| | Auditory testing profiles of Pelizaeus-Merzbacher disease☆Received 1 September 2009; received in revised form 24 December 2009; accepted 5 January 2010. published online 08 February 2010.
Corrected Proof Abstract To characterize the auditory manifestations of patients diagnosed with Pelizaeus-Merzbacher Disease (PMD), a rare X-linked disorder of myelin classically characterized by nystagmus, spastic quadriparesis, ataxia, and cognitive delay in early childhood or progressive disease in adulthood. A prospective case study of 5 pediatric and 3 adult patients diagnosed with PMD who demonstrate varying degrees of abnormal auditory function. These patients underwent comprehensive audiological evaluations (audiometry, tympanometry, otoacoustic emissions), auditory processing tests (Dichotic Listening, Frequency Pattern Test, Duration Pattern Test), and electrophysiological measures (Auditory Brainstem Response). Abnormal electrophysiological findings with normal cochlear function were found in all test subjects. Further testing completed on adult subjects revealed further central auditory dysfunction via auditory processing tests. All the adult test subjects had abnormal results on auditory processing tests including significant left ear deficits on dichotic digits and poor duration pattern test scores. Auditory processing test results indicated strong right ear advantages for all adult PMD test subjects in Dichotic Digit testing. The degree of audiological central dysfunction findings was more severe in subjects with greater symptoms of the disease. Our findings indicate the need for a full audiological test battery on all patients with Pelizaeus-Merzbacher disease and other severe neurological disorders. 1. Introduction  Pelizaeus-Merzbacher disease (PMD) is a rare sex linked recessive disorder that results in central nervous system demyelination. Defects in the proteolipid protein gene (PLP1) located on the long arm of the X chromosome (Xq22) have been found to cause most of the clinical manifestations of PMD. PLP1 encodes two major products, PLP1 itself and a smaller protein, DM20, that results from alternative splicing. These proteins constitute about 50% of the mass of central nervous system white matter and are believed to serve an important structural function in compact myelin [1]. Pelizaeus-Merzbacher disease (PMD) has varying degrees of severity, depending both on type of chromosomal mutation and other genetic and environmental influences. The presentation of classic PMD is infantile-onset, typically within the first 2 months of life. Early physical signs include nystagmus and weakness, followed by the development of ataxia, cognitive delay, and spasticity. Most individuals acquire normal language abilities, but the speed of language output is usually slow and may suggest a more severe degree of mental retardation than is present. These patients may survive to the sixth decade of life or longer [2]. Individuals with the connatal PMD form are typically affected earlier and to a greater extent than the classical form. The connatal form usually results from missense substitutions. These severe mutations are believed to result in misfolding of the newly synthesized protein, which then accumulates in the endoplasmic reticulum and triggers apoptosis. Thus, oligodendrocyte numbers are severely reduced, and little myelin is produced. These patients have nystagmus present from early infancy, often have stridor and respiratory difficulty and hypotonia, and possible seizures. These patients typically have limited language skills, never ambulate, and develop severe spasticity with little voluntary movement. These individuals usually die before the third decade of life. Individuals with the least severe form of PMD, present with childhood-onset spastic paraplegia, mild cognitive impairment, and ataxia. Survival to the sixth decade of life or later is characteristic. Typically, neurological signs progress, but at a gradual rate with reported periods of relative stability. In each form of PMD, loss of hearing is known to be secondary to insufficient or inappropriate myelination of the brainstem. Auditory dysynchrony, auditory asynchrony, or auditory neuropathy is a disorder characterized by absent or grossly abnormal auditory brainstem response (ABR), absent acoustic reflexes, normal otoacoustic emissions, and poor speech recognition. In some cases there is only a cochlear microphonic present in ABR testing with normal otoacoustic emissions. Kaga et al. reported ABR abnormalities in the presence of normal audiograms in neurologically impaired pediatric subjects, including many PMD patients. Waves I and II or only Wave I were present in the 11 children they tested [3]. Bamiou et al. found abnormal audiological findings in a subject with a demyelinating disease called X-linked adrenoleukodystrophy. The findings revealed a normal audiogram, abnormal MRI, auditory processing deficits, and prolonged ABR latencies. The auditory processing findings included abnormal bilateral Dichotic Digit scores with a strong right ear advantage, abnormal temporal processing results in Frequency Pattern test, and abnormal results on Gaps-in-noise test [4]. Kraus et al. described auditory findings in a woman diagnosed with auditory neuropathy. This woman had normal audiograms, speech recognition in quiet, middle ear function, and otoacoustic emissions. However, there was an abnormal ABR, absent acoustic reflexes, and degradation in speech performance in the presence of noise [5]. We performed a comprehensive audiological test battery on PMD patients to assess hearing acuity and site of lesion of hearing loss. Further test procedures such as audiograms, acoustic reflexes, speech testing, and auditory processing procedures were performed on older subjects due to test age requirements and developmental delays in the pediatric subjects. 