Prediction & Mechanisms of Recovery Following IEDS

Decompression Sickness Clinical Trial

Official title:

A Prospective and Retrospective Observational Study of Symptoms and Mechanisms of Recovery in People With Inner Ear Decompression Sickness (IEDS)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06370897
• Other study ID #: 337421
• Status: Not yet recruiting
• Start date: June 2024
• Est. completion date: September 2028

Study information

• Verified date: May 2024
• Source: University of Plymouth
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Inner Ear Decompression sickness (IEDS) accounts for 20% of all types of decompression sickness (the bends) in divers. The condition commonly affects the peripheral vestibular system (inner ear). IEDS results in acute symptoms of dizzyness (vertigo) and imbalance. Even with the recommended treatment of hyperbaric oxygen therapy some people do not recovery fully. However, even in the presence of a permanent vestibular deficit many people can show a behavioural recovery where symptoms improve over time. Recovery can be aided by vestibular rehabilitation (VR) which is now routine for acute IEDS but was not provided before 2021, and is not widespread across the UK (United Kingdom) or world, meaning people may have a suboptimal recovery.

This project will investigate if and how people recover after an acute episode of IEDS and whether people who had IEDS in the past show changes in the central (brain) processing of vestibular function and in symptoms of dizziness, balance and posture.

This project has two main parts. Part one is a prospective observational study where people with an acute onset of IEDS are serially monitored while they are receiving hyperbaric treatment and VR over 10-14 days. Part two is a retrospective observational study where who have had IEDS in the past 15 years are re-assessed in a one-off session. The tests in both parts involve clinical tests and specialist eye movement recordings that assess vestibular function. We will also determine the site of any vestibular pathology by using selective stimulation of the vestibular end organ or nerve and assess whether there are any changes in how the structure and function of central vestibular pathways in the brain. In people with chronic IEDS with vestibular symptoms we will offer participants a course of VR over 12 weeks and assess whether this is associated with any improvement in symptoms.

Description:

Decompression sickness after diving can occur following a rapid ascent. Here, nitrogen, absorbed by the body when breathing compressed air at depth, comes out of solution and forms microbubbles in the blood. Inner ear decompression sickness (IEDS) accounts for approximately 20% of all cases of decompression sickness. The vestibular system is involved in ~85% cases of IEDS resulting in symptoms of vertigo, nausea, vomiting and unsteadiness with hearing loss and tinnitus.

The strong association of IEDS with a patent foramen ovale (50-73% of cases) suggests that a shunted venous gas embolism causes damage to the vestibular apparatus, which is particularly vulnerable due to its low perfusion and thus slow inert gas washout, compared to the cochlea and other brain structures. It is hypothesised that the nitrogen bubbles within the blood vessels trigger an inflammatory reaction in the endothelium with a coagulation cascade that leads to hypoxic injury and/or that there is direct damage to the membranous labyrinth. Animal models of rapid decompression suggest that it can cause a haemorrhage within the labyrinth with ectopic bone growth and fibrosis occurring over the next month. Advances in the imaging of the inner ear using a gadolinium-based contrast agent (GBCA) allow us to explore structural changes in human divers. Imaging can also help to differentially diagnose another potential cause of diving induced dizziness, superior structural dehiscence syndrome

Decompression sickness and the subsequent inflammatory response requires emergency treatment using with hyperbaric oxygen. The effects of hyperbaric therapy and rehabilitation are not uniform across participants, factors affecting recovery include a high clinical score on admission and a delay in hyperbaric recompression of over 6 hours. Complete recovery is seen in only about 30% of cases. Previous studies have highlighted that people who do not fully recover can have a variety of symptoms that can affect work, hobbies and well-being. These include feelings of instability in some situations (working at a height and with movement) and imbalance in the dark or when changing position.

