By CDR Glen Rovig, MSC
Operational Audiology Officer
YOU HAVE PROBABLY SEEN some recent national publicity concerning research into new types of treatment and prophylaxis for sensorineural hearing loss. Two researchers at NAVMEDCEN San Diego are working with a micro-catheter to deliver medication to the cochlear fluids via absorption through the round window. They (and others) are also looking at the contribution of free radicals to noise and toxin-induced hearing loss, and the preventive effects of antioxidants. After doing some background reading, I communicated with one of the researchers, otolaryngologist LCDR Mike Hoffer, MC, USN. He was kind enough to answer a series of questions for me, and I thought the information might be useful to the Occupational Health community.
First, a few basics:
Loud noise causes reduced microcirculation within cochlear blood vessels.
This somehow releases higher than normal numbers of radical oxygen species (ROS) or "free radicals" which can react with and damage cellular protein, DNA, and unsaturated lipids. (My grasp of autocatalytic events is a bit tenuous, so I cannot give you much clarification here.)
The body's normal antioxidant defenses cannot counter the excess free radicals. TTS and PTS may follow with prolonged noise exposure. This is a gradual, noise-induced permanent threshold shift model, as opposed to acoustic trauma, which may physically damage the tectorial and/or basilar membranes and associated structures.
One study involving chinchillas is representative. Each animal was treated with saline (control) applied to the distal surface of one round window membrane, and an antioxidant applied to the opposite round window. The animals were then exposed to 4 kHz noise at 105 dBSPL for four hours. Antioxidant-treated ears showed significantly less TTS and reduced PTS as well as significantly less outer hair cell loss compared to the control ears.
Augmenting the antioxidant defense system with additional "free radical scavengers" holds promise for preventing/minimizing hearing loss from toxins and noise exposure.
A second area of research is delivering medications to the cochlear fluids via micro-catheter. Entering the middle ear via a small hole in the TM, the catheter is placed against the round window, where medication is absorbed through the membrane over a period of several days. A major benefit is that medication goes directly to the target area and avoids side effects associated with oral administration.
Here are LCDR Hoffer's replies to my emailed questions:
Q: What types of patient care are being envisioned for the catheter?
A: The catheter is a FDA-approved device for irrigation of the round window membrane. We have done all of the pioneering basic research with the device and had the original and largest experiment on humans. The catheter is, however, being used for multiple indications at other (select) institutions. Most of these institutions are following protocols which we established. Indications for the catheter include, but are not limited to, Meniere's Disease, sudden sensorineural hearing loss of a variety of etiologies, tinnitus treatment, and toxic insults to the inner ear (hearing and balance). The catheter has been used on approximately thirty patients at our institution. Six patients with sudden hearing loss have been treated. All three patients who were seen in under four weeks showed a dramatic improvement after treatment. The other three patients seen (longer time since injury) had no improvement. Contraindications to catheter use include all standard ear surgery contraindications and all contraindications to surgery. We have seen no complications directly caused by the catheter.
Q: Is there any projection to use catheters to deliver antioxidants to humans, either before or after noise exposure?
A: The treatment of inner ear disorders (hearing and balance) is a complicated issue. For many disorders the treatment depends on using the right medicine (antioxidant, etc.) and having the appropriate concentration reach the target organ at the appropriate time. If oral administration achieves this end, and surgery can be avoided, that's fine. Undoubtedly, certain medicines (and certain antioxidants) will need to be delivered in an other than oral fashion. Severe sudden noise induced hearing loss (e.g. after a blast injury), is one example, of a disorder that may only be rescued with microcatheter delivery of antioxidants. Prophylaxis will be accomplished through some type of oral medication.
Q: The news release focuses on prednisone/steroid therapy for acute cochlear conditions. Is there an application for prednisone with NIHL? Does prednisone act the same way as an antioxidant?
A: There is basic science work that indicates that corticosteroids can rescue noise induced hearing loss and have antioxidant properties. Methylprednisolone, for example, up-regulates antioxidant enzyme activity in neural tissue. It also has other effects such as neuroprotection, increasing cochlear blood flow, and antiapoptotic and anti-inflammatory effects.
Q: Any projection for how soon someone will start delivering antioxidants orally as prophylaxis for NIHL? Sounds like there are some FDA-approved substances used for other applications (per Kopke, Feghali and Henderson). When/where will there be trials?
A: We have already used an FDA-approved oral agent for rescue of noise induced hearing loss. Basic science studies are being completed in the area of prophylaxis and pre-clinical trials are now underway. We, and others, anticipate clinical trials in under two years.
Q: The news release quotes $1.5 billion annually going toward treatment of NIHL. Where does that figure come from?
A: The $1.5 billion dollar figure was for both hearing and balance disorders. The figure breaks down to $1 billion on hearing and $500 million on balance. Many individuals feel this is an underestimation of costs. The costs include lost equipment, cost of lost training in combat arms, VA compensation, and expenditures for civilian hearing loss compensation charged back to installation commanders. This figure came from NAMRL and from the Chairman of the DoD Working Group on Hearing Conservation.
Q: Do you have any projected cost data for the catheter? How is your catheter different from the others in use for applying medications to the middle ear?
A: There is currently no other catheter available and the current catheter is patent protected by IntraEar Corporation. The cost of the catheter is approximately $650 depending on the number bought.
