- Email: [email protected]
R092: The Vestibuloocular Reflex and the Yoked Extraocular Muscles
Research Posters—Thursday
R090 Transcranial Magnetic Stimulation in Veterans with Tinnitus Scott L Lee, MD (presenter); Steven M Silver, MD; Anthony Cacace, MD PROBLEM: Excessive neural activity in the left superior temporal gyrus may be perceived as tinnitus. The study’s hypothesis is that repetitive transcranial magnetic stimulation (rTMS) applied to this region would suppress tinnitus in veterans. METHODS: Eight patients with tinnitus received five consecutive days of rTMS (0.5 Hz, 20 min) to the left temporoparietal area. Tinnitus Handicap Inventory (THI) measures prior to sessions 1 & 3, and after session 5, were used to evaluate efficacy. RESULTS: Patient 1’s THI decreased: 40 to 34 to 26 (R2⬎0.99), patient 4 improved subjectively, patient 8 withdrew, and the remaining patients reported no improvement. Adverse effects included temporary soreness, restlessness, and photophobia. CONCLUSION: Available evidence suggests tinnitus arises from excessive spontaneous activity in the central auditory pathways and that rTMS may suppress this activity. Contrary to success reported in the literature, rTMS in this study population did not improve tinnitus. There were no permanent adverse outcomes. SIGNIFICANCE: rTMS may be safe in the temporary sup-
pression of tinnitus, but efficacy and therapeutic parameters require further research.
R091 Aquaporin2 Regulation in Water-Deprived Guinea Pig Inner Ear Sungsu Lee (presenter); Kak Kim, MD; Hyong-ho Cho, MD; Yong-Bum Cho, MD, PhD; Jeong-Hyun Kim, MD; Soowan Kim, MD; Jongun Lee, MD PROBLEM: Although the existence of aquaporin (AQP) water channels has been known in the inner ear, their role has not been established. Water supplementation has been adapted as one treatment-regimen in Meniere’s disease. The purpose of the present study was to determine the effect of water deprivation on the regulation of AQP2 in the inner ear. METHODS: Adult male guinea pigs, weighing about 250g, were used. They were with positive preyer’s reflex. The experimental group underwent a 72-hour period of water deprivation. The control group was water-loaded by supplying sucrose drinking solution (600 mM) ad libitum. Plasma AVP levels and urine osmolalities were measured. Cochlea and endolymphatic sac were harvested to determine their expression of AQP2 mRNA and proteins, by real time polymerase chain reaction and immunoblotting, respectively. Immunoperoxidase microscopy was used to evaluate the distribution of AQP2 proteins in the inner ear. RESULTS: Electrocochleography showed that SP/AP ratios were 0.55 in the water-deprivation group and 0.29 in the control, being significantly higher in the former than in the latter. Plasma AVP levels and urine osmolalities were markedly elevated in the water-deprivation group. Immunoperoxidase microscopy revealed that AQP2 channels were mainly expressed in the endolymphatic sac and stria vascularis in both groups. The expression of AQP2 mRNA and proteins were significantly increased in the water-deprivation group, especially in the endolymphatic sac. CONCLUSION: The expression of AQP2 water channels in the endolymphatic sac suggests their role in the fluid homeostasis of the inner ear. Water deprivation can aggravate endolymphatic hydrops, with which an upregulation of inner ear AQP2 expression may be causally related. SIGNIFICANCE: AQP2 channels could be a target in the treatment of Meniere’s disease. Water restriction could aggravate the severity of the disease. SUPPORT: Special thanks to Eunhwa Oh, InJin Kim, Dr. Kyungsun Seo, Dr. Hyuche Cho for there fine support.
