Audiovestibular Function in Infratentorial Superficial Siderosis (AViSS)

Clinical and Imaging Biomarkers of Audiovestibular Function in Infratentorial Superficial Siderosis

One in six people in the United Kingdom and over 400 million people worldwide have disabling hearing loss. This figure will double by 2050 as predicted by the World Health Organisation. There is an urgent need to improve our knowledge regarding hearing loss, its underlying mechanisms, optimal diagnostic modalities, reliable and accurate functional and imaging biomarkers.

A less-well studied condition associated with progressive hearing loss is infratentorial superficial siderosis (iSS). It results from iron deposition along the surfaces of brain structures which control hearing and balance. It is currently considered uncommon, but may well be under-recognised and therefore under-reported. Despite its severity, our current understanding of its impact on the hearing (auditory) and balance (vestibular) functions is limited, and this has an adverse impact on the treatment offered to these patients. Additionally, iSS patients have been reported to have cognitive impairment yet literature reports of cognitive assessment in iSS are few. The cognitive dysfunction may be specific to iSS or due to progressive hearing impairment or a combination of both, and further studies are required to establish this. Olfaction is also known to be affected in patients with iSS yet is rarely reported in the literature.

Due to the significant morbidity and progressive nature, there is a clear need to improve our understanding of the audiovestibular dysfunction resulting from iSS.

The aim of this study is to comprehensively assess audiovestibular function in iSS compared to age-related hearing loss and the controls/normative data and as a means to quantify deficits for monitoring disease progression and response to treatment, to assess the impact on the quality of life, to analyse clinically-obtained data (including imaging, cognitive and laboratory data), and correlate these with functional findings in iSS.

Study Overview

• Status: Completed
• Conditions: Rare Diseases; Siderosis; Presbycusis; Neurological Disorder; Age Related Hearing Loss
• Intervention / Treatment: Diagnostic test: Hearing assessment; Diagnostic test: Vestibular/balance assessment; Other: Quality of life assessment; Diagnostic test: Olfactory (smell) function testing; Genetic: DNA bio-banking

Detailed Description

This study focuses on a rare condition called infratentorial superficial siderosis (iSS)-a disease where iron gradually accumulates in the superficial layers of the brain and spinal cord. Over time, this buildup can damage the nerves responsible for hearing and balance amongst others, leading to symptoms like progressive hearing loss, dizziness, and problems with coordination. iSS has not been well studied in the past. The hearing and balance function in persons with iSS has been described as variable - meaning, there has not been a specific pattern of hearing loss or imbalance or dizziness that can be associated with iSS. The studies to date have been with small groups of patients but mainly case reports.

The aim of the AVISS study has been to address this gap in the knowledge. This study investigates how iSS affects hearing, balance, and even sense of smell by studying three groups of people:

1. People with iSS, who already have hearing and balance problems.
2. People with age-related hearing loss, to compare how hearing declines over time.
3. People with normal hearing, serving as a control group.

The study will take place over three years, using a range of tests to assess hearing and balance:

• Hearing tests like pure tone audiometry, speech-in-noise assessments, and auditory brainstem response.
• Balance tests such as vestibular evaluations, gait assessments, and head impulse testing.
• Olfactory (smell) tests, since iSS might also affect sensory perception. By collecting this data, the study aims to improve how iSS is diagnosed, identify better rehabilitation methods, and explore new treatment options for those affected.

The study is funded by NIHR UCLH Biomedical Research Centre and the Bernice Bibby Research Trust, ensuring experts have the resources needed to make meaningful discoveries. Ultimately, the goal is to help doctors recognize iSS earlier, support affected individuals more effectively and improve their overall quality of life.

• Study Type: Observational
• Enrollment (Actual): 11

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust
  • London, United Kingdom
    • UCL Ear Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Three groups of participants will be recruited into the study (as defined by the eligibility criteria): a) participants with a known diagnosis of iSS (siderosis group); b) participants with age-related hearing loss (ARHL group); c) participants with no previous history of hearing loss (control group).

