This video was passed along to me. It was shared by Giuseppe Attanasio, an ENT specialist and professor at Sapienza’s University, Rome. Thought I'd pass it along to you...
Tuesday, June 13, 2017
Sunday, April 30, 2017
Asking for Support and Understanding
I've recently heard from someone who is feeling alone and scared in their struggle with Meniere's. Having an invisible illness can be very hard not only on us, but also our friends and family since it can be hard to feel compassion for something you cannot see or relate to. Here's a letter that might help.
Dear Friends and Family,
I'm feeling scared, alone, and overwhelmed right now. I've probably told you that I have Meniere's disease, but I understand most people don't know what that is or how it affects me. If I haven't explained it well to you yet, I'm sorry. I'm still figuring out how it affects me, too. Some days are better than others. Some are really, really bad. I know it's hard for you to understand me right now. I don't understand myself what is happening to me. My body and my life are out of my control right now and I need as much support as I can get.
I know I'm not myself. I might seem self-centered and needy right now. And I am. My body is out of my control which has made everything about my life unpredictable and scary. I want to do all the things I used to do, but there are many reasons why I can't or am afraid to do them. I am trying very hard to learn how to cope with all of this, but it takes time and I'm not feeling very patient with any of it.
For one thing, I cannot hear well anymore. My ear or ears ring constantly and loudly. Being in places where there is a lot of background noise are difficult and sometimes even physically painful. Even in a quiet environment, I may not understand what you're saying if you don't speak clearly and are not facing me. I'm sorry. I know it's frustrating for you, but it is even more frustrating to me. I hate having to ask you to repeat yourself. But do know that I DO want to hear what you have to say, even if you don't feel it's something important enough to repeat. And trying to hear and follow a conversation with more than one person or in a public place is even harder. It's like watching TV with the sound muffled. This all makes me feel isolated and alone.
I also feel dizzy or disoriented a lot of the time. This requires that I use my full attention to walk or navigate myself through space. Imagine having to will yourself to literally put one foot in front of the other to walk. And keeping my balance to stay upright is like walking above the ground on a tightrope. It takes all of my attention and effort, which doesn't leave much left for thinking about anything else. It is similar to what you might feel after getting off a boat or ride at the fair, but it is constant and doesn't go away. Some days are better than others.
At it's worst, I have vertigo. I might only get it a few times a month or year, or I might have it several times a week, for 4 to 12 hours or longer. Afterward, I feel very shaky and tired, sometimes for days. This is hard to explain to someone who has never had vertigo, but the best explanation I can use is that it feels like being on a fair ride that is some combination of the teacups and a roller coaster with many loops. And it goes on for hours without a break. Often I cannot tell up from down, even crawling across the floor can be physically impossible. Walking might be completely out of the question - my brain cannot sense where my body is in space. Or, another way to imagine how vertigo feels, is it's like a very, very bad hangover: the spinning, the nausea, even diarrhea and vomiting to the point of dry heaving over and over. And there is no medication that stops it. The only things that might sometimes take the edge off the misery are drugs like Valium, which happens to suppress the vestibular system, and anti-nausea medicines, like Zofran. But these do not stop a vertigo attack, they only might help minimize the severity of the symptoms.
Finally, I get severe brain fog or cognitive impairment. This is beyond my control. I hate it and wish I could get rid of it. It impacts my short-term memory and my ability to think clearly. You may have to tell me things more than once. Heck, even I have to tell myself things more than once. I might walk into a room or even be mid-task and forget what I'm doing. It is very hard to make even the simplest of decisions. If you ask me what I want to eat, I may not be able to tell you. It is hard to watch a movie, follow the plot of a book (if my eyes are even able to stay still enough to read - I often have nystagmus, or darting of the eyes), or follow a conversation.
