{'fraction_non_alphanumeric': 0.0333544856032363, 'fraction_numerical': 0.01959228999762037, 'mean_word_length': 4.941328934967013, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Outcomes of Cochlear Implantation in Patients with Superficial Siderosis: A Systematic Review and Narrative Synthesis

Submitted: 06.29.2020 • Revision Received: 08.24.2020 • Accepted: 08.27.2020 Available online at www.advancedotology.org INTRODUCTION Superficial siderosis (SS) was first described in 1908 by Hamill et al.[1] as a rare progressive disorder caused by recurrent hemorrhage in the subarachnoid space. The hemorrhaging leads to the spread of heme by circulating cerebrospinal fluid (CSF) and subsequent deposition of hemosiderin and other iron-containing pigments in the central nervous system (CNS). This accumulation occurs over several months, causing damage to the leptomeninges, brain surface, brainstem, cerebellum, cranial nerves, and spinal cord. These deposits propel lipid peroxidation, which ultimately leads to localized cell and tissue necrosis[2]. Iwanowski and Olszewski[3] were the first people to describe the mechanisms of SS, and they did this by successfully reproducing SS in dogs via repeated injections of blood or iron dextran into the subarachnoid space. With the emergence of magnetic resonance imaging (MRI), SS could be diagnosed in vivo, rather than only through postmortem examination. Through radiological advancements in the 1980s, the diagnosis of SS became more precise, and this rare condition could now be identified through the presence of a rim of hypointensity around the cerebellum, brainstem, cranial nerves, and spinal cord on T2-weighted and/or gradient echo sequence MRI scans[4]. Other diagnostic investigations that have emerged for SS include the presence of xanthochromia, increased blood cell count, and high protein levels in the CSF[5]. However, these findings are not universal as they can appear normal if the subarachnoid bleeding occurs intermittently[6]. This study aimed to establish outcomes following cochlear implantation (CI) in patients with superficial siderosis (SS). MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov databases were searched for this systematic review. No limits were placed on the language or the year of publication. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Of a total of 46 studies, 19 studies met the inclusion criteria reporting outcomes in 38 patients. Of the 44 implants, 23 implants (52.27%) had good hearing outcomes at the last follow-up, 9 (20.45%) were initially beneficial for the patient, but then the performance deteriorated (4 of which were re-implanted), and 12 (27.27%) were not beneficial for the patient. All studies were classified as grade 4 studies using the Oxford Centre for Evidence-Based Medicine (OCEBM) grading system, being retrospective in nature and consisting of case reports and noncontrolled case series with a small number of patients. Of the 44 implants, 32 (72.73%) showed improved hearing outcomes following CI for SS at some point in time, of which 23 (52.2%) implants showed sustained benefit at the last follow-up (average follow-up time was 21.97 months). It is difficult to predict the longevity of benefit owing to the progressive nature of the disease or the patients in whom it may be beneficial, as the preoperative investigations inadequately predict benefit. Preimplantation and postimplantation counseling with the patient and their family regarding the potential limited benefit and eventual parallel decline with the neurological disease are crucial, along with thorough clinical investigations.


