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The Laryngoscope C 2015 The American Laryngological, V Rhinological and Otological Society, Inc. Magnetic Resonance Imaging in a Guinea Pig Model of Inner Ear Decompression Sickness and Barotrauma Nathan E. Pierce, MD; G. Joseph Parell, MD; Reordan O. De Jesus, MD; Carolyn P. Ojano-Dirain, PhD; Patrick J. Antonelli, MD Objectives/Hypothesis: Scuba diving may cause severe hearing loss and vertigo due to inner ear barotrauma and decompression sickness. These may be difficult to differentiate clinically. Decompression sickness requires costly and potentially dangerous hyperbaric therapy, whereas such treatment may worsen barotrauma. The objective of this study was to assess the potential utility of magnetic resonance imaging to identify and distinguish blood from air in the inner ear, manifestations of barotrauma and decompression sickness, using a guinea pig model. Study Design: Prospective animal trial. Methods: Magnetic resonance of the head was performed at 3 Tesla, pre- and postinjection of 2, 4, or 10 lL of air or blood through the round window into the perilymph. With this model, 2 lL has been shown to cause hearing loss. Images were reviewed by a neuroradiologist blinded to the treatment. Results: All 14 normal ears, five of seven blood- and five of seven air-injected ears, were correctly interpreted. Two blood- and one air-injected ear were interpreted as indeterminate. One air-injected ear was incorrectly interpreted as blood. Conclusions: Magnetic resonance reliably distinguishes small volumes of air and blood in the guinea pig inner ear. Magnetic resonance should be evaluated for its utility in the diagnosis of inner ear barotrauma and decompression sickness in scuba divers. Key Words: Magnetic resonance imaging, decompression sickness, barotrauma, inner ear. Level of Evidence: NA Laryngoscope, 126:2106–2109, 2016 INTRODUCTION Scuba diving is a common commercial, recreational, and military activity. High-pressure environments, such as scuba diving and hyperbaric chambers can cause unique disorders, including barotrauma, decompression sickness, and arterial gas embolism. Otolaryngologic complaints account for approximately 80% of all scuba diving–related disorders.1 In a series of 306 scuba divers presenting to an otolaryngology clinic, 18% had disorders involving the inner ear.2 Scuba diving–related disorders involving the inner ear fall largely into two categories: inner ear barotrauma (IEBT) and inner ear decompression sickness (IEDS).3 From the Department of Otolaryngology (N.E.P., G.J.P., C.P.O.-D., and the Department of Radiology (R.O.D.), University of Florida, Gainesville, Florida, U.S.A. Editor’s Note: This Manuscript was accepted for publication November 6, 2015. Presented at the Triological Society Combined Sections Meeting, Coronado, California, U.S.A., January 22–24, 2015. A portion of this work was performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory’s AMRIS Facility, which is supported by National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida. Financial support for this study was provided by the University of Florida, Gainesville, Florida. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Patrick J. Antonelli, MD, University of Florida, Otolaryngology Head & Neck Surgery, PO Box 100264, Gainesville, FL 32610. E-mail: [email protected] P.J.A.), DOI: 10.1002/lary.25811 Laryngoscope 126: September 2016 2106 Dive profiles and history can help to distinguish these two entities. However, there is evidence that overlap can exist,4 and differentiation can prove difficult. IEBT usually occurs during descent with difficulty equalizing middle ear pressure by forceful autoinflation. This is thought to cause rupture of Reissner’s membrane, bleeding into the inner ear, or perilymph fistula formation.5–7 IEBT may show signs of middle ear barotrauma.8 Treatment of IEBT is bed rest, head elevation, and precautions to decrease cerebrospinal fluid and middle ear pressures.7,9 Exploratory tympanotomy for a possible perilymph fistula may be considered if symptoms do not improve with conservative treatment.6 IEDS develops as a result of nitrogen bubbles accumulating in the tissues. The risk of IEDS is directly dependent on the amount of nitrogen dissolved in the tissues—a function of both the depth and the duration of the dive—and the rate of ascent. Classically, decompression sickness presents with skeletal pain, skin marbling, and neurologic changes caused by gas bubbles forming out of solution. Irreversible hearing loss and vestibular symptoms may be prevented with rapid recompression.8,10 Objective testing to help guide clinical decision making in scuba diving–related inner ear injuries is lacking. Magnetic resonance imaging (MRI) holds tremendous potential for the differentiation of IEDS from IEBT. MRI can demonstrate gas—the hallmark of IEDS—in soft tissues and fluid filled spaces (e.g., the inner ear). It can also demonstrate the presence of blood— found in both Pierce et al.: MRI in a Guinea Pig Model of IEDS and IEBT TABLE I. Number of Guinea Pig Ears Interpreted Correctly, Incorrectly, and Indeterminate for Each Blood Injection, Air Injection, and No Injection. Correct No injection Blood Air Incorrect Indeterminate 14 0 0 5 5 0 1 2 1 IEDS and IEBT—from other fluids (e.g., normal spinal fluid or perilymph). MRI at 3 Tesla (T) is a relatively safe diagnostic