2. Methods and materials 2.1. Participants The study sample included five male children and three male adults diagnosed with the classical form of PMD. These patients ranged from 4 to 42 years of age. Two of the three adult subjects examined (subjects F and G) are brothers. The oldest pediatric patient (subject A) had gross motor delays, but had milder symptoms than the remaining four pediatric subjects. He was the only pediatric subject able to perform audiometric and electrophysiologic testing. The remaining pediatric subjects had severe developmental delays, mental retardation, and poor motor function thus limiting their ability to cooperate with audiometric and behavioral testing. Table 1 demonstrates patient demographics and symptom severity. 3. Equipment/procedures 3.1. Audiometry Pure-tone audiometric testing was completed with one subject using a Madsen audiometer. The three adult test subjects were tested using a GSI 61 audiometer in a calibrated soundbooth. Insert earphones were used for all test subjects. Visual Reinforcement Procedures (VRA) were attempted in a soundbooth with the other pediatric test subjects, but no reliable responses could be obtained. Word recognition testing was performed using the Northwestern University Test NU-6 Word lists. 3.2. ABR The Bio-logic Navigator Pro electrophysiological equipment was used to perform auditory brainstem response (ABR) testing on all test subjects without sedation. A single channel click stimulus recording with input 1 CZ, input 2 Aipsi (earlobe placement), and the opposite earlobe as common. The following parameters were used: rate 13.30, rarefaction polarity, click duration 100 μs, insert delay 0.80, gain 100,000, artifact reject 23.80, low filter 100, high filter 1500, and 50–55 dBHL masking. Nine millimeter silver disc electrodes were used throughout testing. Published normative data was utilized to assess latencies. Click recordings were obtained at 80dBnHL with 50–55dBHL masking in all subjects except for subject D. In this subject, it was difficult to keep both insert earphones because the test subject moved his head frequently. 3.4. Otoacoustic emissions Distortion Product Otoacoustic emissions testing was performed on all subjects using the Bio-logic Scout software. The right ear of subject C could not be obtained as the smallest newborn sized tip was too large for the ear canal. 3.5. Speech-in-noise Word recognition testing was completed again in both ears at the same intensity level as word recognition in quiet using a different NU-6 word list. Speech noise was presented at 5dB below the speech presentation level. 3.6. Dichotic digits Taped numerical digits were presented to both ears simultaneously via earphones at 50 DBSL. In the Single Digit test, one digit was presented to each ear at the same time and the patient was asked to repeat back both digits. In the Double Digit test, a pair of numbers was presented to both ears at the same time and the patient was asked to repeat all four numbers. The number correct was used to obtain accuracy. Normal adults should score 90% or better bilaterally. 3.7. Frequency pattern test Taped tonal stimuli were presented under earphones at 50dBSL. The tones varied from high pitched (1122Hz) or low pitched (880Hz) and presented in series of three tones. The patient was asked to verbally label each series as “high, high, low”, “low, high, low”, etc. A reversal was considered incorrect. The number correct was used to obtain percent accuracy. Normal adults should score better than 75% bilaterally. If a patient is unable to verbally label the tonal series, they were asked to hum the series. 4. Results 4.1. Subject A Subject A is a 9-year-old male with milder symptoms of the disease. He demonstrated gross motor abnormalities, but walked unassisted and was able to perform behavioral testing. Audiometric testing indicated normal hearing sensitivity in both ears. Tympanometry revealed normal middle ear pressure and compliance bilaterally. Distortion Product Otoacoustic emissions were within normal limits. Auditory Brainstem Response test results were abnormal. Waves I and II were present in both ears and the absolute latencies of Wave I were within normal limits. Questionable Wave Vs were present in both ears. If they are in fact Wave Vs, the absolute latencies of Wave V and Wave I–V interpeak latencies were within normal limits. The waveform morphology was poor (Fig. 1). 4.2. Subject B Subject B is a 7-year-old male with significant developmental delays, poor motor control, and wheelchair bound. No reliable behavioral testing could be completed. Tympanometry revealed normal middle ear pressure with reduced middle ear compliance in the left ear and normal middle ear pressure and compliance in the right ear. Distortion product otoacoustic emissions were present in both ears. Auditory Brainstem Response test results were abnormal. Waves I and II were present in both ears and the absolute latencies of Wave I were within normal limits. There was a questionable Wave V in the left ear, but not the right ear. The questionable Wave V response for the left ear had a delayed absolute latency with a delayed Wave I–V interpeak latency. 