You might think I'm "just" depressed. Yes, I am depressed because I can no longer live the life I used to live or feel hopeful about the future life I had hoped for myself. But it is not the cause of Meniere's disease. To help myself, I will, if I haven't already, seek out professional counseling and, if needed, take medication. But what would really help me is just knowing I have people who will listen to me and let me feel all the grief I am feeling.
Yes, I am grieving. I have lost much of my independence, maybe even my career, and my identity. Because of this, I am going through the stages of grief - and if you are close to me, you might be experiencing some of them, too. But it is normal to have these feelings in this situation. They are denial/isolation, anger, bargaining, depression, and acceptance. I have to go through these and I might bounce from one to the other and back again. I promise to do what I can to help myself, but be please be patient with me while I go through this. I need someone who will listen and accept me as I am. Even though I am going through all of these things, I promise to still be the best _______ I can be in return to you. I am still me, after all.
Finally, I know I seem anxious to you. Well, I am!! My life has become very unpredictable and it's scary. I do still very much want to make plans with you, to work, travel, and do all the little and big things I used to do. But I never know when I might get vertigo. Once vertigo hits me, I may not be able to walk. I certainly cannot drive or get myself out of a public place alone. If I am in a public place, this can be very, very scary and embarrassing. People might think I'm drunk or having a stroke or some other medical emergency. But what I need in these situations is someone to help me get to a safe place. I might vomit or need to use the bathroom urgently. I might have some medications I need to take to calm the attack or reduce the nausea I feel. During these attacks, my body is out of my control and I really just need someone to talk to me and reassure me that I can get through this. I need to stay calm, breath, and know I'm not alone.
I want and need you all to know that I am doing the best I know how to do. I don't always know how to do this. Even the best Meniere's doctors don't know what causes this disease or how to treat it. There are things we can keep trying to get my symptoms under better control and I will keep seeking help from them, but please understand that there are no easy answers. There are probably few diet or lifestyle changes I haven't already tried by now, believe me when I say I've done my research and have tried everything. Unfortunately, there are no easy answers for many of us with Meniere's disease.
Thank you for listening. I will continue to keep the lines of communication open and do my very best to still be a good friend/daughter/mother/son/father/spouse to you. I will try to help you understand how I am feeling. I don't want to be burden, I just hope I can count on you to help me as I figure out what my new normal is.
Sunday, March 26, 2017
No News is Good News... and The Viral Theory of Meniere's
I have been remiss in updating this blog, I know. But it is only because since completing the Stephen Spring Treatment Protocol (SSTP) nearly 2 years ago, my MD symptoms have been extremely stable. Amazingly, my life has gone on and I am still in shock when I stop to think how far I have come. I am living a full, unrestricted life. But if MD has taught me anything, it is don't take anything for granted. Given the lack of trials or data on the long-term effectiveness of this approach, I fully appreciate that the beast could come back anytime. But, unlike before, I don't think about MD every minute of everyday and that alone has been freeing.
This morning I was explaining in an email exchange with a fellow MD sufferer that I still have hearing loss, tinnitus that sounds like air hissing from an air mattress, and infrequent bouts of buzzing in my ear and mild brain fog - not necessarily at the same time. Either way, these episodes are relatively innocuous and last only hours , or maybe a day or two at the most, which is a vast improvement over what I was experiencing pre-SSTP.
I also continue to experience a very subtle degree of chronic disequilibrium. The best way I can describe it is a loss of the "crispness" of my sense of orientation in space. It is hard to know if this is a result of four years of repeated vertigo attacks or, more likely, related to having had three gentamicin injections in my right ear. Either way, it is tolerable and nothing like the symptoms of mal de debarquement syndrome - or chronic vestibular dysfunction or disequilibrium not otherwise specified, or NOS in medical terms - that I was suffering from just before starting SSTP.
On another note, I had to share this article (copied below) just brought to my attention. Written by Prof. Bill Gibson, it was published by The Whirled Foundation, an organization that "seeks to promote community awareness of the impact of vertigo and the various underlying vestibular disorders."