Description

Inclusion Criteria:

• Siderosis group: adults (male and female) of 18+ years old with a known diagnosis of iSS (defined using standardised radiological criteria) confirmed by a consultant neurologist with expertise in this condition at University College London Hospitals National Health Service (NHS) Foundation Trust
• Age-related hearing loss (ARHL) group: adults (male and female) of 18+ years old with ARHL
• Control group: adults (male and female) of 18+ years old with no previous diagnosis of hearing loss or no known neurological disorder (including iSS) that affects hearing, with the aim to recruit such participants of 50 years of age and above; however, should difficulty with the recruitment of such participants arise, participants of 18 years of age and above will be invited to participate in the study.

Exclusion Criteria:

• All groups: individuals younger than 18 years old; individuals with a physical or mental impairment that prevents the potential participant from giving informed consent or undergoing the hearing and/or vestibular assessment;
• Siderosis group: individuals with no prior diagnosis of iSS
• Age-related hearing loss (ARHL) group: individuals with no previous diagnosis of ARHL or with a diagnosis of hearing loss of aetiology other than age-related; individuals with a history of exposure to high-intensity noise or ototoxic drugs or evidence of middle ear disease/dysfunction or family history of non age-related hearing loss;
• Control group: individuals with a known history of hearing loss (of any cause) or with a known neurological disorder that affects their hearing; individuals with history of exposure to high-intensity noise or ototoxic drugs or evidence of middle ear disease or family history of non age-related hearing loss;

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Siderosis (iSS) group; participants with a known diagnosis of infratentorial superficial siderosis (defined using standardised radiological criteria) confirmed by a consultant neurologist with expertise in this condition at University College London Hospitals National Health Service (NHS) Foundation Trust	Diagnostic test: Hearing assessment; All study participants will undergo hearing tests, including hearing-specific questionnaires; Diagnostic test: Vestibular/balance assessment; Siderosis group participants will undergo vestibular/balance tests, including gait assessment and balance-specific questionnaires; Other: Quality of life assessment; All study participants will be asked to complete a set of quality of life questionnaires; Diagnostic test: Olfactory (smell) function testing; Siderosis group participants will undergo a formal smell identification testing by means of self-administered smell chart to identify the revealed scents; Genetic: DNA bio-banking; Siderosis group participants will be asked to provide a saliva sample for DNA bio-banking
Age-related hearing loss (ARHL) group; participants with age-related hearing loss (as identified from participant's clinical history and examination, with hearing thresholds confirmed on a pure-tone audiogram)	Diagnostic test: Hearing assessment; All study participants will undergo hearing tests, including hearing-specific questionnaires; Other: Quality of life assessment; All study participants will be asked to complete a set of quality of life questionnaires
Control group; participants with no known or previously reported hearing loss (as identified from participant's clinical history and examination, with hearing thresholds confirmed on a pure-tone audiogram)	Diagnostic test: Hearing assessment; All study participants will undergo hearing tests, including hearing-specific questionnaires; Other: Quality of life assessment; All study participants will be asked to complete a set of quality of life questionnaires

