CE: S.S.; ON-17-300; Total nos of Pages: 6; ON-17-300 Otology & Neurotology xx:xx–xx ß 2017, Otology & Neurotology, Inc. Cochlear Implant Associated Labyrinthitis: A Previously Unrecognized Phenomenon With a Distinct Clinical and Electrophysiological Impedance Pattern Deeyar A. Itayem, Douglas Sladen, Colin L. Driscoll, Brian A. Neff, Charles W. Beatty, and Matthew L. Carlson Department of Otolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota Objectives: To report a unique clinical entity ‘‘cochlear implant associated labyrinthitis,’’ characterized by a distinct constellation of clinical symptoms and pattern of electrode impedance fluctuations. Study Design: Retrospective chart review. Methods: All patients that underwent cochlear implantation between January 2014 and December 2016 were retrospectively reviewed. All subjects with acute onset dizziness, device performance decline, and characteristic erratic pattern of electrode impedances occurring after an asymptotic postoperative interval were identified and reported. Results: Five patients with the above criteria were identified, representing 1.4% of all implant surgeries performed during this time. The median age at time of implantation was 71 years, and the median time interval between implantation and onset of symptoms was 126 days. All patients exhibited acute onset dizziness, subjective performance deterioration, erratic impedance pattern, and two experienced worsening tinnitus. Two of five patients underwent subsequent CT imaging, where good electrode placement was confirmed without cochlear ossification. Two of five patients received oral prednisone therapy. All patients reported a subjective improvement in symptoms and stabilization of electrode impedances. Three patients subsequently received vestibular testing, where significantly reduced peripheral vestibular function was identified. Conclusions: We describe a unique clinical entity, ‘‘cochlear implant associated labyrinthitis,’’ characterized by a distinct constellation of clinical symptoms and corresponding electrode impedance anomalies. The exact cause for this event remains unknown, but may be related to viral illness, delayed foreign body reaction to the electrode, or a reaction to electrical stimulation. Future studies characterizing this unique clinical entity are needed to further elucidate cause and optimal management. Key Words: Cochlear implant—Impedance—Labyrinthitis. Cochlear implantation (CI) remains the gold standard for aural rehabilitation of children and adults with bilateral severe to profound sensorineural hearing loss. Despite significant advances in device design and refinements in surgical technique, a small subset of patients experience unforeseen surgical and device-related events. Examples of such events include scalp flap complications, meningitis, documented internal device failure, and unexplained deterioration of performance (1). Such complications are distressing to the patient and surgeon alike and result in patient morbidity, unanticipated costs, and interruption in device use. Perioperative complications and other events that threaten device explantation have been well characterized by a number of clinical studies (2–5). In recent years the authors have identified a distinct pattern of transient device malfunction in a subset of established implant users characterized by acute onset dizziness, device performance decline, and distinctive erratic pattern of electrode impedances. In sharing this experience, providers at other centers have also observed this unique constellation of findings in a small number of patients. Raising awareness regarding this process and further characterizing the clinical syndrome may help facilitate timely recognition and management and potentially reduce risk of overtreatment. Otol Neurotol 38:xxx–xxx, 2017. Address correspondence and reprint requests to Matthew L. Carlson, M.D., Department of Otolaryngology–Head and Neck Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905; E-mail: carlson. email@example.com Financial Material & Support: No financial support was used in this study. The following manuscript was presented in oral form at the Combined Otolaryngology Spring Meeting (COSM), San Diego, CA 2017. This material has not been previously published in part or whole, and is not currently under consideration for publication elsewhere. M.L.C. and C.L.D. are consultants for Advanced Bionics