procedure in individuals without ferromagnetic implants or foreign bodies.11,12 Though transient sensory symptoms (e.g., vertigo, nausea, and dysgeusia) are not uncommon, no serious health effects have been reported below 8 T.11 To date, no studies have assessed the sensitivity of clinically available MRI for detecting signs of IEBT and IEDS. The goal of this study was to explore the feasibility of 3 T MRI for detecting air and blood in the inner ear using a guinea pig model. MATERIALS AND METHODS Experimental Design This study was approved by the University of Florida Institutional Animal Care and Use Committee (IACUC). Seven mixed gender, Cavia albino, 350-g Hartley guinea pigs (Charles River, Wilmington, MA) underwent surgery as previously described,13–16 with injection of blood or air into the scala tympani to serve as a model for IEBT and IEDS. MRI scans were obtained before and after inner ear injections. Therefore, each animal ear served as its own control. Animals were sacrificed under deep anesthesia after conclusion of the final scan. The entire volume of the inner ear space in a guinea pig is 20.9 lL and the perilymph is 15.94 lL.17 It has also been shown that injection of 1.5-2 lL of air into the inner ear space of guinea pigs causes measurable changes in otoacoustic emissions.18 The IEDS model was established by injecting air into the inner ear space through the round window, and the IEBT model was established by injecting blood into the inner ear space through the round window. MRI Anesthetized animals underwent pre- and postinjection MRI scans of the head with attention given to the inner ear. Scans were obtained on a Philips Achieva 3.0 Tesla clinical scanner (3.2.1 software; Philips Healthcare, Amsterdam, the Netherlands). T1 fluid-attenuated inversion recovery (FLAIR) and T2 driven equilibrium pulse (DRIVE) images were obtained. T1 and FLAIR imaging techniques were chosen due to the ability to adequately visualize blood. T2 DRIVE, which demonstrates a high fluid signal of the perilymph, was hypothesized to visualize air well, due to the signal void it would produce. Imaging protocols were developed by a neuroradiologist and an imaging scientist by modifying existing human protocols. Acquired images were stored for later blinded review by the neuroradiologist. The radiologist’s interpretation on the presence or absence of blood or air in the inner ear was recorded and compared to the known exposure condition. Given the small sample sizes involved, only qualitative comparisons were performed. RESULTS All seven guinea pigs completed the surgery and imaging protocol. Four animals were injected with 4 lL, two animals were injected with 2 lL, and one was injected with 10 lLl as a positive control. The blinded radiologist correctly interpreted all 14 negative control (no injection) ears. Five of seven blood and five of seven air-injected ears were correctly interpreted. One airinjected (4 lL) ear was incorrectly interpreted. Two the blood-injected (2, 4 lL) ears were interpreted as indeterminate. One of the air-injected (2 lL) ears was interpreted as indeterminate (Table I). T1 imaging showed blood well, but air was poorly visualized. Similarly, FLAIR images identified blood, but air was not well seen. T2 DRIVE easily identified air. Injected blood was also discernible but not as well visualized as in the T1 and FLAIR imaging (Figs. (1 and 2), and (1 and 3)). DISCUSSION Anesthesia was induced with xylazine (5 mg/kg subcutaneous [SC]) and ketamine (40 mg/kg SC). After a 5-minute period of quiet, the hair was clipped, and lidocaine was injected SC over the mastoid bullae and skull dorsum for local anesthesia. Thermal support was provided preoperatively, intraoperatively, and postoperatively. After betadine skin preparation, oblique skin incisions were made over the nuchal crest and extended posteriorly and laterally. A third incision was carried anteriorly along the midline. The temporalis muscle was elevated anterolaterally. The mastoid bulla was entered with a cutting bur. The round window was fully exposed. At that point, the incision was lightly closed with suture and the preinjection MRI was performed. After imaging, the wound was opened and each round window was injected with either blood or air using a Hamilton syringe and a 32-gauge needle. The volumes of injections were 2, 4, or 10 lL. The incision was again lightly closed. Postinjection scans were obtained. Thereafter, the animal was sacrificed under deep anesthesia. Scuba diving–related inner ear diving injuries are known to result from failure to equilibrate, with bleeding into the tissues and spaces (i.e., IEBT), or accumulation of nitrogen bubbles in the tissues due to overly rapid ascent (i.e., IEDS).3–8 To date, differentiation of these disorders has relied on dive parameters and clinical history. No diagnostic testing has been validated for the distinction of these disorders. In this study, we sought to determine if small volumes of blood and air in the inner ear could be visualized using MRI. Using a guinea pig model, which has an inner ear volume much smaller than that of a human, we found that small —but enough to induce auditory dysfunction18,19—volumes of either blood or air within the inner ear were easily visualized and differentiated with a clinical MRI scanner. Diagnostic imaging is an established method of diagnosing a range of scuba diving–related injuries, including