Inner Ear Deficits in Irradiated Nasopharyngeal Carcinoma Survivors

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Inner Ear Deficits in Irradiated Nasopharyngeal Carcinoma Survivors Fan-Hsiang Chi, MD; Yi-Ho Young, MD Objectives/Hypothesis: Despite the advancement of concurrent chemoradiotherapy, inner ear symptoms such as hearing loss, tinnitus, or vertigo/dizziness are still experienced in irradiated nasopharyngeal carcinoma (NPC) survivors. This study utilized an inner ear test battery to assess the causes and sequence of inner ear deficits in irradiated NPC survivors with a mean interval of 10 years after radiotherapy. Study Design: Retrospective study. Methods: Thirty-six irradiated NPC survivors were enrolled. Otoscopy and an inner ear test battery comprising audiometry were performed, as well as ocular vestibular-evoked myogenic potential (ovemp), cervical VEMP (cvemp), and caloric tests. Results: Otoscopic examination revealed middle ear complications in 37 ears (51%), including radiation-induced otitis media in 32 ears and otitis media with effusion in five ears. Percentages of abnormal cvemp test, ovemp test, boneconducted mean hearing level, and caloric test were 91%, 75%, 67%, and 39%, respectively, exhibiting a significantly declining sequence in inner ear deficits. Most (67%) NPC survivors had inner ear deficit ated from peripheral vestibular lesion, mainly due to sequela of otitis media. In contrast, 33% of them had inner ear deficit caused by central vestibular disorder. Conclusions: A significant sequential decline in inner ear function of irradiated NPC survivors was observed from the saccule to the utricle, cochlea, and semicircular canals. Most of them were due to sequela of otitis media, followed by central vestibular disorder. Key Words: Nasopharyngeal carcinoma (NPC), ocular vestibular-evoked myogenic potential (ovemp), cervical vestibular-evoked myogenic potential (cvemp), chemoradiotherapy, cisplatin, radiation-induced otitis media. Level of Evidence: 4. Laryngoscope, 125: , 2015 INTRODUCTION Nasopharyngeal carcinoma (NPC) frequently affects ethnic Chinese populations, with the mainstream of treatment being external beam irradiation to the nasopharynx and nuchal areas. 1 The last century saw the use of two-dimensional radiotherapy (2DRT) to irradiate target structures; however, it inevitably damaged the adjacent tissues from the skull base to the neck, 2 causing intractable otological complications, that is, otitis media with effusion (OME), radiation-induced otitis media (ROM), sensorineural hearing loss, vestibular deficits, and more severe temporal bone osteoradionecrosis. 3 6 The reason is probably that the temporal bone, including the Eustachian tube, received a significantly From the Department of Otolaryngology, National Taiwan University Hospital, Yun-Lin Branch (F H.C.), Dou-Liou; and the Department of Otolaryngology, National Taiwan University Hospital (Y H.Y.), Taipei, Taiwan Editor s Note: This Manuscript was accepted for publication March 23, This study was supported by a research grant (NSC B MY3) from the National Science Council, Taipei, Taiwan. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Yi-Ho Young, MD, Department of Otolaryngology, National Taiwan University Hospital, 1 Chang-Te St., Taipei, Taiwan. youngyh@ntu.edu.tw DOI: /lary high dosage of irradiation. 7 Recently, concurrent chemoradiotherapy has become the standard treatment regimen for NPC, especially with the application of intensity-modulated radiotherapy (IMRT), which offers a curative dose to the tumor-bearing tissue while sparing normal tissue. 8,9 This treatment modality thus reduces otological complications, improving survival rate and global quality of life However, inner ear symptoms such as hearing loss, tinnitus, vertigo, or dizziness are still experienced in irradiated NPC survivors. Stimulation via air-conducted sound or boneconducted vibration enables recordings of vestibularevoked myogenic potential (VEMP) from the extraocular muscles, which are called ocular VEMP (ovemp), and the cervical muscles, which are called cervical VEMP (cvemp). A recent investigation showed that the cvemp test primarily evaluates the saccular function and the ipsilateral sacculocollic reflex, whereas the ovemp test mainly assesses utricular function and the crossed vestibuloocular reflex. 13 Thus, an inner ear test battery comprising audiometry, as well as ovemp, cvemp, and caloric tests, may comprehensively assess the inner ear function, including the cochlea, utricle, saccule, and semicircular canals. Recently, this inner ear test battery has been widely adopted in clinical patients, such as those with Meniere s disease, chronic otitis media (COM), sudden deafness, vestibular schwannoma, 2565