INTRODUCTION
Superficial siderosis (SS) was first described in 1908 by Hamill et al. [1] as a rare progressive disorder caused by recurrent hemorrhage in the subarachnoid space. The hemorrhaging leads to the spread of heme by circulating cerebrospinal fluid (CSF) and subsequent deposition of hemosiderin and other iron-containing pigments in the central nervous system (CNS). This accumulation occurs over several months, causing damage to the leptomeninges, brain surface, brainstem, cerebellum, cranial nerves, and spinal cord. These deposits propel lipid peroxidation, which ultimately leads to localized cell and tissue necrosis [2] .
Iwanowski and Olszewski [3] were the first people to describe the mechanisms of SS, and they did this by successfully reproducing SS in dogs via repeated injections of blood or iron dextran into the subarachnoid space. With the emergence of magnetic resonance imaging (MRI), SS could be diagnosed in vivo, rather than only through postmortem examination. Through radiological advancements in the 1980s, the diagnosis of SS became more precise, and this rare condition could now be identified through the presence of a rim of hypointensity around the cerebellum, brainstem, cranial nerves, and spinal cord on T2-weighted and/or gradient echo sequence MRI scans [4] . Other diagnostic investigations that have emerged for SS include the presence of xanthochromia, increased blood cell count, and high protein levels in the CSF [5] . However, these findings are not universal as they can appear normal if the subarachnoid bleeding occurs intermittently [6] . SS is generally idiopathic in nature but can be associated with a history of neurosurgical procedures or CNS tumors and trauma [7,8] . If an identifiable source of hemorrhage has been located, then surgical correction may be possible; however, this is usually not a completely curative approach and SS can still continue to progress because of the already present hemosiderin deposits. Nonsurgical approaches so far have included utilization of steroids and iron-chelating medication. However, these management routes have seen limited success, and this could be attributed to their inability to cross the blood brain barrier [6] . Overall, in the absence of any clear management options, SS is typically treated symptomatically.
In many cases, decades pass before any symptoms emerge with the classic triad being progressive bilateral sensorineural hearing loss (SNHL), cerebellar ataxia, and myelopathy [6] . Other features include pyramidal signs (e.g., spastic paraparesis, quadriparesis), dementia, headache, and anosmia [9,10] . The vestibulocochlear nerve (VIII) is suspected to be more vulnerable to hemosiderin deposits when compared with other cranial nerves because of its long glial segment and by being subjected to a high level CSF flow as it passes through the pontine cistern [9,11] . Longitudinal analysis of hearing loss in patients with superficial siderosis suggests a progressive, predominantly high frequency hearing loss. Estimates for annual threshold deterioration rate range from 7-24 dB/year [2] . This hearing loss is the cardinal feature, present in 95% of the patients and generally commences early on in the course of disease, as described by Irving and Graham [12] . Temporal bone histopathology by Nadol et al. [11] in one patient with superficial siderosis showed severe bilateral degeneration associated with iron deposits in the organ of Corti, spiral ligament, stria vascularis, and spiral ganglion cells. A peripheral contribution to etiology is supported by Vanat et al. [13] who found brown fluid in the cochlea of a patient while performing cochlear implantation (CI) surgery.
In these patients, hearing rehabilitation is initially through hearing aids. However, because of the progressive retrocochlear nature of SS, amplification has minimal long-term benefit [2,5] . Once the patients have bilateral severe to profound hearing loss and exhibit poor speech perception capacity, the next step in auditory rehabilitation in various studies includes vibrotactile stimulation, CI, and auditory brainstem implantation. The CI electrode array is placed within the scala tympani and directly stimulates the spiral ganglion cells that are innervated by the auditory nerve. The highly synchronous neural firing initiated by CI may overcome the limitations of a partly damaged auditory nerve. Even though the patients with SS are indistinguishable from the patients with standard CI based on pure-tone audiometry (PTA) alone and speech perception, CI should be considered with caution because of the predominantly retrocochlear nature of the damage, but potential iron deposited within the cochlea may also affect the spread of excitation within the cochlea [15] .
In 2012, a systematic review (SR), by Tyler et al. [2] reported a clear sustained benefit in 7 of the 15 SS cases. They concluded that early implantation could be more beneficial, and outcomes were dependent on the site of lesion, neural deterioration, and the degree of cochlear nerve functionality. Three years later, Modest et al. [5] also published a SR concluding that CI is a viable option for auditory rehabilitation and that most patients received benefit from it. This SR aimed to pool all the available data via a rigorous SR methodology and to provide clinicians with the best evidence to date and advice on the use of CI in patients with confirmed SS.

Objectives
In this review, we looked at cochlear implant outcomes for patients with SS.
Population: Children or adults with SS. Intervention: CI. Comparison: No comparison group. Outcomes: Preimplantation vs. postimplantation audiometric outcomes (where preimplantation outcomes were not available, we looked only at postimplantation audiometric outcomes).

MATERIALS AND METHODS
The study protocol was registered in the PROSPERO prospective database of systematic reviews (CRD42020191141).