Corporation, Cochlear Corporation, and MED-EL GmbH. The authors disclose no conflicts of interest. DOI: 10.1097/MAO.0000000000001615 MATERIALS AND METHODS Following Institutional Review Board approval (IRB # 16– 006130) all patients that underwent cochlear implantation between January 2014 and December 2016 at the authors’ 1 Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited. CE: S.S.; ON-17-300; Total nos of Pages: 6; ON-17-300 2 D. A. ITAYEM ET AL. center were retrospectively reviewed. Nineteen patients with a distinct erratic impedance pattern were identified. Of these, five patients had acute onset dizziness and device performance decline after an asymptomatic postoperative period. Patients with neurological conditions such as hydrocephalus, stroke, or vestibular migraines that could account for their symptoms were excluded. Data regarding these five cases are presented using descriptive statistics. In each case, electrical impedances were tested on all intracochlear contacts at baseline, during disease presentation, and following symptom cessation. A 25-microsecond biphasic pulse was presented to each contact using a stimulation level of 80 clinical units. A normal value falls between 566 V and 30 kV. A value below this range designates a short circuit, and a value above this range is classified as an open circuit. Speech perception reported subjectively by the patients was used as a surrogate for device performance as formal word and sentence recognition testing was not routinely performed during episodes. 6 months before onset of symptoms. Two patients had a history of previous otologic surgery in the implanted ear—tympanoplasty (S2) and a left middle ear exploration (S5). The underlying cause of sensorineural loss was hereditary (S1), iatrogenic (S2), noise-induced (S3), idiopathic (S4), and Menière’s disease (S5). Further baseline patient data are presented in Table 1. All patients had lateral wall electrode designs: three were implanted with the Cochlear Nucleus CI522 device and two with the Nucleus CI422 device (Cochlear Americas, Englewood, CO). All patients had good initial device performance before the development of symptoms as demonstrated by speech perception scores (Table 2). In addition, all were asymptomatic for at least 8 weeks following surgery, with four of the five patients reporting onset of symptoms more than 12 weeks later. The median time interval between implantation and onset of symptoms was 126 days. RESULTS Patient Characteristics Five patients met study criteria, representing 1.4% of all cochlear implant surgeries performed during the time period. The median age at the time of implantation was 71 years old (range, 55–81), four patients were men, and four had left-sided implants. One patient (S5) had a history of Ménière’s disease without any attacks for TABLE 1. Patient No., Sex, Age Device Type S1, M, 71 Nucleus 422 S2, F, 24 Nucleus 522 S3, M, 81 Nucleus 422 S4, M, 72 Nucleus 522 S5, M, 55 Nucleus 522 Disease Presentation and Management Presenting symptoms are listed in Table 1. All patients experienced acute onset dizziness exacerbated by head movement and subjective performance deterioration. Two patients experienced worsening tinnitus compared with preimplantation including one with new onset tinnitus. None experienced other symptoms of non-auditory stimulation such as facial spasm or pain. Characteristics of five patients with ‘‘cochlear implant associated labyrinthitis’’ Presenting Symptoms ‘‘Motion Sickness’’; lightheadedness exacerbated by head movement; worsening tinnitus; left aural fullness; worsening speech perception Nausea; positional dizziness; vertigo; headache; worsening speech perception Dizziness; gait instability; right beating nystagmus; worsening speech perception Imbalance especially with quick head movement; mild vertigo (began a week after imbalance onset); worsening speech perception Dizziness; oscillopsialike experience with head movement; static sounds; (baseline stable Menière’s disease); worsening speech perception Tinnitus Onset of Symptoms Post-op Yes 164 days Imbalance remains at visit 17 months after symptom onset Prednisone; 40 mg taper (10 days) Yes No 57 days <1 week Meclizine and Ondansetron No No 685 days No symptoms at visit 6 weeks after symptom onset None No No 126 days 16 weeks ¼ ‘‘70% improvement’’ after 2nd course of prednisone Prednisone; 60 mg taper three courses Yes Yes 88 days Symptoms