2 and superior canal dehiscence syndrome, but is less applied to the irradiated NPC survivors. 12,19,20 This study utilized an inner ear test battery to assess the causes and sequence of inner ear deficits in irradiated NPC survivors. PATIENTS AND METHODS From January 2005 to December 2013, there were 1,473 cases of fresh NPC undergoing radiotherapy at our hospital. Meanwhile, a total of 36 irradiated NPC survivors with inner ear symptoms such as tinnitus, hearing loss, or vertigo/dizziness were consecutively encountered at our neurotological clinic. Exclusion criteria consisted of previous middle or inner ear anomaly, tumor persistence or recurrence, distant metastasis, failure to complete the whole course of radiotherapy, and more than one course of radiotherapy. Twenty-one patients were males and 15 were females, with the ages ranging from 29 to 71 years (mean 56 years). Stage I was identified in four patients, stage II in eight, stage III in 11, and stage IV in 13. Those in stages I and II were treated by radiotherapy alone, whereas those in stages III and IV were treated with concurrent cisplatin-based chemoradiotherapy (Table I). Radiation dosage to the nasopharynx ranged from 68 to 80 (mean 71) Gy, and mean interval from completeness of radiotherapy to the presentation was years. Another 20 non-npc head and neck cancer patients having previous radiotherapy (9 males, 11 females, aged years, mean 54 years), including eight patients with tongue cancer, seven with buccal cancer, and five with others were also enrolled for comparison. There were no significant differences between the NPC and non-npc groups in terms of age and gender distribution (P > 0.05, unpaired t test, or Chi-square test). All patients received a detailed history taking, otoscopic examination, and local checkup of the nasopharynx. Then, patients underwent audiometry, ovemp, cvemp, and caloric tests, and image study of the temporal bones. This study was approved by the institutional review board of National Taiwan University Hospital in Taipei, Taiwan, and each subject signed the informed consent to participate. Audiometry Mean hearing level (MHL) was calculated as the averaged hearing threshold from four frequencies (500; 1,000; 2,000; and 3,000 Hz) of the audiogram. Cochlear involvement was to be expected when the bone-conducted (BC) MHL at the frequency of 500; 1,000; and 2,000 Hz was > 25 db. Caloric Test Bithermal caloric test was conducted with an electronystagmographic (ENG) recorder. The norm of slow phase velocity (SPV) of caloric nystagmus at our laboratory is (mean- 6 standard deviation [SD]) o /s. Canal paresis is defined when the mean SPV of caloric nystagmus in the lesion ear is <17 o /s, or as a greater than 25% difference between maximum SPV measurements for each ear as compared with the sum of SPVs from each ear. If caloric response was not elicited, the subject underwent ice saline (4 o C, 10 ml) caloric test to further confirm the caloric areflexia. ovemp Test The subject was in a sitting position. Two active electrodes were placed around 1 cm below the center of the two lower eyelids. The other two reference electrodes were positioned TABLE I. Basic Information in 36 Irradiated Nasopharyngeal Carcinoma Survivors With Inner Ear Deficits. No. Age Sex Stage Therapy Dosage (Gy) Interval (Y) Diagnosis 1 65 F II RT 70 8 Sequela of OM 2 44 M II RT 70 9 Sequela of OM 3 49 M III CCRT Vertigo, central 4 61 F IVB CCRT 70 3 Vertigo, central 5 57 M I RT Sequela of OM 6 53 F III CCRT 70 5 Sequela of OM 7 55 M IVA CCRT 70 5 Peripheral vertigo 8 42 F IVC CCRT Sequela of OM 9 56 F IVA CCRT 70 1 Sequela of OM M IVB CCRT 70 1 Endolymph F IVA CCRT Sequela of OM M II RT Vertigo, central M III CCRT Sequela of OM F IVB CCRT Sequela of OM M III CCRT 70 9 Endolymph F IVA CCRT Sudden deafness M IVB CCRT 70 3 Vertigo, central F III CCRT 70 2 Vertigo, central F III CCRT Sequela of OM M II RT Endolymph F III CCRT Vertigo, central M III CCRT Dyslipidemia M IVA CCRT 70 9 Sequela of OM M III CCRT 70 4 Sequela of OM M II RT 80 3 VBI M I RT Sequela of OM M I RT VBI F IVB CCRT Sequela of OM F III CCRT 70 1 Sequela of OM F II RT 70 1 Vertigo, central M III CCRT Sudden deafness M IVA CCRT Sequela of OM M II RT Sequela of OM M IVA CCRT Sequela of OM M I RT 70 1 Endolymph F II RT Peripheral vertigo CCRT: concurrent chemoradiotherapy; F, female; M, male; OM: otitis media; RT: radiotherapy; VBI: vertebrobasilar insufficiency 2566