In people with permanent vestibular pathology, symptoms can still improve due to central adaptive processes within the brain termed vestibular compensation. Clinical studies in other types of peripheral vestibular dysfunction show that it is possible to facilitate the compensation process and symptom recovery through vestibular rehabilitation. Early access to vestibular rehabilitation is now routine practice at the Diving Diseases Research Centre (DDRC) where patients are treated in the South-West UK. This is coupled to diagnosis and monitoring of vestibular function using objective laboratory tests (rotary testing) and clinical tests.

Animal studies highlight the mechanisms underlying vestibular compensation following a peripheral nerve lesion. These focus on changes in the interconnections between brainstem nuclei (e.g. vestibular nuclei) and the cerebellum and re-weighting of the relative importance of multi-sensory sensory inputs. Human studies in chronic peripheral dysfunction also suggest there are recovery-related changes in cortical areas that normally process vestibular information over time. Functional changes in the acute stages include an increase in contralesional activity in the parietoinsular vestibular cortex as well as interlinked subcortical areas (posterolateral thalamus, anterior cingulate gyrus, pontomesencephalic brainstem, hippocampus) with a decrease in activity was seen in the visual, somatosensory and auditory cortices. Structural changes over the first 3 months post lesion include increases in grey matter volume in the vestibular cortex, bilateral hippocampus, visual cortices and the cerebellum.

Within the DDRC vestibular rehabilitation has only been routinely undertaken for people diagnosed with IEDS since 2021. As complete recovery is seen in only about 30% of cases [9]; this suggests that there may be a cohort of patients with residual vestibular symptoms. In surveys of the aural and vestibular effects of diving, including those conducted by the DDRC, 79% (of 790 respondents) have reported aural related problems after learning to dive. Of those with reported problems 46% did not seek any medical advice and 39% specifically reported dizziness / vertigo. In total this suggests that at least 14% of all divers may have undiagnosed vestibular problems that could benefit from vestibular rehabilitation. A case review highlights that since 1999 there have been 79 cases of clinically diagnosed IEDS at the DDRC. Therefore, there is a need to assess and provide rehabilitation support to people with past IEDS and potentially in the future a larger cohort of divers with previously undiagnosed symptoms.

This study plans to:

undertake a prospective observational study where people with acute onset IEDS are followed up. This will include the current battery of clinical and laboratory (rotary) tests but also additional optional clinical and physiological testing (Vestibular Evoked Myogenic Potentials VEMPs), imaging (Diffusor Tensor Imaging DTI and functional Magnetic Resonance Imaging f MRI) and semis-structured interviews in the acute (1-14 days) and chronic (3 months and 12 months) stage.

We will also:

undertake a retrospective cross-sectional study of people who have previously been managed for IEDS by the DDRC. Here we will undertake the same battery of tests as for the prospective study which includes measures of potential risk factors and patient reported outcome measures. We will also take this opportunity to explore people's symptoms post IEDS and their views on future rehabilitation trials. In those with remaining vestibular symptoms and signs we will provide advice on vestibular rehabilitation by qualified personnel with follow up as required. We will compare our data to a cohort of healthy controls of a similar age and gender distribution.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 41
• Est. completion date: September 2028
• Est. primary completion date: April 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Prospective Study :

Inclusion

• Divers admitted with suspected IEDS

Exclusion

• Medically unstable

• Unstable orthopaedic deficits

Retrospective study :

Inclusion

• Divers diagnosed with IEDS at DDRC within past 10 years

Exclusion

• We will include all co-morbidities as these could affect prognosis and recovery following IEDS.

Healthy control comparator group :

Normative data will be gathered on an age matched group. There will be at least 10 participants for each decade (<30yrs ,30-40yrs, 40-50 yrs,50-60yrs,60-70 yr.)

Inclusion criteria:

• Adults over 18 years

Exclusion criteria:

• Neurological, sensory or orthopaedic conditions that could affect balance.