improved at 8 weeks None Yes Estimated Time to Recovery After Symptom Onset Medical Management Otology & Neurotology, Vol. 38, No. xx, 2017 Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited. Vestibular Rehab? CE: S.S.; ON-17-300; Total nos of Pages: 6; ON-17-300 COCHLEAR IMPLANT ASSOCIATED LABYRINTHITIS TABLE 2. Patient S1 S2 S3 S4 S5 3 Speech perception scores before cochlear implantation, and postoperatively before symptom onset Pre-Cochlear Implantation Post-Cochlear Implantation (And Before Symptoms) Right (hearing aid): CNC word test list 2: 30% correct for words and 58% correct for phonemes; AzBio sentence test in quiet list 4: 57% correct; AzBio sentence test at þ5SNR list 5: 13% correct; BKB-SIN sentence test in noise: four list average (paired lists 9 and 10) 9.75 Db SNR for 50% correct; Left (hearing aid): CNC word test list 4: 22% correct for words and 54% correct for phonemes; AzBio sentence test in quiet list 2: 48% correct; AzBio sentence test at þ5SNR list 7: 14% correct; BKB-SIN sentence test in noise; four list average (paired lists 5 and 6) 12 dB SNR for 50% correct Left (hearing aid): CNC words (list 3): 25% words, 38% phonemes; AzBio sentences (list 4): 32%; BKB-SIN (lists 7, 8 ab): 23.5 dB SNR for 50% correct; R-SPACE HINT (lists 1, 2): 2.1 dB SNR for 50% correct Right (hearing aid): CNC words (list 10): 44% words, 70% phonemes; AzBio sentences (list 10): 66%; Left (hearing aid): CNC words (lists 10, 9): 62% words, 75% phonemes. AzBio sentences (list 10, 9): 65%; Bilateral (hearing aid): CNC words (list 10): 60% words, 83% phonemes; AzBio sentences (list 10): 62%; BKB-SIN (lists 7ab8ab): 12.5 dB SNR Left (hearing aid): CNC word (list 2): 8% correct words, 32% correct phonemes Bilateral (hearing aid): CNC word (list 1): 0% correct for words and 32% correct for phonemes; AzBio sentence, quiet list 9: 7% correct; BKB-SIN sentence: four list average (paired lists 9 and 10) 22.25 dB SNR for 50% correct Left (cochlear implant): CNC words, quiet (list 1): 46% words; AzBio sentences, quiet (list 1): 71% Left (cochlear implant): CNC words, quiet (list 2): 64% words, 80% correct phonemes; AzBio sentences in quiet test (list 2): 85% correct Right (cochlear implant): CNC words: 75% words Left (cochlear implant): CNC words, quiet (list 3): 56% words, 73% phonemes; AzBio sentences, quiet (list 3): 49% Left (cochlear implant): CNC words, quiet (list 2): 40% words, 61% phonemes; AzBio sentences, quiet (list 2): 58% BKB-SIN indicates Bamford-Kowal-Bench speech in noise test; CNC, consonant-nucleus-consonant. Imaging was obtained in cases S1 and S3; these scans confirmed adequate device placement and revealed no evidence of cochlear ossification. A head CT was obtained for S1. Patient S3 had a head CT without contrast, head magnetic resonance imaging with contrast, and MR angiography of the head and neck. Neurology was also consulted from the Emergency Department for patient S3 to rule out stroke or other cerebral etiologies. Patients S2, S4, and S5 did not have imaging after symptoms began. No lab tests were performed on any patient. Two patients received steroids (S1 and S4). The duration between symptom onset and steroid treatment was 52 and 85 days, respectively. Doses varied between the two patients—40 mg taper for 10 days and three courses of 60 mg taper for 14 days, respectively. Three patients underwent vestibular rehabilitation. Patient S1 was not initially prescribed steroids when he presented with symptoms. Instead, vestibular rehabilitation was trialed first. Patient S2 was not prescribed steroids since her symptoms largely resolved between the time she was evaluated by audiology and seen in clinic. Steroids were not initiated for patient S3 while other causes of his symptoms were ruled out. Adjustments in CI programming seemed adequate to improve his speech perception decrement. Patient S4 first underwent vestibular testing and rehabilitation before beginning his steroid course. However, once initiated, the first two courses of steroids provided ‘‘30%’’ and ‘‘70%’’ subjective improvement in symptoms, respectively. S5 was not prescribed steroids. Instead, Meclizine and Ondansetron were chosen for symptom management. All patients reported subjective improvement in symptoms at last follow up. Tinnitus and vertigo has resolved in patient S1, however, motion provoked unsteadiness remains. All symptoms completely resolved in patients S2 and S3. Residual