Study Inclusion Criteria
Because of the limited number of reported cases, we placed no restriction on the types of studies and thus included all case-control studies, cohort studies, and case series/reports where outcomes of CI in patients with a confirmed diagnosis of SS were reported. Animal studies and human studies without the report of postoperative audiometric outcomes or where the abstract or full text were unavailable were excluded. The initial search yielded 95 articles and after removing duplicates, the total remaining number was 46 which then underwent title, abstract, and full-text screening leaving 19 studies for inclusion.

Search Strategy
A total of 2 reviewers (AC/DC) independently ran the searches and screened the abstracts. The following databases were searched: MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov. The search terms used were: 1) "Cochlear Implantion.mp. OR Cochlear Implantation/" 2) "Cochlear Implants.mp. OR Cochlear Implants/"

Selection of Studies
As mentioned above, 2 reviewers (AC/DC) independently screened all the records by title and abstract identified from searches retrieved from the database searches. Studies describing CI in patients with SS were assessed against the inclusion and exclusion criteria with any disagreement resolved by discussion with a third reviewer (JM). Studies without accessible abstract or full text after the title/abstract screening were followed up by attempting to contact the study authors. If they were unavailable, the study was excluded. Studies were also excluded if they did not report postintervention audiometric outcomes. Potentially relevant studies identified from the initial searches and abstract screening then underwent full-text screening by the 2 independent reviewers (AC/DC) before data extraction. Conflicts on the selection were resolved by discussion between the reviewers.

Data Extraction
The data was extracted by the first reviewer (AC) and then checked by the second reviewer (DC). The extracted data were arranged in a spreadsheet (Excel, Microsoft Corp, WA, USA).

Risk of Biased Quality Scoring
The risk of bias was evaluated by 2 independent reviewers using the Brazzelli risk of bias tool for nonrandomized studies [15] . The Oxford Centre for Evidence-Based Medicine (OCEBM) grading system [16] was utilized to grade the studies. Any discrepancies between the reviewers were resolved by discussion. Quality assessment of the studies is summarized in Table 1.

RESULTS
The searches were initially run on March 21, 2020. Figure 1 shows a flowsheet detailing the study selection according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Description of Studies
A total of 19 studies met the inclusion criteria with a total of 38 patients and 44 implants (2 bilateral, 13 right, 17 left-sided implants, and 4 re-implants). There were 11 case reports and 8 case series with the number of patients ranging from 2-7. All studies were published between 1999 and 2019. Since the last SR by Modest et al. [5] , there have been 11 additional cases. All the patients were adults with the exception of one who was a child [5] . According to the available data, there were 25 men and 9 women. The average age at the time of CI was 50 years (ranging from . Of the studies include, 4 did not mention the type of implant used [5,[17][18][19] . Alshehabi et al. [20] mentioned the type of implants used, however, failed to clarify who the recipients were. Grover et al. [21] reported the implant type in only 1 of the 2 patients. Only 2 studies measured quality of life as a postoperative outcome [20,22] . There was lack of data for 1 of the studies [18] , and thus, we were not able to access the number of implants or other demographic data. The same patient was described in 2 papers; the first [23] discussing the implantation and follow-up of 5 years and the second [24] describing follow-up for an additional 3 years. From the reported data, the origin of SS can be credited to neurosurgical procedures in 11 cases (40.74%), history of head trauma in 11 cases (40.74%), and idiopathic causes in 5 cases (18.52%). The majority of SS diagnosis was based on MRI. Study characteristics are summarized in Table 2.

Quality of Studies
Our review contains 11 case reports and 8 case series that were noncontrolled and consisted of a small number of patients. All the studies were retrospective in nature, and thus the level of evidence based on methodology was 4 using the OCEBM grading system [16] . A meta-analysis could not be conducted because of the heterogeneity of audiological and speech perception outcomes. Limitations were also seen in implants used, surgical technique, and rehabilitation details.