R092 The Vestibuloocular Reflex and the Yoked Extraocular Muscles Philip D Littlefield, MD (presenter); Arvind Kumar, MD; Richard R Gacek, MD
RESEARCH POSTERS
terval) to exclude periodic artifact influxed from the spontaneous potential, i.e., EEG, and (3) filtering fast component artifacts. To shorten test time without any deterioration of accuracy, “automated quasi Bekesy method” was adopted in the automated BERA. Hearing thresholds obtained from the conventional BERA were compared with those of the present automated BERA at 0.5, 1, 2, 4 KHz (18 subjects, 36 ears). RESULTS: Both conventional and automated BERA predicted well the behavioral thresholds. However, there was a big time saving in the automated BERA proposed by the present study. While 60⬃80 minutes were required to obtain a complete objective audiogram at 4 frequencies in the conventional BERA, only 6⬃8 minutes were needed in the present automated BERA. CONCLUSION: This study suggests the following: (1) a significant improvement of signal-to-noise ratio can be achieved by adopting the two new complementary methods, triple artifact-rejection method and automated quasi Bekesy method; and (2) a large amount of test time can be saved by focusing on the difference between Wave V and SN10 amplitudes. SIGNIFICANCE: Frequency-specific BERA may be completed within 10 minutes.
P181
P182
Otolaryngology-Head and Neck Surgery, Vol 137, No 2S, August 2007
PROBLEM: The neuroanatomy of the vestibuloocular reflex (VOR) and the anatomy and function of the yoked extraocular muscles are complex. Descriptions of the whole VOR are scattered in the literature of several different disciplines. The purpose of this paper is to provide a conceptual framework of the anatomy of the various nuclear groups involved in the VOR, delineate their connections, and describe the anatomy of yoked eye muscles and their function following utriculopetal and utriculofugal deflections of the canal cupulae. METHODS: The English world literature on this subject was identified by entering appropriate keywords into MEDLINE from 1966 to date. The selection of the articles was based on their relevance to the subject. Data were extracted from review articles on this subject, from papers that described the experimental delineation of nuclear groups of the VOR, as well as from clinical case reports describing VOR deficits resulting from brainstem lesions. RESULTS: Unilateral stimulation of the semicircular canals results in conjugate eye movements even though the innervation of each set of extraocular muscles is unilateral. This is because the VOR pathways cross, and because of the horizontal and vertical gaze centers, the PPRF and the riMLF. A detailed description of all nuclear groups and pathways is provided. CONCLUSION: Stimulation of any semicircular canal results in conjugate eye movements. SIGNIFICANCE: Theories regarding the mechanisms of benign paroxysmal positional vertigo should be unified with these concepts. SUPPORT: None
R093 Characterization of Knockout Mouse Model for USH1C Xue Z Liu, MD (presenter); Denise Yan, PhD; Xiaomei Ouyang; Li Lin Du, MD PROBLEM: Usher syndrome (USH) is an autosomal recessive disorder characterized by combined hearing loss and retinal degeneration. In hair cells of the inner ear, the proteins encoded by the USH genes are part of a protein complex, in which, the PDZ-domain containing protein, harmonin, might coordinate the activities of the USH proteins and bridge them to the cytoskeleton of the hair cell. Disruption of the USH proteins network would lead to stereociliary disorganization. To further understand the role of harmonin in the pathogenesis that leads to USH1, the researchers have generated a knockout mouse model for USH1C. METHODS: Hearing in Ush1c-/- mice was assessed by auditory-evoked brainstem response (ABR) measurement. Inner ear morphology analysis was performed by light microscopy and scanning electron microscopy (SEM). Immunochemistry
staining using peptide antibodies specific to Ush1 proteins was carried out for subcellular expression analysis. RESULTS: Homozygous mice (Ush1c-/-) exhibit typical behavior associated with inner ear defects and are completely deaf. Inner ear morphology analysis by light microscopy and SEM revealed that, at three weeks of age, outer hair cells (OHCs) of Ush1c-/- mice showed disorganized stereocilia compared to the well-organized pattern and rigid structure observed in Ush1c⫹/- littermates. Subcellular localization of the known USH 1 proteins in Ush1c-/- cochleas showed a mislocalization of the Pcdh15 (Usher 1-f) and Sans (Usher 1-g) proteins in Ush1c-/- knock-out mice, that is characterized by a shift of the immunoreactivity of the proteins toward the basal body of the hair cells. CONCLUSION: In this study, an Ush1c null mutation knockout mouse was generated, and showed that sterocilia defect in Ush1c-/- led to a mislocalization of the Pcdh15 (Usher 1-f) and Sans (Usher 1-g) proteins. SIGNIFICANCE: Generation and characterization of an Ush1c knockout mouse will provide a means to understand the bases for the sensory defects associated with USH syndrome. SUPPORT: The work is supported by NIH DC 05575.