Related Conditions & MeSH terms

• Decompression Sickness

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Plymouth

References & Publications (15)

Bense S, Bartenstein P, Lochmann M, Schlindwein P, Brandt T, Dieterich M. Metabolic changes in vestibular and visual cortices in acute vestibular neuritis. Ann Neurol. 2004 Nov;56(5):624-30. doi: 10.1002/ana.20244. — View Citation

Curthoys IS, Halmagyi GM. Vestibular compensation: a review of the oculomotor, neural, and clinical consequences of unilateral vestibular loss. J Vestib Res. 1995 Mar-Apr;5(2):67-107. — View Citation

Darlington CL, Smith PF. Molecular mechanisms of recovery from vestibular damage in mammals: recent advances. Prog Neurobiol. 2000 Oct;62(3):313-25. doi: 10.1016/s0301-0082(00)00002-2. — View Citation

Gempp E, Louge P, de Maistre S, Morvan JB, Vallee N, Blatteau JE. Initial Severity Scoring and Residual Deficit in Scuba Divers with Inner Ear Decompression Sickness. Aerosp Med Hum Perform. 2016 Aug;87(8):735-9. doi: 10.3357/AMHP.4535.2016. — View Citation

Gempp E, Louge P. Inner ear decompression sickness in scuba divers: a review of 115 cases. Eur Arch Otorhinolaryngol. 2013 May;270(6):1831-7. doi: 10.1007/s00405-012-2233-y. Epub 2012 Oct 26. — View Citation

Helmchen C, Klinkenstein J, Machner B, Rambold H, Mohr C, Sander T. Structural changes in the human brain following vestibular neuritis indicate central vestibular compensation. Ann N Y Acad Sci. 2009 May;1164:104-15. doi: 10.1111/j.1749-6632.2008.03745.x. — View Citation

Hong SK, Kim JH, Kim HJ, Lee HJ. Changes in the gray matter volume during compensation after vestibular neuritis: a longitudinal VBM study. Restor Neurol Neurosci. 2014;32(5):663-73. doi: 10.3233/RNN-140405. — View Citation

Kurata N, Kawashima Y, Ito T, Fujikawa T, Nishio A, Honda K, Kanai Y, Terasaki M, Endo I, Tsutsumi T. Advanced Magnetic Resonance Imaging Sheds Light on the Distinct Pathophysiology of Various Types of Acute Sensorineural Hearing Loss. Otol Neurotol. 2023 Aug 1;44(7):656-663. doi: 10.1097/MAO.0000000000003930. Epub 2023 Jun 29. — View Citation

Landolt JP, Money KE, Topliff ED, Ackles KN, Johnson WH. Induced vestibular dysfunction in squirrel monkeys during rapid decompression. Acta Otolaryngol. 1980;90(1-2):125-9. doi: 10.3109/00016488009131707. — View Citation

Landolt JP, Money KE, Topliff ED, Nicholas AD, Laufer J, Johnson WH. Pathophysiology of inner ear dysfunction in the squirrel monkey in rapid decompression. J Appl Physiol Respir Environ Exerc Physiol. 1980 Dec;49(6):1070-82. doi: 10.1152/jappl.1980.49.6.1070. — View Citation

McDonnell MN, Hillier SL. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev. 2015 Jan 13;1:CD005397. doi: 10.1002/14651858.CD005397.pub4. — View Citation

Mitchell SJ, Doolette DJ. Pathophysiology of inner ear decompression sickness: potential role of the persistent foramen ovale. Diving Hyperb Med. 2015 Jun;45(2):105-10. — View Citation

Song CI, Pogson JM, Andresen NS, Ward BK. MRI With Gadolinium as a Measure of Blood-Labyrinth Barrier Integrity in Patients With Inner Ear Symptoms: A Scoping Review. Front Neurol. 2021 May 20;12:662264. doi: 10.3389/fneur.2021.662264. eCollection 2021. — View Citation