3 No. TABLE II. Audiovestibular Test Results in 36 Irradiated Nasopharyngeal Carcinoma Survivors. Otoscopy(R/L) AC MHL (db)(r/l) BC MHL (db) (R/L) Caloric Test (R/L) 1 Perforation/perforation 63/69 17/20 /cp 2 Atelectasis/n 75/20 70/12 n/n 3 n/n 20/50 15/43 /n 4 n/n 44/60 38/57 n/n 5 Atelectasis/atelectasis 38/37 28/28 n/n 6 OME/OME 58/64 53/60 /cp 7 n/n 37/38 27/28 n/cp 8 Perforation/perforation 58/54 27/27 n/ 9 n/otorrhea 22/50 17/15 n/n 10 n/n 62/20 57/15 n/n 11 Perforation/perforation 59/62 35/32 cp/cp 12 n/n 25/23 20/18 n/n 13 Perforation/perforation 90/85 48/48 /cp 14 Perforation/perforation 48/55 13/18 n/cp 15 n/n 75/48 70/43 n/n 16 OME/n 98/27 68/22 /n 17 n/atelectasis 25/35 20/30 n/cp 18 n/n 40/45 35/40 cp/n 19 Perforation/perforation 99/49 67/35 cp/cp 20 n/n 52/45 47/40 n/n 21 n/n 75/75 70/70 / 22 n/n 17/17 12/12 n/n 23 Perforation/perforation 81/71 45/45 n/n 24 Otorrhea/n 64/30 33/25 cp/n 25 Atelectasis/atelectasis 75/75 70/70 / 26 OME/OME 70/68 65/63 / 27 n/n 22/30 18/25 n/n 28 Perforation/perforation 40/103 18/62 n/n 29 Atelectasis/atelectasis 52/42 47/37 cp/cp 30 n/n 12/25 7/20 n/n 31 n/n 57/75 52/70 /cp 32 Perforation/perforation 102/88 60/53 n/n 33 Perforation/perforation 94/61 53/30 n/n 34 Perforation/perforation 85/59 48/27 n/n 35 n/n 15/52 10/47 n/n 36 n/n 25/25 20/20 n/n, absent; AC, air-conducted; BC, bone conducted; cp, canal paresis; L, left; MHL, mean hearing level; n, normal; OME, otitis media with effusion; R, right. about 1 to 2 cm below the active ones, and one ground electrode was placed on the sternum. During recording (Smart EP 3.90, Intelligent Hearing Systems, Miami, FL), the subject was instructed to look upward at a small fixed target >2 m from the eyes. The stimulation rate was 5/s. The duration of analysis of each response was 50 ms, and 30 responses were averaged for each run. The operator held the vibrator by hand and delivered a repeatable tap on the subject s forehead. The input signal was 500 Hz sine wave with a peak force equivalent to 144 db force level. 21 The initial negative positive biphasic waveform comprised peaks ni and pi. Consecutive runs were performed to confirm the reproducibility of peaks ni and pi, and ovemps were deemed to be present. cvemp Test Each subject was in a supine position. Two active electrodes were placed on the upper half of the sternocleidomastoid muscles; one reference electrode was positioned on the suprasternal notch; and a ground electrode was situated on the forehead. The other settings were the same as in the ovemp test, except that the vibrator delivered a repeatable tap on the subject s head at inion. 22 The subjects elevated their heads during testing. A total of 50 responses were averaged and recorded bilaterally. The first positive and second negative polarities of biphasic waveform were termed waves p13 and n23, respectively. Consecutive runs were performed to confirm the reproducibility of peaks p13 and n23, and cvemps were deemed to be present. Statistical Methods The mean age, dose, and interval between the two groups were compared by unpaired t test. Prevalence of systemic disease between the two groups was compared by Fisher s exact test. Percentages of abnormality in the inner ear test battery were compared by Chi-square or Fisher s exact test. A significant difference indicates P < RESULTS Clinical Manifestation Clinical manifestations in 36 NPC survivors comprised hearing loss in 32 patients (89%), followed by tinnitus (75%), vertigo/dizziness (61%), aural fullness (58%), nausea/vomiting (28%), headache (28%), diplopia (8%), and ataxia (8%). Spontaneous nystagmus was observed in one patient. Otoscopic examination revealed middle ear complications in 37 ears (51%), including ROM (perforation, otorrhea, atelectasis) in 32 ears and OME in 5 ears. ROM is defined as chronic inflammation of the middle ear that follows irradiation of the head and neck region. It differs from conventional COM in the heterogeneity of its pathology. 