arterial gas embolism, pneumocephalus, pulmonary barotrauma, and is occasionally used forensically.20–22 Imaging is not routinely used in obvious cases of systemic decompression sickness due to the urgency of recompression.10 Cases of isolated IEDS (i.e., without systemic signs of decompression sickness) should be Laryngoscope 126: September 2016 Pierce et al.: MRI in a Guinea Pig Model of IEDS and IEBT Surgical Technique 2107 Fig. 1. T1-weighted images. (A) Preinjection image. (B) Postinjection image shows increased signal to injected blood (solid arrow) and absence of signal due to injected air (dashed arrow). Fig. 2. Fluid-attenuated inversion recovery images. (A) Preinjection image. (B) Postinjection image shows increased signal due to injected blood (solid arrow) and absence of signal due to injected air (dashed arrow). rare, as decompression sickness is a systemic process. Not surprisingly, little has been published on imaging in IEDS. The sole article on imaging in IEDS reported the cause to be cerebellar infarction.23 Similarly, very little has been published on IEBT.24 Pneumolabyrinth, an expected finding in IEDS, has ironically been reported related to barotrauma.25,26 Hemolabyrinth has been ascribed to a range of disorders including idiopathic sudden sensorineural hearing loss27 and IEDS.4 Thus, it is possible that both blood and gas may be found in the inner ear in both IEDS and IEBT. Being able to radiographically visualize gas and blood in the inner ear using MRI may allow for improved understanding of the pathophysiology of these scuba diving– related inner ear injuries, as well as possibly being able to guide treatment. The latter has been a point of controversy.28,29 MRI has long been held as the imaging modality of choice for nonosseous, acquired lesions of the inner ear, particularly in cases of sudden sensorineural hearing loss or acute onset of vertigo.27,30–33 Our findings suggest that the 3 T MRI protocols we employed are far from 100% accurate for the identification of blood and air in the guinea pig inner ear. Computed tomography (CT) might also be of value in distinguishing IEBT from IEDS, as it has been shown to be capable of demonstrating small volumes of air in the labyrinth.34 Although CT has been shown to be highly accurate in identifying blood in cerebrospinal fluid following subarachnoid hemorrhage,35 blood would not be resolved in the labyrinth in most Fig. 3. T2 driven equilibrium pulse images. (A) Preinjection image. (B) Postinjection image shows diffuse decrease in cochlear signal due to injected blood (solid arrow) and loss of signal in the basal turn of the cochlea from the injected air (dashed arrow). Laryngoscope 126: September 2016 2108 Pierce et al.: MRI in a Guinea Pig Model of IEDS and IEBT situations with standard techniques. MRI has been reported to be more sensitive in the identification of blood,36 especially in more chronic situations.37 MRI has long been known to be superior to CT in the identification of central nervous system manifestations of decompression sickness38 and retrolabyrinthine pathology,39 which may help in the management of patients with scuba diving–related inner ear symptoms. Thus, though we would expect MRI to be superior to CT for evaluating scuba diving–related inner ear injuries, CT may also prove helpful. This study utilized modifications of existing human MRI protocols for use in guinea pigs. We refined these protocols by studying three animals in a pilot study. In T1 and FLAIR techniques, blood was seen as diffuse increase of signal within the cochlea. Neither imaging modality showed injected air well. Air was better visualized as a loss of signal in the T2 DRIVE imaging, and blood was seen as a diffusely decreased signal. Further improvements are likely with additional refinements in the imaging protocol. Use of the guinea pig model may also introduce differences from what may be seen in humans. For example, the guinea pig has a patent cochlear aqueduct, whereas the human does not.40 Also, the guinea pig cochlea is more uniformly surrounded by air than the human cochlea, increasing susceptibility artifacts. Both would, however, be expected to bias our findings toward lower sensitivity of MRI to air and blood in the inner ear of the guinea pig. As it is impossible to atraumatically introduce air into the inner ear, further bias may have been introduced. CONCLUSION MRI reliably distinguishes small volumes of air and blood in the guinea pig inner ear. MRI should be evaluated for its utility in the diagnosis of IEBT and IEDS in scuba divers. Acknowledgments The authors extend thanks to Song Lai, PhD, and Tammy Nicholson for assisting in acquiring the images. BIBLIOGRAPHY 1. Roydhouse N. 1001 disorders of the ear, nose and sinuses in scuba divers. Can J Appl Sport Sci 1985;10:99–103. 2. Klingmann C, Praetorius M, Baumann I, Plinkert PK. Otorhinolaryngologic disorders and diving accidents: an analysis of 306 divers. Eur Arch Otorhinolaryngol 2007;264:1243–1251. 3. Molvaer OI, Natrud E. Ear damage due to diving. Acta Otolaryngol Suppl 1979;360:187–189. 4. McCormick JG, Holland WB, Brauer RW, Holleman IL Jr. Sudden hearing loss due to diving and its prevention with heparin. Otolaryngol Clin North Am 1975;8:417–430. 5. Antonelli PJ, Parell GJ, Becker GD, Paparella MM. Temporal bone pathology in scuba diving deaths. 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