I was thrilled to see brain fog listed as one of the symptoms of MD. I don't know about you, but brain fog could be nearly as disabling - and maddening - as vertigo when I was at my worst. However, I would have liked the author to have added vestibular dysfunction as a persistent symptom in the "burn out" stage of the disease. It is worth noting that some experts disagree on burn out, whether everyone will get to this stage or whether it exists at all.
Ultimately, though, it is especially heartening to know that researchers at the Meniere's Research Fund are considering, or reconsidering, the viral theory as a possible cause of Meniere's disease. Prof. Gibson also makes mention of Stephen Spring, validating that he has in fact been instrumental in reviving this line of thinking when it comes to future treatment options.
Since websites come and go and links can eventually go bad, I've pasted the text of Prof. Bill Gibson's article below. Visit The Whirled Foundation's website to check out other articles and resources and consider supporting their efforts!
VIRAL THEORY FOR MENIERE’S DISEASE
By Professor William Gibson AM M.D., F.R.A.C.S. F.R.C.S.
Professor of Otolaryngology, University of Sydney
Meniere’s disease was first described by Prosper Ménière in 1861. His idea that vertigo was caused
by an inner ear disorder was not accepted by the scientific community who supported the concept
that vertigo was a brain disorder.
Ménière accurately described the condition but his original paper was not published because of the
adverse scientific opinions. Fortunately several of his subsequent papers were published. Prosper
Ménière died in 1862 after contracting pneumonia. It was ten years later that Ménière’s ideas
became accepted so he never received any acknowledgement during his lifetime.
Meniere’s disease causes four major symptoms; attacks of vertigo which tend to occur in clusters, a
fluctuating and usually progressive hearing loss in the affected ear, tinnitus and a sensation of aural
fullness. Other symptoms such as tiredness, ‘brain fog’, and poor memory are less commonly
mentioned.
It is estimated that approximately 50,000 people in Australia suffer from Meniere’s disease.
Meniere’s disease tends to occur initially in mid adult life with a median age of 50 years. The attacks
of vertigo tend to occur in clusters lasting a few months followed by variable periods of remission.
Eventually the attacks of vertigo peter out when the hearing becomes poor, which is known as ‘burn
out’ or stage 3 of the condition.
The attacks of vertigo cause great distress. The sensation of spinning can last for several hours
associated with nausea and vomiting. The attacks are unpredictable and often the bread winner
cannot continue work or a parent is unable to cope with the family. Often the sufferer hopes for
‘burn out’ even though they become very deaf in the affected ear and may continue to be plagued
by tinnitus. Discovering the cause of the attacks of vertigo must be the first step towards finding the
cure for this terribly disabling condition.
Discovering the cause of the attacks of vertigo
The initial concept was that the vertigo was due to vascular spasms within the inner ear. In the
period after WW2, this belief led to the use of medications which dilate the blood vessels such as
nicotinic acid and an operation called cervical sympathectomy [1]. To avoid the skin of the face
reddening, Betahistine (Serc®) was developed and this still remains a popular treatment. The
concept that constriction of the blood vessels in the inner ear caused the attacks was the reason
why doctors told their patients to avoid coffee, caffeine drinks and nicotine. As Meniere’s disease
occurs in a younger age group than vascular disease and there is no increased prevalence of
Meniere’s disease amongst people with vascular problems, the concept that Meniere’s is due to
vascular spasm has been mostly abandoned.
In the 1930’s, Swedish doctors noticed that many people noticed that salty foods could precipitate
attacks of vertigo [2]. In the 1950’s two English researchers (Harrison and Naftalin) gave Meniere’s
disease sufferers salt loads and demonstrated that vertigo attacks occurred when increased salt was
excreted in the urine [3]. It is not possible to do a proper ‘double blinded trial’ of salt but the
anecdotal evidence does suggest that salt loading is a significant factor.