23,24 Audiometry The air-conducted (AC) MHL, BC MHL, and mean ABG in 36 NPC survivors (72 ears) were (mean 6 SD), , and dbhl, respectively (Table II). Because most patients had middle ear complications, abnormal hearing was defined as BC MHL >25 db HL, which accounted for 48 ears (67%); whereas normal BC MHL was identified in 24 ears (33 %, Table III). Thirty-six NPC survivors (72 ears) were divided into two groups according to the otoscopic findings, namely the normal eardrum (n 5 35 ears) and pathologic eardrum (n 5 37 ears). Abnormal BC MHL was identified in 17 ears (49%) of the normal eardrum group and 31 ears (84%) of the pathologic eardrum group, exhibiting a significant difference (P < 0.01, Table III). Additionally, 36 NPC survivors (72 ears) were redivided into another two groups based on their treatment modalities. Of those, 12 patients (24 ears) with stages I and II underwent radiotherapy only, and 12 ears (50%) revealed abnormal BC MHL. In contrast, 24 patients (48 ears) with stages III and IV received concurrent 2567

4 TABLE III. Comparison of Cochlear Involvement in Various Conditions. N (ears) BC MHL 25dB BC MHL > 25dB P Value* (67%) Otoscopy Normal eardrum (49%) < 0.01 Pathologic eardrum (84%) Treatment RT only (50%) CCRT (75%) > 0.05 *Chi-square test. BC MHL, bone-conducted mean hearing level; CCRT, concurrent chemoradiotherapy; RT, radiotherapy. chemoradiotherapy, and 36 ears (75%) showed abnormal BC MHL. Both groups did not differ significantly in this regard (P > 0.05, Table III). Because bilateral symmetric, high-tone (4,000 and 8,000 Hz) sensorineural hearing loss served as a characteristic feature of ototoxicity, 10 patients with asymmetric sensorineural hearing loss and nine patients with global profound deafness were therefore excluded. Consequently, the remaining five patients (21%) with bilateral symmetric, high-tone sensorineural hearing loss were attributable to the additional chemotherapeutic ototoxicity. Vestibular Test Battery Bithermal caloric test showed normal responses in 44 ears and abnormal responses in 28 ears (39%), including canal paresis in 15 ears and caloric areflexia in 13 ears (Table II). Because cvemp and ovemp tests were introduced to our department after 2000 and 2008, respectively, only 10 to 11 patients underwent VEMP testing. The ovemp test performed in 10 NPC patients (20 ears) revealed normal responses in five ears and absent responses in 15 ears (75 %). In contrast, the cvemp test performed in 11 patients (22 ears) revealed absent responses in 20 ears (91%) and normal responses in two ears (Table IV). Figure 1 illustrates an NPC patient with ROM on the left ear who had absent ovemps and cvemps on the left ear, whereas the right intact ear showed normal ovemps and cvemps. In sum, the abnormal percentages of the cvemp, ovemp, BC MHL, and caloric tests in NPC survivors were 91%, 75%, 67%, and 39%, respectively, showing a significant sequential decline in inner ear function from the saccule to the utricle, cochlea, and semicircular canals (P < 0.01, Chi-square or Fisher s exact test). In contrast, abnormal percentages of the ovemp, cvemp, BC MHL, and caloric tests in another 20 non- NPC head and neck cancer patients without ear symptoms were 90%, 72%, 28%, and 22%, respectively, exhibiting a significant sequential decline in inner ear deficits (P < 0.01). However, the decreasing order of abnormal function from the utricle, saccule, and cochlea to the semicircular canals in the non-npc group is different from that in the NPC group. Further, significant difference in the BC MHL was identified between the two groups (P < 0.001, Chi-square test). Comparison Between Peripheral and Central Vertigo In ENG examination, percentages of abnormal pursuit, saccade, and optokinetic nystagmus tests were 30%, 14%, and 47%, respectively. Based on the presence of central signs in ENG results, that is, saccadic pursuit, dysmetria, overshoot, or undershoot, 36 NPC survivors were divided into two groups. Group A, comprising 24 patients (67%) without central signs in ENG examination, were referred to peripheral vestibular lesions, including sequela of OM in 18 patients, endolymphatic in four, and nonspecific peripheral vertigo in two. Group B had 12 patients with central vestibular disorders consisting of vertebrobasilar artery insufficiency, dyslipidemia, and nonspecific central vertigo (Table I). Notably, most NPC survivors (67%) had inner ear deficit ating from peripheral vestibular lesion, mainly caused by sequela of OM. Comparison between groups A and B revealed nonsignificant differences in terms of age, radiation dosage, and postirradiation interval (P > 0.05, Table V). Conversely, NPC survivors with systemic diseases, that is, diabetes mellitus, hypertension, coronary artery disease, and