imbalance and intermittent tinnitus remains in patient S4, however, all other symptoms resolved. Occasional imbalance remains in patient S5 with quick head movement, but he has otherwise resumed normal daily activities without additional lasting sequelae. All patients experienced stabilization of electrode impedance levels that correlated with improvement in symptoms. Follow up with four of five patients continues while one patient now receives follow up care closer to home. The estimated time to recovery for individual subjects is reported in Table 1. Impedance Pattern All patients exhibited an erratic impedance pattern that was particularly prominent in the basal electrodes as shown in Figure 1. Device programming was performed to minimize the out of range compliance values. Specifically, the pulse width of the stimulating electrodes was increased, which resulted in lower stimulation levels needed for adequate loudness growth. Achieving lower stimulation levels allowed the contact to stay in compliance and remain active. However, some patients demonstrated compliance levels that were far out of range and programming alterations were unable to minimize the compliance conflicts. In those cases, select electrodes were deactivated. The degree of electrode fluctuations and stabilization correlated with symptom decline and Otology & Neurotology, Vol. 38, No. xx, 2017 Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited. CE: S.S.; ON-17-300; Total nos of Pages: 6; ON-17-300 4 D. A. ITAYEM ET AL. FIG. 1. Fluctuating impedance values (in kV) in patients who reported dizziness and sudden onset device decline months after an asymptomatic postoperative period. Baseline values, maximum divergent values, and the most recent impedance scores are shown for each patient (S1–S5). Electrode number listed from basal (1) to apical (22). improvement as subjectively reported by patients. For example, patient S1 explained that his balance was ‘‘80% of normal’’ which is supported by the audiologist report of incomplete stabilization of impedance levels. Figure 1 depicts the baseline impedance levels, maximum divergence, and then return to baseline for each of the five patients described (S1–S5). Contacts that had been disabled were once again activated when electrical impedance values returned to baseline. DISCUSSION The primary objective of this paper was to describe a previously unrecognized, distinct symptom complex with its corresponding objective impedance abnormality: patients with initial successful cochlear implant use for months to years developed acute decline in device performance, dizziness, and an erratic impedance pattern. These impedance values both fluctuated with onset of symptoms and stabilized with improvement of symptoms, providing an objective quantification of patients’ subjectively reported symptoms. Although it can occur in any of the electrodes, the sawtooth impedance pattern specifically appeared in the most basal electrodes in all five patients, localizing the anomaly to that region. We hypothesize that non-suppurative labyrinthitis may be responsible for this clinical presentation and term the process ‘‘cochlear implant associated labyrinthitis’’ as the development of symptoms may be related to a delayed foreign body reaction, electrical stimulation, delayed perilymphatic leak or perhaps some other unrecognized process. Since the clinical picture involved a sudden onset of symptoms with gradual improvement, labyrinthitis is suspected as opposed to the recurrent symptomatology that would occur with Otology & Neurotology, Vol. 38, No. xx, 2017 Copyright © 2017 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited. CE: S.S.; ON-17-300; Total nos of Pages: 6; ON-17-300 COCHLEAR IMPLANT ASSOCIATED LABYRINTHITIS endolymphatic hydrops, for example. While further research is necessary to elucidate the exact mechanism, improvement with steroid therapy in two patients additionally supports the possibility of an inflammatory hypothesis. It is generally accepted that impedance levels increase immediately following implantation as a result of inflammatory remodeling secondary to the trauma of surgery and electrode insertion (6–8). Delivery of corticosteroids locally during surgery may decrease electrode impedance values further suggesting that an inflammatory process plays a key role in altering impedance (9–12). Genes involved in tissue remodeling such as MMP2 and MMP9 