In 1960, Schucknect at Boston showed small ruptures had occurred in the membranes in the inner
ear which had healed up but left some tell-tale scarring. He proposed a rupture theory [4]. This
theory suggested that an increase in the inner ear fluid called endolymph bulged the membrane
causing ruptures which allowed potassium from the endolymph to poison the balance nerve endings
leaving the ear. This caused a temporary loss of function resulting in vertigo until the rupture was
closed off and the ionic balance restored. This theory has been favoured for the past 50 years.
The cause of the increased endolymph volume was attributed to a failure of the flow of endolymph
to the endolymphatic sac. It was thought that there was a constant ‘longitudinal’ flow of endolymph
toward the sac, and if a blockage occurred there was a build up of endolymph in the inner ear until
the membranes ruptured. This led to the concept of endolymphatic shunt surgery, where a tube or
sialastic sheeting was placed in the endolymphatic sac to facilitate its ability to absorb the fluid. This concept has now been largely discounted. Swedish workers have shown that the endolymphatic sac is a sponge like structure and not a sac which passively accepts endolymph [5]. Endolymph is only attracted into the sac when it secretes and reabsorbs glycoproteins. Salt and his co-workers have demonstrated that there is no constant flow of endolymph to the endolymphatic sac but longitudinal flow only occurs when there is a sudden increase in endolymph volume [6].
Furthermore, audiological studies and electrophysiological studies undertaken by the author and
others have shown no loss of cochlear function during the attacks of vertigo [7]. In a controversial
study the author has shown that removal of the endolymphatic sac rather than shunt surgery
provides a better outcome as it hastens the ‘burn out’ stage of MD [8].
The search is now on to find the real cause of the attacks of vertigo. The Meniere’s Research
Laboratory has been established in Sydney under the care of Dr Daniel Brown. Here work has been
undertaken to increase the volume of endolymph in the inner ear while observing the changes in the
firing of the vestibular and cochlear nerves. Studies suggest that sudden changes in endolymph
volume cause a stretching or collapse of the vestibular hair cells within the cristae of the semicircular canals. The author proposed a ‘drainage theory’ which postulates that the increased volume of endolymph inside the utricle (vestibular portion) is due to reflux of endolymph from the cochlear part of the inner ear during periods of longitudinal drainage [9]. Further studies are presently occurring.
Gibson’s drainage theory proposes that there is an initial increase in endolymph volume due to an
inflammatory reaction inside the inner ear. Once this extra volume of fluid is present minor
fluctuations in the level of excess endolymph could be the trigger for each attack: for example, after
ingestion of salt or when stress causes a hormone (vasopressin) to be released. After a series of
attacks the excess volume decreases and a period of remission from attacks occurs until another
inflammatory event occurs causing another cluster of attacks.
What causes the initial increase in endolymph volume and the recurrent attacks of vertigo?
Many researchers consider that Meniere’s Disease is multifactorial and there are many different
causes which lead to the situation which results in Meniere’s disease.
It is known that the bony vestibular duct which contains the membranous duct leading to the
endolymphatic sac is narrow in Meniere’s disease sufferers although it is also narrow in some people
who do not suffer with Meniere’s disease. Furthermore, there is a genetic abnormality associated
with Meniere’s disease.
Possible causes include congenital disorders such as viral illness during the pregnancy including
rubella (German measles) and toxoplasmosis. Diseases of the bone surrounding the ear such as
otosclerosis or Padgets disease, tumours of the endolymphatic sac or vestibular nerve, allergies
especially to food substances, various infections caused by syphilis, yaws or viruses, autoimmune
problems and failure of the immunodefence mechanism.
If the cause of the increased endolymph is due to an inflammatory reaction inside the inner ear,
then steroids should limit this inflammation. There has been a vogue towards using oral or
intratympanic steroids to stop clusters of attacks of vertigo. The validity of this approach has yet to
be clearly shown although clinical evidence does seem to suggest it is an effective treatment.
Is a virus the most common cause of Meniere’s disease?
