**4. Discussion**

apex and dilated vestibule, which is shown in **Figure 3**. All detected anomalies were bilateral except for the dilated vestibule (right ear, pt. # 14). The middle ear pathological findings consisted in 15 cases of sero-mucinous effusion in the mastoid cells and in the tympanic cavity, 9 bilateral and 4 unilateral (always the right side). In no instance an enlarged vestibular aqueduct was detected. Similarly, no pathological conditions were identified along the central

**Figure 3.** Detail of axial T2-weighted MRI scan of the right ear of patient #14, showing cystic cochlear apex (thin arrow)

We further stratified the 37 MR+ patients in 3 subgroups related to age: 5 (13.51%) patients were under 1 years old, only 2 children (5.4%) were between 1 and 2 years old and 30 children

**Table 4.** Incidence of pathological ABRs and MRIs at different ages in the subgroup of 37 MPS patients who underwent

**Age # of patients (%) Rate of pathological ABRs Rate of pathological brain MRIs**

<1 year 5 2 (40%) 3 (60%) 1–2 years 2 2 (100%) 1 (100%) 2–6 years 30 23 (77.7%) 22 (72.2%) Total 37 27 (72.9%) 26 (70.2%)

auditory pathways in any young MPS patients.

and enlarged vestibule (empty arrow).

62 An Excursus into Hearing Loss

both investigations.

The MPSs are a group of monogenic disorders due to lysosomal storage of glycosaminoglycans (GAGs), previously called mucopolysaccharides [14]. The deficiency of one of the enzymes participating in the GAGs degradation pathway causes progressive storage in the lysosomes and cytoplasm, leading to cell swelling and multiple organs dysfunction. The damage is both direct or by activation of secondary and tertiary pathways among which a role is played by inflammation. [15] All MPSs have an autosomal recessive transmission with the exception of MPS type II (Hunter syndrome) which is X-linked [16].

The incidence of MPSs as a group is reported between 1:25,000 and 1:45,000 [17]. At present, 11 different enzyme deficiencies are involved in MPSs producing 7 distinct clinical phenotypes [14] (**Table 1**). Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparin sulfate, keratin sulfate, chondroitin sulfate, or hyaluronan may be impaired, singularly or in combination.

MPSs virtually affect all organs and tissues and show a progressive worsening with time. Diagnosis is suspected clinically on the basis of rather constant physical appearance (signs can be subtle or overt) such as: coarse facial features; short stature; "claw hand" and/or joint stiffness or ligamentous laxity (seen in MPS VI); corneal clouding (from very mild to severe), retinopathy, glaucoma; chronic nasal congestion, noisy breathing; abdominal protuberance owing to liver and spleen enlargement; spinal deformity (gibbus, scoliosis, kyphosis, lordosis); abnormal gait (e.g., toe walking); hearing deficits and brain involvement with progressive cognitive delay. In MPS III and II, mental retardation at 2–3 years may be the only, or most evident, presenting sign. Heart failure and severe valve disease in the first year of life are reported as the first presenting symptom in the *severe* forms [18–20]. In these patients, quality of life and life span are generally substantially reduced [21, 22].

The *attenuated* forms have widely variable clinical presentations with different presenting signs at different ages, often one or few organs only clinically manifest the disease [2, 3]. In these milder forms the progression of signs and symptoms is much slower than in the severe ones. These patients may have a presentation apparently limited to one organ only and are often seen by a specialist for years before reaching the diagnosis [2, 3], that is usually accomplished by means of biochemical, enzymatic and molecular tests.

Currently, specific treatments such as hematopoietic stem cell transplantation in selected cases of severe MPS I and enzyme replacement therapy for MPS I, II, IV and VI are available [23]. These treatments are able to improve the clinical course of the disease if started early. This brings along the responsibility for the clinician to recognize these diseases at the first signs to allow access to treatment before a severe damage has been established.

Although similar, each type of MPSs has a peculiar phenotypic expression [14]; besides, within the same type of MPSs, the phenotypic spectrum is largely variable, as a result of the different severity of mutations and overall genetic background of the single individual.