4.3. Subject C Subject C is a 5-year-old male with significant developmental delay, delayed physical development, and poor motor control. This subject was confined to an infant car seat. Reliable behavioral test results could not be obtained. Tympanometry with the standard 226Hz probe tone suggested minimal or no middle ear compliance. Testing was then completed with a 678Hz probe tone due to the subject's small size which revealed normal middle ear function, bilaterally. Distortion product otoacoustic emissions were present in the left ear using the smallest newborn sized tip. Otoacoustic emission testing could not be completed in the right ear due to poor probe fit. Auditory brainstem response test results were abnormal. Wave I was present in both ears with normal absolute latencies. No other repeatable waveforms were present (Fig. 2). 4.4. Subject D Subject D is 4-year-old male with significant motor delays, but demonstrated some head mobility. Audiometric testing could not be completed due to severe developmental delay. Tympanometry revealed normal bilateral middle ear function. Distortion product otoacoustic emissions were present bilaterally. Auditory brainstem response test results were abnormal. Wave I was present in both ears with normal absolute latencies. No other repeatable waveforms were obtained. 4.5. Subject E Subject E is a 4-year-old male with developmental delay and poor motor function. Behavioral testing could not be obtained. Distortion product otoacoustic emissions were present in both ears. Tympanometry was not completed due to the normal otoacoustic emissions. Auditory brainstem response test results were abnormal. Waves I and II were present in both ears with normal Wave I absolute latencies. No other repeatable waveforms were present. 4.6. Subject F Subject F is a 42-year-old wheelchair bound male with moderate motor deficits. Audiometric testing indicated normal hearing in the right ear. There was normal hearing in the left ear except for a mild sensorineural hearing loss at 2000Hz. Word recognition scores were excellent in quiet and in noise with a +5 signal to noise ratio. Tympanometry revealed normal middle ear pressure and compliance bilaterally. Ipsilateral acoustic reflexes were present at normal sensation levels in the right ear, but elevated and/or absent in the left ear. Distortion product otoacoustic emissions were present bilaterally. Dichotic digits were within normal limits in the single digit version, but revealed a significant left ear deficit in the double digit version. Frequency pattern test results were within normal limits. Durational pattern test results were abnormal. Auditory brainstem response test results were abnormal. Waves I, III, and V were present, but all absolute and interpeak latencies were delayed (Fig. 3). 4.7. Subject G Subject G is a 35-year-old left handed male. Subject G also exhibited poor motor control, but was able to walk with use of a cane. Audiometric testing indicated normal hearing in both ears. Word recognition scores were excellent in quiet and in noise with a +5 signal to noise ratio. Ipsilateral acoustic reflexes were elevated or absent in both ears. Distortion product otoacoustic emissions were present in both ears. Dichotic digit testing was within normal limits in the single digit test, but revealed a significant left ear deficit in the double digit test. Frequency pattern test results were within normal limits. Durational pattern test results were abnormal, but better than the scores of Subject F. Auditory Brainstem Response test results were abnormal. Waves I, III, and V were present, bilaterally. The absolute latencies of all waves were delayed in both ears. Waves I–III interpeak latencies were delayed in both ears. Waves III–V interpeak latencies were within normal limits for both ears. Waves I–V interpeak latencies were within normal limits in the left ear and delayed in the right ear. 4.8. Subject H Subject G is a 21-year-old male with significant motor dysfunction. He had limited mobility, was wheelchair bound, and had difficulty holding his head up. He had verbal ability, but responded very slowly and with little to no inflection. Audiometric testing indicated normal hearing in both ears. Word recognition scores were excellent in quiet bilaterally. Word recognition scores in noise with a +5 Signal to noise ratio were good. The scores dropped from 92% to 76% in the right ear and from 88% to 80% in the left ear when speech noise was added. Tympanometry was within normal limits for both ears. Ipsilateral acoustic reflexes were present in both ears, but contralateral acoustic reflexes were elevated or absent bilaterally. Distortion product otoacoustic emissions were present in both ears. Dichotic digit testing revealed abnormal results bilaterally in the single digit test with a significant right ear advantage. Subject H could not perform either the frequency pattern or duration pattern tests in either the verbal or humming conditions. Auditory brainstem response (ABR) results were abnormal. Wave I absolute latencies were within normal limits. Waves III and V absolute latencies were delayed. All interpeak latencies were delayed. 5. Discussion All subjects had essentially normal peripheral and abnormal central auditory test findings. The severity of the central dysfunction varied by subject and appeared to correlate with the severity of physical symptoms. All subjects revealed normal otoacoustic emissions, indicating normal cochlear outer hair cell function. Audiometric results were normal for all test subjects that could provide reliable behavioral results except for a mild, unilateral loss in subject F. The abnormal acoustic reflexes in subject F are not consistent with the degree of loss, suggesting neural origin (Fig. 4). Acoustic reflex thresholds were elevated or absent in the adult subjects tested. All the adult test subjects had abnormal results on auditory processing tests including significant left ear deficits on dichotic digits and poor durational pattern test scores. 