R094 Malignant External Otitis by Histoplasmosis in HIV Patient Marise Marques, MD (presenter) PROBLEM: Histoplasma capsulatum infection in HIV patients is a disease that may occur in various sites, but is rarely in the ENT region. The author reports a case of malignant external otitis (MEO) in a HIV-positive patient that was submitted on a surgical debriment, and the isolation of Histoplasma capsulatum provided the definitive diagnosis. There is no case described in the literature consulted. METHODS: Case Report: A 38-year-old man resident in Brazil, serum antibodies positive to HIV 1 with a CD4⫹ T lymphocyte count of 869 cells/mm3, with complaints of fever, otalgia and otorrhea of one-month duration. The patient was treated by another physician with topical and systemic Ciprofloxacin. RESULTS: Local signs included an ear canal filled with granulation material, edematous overlying skin, and sensitivity to palpation. There were no facial or other cranial nerve palsies. Cultures taken from the external ear were positive for Pseudomonas aeruginosa. Imaging studies: computed tomographic scanning and technetium Tc 99m medronate bone scanning were positive. The patient underwent surgical debridement and long-term itraconazole. Histopathological analysis revealed chronic inflammatory process with granulomas containing Histoplasma-like organisms. The follow-up is about six years without any recurrence. CONCLUSION: Histoplasma capsulatum caused invasive external otitis associated with HIV infection without AIDS. A
R090 Transcranial Magnetic Stimulation in Veterans with Tinnitus Scott L Lee, MD (presenter); Steven M Silver, MD; Anthony Cacace, MD PROBLEM: Excessive neural activity in the left superior temporal gyrus may be perceived as tinnitus. The study’s hypothesis is that repetitive transcranial magnetic stimulation (rTMS) applied to this region would suppress tinnitus in veterans. METHODS: Eight patients with tinnitus received five consecutive days of rTMS (0.5 Hz, 20 min) to the left temporoparietal area. Tinnitus Handicap Inventory (THI) measures prior to sessions 1 & 3, and after session 5, were used to evaluate efficacy. RESULTS: Patient 1’s THI decreased: 40 to 34 to 26 (R2⬎0.99), patient 4 improved subjectively, patient 8 withdrew, and the remaining patients reported no improvement. Adverse effects included temporary soreness, restlessness, and photophobia. CONCLUSION: Available evidence suggests tinnitus arises from excessive spontaneous activity in the central auditory pathways and that rTMS may suppress this activity. Contrary to success reported in the literature, rTMS in this study population did not improve tinnitus. There were no permanent adverse outcomes. SIGNIFICANCE: rTMS may be safe in the temporary sup-
pression of tinnitus, but efficacy and therapeutic parameters require further research.
