suggesting hypomyelination.
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Fig. 2. Distortion product otoacoustic emissions recorded from the left ear. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
examination, a tentative diagnosis of HLD was made with a recommendation for a second MRI in a years’ time. The child was put on general vitamin supplements and referred to the departments of Child & Adolescent Psychiatry, and Speech Pathology & Audiology for further management. 3. Audiological assessment Auditory behavior: It was observed at the department of Speech Pathology & Audiology that the child responded to both verbal and nonverbal stimuli though inconsistently. Head turning was observed even for soft sounds. The child could differentiate parent’s voice from those of others. A detailed speech-language evaluation was not possible because of time consideration. The child could utter a few monosyllables, but there was no evidence that the child could understand speech-language of others. However, the child could follow some simple instructions presented through the auditory-visual mode (with gestures). Distortion product otoacoustic emissions (OAE) were recorded (Echoport ILO 292-II). Intensity of the tone pairs was 65 and 55 dB SPL for L1 and L2, respectively. Two separate runs for each ear were collected for determining repeatability. Validity and reliability of normal outer hair cell function was determined by analyzing each
distortion product frequency separately. An OAE response was considered valid if the distortion product amplitude (signal to noise ratio) was greater than or equal to 6 dB (Figs. 2 and 3). The results of otoscopic and tympanometric evaluations were typically normal suggesting a normal outer and middle ear. A recording of BAERs (IHS, Miami, Florida) was carried out with the following protocol: Recordings were made between the upper forehead and ipsilateral mastoid, with the opposite mastoid used as ground; bandpass filtering was set between 100 and 3000 Hz, with manual and automatic artifact rejection; rarefaction and condensation polarity click stimuli were presented at 90 dB nHL through insert earphones (ER-3A) at a stimulus rate of 11.1 clicks per second. Electrode impedance was maintained at <5 kOhms. Two recordings for rarefaction and one for condensation stimuli of 2,000 samples each were obtained (Figs. 4 and 5).
4. Audiological test results Blue lines in Figs. 2 and 3 show the OAEs while the red line indicates noise floor. The numbers at the top (in blue) show the absolute amplitude of the emissions (in dB) at each frequency. The responses were robust and the difference between absolute
Fig. 3. Distortion product otoacoustic emissions recorded from the right ear. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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Fig. 4. Absence of BAERs and clear presence of cochlear microphonics in the left ear.
Fig. 5. Absence of BAERs and clear presence of cochlear microphonics in the right ear.
amplitude and noise floor was greater than 6 dB across all tested frequencies in both ears. BAERs were absent in both the ears. Clear ringing CMs were observed as evident on the reversal seen for rarefaction and condensation stimuli (Figs. 4 and 5). Tube clamp1 was done to confirm the presence of cochlear microphonics. 1 Stimulus artifact is seen at the very onset of the waveform while cochlear microphonics (CM) appear after a brief latency of 0.5 to 1 ms. This is because the stimulus has to travel through the sound tube, outer and middle ear. Tube clamping is done to determine whether the components in the response are biologic in origin (CM) or a recording artifact of the electrical input to the earphone or a stimulus artifact. The stimulus artifact will persist and CM will disappear when stimuli are withdrawn by clamping the sound tube.
The results of audiological evaluation are consistent with the audiological findings reported in the literature in persons with ANSD [13] and meet the criteria for a diagnosis of ANSD. According to Starr, Sininger and Pratt [13], ANSD is characterized by presence of OAEs and CM with absent BAERs. BAERs are not present because of dys-synchrony in the firing of the auditory nerve fibers to stimulation. In addition, Starr, Sininger and Pratt [13] report that individuals afflicted with ANSD may show normal to severe hearing loss for pure tones and that their speech identification scores will be disproportionate to the degree of hearing loss. However, we could not conduct either pure tone or speech audiometry as the patient was only 26 months old.
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5. Discussion
Conflict of interest statement
ANSD is a hearing disorder in which afferent neural conduction in the auditory pathway is disordered. This form of hearing impairment is variously known as ‘‘auditory neuropathy’’ [14], or auditory dys-synchrony [15], and at present as ANSD [16]. The clinical findings that define ANSD are the presence of outer hair cell activity and CM; and the absence of evoked neural activity at the level of the eighth nerve (absent BAER). The identified/ hypothesized etiologies of ANSD fall into two broad ‘categories: one, neuropathies originating from hereditary or congenital conditions such as Friedreich’s ataxia or Charcot-Marie-Tooth disease and two, acquired conditions such as hyperbilirubinemia or hypoxia [17]. Some of the other pathologies that result in ANSD include specific damage to the cochlear inner hair cells (IHC), abnormality of IHC—auditory nerve synapse [18], spiral ganglion cell disorder [19], depleted neuronal populations in the auditory brainstem [20], and demyelination of the auditory nerve [14]. Other neurological and genetic disorders that have been reported in over one-third of persons with neuropathies include absent 8th nerve [21], Charcot-Marie-Tooth Disease and Mohr–Tranebjaerg syndrome [14,22] and mitochondrial diseases [23–25]. Starr et al. [14] documented evidence that auditory (axonal) degeneration or demyelination may lead to auditory neuropathy. Myelin plays an important role in the rapid conduction of nerve impulses along axons. Demyelination or degeneration causes a conduction block of auditory nerve fibers; therefore, no compound nerve action potentials distal to the conduction block are generated. Demyelination results in a lack of neural synchrony and poor temporal encoding. This theory accounts for the grossly abnormal or absent BAERs and degraded speech perception in patients with ANSD. Histological studies have reported a reduction of eighth nerve fibers in persons with ANSD [26]. Auditory neuropathy encompasses a broad diagnostic label rather than a single neuropathy affecting just the auditory pathway. Many patients have additional multiple neuropathies outside the auditory pathway. The majority of cases reported are of genetic or idiopathic origin [14] though other pathologies can result in ANSD as detailed above. Though the literature suggests that a generalized demyelinating condition could lead to ANSD, specific report of ANSD in leukodystrophy is yet to be reported. The parents of the child in the present report did not suspect any hearing loss in the child and the child was referred for management of delayed speech and language development rather for any evaluation of auditory behavior. The present report is not only a specific documentation of the nature of hearing disorder in some patients with HLD, but also gives an insight into the precipitating factors leading to delayed or absence of speech and language development in the child. Management of patients with auditory neuropathy poses a formidable challenge with most reports suggesting that persons with ANSD do not benefit from hearing aid amplification though they may benefit from cochlear implantation. The findings of the present case report strongly indicate the need for detailed audiological evaluation in children who show any kind of leukodystrophy. Such an examination may help in identifying the underlying hearing loss (if present) so that an audiologist can put in place, as early as possible, a set of management strategies to teach auditory behaviors to such children.
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