dyslipidemia, may experience inner ear deficits ating from central vestibular disorders more frequently than peripheral vestibular lesion (P < 0.05, Table V). DISCUSSION By modulating the intensity of the radiation beam in multiple small volumes, IMRT allows for the radiation to conform precisely to the three-dimensional shape of the tumor and thus minimizes the dose to surrounding normal structures. Accordingly, radiation dose is reduced to < 60% of total dose in IMRT for the anterior brainstem, and 50% for the middle and inner ear. 12 Compared TABLE IV. Ocular and Cervical VEMP Test Results. No. ovemp (R/L) cvemp (R/L) 10 No test/no test Absent/absent 15 Absent/absent Absent/absent 16 Absent/absent Absent/absent 20 Absent/n Absent/absent 23 Absent/absent Absent/absent 28 n/absent n/absent 30 n/n Absent/absent 31 n/absent Absent/absent 32 Absent/absent Absent/absent 33 Absent/absent Absent/n 35 Absent/absent Absent/absent cvemp, cervical vestibular-evoked myogenic potential; ovemp, ocular vestibular-evoked myogenic potential; L, left; n, normal; R, right. 2568

5 Fig. 1. Female, 52 years, nasopharyngeal carcinoma with radiation-induced otitis media on the left ear (case 28). Absent ovemps and cvemps are observed on the left ear, whereas the right ear shows normal ovemps and cvemps. cvemp, cervical vestibularevoked myogenic potential; ovemp, ocular vestibular-evoked myogenic potential; L, left; R, right. to the 2DRT, improvement in survival and reduction in toxicity, that is, xerostomia, have been achieved in NPC patients treated with IMRT. Coupled with better imaging and potent chemotherapy, the tumor control rate has increased significantly. 25 Nevertheless, prevalence of inner ear symptoms such as hearing loss or vertigo did not decrease in NPC survivors, probably because the medial half of the Eustachian tube receives > 95% of total dose despite 2DRT or IMRT. 12 Four major causes for inner ear deficits have been posited, namely, high radiation dosage, tumor invasion, sequela of OM, or chemotherapeutic ototoxicity. Human temporal study in an NPC patient with tumor recurrence, who received two courses of radiotherapy with an accumulated dose of 106 Gy to the primary site, demonstrated that the organ of Corti and other sensory cells of both maculae and cristae were well preserved. 26 However, the results of this human histopathological study contradicted those of an animal study. 27 In experimental animals, a single large dose of radiation is given, which is six times more lethal than an equivalent amount administered, over a longer period in appropriate fractions. Thus, although inner ear damage after irradiation was shown in animals, inner ear structures of the humans were essentially resistant to fractionized dose of radiation. Therefore, causes other than high radiation dosage must be considered for inner ear deficits in irradiated NPC survivors. Because NPC patients with tumor persistence, recurrence, or distant metastasis were excluded from the beginning of this study, the remaining two factors that contributed to the inner ear deficits were considered, namely, the sequela of OM and ototoxicity by TABLE V. Comparison Between Peripheral and Central Vestibular Disorders in NPC Survivors. Lesion N Age (Y) Dose (Gy) Interval (Y) Systemic Disease Peripheral % Central % P value Data are expressed as mean 6 standard deviation; P value, unpaired t test or Fisher s exact test. 2569

6 cisplatin. Hence, an inner ear test battery was applied to differentiate these two causes of inner ear deficits in NPC survivors. Deficits in the Utricle and Saccule Via an inner ear test battery, abnormal percentages of cvemp, ovemp, BC MHL, and caloric tests in irradiated NPC survivors were 91%, 75%, 67%, and 39%, respectively, indicating a significant sequential decline in the inner ear function from the saccule to the utricle, cochlea, and semicircular canals. Likewise, in our recent report, 15 abnormal percentages of 117 conventional COM ears also run the same declining sequence in inner ear function, namely, cvemp (65%), ovemp (62%), BC MHL (37%), and caloric (27%) tests. Because more than 50% of NPC patients have OME as an initial symptom, 3 and more than 50% of ears of NPC long-term survivors develop ROM, it is believable that irradiated NPC survivors with ROM and patients with conventional COM may at least in part share the same mechanism for the inner ear deficits. Restated, inner ear deficit in NPC survivors is partly attributed to the sequela of OM, with the toxin and pathogens themselves entering the labyrinth via the round window membrane and then affecting the posterior ampulla. 