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hearing Evaluation - Pure Tone Audiometry	Clinical audiological (hearing) tests were performed to assess hearing function. The hearing tests included psychophysical, physiological and electrophysiological measures, (pure-tone audiometry, tympanometry, auditory brainstem responses and acoustic reflexes). The tests were perfomed in line with the procedure guidelines by the British Society of Audiology (www.thebsa.org.uk). The mean value of pure-tone audiometric thresholds for both ears measured in decibel hearing level (as described in the guidelines by the British Society of Audiology) was calculated and reported. Other parameters were reported as normal or abnormal (in at least one ear) or inconclusive.	Baseline visit
Vestibular/Balance Evaluation	Clinical vestibular and balance tests were performed to assess vestibular/balance function.	Baseline visit
Hearing Evaluation - Auditory Brainstem Responses/Acoustic Reflexes	Clinical audiological (hearing) tests were performed to assess hearing function. The hearing tests included psychophysical, physiological and electrophysiological measures, (pure-tone audiometry, tympanometry, auditory brainstem responses and acoustic reflexes). The tests were perfomed in line with the procedure guidelines by the British Society of Audiology (www.thebsa.org.uk). The mean value of pure-tone audiometric thresholds for both ears measured in decibel hearing level (as described in the guidelines by the British Society of Audiology) was calculated and reported. Other parameters were reported as normal or abnormal (in at least one ear) or inconclusive.	Baseline visit
Hearing Evaluation - Tympanogram	Clinical audiological (hearing) tests were performed to assess hearing function. The hearing tests included psychophysical, physiological and electrophysiological measures, (pure-tone audiometry, tympanometry, auditory brainstem responses and acoustic reflexes). The tests were perfomed in line with the procedure guidelines by the British Society of Audiology (www.thebsa.org.uk). The mean value of pure-tone audiometric thresholds for both ears measured in decibel hearing level (as described in the guidelines by the British Society of Audiology) was calculated and reported. Other parameters were reported as normal or abnormal (in at least one ear) or inconclusive.	Baseline
Hearing Evaluation - Otoacoustic Emissions	Clinical audiological (hearing) tests were performed to assess hearing function. The hearing tests included psychophysical, physiological and electrophysiological measures, (pure-tone audiometry, tympanometry, auditory brainstem responses and acoustic reflexes). The tests were perfomed in line with the procedure guidelines by the British Society of Audiology (www.thebsa.org.uk). The mean value of pure-tone audiometric thresholds for both ears measured in decibel hearing level (as described in the guidelines by the British Society of Audiology) was calculated and reported. Other parameters were reported as normal or abnormal (in at least one ear) or inconclusive.	Baseline
Hearing Evaluation - Listening in Spatialised Sentences Noise Test	Clinical audiological (hearing) tests were performed to assess hearing function. The hearing tests included psychophysical, physiological and electrophysiological measures, (pure-tone audiometry, tympanometry, auditory brainstem responses and acoustic reflexes). The tests were perfomed in line with the procedure guidelines by the British Society of Audiology (www.thebsa.org.uk). The mean value of pure-tone audiometric thresholds for both ears measured in decibel hearing level (as described in the guidelines by the British Society of Audiology) was calculated and reported. Other parameters were reported as normal or abnormal (in at least one ear) or inconclusive. Cameron S, Dillon H. The listening in spatialized noise-sentences test (LISN-S): comparison to the prototype LISN and results from children with either a suspected (central) auditory processing disorder or a confirmed language disorder. J Am Acad Audiol. 2008 May;19(5):377-91.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation Between Clinically Obtained Imaging (Siderosis Group Participants) and the Hearing and Balance Assessment Results	Siderosis group participants underwent formal imaging procedures as part of their clinical care pathway. The imaging results were reviewed with the results obtained from hearing and vestibular/balance assessments. All participants had MRI Brain, as part of their clinical care pathway; susceptibility-weighted images were reviewed to identify the appearance of superficial siderosis, in keeping with the radiological diagnostic criteria (Reference: Wilson et al, 2017).	Baseline visit
Correlation Between Clinically Obtained Results of Cognitive Function Assessment (Siderosis Group Participants) and the Hearing and Balance Assessments	Siderosis group participants underwent a formal neuro-cognitive assessment as part of their clinical care pathway. The results of this clinical assessment were reviewed to determine if an association exists between the cognitive assessment results and the results obtained from hearing and vestibular/balance assessments performed during the study. A formal neuro-cognitive assessment was performed using the Wechsler Adult Intelligence Scale test. Cognitive impairment in a domain was defined as scoring at or below the fifth percentile on any one test in that domain.	Baseline visit
Smell Identification Test	University of Pennsylvania Smell Identification Test (UPSIT, British version) was performed (siderosis group participants) to assess their olfactory function. UPSIT is a forced-choice 40-item self-administered test. The scores are calculated using manufacturer's answer key as the sum of correct answers (maximum best = 40, minimum score 6; anosmia <19(males, females); normosmia >33 (males) and >34 (females)), and compared to the age- and gender-matched norms. The scores are also grouped into categories (ranging from normosmia to anosmia), with higher scores indicating better olfactory function.	Baseline visit

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: NIHR UCLH Biomedical Research Centre (BRC); Bernice Bibby Research Trust
• Investigators: Principal Investigator: Doris-Eva Bamiou, Professor, UCL Ear Institute; UCLH NHS Foundation Trust, UK; Principal Investigator: David J Werring, Professor, Stroke Research Centre UCL IoN; UCLH NHS Foundation Trust, UK