Audiological and Implant Outcomes
Of the 44 implants, 23 (52.27%) produced good hearing outcome at the last follow-up, 9 (20.45%) initially benefited but then regressed with time (4 of which were re-implants), and 12 (27.27%) did not benefit from them. The average follow-up period was 22 months (ranging from 3 months-84 months). The average duration of benefit per implant that reported benefit for any amount of time and follow-up is 22.5 months ranging from 4 months-84 months. Because of the heterogeneity of both pre-and postoperative tests, data, and time of reporting, an overall criterion for benefit could not be established, and was necessarily based on the individual criteria of each study.
Of the 4 re-implants, the first re-implanted patient initially showed promising results, however, soon exhibited a decreasing response which was owing to broken wires in the straight section of the electrode lead indicating mechanical fatigue [20] . He was successfully re-implanted in the ipsilateral ear a year after the original procedure without any compilations and benefited once again. The second patient that required re-implantation reported discharge from the surgical site 1 week postoperatively. Despite treatment with multiple courses of broad-spectrum antibiotics and multiple hospitalizations over the next 4 months, the device had to be explanted [20] . He was also successfully re-implanted in the ipsilateral ear a year after the original procedure in spite of it being heavily sclerotic. The third patient with a re-implant suffered from device infection postoperatively and subsequently required re-implantation 4 months later [5] .
Another re-implantation took place 3 years later when the device experienced hard failure. The third implant was successful and functioning at the 7-month follow-up.
All studies, except 1 [24] , presented preimplantation audiometric data, and all the patients had suffered from progressive SNHL.