Over fifty years ago Lempert and his co-workers suggested that Meniere’s disease was caused in the
majority of ears by a herpes virus [10]. The herpes family of viruses consist of at least 8 members
including HSV1 (causes cold sores), HSV2 (causes genital herpes), VCV (causes chicken pox and
shingles), EBV (causes glandular fever) and CMV (causes birth defects).
The herpes virus has been found in autopsy specimens obtained from Meniere’s disease sufferers in
both the endolymphatic sac and in the ganglion of the vestibular and cochlear nerves. However ears
from non Meniere’s disease sufferers often also contain the virus.
The idea of a herpes virus causing the initial inflammatory response in the inner ear is compelling.
For example, herpes simplex virus causes cold sores which erupt on the lip and then the virus lies
latent or hides in the nerve for a while and then can erupt again causing more cold sores. It is
postulated that a similar virus causes an initial inflammatory response in the ear and results in
inflammation which causes excess endolymphatic fluid (endolymphatic hydrops). As the virus lies
latent within the ear, it can erupt again causing another cluster of attacks.
Unfortunately there is no medical treatment which can kill the virus when it goes into its latent
state. Anti-virals may be effective in stopping eruptions of the virus but would have to be taken
continually.
The need for research into a viral cause
The first step in the research will be to find out which Meniere’s disease sufferers have a viral cause
for their condition. A prolonged, double blind trial needs to be undertaken to determine if antiviral
drugs can prevent clusters of attacks occurring. A double blind trial means that a placebo which
looks exactly like the antiviral agent is used in some subjects and the actual antiviral medication is
used in others. Neither the doctor nor the patient will know which is being used. If a subject has
another cluster of attacks, the secret is revealed and if that person is on the placebo, they will be
offered the active medication.
Why do some ears have the virus present but do not develop Meniere’s disease?
While the virus lies latent (hidden) within the inner ear structures, the function of the ear is
unaffected. When the virus erupts it causes the inflammatory response resulting in the production
of excess endolymph. If the ear can mount an adequate defence mechanism, the virus can be
destroyed before it causes an excessive inflammatory reaction. Some ears can mount this defence
mechanism, whereas ears affected by Meniere’s disease cannot.
The immune system clears viruses and other pathogens from the body using special cells called
lymphocytes. Lymphocytes are developed in the bone marrow (B lymphocytes) and in the thymus (T lymphocytes or T cells). Viruses are cleared by a specific lymphocyte known as Th1 and the ear needs lots of these Th1 lymphocytes to prevent the virus from causing the inflammatory reaction.
T cells are made specifically for certain tasks. T cells develop from immature T cells in the thymus
and these can differentiate into specific types with highly specialised tasks. Some may develop into
T1 cells and these can be measured with a blood test using a special marker called CD8+. Other
immature T cells develop into Th2 cells which communicate with B lymphocytes (which produce
anti-bodies to combat bacterial infections and parasites). Th2 cells have a CD4+ marker.
Furthermore, other T cells are produced that limit the immune system so the body does not attack
its own tissues, a process known as autoimmunity.
Perhaps if a person with Meniere’s disease has insufficient or inefficient specialised immune cells,
they may be unable to prevent the virus erupting and causing inflammation in the inner ear. This
may be the reason why some ears which contain the virus do not suffer from Meniere’s disease.
Stephen Spring, himself a Meniere’s disease sufferer, has discovered a possible means of altering the
T1/T2 balance which may provide long term relief and we hope to be able to properly evaluate his
ideas at the University, but such is the fickle nature of Meniere’s disease that isolated cures cannot
be taken as definite proof of efficacy.
Our hopes for the future
It is our aim at the University of Sydney to be able to explain the mechanism which causes Meniere’s and to find an eventual cure. We feel that some definite strides towards this goal have already been made. We are desperately keen to be able to complete the tasks and hope that there will be sufficient funding to make this possible. The Meniere’s Research Fund under the superb leadership of Bruce Kirkpatrick has been the lifeline and we urge all Meniere’s disease sufferers and their families to continue to support this cause.