R091 Aquaporin2 Regulation in Water-Deprived Guinea Pig Inner Ear Sungsu Lee (presenter); Kak Kim, MD; Hyong-ho Cho, MD; Yong-Bum Cho, MD, PhD; Jeong-Hyun Kim, MD; Soowan Kim, MD; Jongun Lee, MD PROBLEM: Although the existence of aquaporin (AQP) water channels has been known in the inner ear, their role has not been established. Water supplementation has been adapted as one treatment-regimen in Meniere’s disease. The purpose of the present study was to determine the effect of water deprivation on the regulation of AQP2 in the inner ear. METHODS: Adult male guinea pigs, weighing about 250g, were used. They were with positive preyer’s reflex. The experimental group underwent a 72-hour period of water deprivation. The control group was water-loaded by supplying sucrose drinking solution (600 mM) ad libitum. Plasma AVP levels and urine osmolalities were measured. Cochlea and endolymphatic sac were harvested to determine their expression of AQP2 mRNA and proteins, by real time polymerase chain reaction and immunoblotting, respectively. Immunoperoxidase microscopy was used to evaluate the distribution of AQP2 proteins in the inner ear. RESULTS: Electrocochleography showed that SP/AP ratios were 0.55 in the water-deprivation group and 0.29 in the control, being significantly higher in the former than in the latter. Plasma AVP levels and urine osmolalities were markedly elevated in the water-deprivation group. Immunoperoxidase microscopy revealed that AQP2 channels were mainly expressed in the endolymphatic sac and stria vascularis in both groups. The expression of AQP2 mRNA and proteins were significantly increased in the water-deprivation group, especially in the endolymphatic sac. CONCLUSION: The expression of AQP2 water channels in the endolymphatic sac suggests their role in the fluid homeostasis of the inner ear. Water deprivation can aggravate endolymphatic hydrops, with which an upregulation of inner ear AQP2 expression may be causally related. SIGNIFICANCE: AQP2 channels could be a target in the treatment of Meniere’s disease. Water restriction could aggravate the severity of the disease. SUPPORT: Special thanks to Eunhwa Oh, InJin Kim, Dr. Kyungsun Seo, Dr. Hyuche Cho for there fine support.
R092 The Vestibuloocular Reflex and the Yoked Extraocular Muscles Philip D Littlefield, MD (presenter); Arvind Kumar, MD; Richard R Gacek, MD
RESEARCH POSTERS
terval) to exclude periodic artifact influxed from the spontaneous potential, i.e., EEG, and (3) filtering fast component artifacts. To shorten test time without any deterioration of accuracy, “automated quasi Bekesy method” was adopted in the automated BERA. Hearing thresholds obtained from the conventional BERA were compared with those of the present automated BERA at 0.5, 1, 2, 4 KHz (18 subjects, 36 ears). RESULTS: Both conventional and automated BERA predicted well the behavioral thresholds. However, there was a big time saving in the automated BERA proposed by the present study. While 60⬃80 minutes were required to obtain a complete objective audiogram at 4 frequencies in the conventional BERA, only 6⬃8 minutes were needed in the present automated BERA. CONCLUSION: This study suggests the following: (1) a significant improvement of signal-to-noise ratio can be achieved by adopting the two new complementary methods, triple artifact-rejection method and automated quasi Bekesy method; and (2) a large amount of test time can be saved by focusing on the difference between Wave V and SN10 amplitudes. SIGNIFICANCE: Frequency-specific BERA may be completed within 10 minutes.