Based on the ABR response, the hearing loss was of the "cochlear" type in 83.3, 77.8 and 85.7%

Characterization of Hearing Loss in Children with Mucopolysaccharidosis

http://dx.doi.org/10.5772/intechopen.74196

65

The retrocochlear patterns of auditory evoked potentials observed in four of our patients with sensorineural hearing loss highlighted a conduction delay within the central auditory system,

Up to date, the reason for the sensorineural component of the hearing loss has not been fully ascertained: some alterations, such as the presence of lysosomal deposit in the outer and /or inner hair cells suggest a dysfunction of the cochlear sensorial structures; conversely, the findings of PAS+ material occupying the cytoplasm of the spiral and vestibular ganglion cells might indicate an altered neural transmission [27, 28]. Furthermore, animal studies also showed an alteration in the mechanical properties of the Reissner's and Basilar

The most characteristic modification in the CNS is the dilatation of the perivascular spaces, caused by extracellular storage of GAGs; it appears as a variable amount of tiny spot-like cystic lesions with CSF-like signal in all sequences. It is probably determined by large GAG inclusions between vascular adventitial cells, typically at basal ganglia, subcortical parietal and occipital white matter, and in the corpus callosum, with radial orientation along the vascular developmental lines [29]. Widening of liquoral spaces and hydrocephalus, secondary to pathologic leptomeningeal thickening with resorption deficit by the Pacchioni's granulations and/or obstruction of the CSF flow, can lead to severe neurologic compromise (requiring a shunt) or to neuronal loss and decrease of association fibers and atrophy [30]. The expression of white matter dystrophy in mucopolysaccharidoses, probably on a microvascular basis, is common also to several other diseases that share the same vulnerable areas, such as the peritrigonal white matter. Compared to dilated perivascular spaces, these lesions show brighter


The interpretation of these neuroimaging findings is somehow challenging, because a clear relationship with cognitive insufficiency in MPS patients is lacking [30, 31], although mental

retardation has been reported in the more severe forms of MPS 1 [32–37].

of MPS I, MPS II and MPS III, respectively; purely "central" lesions were excluded.

possibly related to progressive storage of GAGs.

membranes [12].

(hyperintense) signals both in T2

auditory pathways.

The otorhinolaryngological involvement is represented by otitis media with effusion, progressive mixed hearing loss, OSAHS, pathology of the Waldeyer lymphatic ring and difficulties during intubation [24].

In the *severe* forms, which most frequently present in the first 2–3 years of life with skeletal abnormalities dysmorphic facies, organomegaly and multiple hernias, children suffer abnormally frequent and severe upper airways infections, chronic rhinitis and otitis media. Hearing loss is a frequent feature of the more severe forms of MPS; therefore, it should be identified as early as possible in order to help assessing a correct diagnosis and provide an etiological treatment [33].

It occurs frequently in the early childhood, mainly as a consequence of recurrent episodes of otitis media. It is often discovered occasionally, during an otorhinolaryngological referral requested for the control of the upper airways. OME is the most frequent finding: if the clinical history is silent, it may be overlooked; its incidence in children affected by MPS is higher than in the general population [24].

A middle ear effusion can easily mask an underlying sensorineural hearing loss. The inner ear involvement has been generally neglected in the literature; the major pathologic alterations have been found in the Corti organ, tectorial and Reissner's membranes, ciliated cells and auditory nerve [13]. In the *attenuated* forms of MPS, hearing loss occurs more frequently at a later stage, but it sometimes develops already in first infancy. If correctly recognized, it can be effectively rehabilitated with hearing aids, reducing the already existing disability related with the multi-organ dysfunction.

In our series, 32% of the young patients were affected by mixed hearing loss, 28% by purely conductive, 16% by sensorineural type and 24% were normally hearing. This distribution is coherent with other reports [25, 26]. The degree of hearing loss in purely sensorineural involvement ranged between 40 and 60 dB (average 55.62 dB HL).

In our MPS children, auditory brainstem responses to click stimuli were morphologically normal with peak latencies within normal limits (avg ± 1 SD) in 25 out of 47 subjects (53.2%), whereas 22 tracings showed abnormalities (46.8%). At a stimulus intensity of 90 dB HL, the 3 main peaks of the typical ABR waveform were recognizable, or only wave I was missing, in 18 of these 22 cases. Reduced amplitudes and delayed latencies with regular interpeak latencies indicated a "cochlear" site of lesion; in 7 children no identifiable response was obtained: in 3 of them the hearing threshold was severe enough to explain the absence of the response; in 4 cases a retrocochlear involvement was suspected. Overall, a retrocochlear involvement was likely in 8.5% of MPS children.