We need to recruit Meniere’s disease sufferers who are willing to become part of our research
programme. Specifically we need sufferers who are experiencing clusters of attacks of vertigo so that
we can discover if antiviral medication can be effective.
If a reader wishes to help us, please contact me (Professor Gibson at 02 9844 6801).
References
1. Passe ERG, Seymour JS (1948) Meniere’s syndrome: successful treatment by surgery on the sympathetic. Brit Med J, 2,
812-816
2. Furstenberg AC, Lashmet FH, Lathrop F (1934) Ann ORL, 43, 1035-1046
3. Harrison MS, Naftalin L (1968) Meniere’s disease: Mechanism and management, Springfield: Charles C Thomas
4. Schuknecht H. Correlation of pathology with symptoms of Meniere’s disease. Otolaryngol Clin N Amer 1968; 1:433-438
5. Bagger-Sjöbäck, Friberg U, Rask-Andersen H: The human endolymphatic sac: an ultrastructural study. Arch Otoalryngol
Head Neck Surg 112: 398-409 1986
6. Salt AN: Fluid homeostasis in the inner ear. In Harris JP (ed) Meniere’s Disease. The Hague, Kugler Publications 93-101 1999
7. McNeil C, Cohen M, Gibson WPR (2009) Changes in audiometric thresholds before, during and after attacks of vertigo
associated with Meniere’s syndrome Acta Otolaryngol. 129, 1404-1409.
8. Gibson WPR (2005) The effect of removal of the extra-osseous portion of the endolymphatic sac in ears affected by
Meniere’s disease. In ‘Meniere’s Disease & Inner ear homeostasis disorders’ Ed Lim DJ. Pages 239-240. House Ear Institute
publication, Los Angeles (ISBN 0-9776204-0-9)
9. Gibson WPR (2010) Hypothetical mechanism for vertigo in Meniere’s Disease. Otolaryngol Clin N Am 43: 1019-1027
10. Lempert J, Wolff D, Rambo JHT, Wever EG, Lawrence M. (1952) New theory for the correlation of the pathology and the
symptomatology of Meniere’s disease; a research study of the vestibular endolymphatic labyrinth. Anna ORL.61,717–746
This morning I was explaining in an email exchange with a fellow MD sufferer that I still have hearing loss, tinnitus that sounds like air hissing from an air mattress, and infrequent bouts of buzzing in my ear and mild brain fog - not necessarily at the same time. Either way, these episodes are relatively innocuous and last only hours , or maybe a day or two at the most, which is a vast improvement over what I was experiencing pre-SSTP.
I also continue to experience a very subtle degree of chronic disequilibrium. The best way I can describe it is a loss of the "crispness" of my sense of orientation in space. It is hard to know if this is a result of four years of repeated vertigo attacks or, more likely, related to having had three gentamicin injections in my right ear. Either way, it is tolerable and nothing like the symptoms of mal de debarquement syndrome - or chronic vestibular dysfunction or disequilibrium not otherwise specified, or NOS in medical terms - that I was suffering from just before starting SSTP.
On another note, I had to share this article (copied below) just brought to my attention. Written by Prof. Bill Gibson, it was published by The Whirled Foundation, an organization that "seeks to promote community awareness of the impact of vertigo and the various underlying vestibular disorders."
I was thrilled to see brain fog listed as one of the symptoms of MD. I don't know about you, but brain fog could be nearly as disabling - and maddening - as vertigo when I was at my worst. However, I would have liked the author to have added vestibular dysfunction as a persistent symptom in the "burn out" stage of the disease. It is worth noting that some experts disagree on burn out, whether everyone will get to this stage or whether it exists at all.
Ultimately, though, it is especially heartening to know that researchers at the Meniere's Research Fund are considering, or reconsidering, the viral theory as a possible cause of Meniere's disease. Prof. Gibson also makes mention of Stephen Spring, validating that he has in fact been instrumental in reviving this line of thinking when it comes to future treatment options.