P181
P182
Otolaryngology-Head and Neck Surgery, Vol 137, No 2S, August 2007
PROBLEM: The neuroanatomy of the vestibuloocular reflex (VOR) and the anatomy and function of the yoked extraocular muscles are complex. Descriptions of the whole VOR are scattered in the literature of several different disciplines. The purpose of this paper is to provide a conceptual framework of the anatomy of the various nuclear groups involved in the VOR, delineate their connections, and describe the anatomy of yoked eye muscles and their function following utriculopetal and utriculofugal deflections of the canal cupulae. METHODS: The English world literature on this subject was identified by entering appropriate keywords into MEDLINE from 1966 to date. The selection of the articles was based on their relevance to the subject. Data were extracted from review articles on this subject, from papers that described the experimental delineation of nuclear groups of the VOR, as well as from clinical case reports describing VOR deficits resulting from brainstem lesions. RESULTS: Unilateral stimulation of the semicircular canals results in conjugate eye movements even though the innervation of each set of extraocular muscles is unilateral. This is because the VOR pathways cross, and because of the horizontal and vertical gaze centers, the PPRF and the riMLF. A detailed description of all nuclear groups and pathways is provided. CONCLUSION: Stimulation of any semicircular canal results in conjugate eye movements. SIGNIFICANCE: Theories regarding the mechanisms of benign paroxysmal positional vertigo should be unified with these concepts. SUPPORT: None
R093 Characterization of Knockout Mouse Model for USH1C Xue Z Liu, MD (presenter); Denise Yan, PhD; Xiaomei Ouyang; Li Lin Du, MD PROBLEM: Usher syndrome (USH) is an autosomal recessive disorder characterized by combined hearing loss and retinal degeneration. In hair cells of the inner ear, the proteins encoded by the USH genes are part of a protein complex, in which, the PDZ-domain containing protein, harmonin, might coordinate the activities of the USH proteins and bridge them to the cytoskeleton of the hair cell. Disruption of the USH proteins network would lead to stereociliary disorganization. To further understand the role of harmonin in the pathogenesis that leads to USH1, the researchers have generated a knockout mouse model for USH1C. METHODS: Hearing in Ush1c-/- mice was assessed by auditory-evoked brainstem response (ABR) measurement. Inner ear morphology analysis was performed by light microscopy and scanning electron microscopy (SEM). Immunochemistry
staining using peptide antibodies specific to Ush1 proteins was carried out for subcellular expression analysis. RESULTS: Homozygous mice (Ush1c-/-) exhibit typical behavior associated with inner ear defects and are completely deaf. Inner ear morphology analysis by light microscopy and SEM revealed that, at three weeks of age, outer hair cells (OHCs) of Ush1c-/- mice showed disorganized stereocilia compared to the well-organized pattern and rigid structure observed in Ush1c⫹/- littermates. Subcellular localization of the known USH 1 proteins in Ush1c-/- cochleas showed a mislocalization of the Pcdh15 (Usher 1-f) and Sans (Usher 1-g) proteins in Ush1c-/- knock-out mice, that is characterized by a shift of the immunoreactivity of the proteins toward the basal body of the hair cells. CONCLUSION: In this study, an Ush1c null mutation knockout mouse was generated, and showed that sterocilia defect in Ush1c-/- led to a mislocalization of the Pcdh15 (Usher 1-f) and Sans (Usher 1-g) proteins. SIGNIFICANCE: Generation and characterization of an Ush1c knockout mouse will provide a means to understand the bases for the sensory defects associated with USH syndrome. SUPPORT: The work is supported by NIH DC 05575.
R094 Malignant External Otitis by Histoplasmosis in HIV Patient Marise Marques, MD (presenter) PROBLEM: Histoplasma capsulatum infection in HIV patients is a disease that may occur in various sites, but is rarely in the ENT region. The author reports a case of malignant external otitis (MEO) in a HIV-positive patient that was submitted on a surgical debriment, and the isolation of Histoplasma capsulatum provided the definitive diagnosis. There is no case described in the literature consulted. METHODS: Case Report: A 38-year-old man resident in Brazil, serum antibodies positive to HIV 1 with a CD4⫹ T lymphocyte count of 869 cells/mm3, with complaints of fever, otalgia and otorrhea of one-month duration. The patient was treated by another physician with topical and systemic Ciprofloxacin. RESULTS: Local signs included an ear canal filled with granulation material, edematous overlying skin, and sensitivity to palpation. There were no facial or other cranial nerve palsies. Cultures taken from the external ear were positive for Pseudomonas aeruginosa. Imaging studies: computed tomographic scanning and technetium Tc 99m medronate bone scanning were positive. The patient underwent surgical debridement and long-term itraconazole. Histopathological analysis revealed chronic inflammatory process with granulomas containing Histoplasma-like organisms. The follow-up is about six years without any recurrence. CONCLUSION: Histoplasma capsulatum caused invasive external otitis associated with HIV infection without AIDS. A