Q: Is it fair to say that we are in the basic science stage with respect to understanding the damaging effects of ROS and the protection afforded by antioxidants? In your opinion, are oral doses of antixodants likely to be a part of our Hearing Conservation Program anytime soon?
A: There is still basic science to be done in this area, but enough is understood about this problem that currently a large clinical study is underway to evaluate the effectiveness of an antioxidant to prevent hearing loss secondary to ROS generation after aminoglycoside administration (similar mechanism to NIHL). We have already used an oral antioxidant as rescue mode and oral antioxidants are very likely to be part or our hearing conservation program in the next three years.
Q: We have seen 2 articles with Dr. Kopke as co-author and they appear to be drafts. Have you published anything?
A: Between Dr. Kopke and me we have over seventeen published articles and dozens of abstracts on hearing and balance disorders relating to protection, rescue, and restoration of function of the inner ear. Dr. Kopke has ten published articles in peer-reviewed journals in the area of protection/rescue of the inner ear from toxins/noise. Several others are in press. Together we have two published articles on inner ear delivery of medicines and have several in press. In addition, we have over ten abstracts addressing inner ear medicine delivery in the last three years. We are presenting four abstracts of our latest work at the 1999 Association for Research in Otolaryngology Midwinter Meeting (February 1999). We also have several additional papers and chapters submitted or in press.
Q: LCDR Keith Wolgemuth (NMCSD Audiologist) tells us you are also doing animal work at NMCSD. What is the focus of that work? Can you summarize?
A: The big picture is that we are researching medicines, and delivery methods for those medicines, to protect and restore inner ear hearing and balance function. The focus of the animal work is delivery of medicines to the inner ear, the effects of medicine on the inner ear, prevention and rescue of NIHL with medicines, and prevention and rescue of inner ear damage from high-energy, low frequency sound underwater. A majority of these projects are highly operational and at pre-clinical stages. One of the projects involves vital national security issues.
Q: What we have read in the press about your work has been extremely optimistic, e.g., a cure for hearing loss is right around the corner. Are you comfortable with what is being said?
A: We don't feel that the articles (and there have been many of them) actually say, "a cure for hearing loss is right around the corner." Of course, we are not always comfortable with what the press says - but we can't completely control the press and all briefings have been conducted while a Navy PAO was present. We made a point that while the research is exciting; it is still somewhat preliminary and needs additional funded study. There is reason for optimism regarding prevention and reversal of many types of hearing and balance disorders, because ROS are involved with many different etiologies of inner ear damage including noise induced hearing loss, toxic injury, autoimmune disease, viral disease, and aging as well as some genetic predisposition to hearing loss. Since there is a final common pathway for injury and we understand the mechanism, therapy can be designed based on this understanding.
Q: Any other comments?
A: ...we and other capable in-house (within DoD) workers are advancing the field of hearing and balance science. For example, capable, in-house individuals exist at our center, at NAMRL, and at NSMRL. Only by doing the work in-house will the therapies be made available to active duty individuals at the earliest possible times. For years the National Institute of Health requested grants for transitional research of NIHL and discovered that no single group (other than ours) had the appropriate population. Therefore, much of the NIH grant money has gone to basic work, which is far from impacting active duty individuals. The Office of Naval Research has already said that in the area of balance the end-user (to implement new developments in motion sickness) will be the DSOC in San Diego and have acknowledged that we are the only facility with the appropriate target population for large scale implementation of projects with regards to hearing loss prevention and rescue.
Dr. Kopke has been working in this area since 1994 and initially worked to prevent and reverse hearing loss due to toxins by counteracting ROS effects. He saw that the concept of ROS damage might be pertinent to NIHL, introduced those concepts and designed initial experiments in Dr. Henderson's lab beginning in 1995. Those initial experiments were successful and have spawned additional work, including the work here at NMCSD. Dr. Henderson utilized Dr. Kopke's expertise as a consultant to successfully compete for a program project grant. Dr. Kopke has been invited by the NIDCD and the ARO to share his expertise in this field at targeted symposiums.
A number of other experienced investigators (i.e. Dr. Jochen Schacht, Dr. Joe Miller, and researchers at the Karolinska Institute) agree that clinical trials to prevent NIHL are likely within the next two years, and have asked for Dr. Kopke's help to accomplish this. The Peoples Republic of China is actively pursuing this line of research and such work has the potential to give their forces a tactical advantage.
I have led our group in work with delivery of medicine to the inner ear for the last five years and we are recognized experts in this area. Dr. Kopke's expertise with therapeutic agents combined with our group's expertise on drug delivery to the inner ear provides a unique research team capability ideally suited to taking this research to the deck plates. The combined efforts of Dr. Kopke, the individuals in place at NMCSD, and me allows us to take work from the bench top to the active duty population delivering the therapeutic modality (medicine) in a number of possible fashions.
LCDR Hoffer and LTC Kopke, his co-researcher, have a couple papers in press and four presentations upcoming at the Assocation for Research in Otolaryngology meeting. One helpful article may be found in Otolaryngology-Head and Neck Surgery, Dec 93, "The Protective Effects of Allopurinol and Superoxide Dismutase on Noise-induced Hearing Loss" (Seidman et al).