Publications and helpful links

General Publications

• Wilson D, Chatterjee F, Farmer SF, Rudge P, McCarron MO, Cowley P, Werring DJ. Infratentorial superficial siderosis: Classification, diagnostic criteria, and rational investigation pathway. Ann Neurol. 2017 Mar;81(3):333-343. doi: 10.1002/ana.24850. Epub 2017 Jan 28.
• Fearnley JM, Stevens JM, Rudge P. Superficial siderosis of the central nervous system. Brain. 1995 Aug;118 ( Pt 4):1051-66. doi: 10.1093/brain/118.4.1051.
• Koeppen AH, Dickson AC, Chu RC, Thach RE. The pathogenesis of superficial siderosis of the central nervous system. Ann Neurol. 1993 Nov;34(5):646-53. doi: 10.1002/ana.410340505.
• Kumar N. Superficial siderosis: associations and therapeutic implications. Arch Neurol. 2007 Apr;64(4):491-6. doi: 10.1001/archneur.64.4.491.
• IWANOWSKI L, OLSZEWSKI J. The effects of subarachnoid injections of iron-containing substances on the central nervous system. J Neuropathol Exp Neurol. 1960 Jul;19:433-48. doi: 10.1097/00005072-196007000-00010. No abstract available.
• Posti JP, Juvela S, Parkkola R, Roine S. Three cases of superficial siderosis of the central nervous system and review of the literature. Acta Neurochir (Wien). 2011 Oct;153(10):2067-73. doi: 10.1007/s00701-011-1116-0. Epub 2011 Aug 7.
• Sydlowski SA, Cevette MJ, Shallop J. Superficial siderosis of the central nervous system: phenotype and implications for audiology and otology. Otol Neurotol. 2011 Aug;32(6):900-8. doi: 10.1097/MAO.0b013e31822558a9.
• Offenbacher H, Fazekas F, Schmidt R, Kapeller P, Fazekas G. Superficial siderosis of the central nervous system: MRI findings and clinical significance. Neuroradiology. 1996 May;38 Suppl 1:S51-6. doi: 10.1007/BF02278119.
• Sydlowski SA, Levy M, Hanks WD, Clark MD, Ackley RS. Auditory profile in superficial siderosis of the central nervous system: a prospective study. Otol Neurotol. 2013 Jun;34(4):611-9. doi: 10.1097/MAO.0b013e3182908c5a.
• Vibert D, Hausler R, Lovblad KO, Schroth G. Hearing loss and vertigo in superficial siderosis of the central nervous system. Am J Otolaryngol. 2004 Mar-Apr;25(2):142-9. doi: 10.1016/j.amjoto.2003.10.001.
• Takeda T, Kawashima Y, Hirai C, Makabe A, Ito T, Fujikawa T, Yamamoto K, Maruyama A, Tsutsumi T. Vestibular Dysfunction in Patients With Superficial Siderosis of the Central Nervous System. Otol Neurotol. 2018 Jul;39(6):e468-e474. doi: 10.1097/MAO.0000000000001844.
• Pribitkin EA, Rondinella L, Rosenberg Si, Yousem DM. Superficial siderosis of the central nervous system: an underdiagnosed cause of sensorineural hearing loss and ataxia. Am J Otol. 1994 May;15(3):415-8.
• Kwartler JA, De La Cruz A, Lo WW. Superficial siderosis of the central nervous system. Ann Otol Rhinol Laryngol. 1991 Mar;100(3):249-50. doi: 10.1177/000348949110000315. No abstract available.
• van Harskamp NJ, Rudge P, Cipolotti L. Cognitive and social impairments in patients with superficial siderosis. Brain. 2005 May;128(Pt 5):1082-92. doi: 10.1093/brain/awh487. Epub 2005 Mar 23.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2020
• Primary Completion (Actual): October 19, 2021
• Study Completion (Actual): October 19, 2021

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 16, 2019

Study Record Updates

• Last Update Posted (Actual): June 10, 2025
• Last Update Submitted That Met QC Criteria: June 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Biomarkers; Hearing loss; Nervous system diseases; Ataxia; Central nervous system; Superficial siderosis, infratentorial; Hearing tests; Auditory pathways; Vestibulocochlear nerve; Vestibular function tests
• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathologic Processes; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Lung Diseases, Interstitial; Ear Diseases; Hearing Disorders; Hearing Loss, Sensorineural; Occupational Diseases; Lung Injury; Pneumoconiosis; Rare Diseases; Nervous System Diseases; Hearing Loss; Deafness; Presbycusis; Siderosis
• Other Study ID Numbers: 121603

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The anonymised participant-level dataset and statistical code for generating the results will not be publicly available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No