DISCUSSION
Across the 19 studies included in our review, we identified 44 implants of which 22 (50%) showed sustained benefit at the last follow-up compared with 47% in Tyler et al. [2] and 59.26% in Modest et al. [5] . From the cases that reported benefit for any period of time (31 implants) and the follow-up period, the average time of benefit per implant in those who declined and those who did not was 22.5 months ranging from 4 months-84 months. The degree of hearing improvement is variable in this group of patients, and there are limited data about the long-term durability with the average follow-up being 21.97 months (range 3 months-84 months). Another interesting point raised by Nadol 2011 et al. [11] is that long-term follow-up may not always be possible because of the patient's ongoing health issues. This point is further amplified in Modest et al. [5] , in which 2 cases died secondary to other causes at 11 months and 13 months postimplantation. Thus, along with monitoring the patient's audiological data, it is also imperative to measure disease progression as part of their ongoing multidisciplinary care as cognitive decline will affect their hearing performance.
Of the 44 implants, 9 (20.45%) showed initial benefit but then deteriorated with time (4 of which required re-implantation) compared with 13.33% in Tyler et al. [2] and 18.52% in Modest et al. [5] The rest of the 5 implants deteriorated because of the progressive nature of the disease. The patient in the study by Hathaway et al. [23] (updated in Yoshikawa and Hirsch [24] ) had benefited for the first 6 years after implantation with a speech recognition threshold of 34 dB and 71% correct on HINT but then deteriorated to 26 dB and 25% after undergoing general decline. One of the patients in Wood et al. [9] reported a marked reduction in hearing after 4 months which coincided with a fall; however, it was ultimately due to progressive neural deterioration. The other patient in Wood et al. [9] reported deterioration to preimplantation levels just 1 week after implantation which was due to compromised adaptation to electrical stimulation, further investigation concluded that he had dementia secondary to SS. The other 2 patients reported in the study by Modest et al. [5] also had similar courses of decline after seeing initial benefit; the first had advancement of initially stable mild dementia, and the second had new onset dementia at 18-24 month postimplant.
Of the 44 implants, 13 (29.55%) failed to demonstrate improvement at any point in time compared with 40% implants in Tyler et al. [2] and 25.93% in Modest et al. [5] Of these implants, 4 were reported in a study by Alshehabi et al. [20] One case was reported in which the implant required extremely high currents for the electrodes and was still unable to produce any meaningful auditory stimulus [21] . In another patient, very high stimulation was need to reach adequate hearing sensation causing facial twitching; and therefore, the implant was deemed unsatisfactory [28] . Modest et al. [5] also reported an implant in the left ear that was not beneficial; however, the patient had a CI in the right ear which was successful and thus benefited overall. Sydlowski et al. [18] failed to provide preoperative data, and thus, we could not conclude which patient benefited. Using their descriptive analysis, we conclude that only 1 of the 5 patients was able to benefit,  28 L Modest et al. [5] NR N N N [3m] 28 R Modest et al. [5] Y N N Y [64m] 29 Sydlowski et al. [ Lee et al. [19] Bittencourt et al. [26] Bittencourt et al. [26] Haferkamp et al. [27] Vanat et al. [13]  achieving average speech recognition for both sentences and monosyllabic words. The last patient who did not benefit was reported by Vanat et al. [13] whose data were also very scarce.
Age, sex, and cause of SS can be predicting factors for the success of CI outcomes. Of the 31 implants that reported benefit for any period of time (from the data available), the average age of patients was 49.2 years, there were 23 men and 8 women, 10 were caused by head trauma and 12 were due to neurosurgical causes. Of the 13 implants that failed to demonstrate improvement at any point in time (from the data available), the average age of patients was 47 years, there were 8 men, 2 were caused by head trauma and 3 were due to neurosurgical causes. However, the dataset was too small to draw any conclusions; thus, these results should be seen as a correlation rather than a causation relationship.
The small number of cases identified may be explained by the low prevalence of SS cases. Another reason for the limited number of patients may be the progressive and ultimately fatal nature of SS, combined with the intensive rehabilitation program required for CI and variable success rates, many patients may choose not to proceed with implantation. Owing to the dominance of case reports and the small number of patients in the case series, there may be reporting bias with departments only publishing about patients on either end of the impact spectrum. Owing to the cohort of patients, the variation in preimplant and postimplant data, variable follow-up periods, and the lack of information on implant details make it difficult to draw a meaningful conclusion regarding the degree and duration of benefit of CI in patients with SS. These problems could be overcome through the mandatory implementation of an implantation recipients register. Hurdles such as funding, legal implications, and oversight are yet to be overcome; however, increase in digital records and interest in patient outcomes are positive signs into the advancement of such a database [29,30] . Likewise, a homogenous approach to publishing pre-and postimplantation data and follow-up period can help amalgamate a larger patient database and hence provide a more accurate reflection of CI in SS.
The site of the hearing pathway damage in the cochlear or retrocochlear area can be hard to define and will likely affect the hearing outcome following CI. One such tool that might help define this is the diagnostic auditory brainstem response (ABR) to look for delayed latencies or abnormal morphology. Of the 38 patients, 15 used ABR (all of which were recorded as absent) as a preoperative measure to determine auditory threshold, degree and type of hearing loss, and detect lesions in the auditory nerve and/or brainstem. Multiple studies support the use of ABR as a preoperative measure to confirm the integrity of the cochlear nerve and thus try to predict positive outcomes [13,28,31] . However, Dhooge et al. [8] reports a patient who despite having reproducible electrical ABR responses at elevated levels before the implant produced disappointing results. A total of 13 patients had otoacoustic emissions (OAE) as a preoperative investigation, all of whom showed absent results. Other recommended preoperative investigations that have not been utilized by any studies so far are electrocochleography (ECochG) [28] and MRI [32] . As 95% of the patients with SS suffer from hearing loss [12] , we recommend periodic hearing assessments, such as PTA, speech perception tests, and tympanometry to enable hearing rehabilitation to be started as soon as possible. There may be a role for additional tests, such as ABR, OAE, ECochG, and MRI; however, given the material available in the published literature, it is not possible to advocate any one test or combination of tests, nor to suggest an optimal testing schedule.
Early diagnosis of SS with MRI and understanding the pathology behind SNHL is crucial for optimal management; however, as mentioned above, preimplant measures are imperfect prognostic factors, perhaps owing to the progressive and diverse course of the disease and lack of data. Therefore, education and having an open and honest communication with the patient is essential to establishing realistic expectations.

CONCLUSION
Of the 44 implants, 31 (70.45%) showed improved hearing outcomes following CI for SS at some point in time, and 22 implants (50%) had sustained benefit at the last follow-up. This supports previous numbers from Tyler et al. [2] and Modest et al. [5] It is difficult to predict the longevity of benefit because of the progressive nature of the disease or the patients in whom it might be beneficial as preoperative investigations are inadequate prognosticators. It is perhaps wise to teach potential candidates other useful communication skills such as lip reading, which will enable the patients to continue communicating, as visual communication methods before hearing is totally lost, understanding that there may be a cognitive decline as well as disease progression. Pre-and postimplantation counseling regarding the potential limited benefit and eventual parallel decline with the neurological disease are crucial with the patient and family to ensure realistic expectations, along with thorough audiometric investigations.