28 Because the utricle and saccule are continuously aligned with the posterior semicircular canal in the membranous labyrinth, not only the saccule but also the utricle were vulnerable to being affected by toxin or pathogens from OM, resulting in high percentages of abnormal cvemps (91%) and abnormal ovemps (75%) in irradiated NPC survivors. Deficits in the Cochlea Radiation can cause conductive or mixed type hearing loss in NPC patients. In this study, 67% of the irradiated ears showed abnormal BC MHL (Table II), which was higher than the 28% of the ears in other irradiated head and neck cancer patients without ear symptoms and higher than 37% of conventional COM ears. 15 The former may indicate that OM factor plays a major role for inducing cochlear deficit; whereas the latter implies that other causal factors, that is, cisplatin ototoxicity, should also be considered. The cisplatin is a potent cell cycle nonspecific chemotherapeutic agent, which has become a first-line agent for the treatment of head and neck cancers. The addition of cisplatin-based chemotherapy warrants concern for delayed onset hearing loss. 29 Wei et al. 9 reported that NPC patients who received radiotherapy and concurrent/adjuvant cisplatin-based chemotherapy experienced greater sensorineural hearing loss compared with patients treated with radiotherapy alone. Similarly, in this study, five NPC survivors (21%) with bilateral symmetric, high-tone (4,000 and 8,000 Hz) sensorineural hearing loss were attributable to the additional chemotherapeutic ototoxicity. Temporal bone study in patients treated with cisplatin demonstrated damage to the inner and outer hair cells and degeneration of the spiral ganglion; but 2570 the vestibular end organs appeared normal, indicating that the cochlear part is more susceptible to cisplatin toxicity than the vestibular part. 30,31 However, sequence of inner deficits in irradiated NPC survivors run from the saccule (91%) to the utricle (75%), cochlea (67%), and semicircular canals (39%), indicating that prevalence of cochlear deficit is less than that of utricular/ saccular deficit. The reason is because BC MHL was measured from three frequencies (500, 1000, and 2000 Hz) excluding hearing levels at 4,000 and 8,000 Hz. Thus, cisplatin ototoxicity may also play an additional causal role for inner ear deficits. Deficits in Semicircular Canals In 85 conventional COM ears, Chang et al. 15 reported 23 ears (27%) with canal paresis or caloric areflexia, which is similar to the 39% caloric abnormality in this study, indicating that the lateral semicircular canal is less affected than the saccule, utricle, and cochlea. The reason is probably that most toxin and pathogens enter the labyrinth via the round window membrane, and the distance from the round window membrane to the lateral semicircular canal is longer than that for other inner ear end organs. Causes of Inner Ear Deficits Inner ear deficits in NPC survivors may be caused by either peripheral or central vestibular disorders. Firstly, most irradiated NPC survivors with inner ear deficits may be due to sequela of ROM, as evidenced by a similar declining sequence of inner ear deficits in cases of conventional COM. Thus, meticulous treatment of the ear inflammation is recommended for irradiated NPC survivors. Secondly, because radiation may also cause advanced atherosclerosis, obliterative endarteritis, and thrombosis, 32 damage to the vasoconnective tissue, especially accompanied by systemic diseases (Table V), may induce impaired perfusion to the inner ear, leading to sudden deafness or vertebrobasilar artery insufficiency. 33 CONCLUSION A significant sequential decline in inner ear function of irradiated NPC survivors was observed from the saccule to the utricle, cochlea, and semicircular canals. Most of them were due to sequela of OM, followed by central vestibular disorder. BIBLIOGRAPHY 1. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;365: Waldron J, Tin MM, Keller A, et al. Limitation of conventional two dimensional radiation therapy planning in nasopharyngeal carcinoma. Radiother Oncol 2003;68: Young YH, Lin KL, Ko JY. Otitis media with effusion in patients with nasopharyngeal carcinoma, post-irradiation. Arch Otolaryngol Head Neck Surg 1995;212: Young YH, Cheng PW, Ko JY. 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