The relationship between the MPS types and the ABR findings is shown in **Table 3**: all children with MPS III demonstrated an altered ABR; the greatest majority of MPS II also proved pathological, as well as half of the MPS I. None of the patients affected by MPS IVA and VI revealed abnormal ABR tracings. On a speculative basis, this might reflect a more severe compromise of the auditory periphery in MPS I-II and III.

Based on the ABR response, the hearing loss was of the "cochlear" type in 83.3, 77.8 and 85.7% of MPS I, MPS II and MPS III, respectively; purely "central" lesions were excluded.

Although similar, each type of MPSs has a peculiar phenotypic expression [14]; besides, within the same type of MPSs, the phenotypic spectrum is largely variable, as a result of the different severity of mutations and overall genetic background of the single individual.

The otorhinolaryngological involvement is represented by otitis media with effusion, progressive mixed hearing loss, OSAHS, pathology of the Waldeyer lymphatic ring and difficul-

In the *severe* forms, which most frequently present in the first 2–3 years of life with skeletal abnormalities dysmorphic facies, organomegaly and multiple hernias, children suffer abnormally frequent and severe upper airways infections, chronic rhinitis and otitis media. Hearing loss is a frequent feature of the more severe forms of MPS; therefore, it should be identified as early as possible in order to help assessing a correct diagnosis and provide an etiological treatment [33]. It occurs frequently in the early childhood, mainly as a consequence of recurrent episodes of otitis media. It is often discovered occasionally, during an otorhinolaryngological referral requested for the control of the upper airways. OME is the most frequent finding: if the clinical history is silent, it may be overlooked; its incidence in children affected by MPS is higher

A middle ear effusion can easily mask an underlying sensorineural hearing loss. The inner ear involvement has been generally neglected in the literature; the major pathologic alterations have been found in the Corti organ, tectorial and Reissner's membranes, ciliated cells and auditory nerve [13]. In the *attenuated* forms of MPS, hearing loss occurs more frequently at a later stage, but it sometimes develops already in first infancy. If correctly recognized, it can be effectively rehabilitated with hearing aids, reducing the already existing disability related

In our series, 32% of the young patients were affected by mixed hearing loss, 28% by purely conductive, 16% by sensorineural type and 24% were normally hearing. This distribution is coherent with other reports [25, 26]. The degree of hearing loss in purely sensorineural

In our MPS children, auditory brainstem responses to click stimuli were morphologically normal with peak latencies within normal limits (avg ± 1 SD) in 25 out of 47 subjects (53.2%), whereas 22 tracings showed abnormalities (46.8%). At a stimulus intensity of 90 dB HL, the 3 main peaks of the typical ABR waveform were recognizable, or only wave I was missing, in 18 of these 22 cases. Reduced amplitudes and delayed latencies with regular interpeak latencies indicated a "cochlear" site of lesion; in 7 children no identifiable response was obtained: in 3 of them the hearing threshold was severe enough to explain the absence of the response; in 4 cases a retrocochlear involvement was suspected. Overall, a retrocochlear involvement was

The relationship between the MPS types and the ABR findings is shown in **Table 3**: all children with MPS III demonstrated an altered ABR; the greatest majority of MPS II also proved pathological, as well as half of the MPS I. None of the patients affected by MPS IVA and VI revealed abnormal ABR tracings. On a speculative basis, this might reflect a more severe com-

involvement ranged between 40 and 60 dB (average 55.62 dB HL).

ties during intubation [24].

64 An Excursus into Hearing Loss

than in the general population [24].

with the multi-organ dysfunction.

likely in 8.5% of MPS children.

promise of the auditory periphery in MPS I-II and III.

The retrocochlear patterns of auditory evoked potentials observed in four of our patients with sensorineural hearing loss highlighted a conduction delay within the central auditory system, possibly related to progressive storage of GAGs.

Up to date, the reason for the sensorineural component of the hearing loss has not been fully ascertained: some alterations, such as the presence of lysosomal deposit in the outer and /or inner hair cells suggest a dysfunction of the cochlear sensorial structures; conversely, the findings of PAS+ material occupying the cytoplasm of the spiral and vestibular ganglion cells might indicate an altered neural transmission [27, 28]. Furthermore, animal studies also showed an alteration in the mechanical properties of the Reissner's and Basilar membranes [12].