Tremolizzo L, Malpieri M, Ferrarese C, Appollonio I. Inner-ear decompression sickness: 'hubble-bubble' without brain trouble? Diving Hyperb Med. 2015 Jun;45(2):135-6. — View Citation

Vargas-Figueroa VM, Caceres-Chacon M, Labat EJ. Scuba Diving-Induced Inner-Ear Pathology: Imaging Findings of Superior Semicircular Canal and Tegmen Tympani Dehiscence. Am J Case Rep. 2024 Jan 2;25:e941558. doi: 10.12659/AJCR.941558. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Side of peripheral vestibular damage: Prospective cohort	Side (left or right) of vestibular dysfunction as determine by video head impulse test (v HIT) testing	T0=baseline within 24 hours of IEDS in the prospective cohort
Primary	Site of peripheral vestibular damage: Prospective cohort	Site of dysfunction: semi-circular canals affected as determine by v HIT testing. One or a combination of Horizontal, anterior or posterior canals.	T0=baseline within 24 hours of IEDS in the prospective cohort
Primary	Extent of peripheral vestibular damage: Prospective cohort	VOR gain (unit less) as measured by v HIT at T0 (Range 0-1 higher values are better outcome)	T0=baseline within 24 hours of IEDS in the prospective cohort
Primary	Side of peripheral vestibular damage: Retrospective cohort	Side (left or right) of vestibular dysfunction as determine by video head impulse test (v HIT) testing	1 time point: 0-10 years post injury
Primary	Site of peripheral vestibular damage:Retrospective cohort	Site of dysfunction: semi-circular canals affected as determine by v HIT testing.One or a combination of Horizontal, anterior or posterior canals.	1 time point: 0-10 years post injury
Primary	Extent of peripheral vestibular damage:Retrospective cohort	VOR gain (unit less) at T0 (Range 0-1 higher values are better outcome)	1 time point: 0-10 years post injury
Secondary	VOR gain v HIT: Prospective Study	Change from baseline (T0) in VOR gain assessed through V HIT test . Gain is unit less and range from 0-1 where higher values indicate a better clinical outcome.	7-10 days , 3 months and 12 months post injury
Secondary	VOR gain: Prospective Study	Change from baseline (T0) in VOR gain assessed through sinusoidal rotation in the dark . Gain is unit less and range from 0-1 where higher values indicate a better clinical outcome.	7-10 days , 3 months and 12 months post injury
Secondary	VOR Time constant:Prospective Study	Change from baseline (T0)in VOR time constant in response to a step rotation (initial 140°/s acceleration/deceleration and a 60°/s fixed-chair velocity) stimulus . Time constant (seconds) where a higher time constant is clinically better. Range 0-40s.	7-10 days , 3 months and 12 months post injury
Secondary	Patient reported outcome measure: Prospective Study	Change from baseline (T0) in PROM (patient reported outcome measure) vertigo severity scale.15 questions rated 0-4. Score range =0-60 where lower scores indicate a better clinical outcome	7-10 days , 3 months and 12 months post injury
Secondary	Clinical measure of walking: Prospective Study	Change from baseline (T0) in Dynamic Gait Assessment (DGA). Eight tasks scored 0-3. Total range = 0-24 with a higher score indicating better walking ability.	7-10 days , 3 months and 12 months post injury
Secondary	Clinical measure of balance: Prospective Study	Change from baseline (T0) in Clinical measures of balance sharpened Romberg (tandem stance). The length of time a person is able to stand in the eyes open, tandem stance position is recorded up to a maximum of 30 seconds.	7-10 days , 3 months and 12 months post injury
Secondary	Posturography: Prospective Study	Change from baseline (T0) in Postural sway quotient. Postural sway (mm/s) is measured via force plates. The ratio of the sway with eyes open and eyes closed is calculated (unitless ratio).	7-10 days , 3 months and 12 months post injury
Secondary	Perception of verticality: Prospective Study	Change from baseline (T0) in Rod and Disk test: The ability to orientate a line to vertical is assessed with / without visual distractors. The error from vertical is recorded in degrees. Outcomes range from 0-180 degrees where lower numbers indicate better verical perception.	7-10 days , 3 months and 12 months post injury