5.1. Electrophysiology findings There are at least two different ABR phenotypes. Wave I was present at normal latencies in all pediatric subjects (A–E) with absent later waveforms and poor morphology. The Wave I did not invert with polarity changes, confirming their presence. Waves II and V were occasionally present, but there were no Wave III's in any of the pediatric subjects. In contrast, Waves I, III, and V all were present in the adult subjects (F, G, and H), with prolonged latencies, including Wave I absolute latency. Significant maturational changes occur in children under 3 years of age. In normal infants, the ABR Waves I and V appear first with long interpeak latencies. As the infant gets older, Waves III, II, and IV appear, interpeak latencies decrease, and morphology improves. It is possible that the ABR phenotype displayed in subjects A, B, C, D, and E result from lack of myelin slowing the normal auditory maturation while subjects F and G had normal auditory function that deteriorated progressively over time. Subject H, the adult with severe motor deficits and considerably worse auditory function than subjects F and G, had normal Wave I latencies similar to subjects A, B, C, D, and E; but had delayed Waves III and Waves V (Table 2). 5.2. Auditory processing findings In dichotic listening, the contralateral neural pathway is dominant over the ipsilateral pathway. Acoustic stimuli is transmitted more efficiently to the opposite right ear, the signal is transferred to the left brain hemisphere where language processing occurs. Auditory stimuli presented to the left ear is transferred to the right brain hemisphere and must than crossover to the left brain hemisphere via the corpus callosum or other inter-hemispheric pathway. A strong right ear advantage or left ear deficit is found in the presence of an abnormality to the brainstem or corpus callosum. Due to maturational effects, the corpus callosum usually is not completely formed until age 10–12 years. A deficit can also be expected in the contralateral ear of a unilateral lesion. It is possible to get a right ear deficit if there is damage to the left brain hemisphere [6]. The frequency pattern and duration pattern tests are similar temporal resolution tests. However, the underlying processes involved in frequency pattern test and durational pattern tests are thought to differ as the duration pattern test can detect cerebral lesions the frequency pattern cannot and vice versa [7]. The standard verbal procedure requires both brain hemispheres and inter-hemipheric communication. The left hemisphere is involved in language processing and the right brain hemisphere is involved with pattern recognition, music, and prosody [8]. If an individual is unable to verbally name the pattern, but can hum it, a corpus callosum or other inter-hemispheric dysfunction is suggested [9]. When an individual cannot verbally name or hum the patterns, a right hemispheric dysfunction is suggested. Auditory processing test results indicated strong right ear advantages for all adult PMD test subjects in dichotic digit testing (Table 3). Subjects F and G both performed normal in the single digit version, but demonstrated left ear deficits in the double digit version. Subject H revealed a bilateral deficit with strong right ear advantage in the single digit version. Subject H also revealed a slight decrease in word recognition ability when speech noise was added while Subjects F and G were unaffected. This demonstrates a greater severity of symptoms in subject H. Subjects F and G both performed normally on the frequency pattern test, but demonstrated poor results on the durational pattern test. Subject F performed worse on the durational patterns than subject G. Subject F was known to be the older brother of subject G who had a more severe progression of the disease. Subject H could not perform either frequency pattern or durational pattern tests in either the verbal or humming condition. Subject H seemed to show similar, but significantly more severe auditory dysfunction than subjects F and G (Table 4, Table 5). 6. Conclusions All subjects had essentially normal peripheral yet abnormal central auditory test findings. The severity of the central dysfunction varied by subject and the degree of dysfunction appears to correlate with the severity of physical symptoms. Auditory processing test procedures yield functional listening status on subjects with PMD and may provide insight into the underlying etiology of the disease (Table 6). 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a Department of Otolaryngology-Head and Neck Surgery, Wayne State University School of Medicine, 540 E. Canfield, 5E-UHC, Detroit, MI 48201, United States b Department of Neurology, Wayne State University School of Medicine, United States c Department of Molecular Medicine and Genetics, Wayne State University School of Medicine, United States  Corresponding author. Tel.: +1 248 357 4151.
☆ Poster presentation at the American Academy of Otolaryngology-Head and Neck Surgery; September 16–20, 2006; Toronto, Canada. PII: S1871-4048(10)00003-1 doi:10.1016/j.pedex.2010.01.001 © 2010 Elsevier Ireland Ltd. All rights reserved. | |
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