The most characteristic modification in the CNS is the dilatation of the perivascular spaces, caused by extracellular storage of GAGs; it appears as a variable amount of tiny spot-like cystic lesions with CSF-like signal in all sequences. It is probably determined by large GAG inclusions between vascular adventitial cells, typically at basal ganglia, subcortical parietal and occipital white matter, and in the corpus callosum, with radial orientation along the vascular developmental lines [29]. Widening of liquoral spaces and hydrocephalus, secondary to pathologic leptomeningeal thickening with resorption deficit by the Pacchioni's granulations and/or obstruction of the CSF flow, can lead to severe neurologic compromise (requiring a shunt) or to neuronal loss and decrease of association fibers and atrophy [30]. The expression of white matter dystrophy in mucopolysaccharidoses, probably on a microvascular basis, is common also to several other diseases that share the same vulnerable areas, such as the peritrigonal white matter. Compared to dilated perivascular spaces, these lesions show brighter (hyperintense) signals both in T2 -weighted and FLAIR images.

In our series of 37 MPS children who underwent MRI, 14 (37.84%) were normal, whereas 23 (62.16%) showed some abnormalities such as dilated perivascular spaces in 12 (32.43%), dilated ventricular cavities in 15 (40.54%), demyelinated and gliotic areas in 9 (24.32%). A globose internal auditory canal was observed in five cases of IAC, and a cystic cochlear apex and dilated vestibule in 1 child. The middle ear pathological findings consisted in 15 cases of sero-mucinous effusion in the mastoid cells and in the tympanic cavity. The limited number of children tested under 2 years of age does not allow to draw general conclusions. Instead, within the group of 30 children aged 2–6 years, the rate of pathological ABRs (77.7%) and of pathological MRI of the brain (72.2%) showed a high degree of correlation. Assuming that the physiological maturation of the central auditory pathways is being completed during this age range, the ABR abnormalities would possibly be attributed no longer to a delayed myelinization. Therefore, the "retrocochlear" ABR findings might be a real expression of "central" auditory dysfunction, although the MRI abnormalities did not seem to involve directly the auditory pathways.

The interpretation of these neuroimaging findings is somehow challenging, because a clear relationship with cognitive insufficiency in MPS patients is lacking [30, 31], although mental retardation has been reported in the more severe forms of MPS 1 [32–37].

Similarly, the relationship with hearing loss is not clear. Nevertheless, a prompt recognition of the hearing difficulties, which can be among the first manifestations of the disease, might help assessing an earlier diagnosis and, therefore, provide a timely treatment.

dB decibel

ENT ear, nose and throat (otorhinolaryngology)

FLAIR fluid attenuated inversion recovery sequence

HSCT hematopoietic stem cell transplantation

OSAHS obstructive sleep apnea/hypopnea syndrome

SSFP 3D–Steady-State Free Procession sequence

TEOAE transient-evoked oto-acoustic emissions

\*Address all correspondence to: diego.zanetti.bs@gmail.com

2-3 kHz; value expressed in dB HL)

\*, Margherita Vezzani2,3, Federica Di Berardino<sup>1</sup>

PTA pure tone average (average of thresholds to pure tone stimuli at 0.5–1–

1 Audiology Unit, Department of Community Health and Clinical Sciences, Università degli Studi di Milano; Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milano, Italy 2 Otorhinolaryngology Department, University of Milano-Bicocca, San Gerardo Hospital,

4 Rare Metabolic Diseases Unit, Department of Pediatrics, University of Milano-Bicocca, San

3 Pediatric Otorhinolaryngology Department, Children's Hospital, Cincinnati, USA

, Serena Gasperini<sup>4</sup>

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67

and

p.e.SPL peak-equivalent sound pressure level

ERT enzyme replacement therapy

FSE Fast Spin-Echo sequence

GAG glycosaminoglycans

IAC internal auditory canal MPS mucopolysaccharidoses

MRI magnetic resonance imaging

OME otitis media with effusion

HL hearing level

MR+ positive at MRI

SD standard deviation

**Author details**

Diego Zanetti<sup>1</sup>

Rossella Parini4

Monza, Italy

Gerardo Hospital, Monza, Italy