Secondary	Functional MRI response to an optokinetic stimulus: Prospective Study	Change from baseline (T0) in Regions of interest will also assess changes in activation with an optokinetic stimulus compared to rest in cortical and subcortical sites that process vestibular information namely the insulo-parietal cortex and hippocampus and sites that process other sensory information namely the visual cortex and somatosensory cortex	7-10 days , 3 months and 12 months post injury
Secondary	Vestibular Evoked myogenic Potentials latency: Prospective Study	Change from baseline (T0) in Galvanic and Auditory Vestibular Evoked myogenic Potentials (VEMPs) will be assessed and the latency of evoked responses measured in milliseconds.	7-10 days , 3 months and 12 months post injury
Secondary	Vestibular Evoked myogenic Potentials amplitude: Prospective Study	Change from baseline (T0) in Galvanic and Auditory Vestibular Evoked myogenic Potentials (VEMPs) will be assessed and the amplitude of evoked responses measured in millivolts.	7-10 days , 3 months and 12 months post injury
Secondary	VOR gain: Retrospective Study	VOR gain assessed through sinusoidal rotation in the dark . Gain is unit less and range from 0-1 where higher values indicate a better clinical outcome.	7-10 days , 3 months and 12 months post injury
Secondary	VOR Time constant: Retrospective Study	VOR time constant in response to a step rotation (initial 140°/s acceleration/deceleration and a 60°/s fixed-chair velocity) stimulus . Time constant (seconds) where a higher time constant is clinically better. Range 0-40s.	1 time point: 0-10 years post injury
Secondary	Patient reported outcome measure: Retrospective Study	PROM (patient reported outcome measure) vertigo severity scale.15 questions rated 0-4. Score range =0-60 where lower scores indicate a better clinical outcome	1 time point: 0-10 years post injury
Secondary	Clinical measure of walking: Retrospective Study	Dynamic Gait Assessment (DGA). Eight tasks scored 0-3. Total range = 0-24 with a higher score indicating better walking ability.	1 time point: 0-10 years post injury
Secondary	Clinical measure of balance: Retrospective Study	Clinical measures of balance sharpened Romberg (tandem stance). The length of time a person is able to stand in the eyes open, tandem stance position is recorded up to a maximum of 30 seconds.	1 time point: 0-10 years post injury
Secondary	Posturography: Retrospective Study	Postural sway quotient. Postural sway (mm/s) is measured via force plates. The ratio of the sway with eyes open and eyes closed is calculated (unitless ratio).	1 time point: 0-10 years post injury
Secondary	Perception of verticality: Retrospective Study	Rod and Disk test: The ability to orientate a line to vertical is assessed with / without visual distractors. The error from vertical is recorded in degrees. Outcomes range from 0-180 degrees where lower numbers indicate better verical perception.	1 time point: 0-10 years post injury
Secondary	Functional MRI response to an optokinetic stimulus: Retrospective Study	Regions of interest will also assess changes in activation with an optokinetic stimulus compared to rest in cortical and subcortical sites that process vestibular information namely the insulo-parietal cortex and hippocampus and sites that process other sensory information namely the visual cortex and somatosensory cortex	1 time point: 0-10 years post injury
Secondary	Vestibular Evoked myogenic Potentials latency: Retrospective Study	Galvanic and Auditory Vestibular Evoked myogenic Potentials (VEMPs) will be assessed and the latency of evoked responses measured in milliseconds.	1 time point: 0-10 years post injury
Secondary	Vestibular Evoked myogenic Potentials amplitude: Retrorospective Study	Galvanic and Auditory Vestibular Evoked myogenic Potentials (VEMPs) will be assessed and the amplitude of evoked responses measured in millivolts.	1 time point: 0-10 years post injury