have been implicated in loss of residual acoustic hearing following cochlear implantation (13), and several studies are investigating the pathways of inflammation specifically in the cochlea (14–19). Zhang et al. (13) found a statistically significant upregulation in inflammatory cytokines in guinea pigs with cochlear implants. O’Malley et al. (14) also hypothesize possible etiologies of delayed hearing loss after implantation in their case report, including intracochlear scarring, dysfunction of hair cells, and synaptic transmission abnormalities. Quesnel et al. (15) further explain that activated macrophages may contribute to ongoing inflammation. Despite the number of publications evaluating immediate post-implantation inflammatory changes and the wide acceptance that impedance changes commonly occur in the early postoperative period, impedance fluctuation months or years after successful implantation is unusual and the exact pathogenesis remains unknown. A review of the literature unveiled one case report that was consistent with the patients described in this study. Wolfe et al. (20) report the clinical course of a patient who experienced sudden performance decline after months of successful implant use and exhibited the impedance pattern we describe. Importantly, both the symptoms and the impedance pattern matched our patient profiles. In the current study, the range of symptom onset after surgery was 2 to 22 months with a median of 126 days, which is similar to Wolfe et al.’s patient whose symptoms surfaced 19 months after implantation. Like our observations, the patient they described partially recovered once steroid treatment was initiated. However, this anti-inflammatory therapy was not administered for 10 months and not until reimplantation was attempted. We agree with Wolfe et al. that ‘‘physical changes of the surrounding tissues could be the cause of the fluctuation of electrode impedances observed’’ and extend their hypothesis to suggest that labyrinthine inflammation may be involved. In discussing our observations, colleagues at other institutions have also anecdotally recognized this unique clinical picture in a small number of patients despite its relative absence in the literature. In closing, several limitations of this study are acknowledged: a small number of patients and their outcome are described. Once this disease is recognized as a distinct entity, a larger study compiling data from multiple implant centers may help characterize the disease complex further. Second, speech perception was reported subjectively since objective speech perception testing was not performed 5 on all patients. Regardless of this limitation, speech perception and severity of symptoms correlated well with objective impedance values. As symptoms worsened, impedance values fluctuated, and as symptoms improved, the impedance pattern stabilized towards baseline (Fig. 1). This retrospective chart review design highlights the association that steroid therapy may provide benefit in management of this subset of patients, however, admittedly, several patients experienced symptom resolution without treatment. Thus, it might be reasonable to consider prompt intervention with steroid therapy although this is only speculative. The duration between symptom onset and steroid treatment initiation was 52 and 85 days (for patients S2 and S5, respectively) making disease outcome predictions difficult. Follow up studies are required to investigate both the pathophysiology and the best course of therapy. CONCLUSION In this study, we describe the clinical manifestations and impedance testing results in a subset of five cochlear implant recipients with sudden onset implant performance decline, dizziness, and a characteristic erratic impedance pattern. Further studies are needed to evaluate the etiology as well as the optimal management of this uncommon but distressing phenomenon. REFERENCES 1. Lassig A, Zwolan T, Telian S. Cochlear implant failures and revision. Otol Neurotol 2005;26:624–34. 2. Terry B, Kelt R, Jeyakumar A. Delayed complications after cochlear implantation. JAMA Otolaryngol Head Neck Surg 2015;141:1012–7. 3. Fayad JN, Baino T, Parsier S. Revision cochlear implant surgery: causes and outcome. Otolaryngol Head Neck Surg 2004;131: 429–32. 4. Stamatiou GA, Kyrodimos E, Sismanis A. Complications of cochlear implantation in adults. 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