Since websites come and go and links can eventually go bad, I've pasted the text of Prof. Bill Gibson's article below. Visit The Whirled Foundation's website to check out other articles and resources and consider supporting their efforts!
VIRAL THEORY FOR MENIERE’S DISEASE
By Professor William Gibson AM M.D., F.R.A.C.S. F.R.C.S.
Professor of Otolaryngology, University of Sydney
Meniere’s disease was first described by Prosper Ménière in 1861. His idea that vertigo was caused
by an inner ear disorder was not accepted by the scientific community who supported the concept
that vertigo was a brain disorder.
Ménière accurately described the condition but his original paper was not published because of the
adverse scientific opinions. Fortunately several of his subsequent papers were published. Prosper
Ménière died in 1862 after contracting pneumonia. It was ten years later that Ménière’s ideas
became accepted so he never received any acknowledgement during his lifetime.
Meniere’s disease causes four major symptoms; attacks of vertigo which tend to occur in clusters, a
fluctuating and usually progressive hearing loss in the affected ear, tinnitus and a sensation of aural
fullness. Other symptoms such as tiredness, ‘brain fog’, and poor memory are less commonly
mentioned.
It is estimated that approximately 50,000 people in Australia suffer from Meniere’s disease.
Meniere’s disease tends to occur initially in mid adult life with a median age of 50 years. The attacks
of vertigo tend to occur in clusters lasting a few months followed by variable periods of remission.
Eventually the attacks of vertigo peter out when the hearing becomes poor, which is known as ‘burn
out’ or stage 3 of the condition.
The attacks of vertigo cause great distress. The sensation of spinning can last for several hours
associated with nausea and vomiting. The attacks are unpredictable and often the bread winner
cannot continue work or a parent is unable to cope with the family. Often the sufferer hopes for
‘burn out’ even though they become very deaf in the affected ear and may continue to be plagued
by tinnitus. Discovering the cause of the attacks of vertigo must be the first step towards finding the
cure for this terribly disabling condition.
Discovering the cause of the attacks of vertigo
The initial concept was that the vertigo was due to vascular spasms within the inner ear. In the
period after WW2, this belief led to the use of medications which dilate the blood vessels such as
nicotinic acid and an operation called cervical sympathectomy [1]. To avoid the skin of the face
reddening, Betahistine (Serc®) was developed and this still remains a popular treatment. The
concept that constriction of the blood vessels in the inner ear caused the attacks was the reason
why doctors told their patients to avoid coffee, caffeine drinks and nicotine. As Meniere’s disease
occurs in a younger age group than vascular disease and there is no increased prevalence of
Meniere’s disease amongst people with vascular problems, the concept that Meniere’s is due to
vascular spasm has been mostly abandoned.
In the 1930’s, Swedish doctors noticed that many people noticed that salty foods could precipitate
attacks of vertigo [2]. In the 1950’s two English researchers (Harrison and Naftalin) gave Meniere’s
disease sufferers salt loads and demonstrated that vertigo attacks occurred when increased salt was
excreted in the urine [3]. It is not possible to do a proper ‘double blinded trial’ of salt but the
anecdotal evidence does suggest that salt loading is a significant factor.
In 1960, Schucknect at Boston showed small ruptures had occurred in the membranes in the inner
ear which had healed up but left some tell-tale scarring. He proposed a rupture theory [4]. This
theory suggested that an increase in the inner ear fluid called endolymph bulged the membrane
causing ruptures which allowed potassium from the endolymph to poison the balance nerve endings
leaving the ear. This caused a temporary loss of function resulting in vertigo until the rupture was
closed off and the ionic balance restored. This theory has been favoured for the past 50 years.
The cause of the increased endolymph volume was attributed to a failure of the flow of endolymph
to the endolymphatic sac. It was thought that there was a constant ‘longitudinal’ flow of endolymph
toward the sac, and if a blockage occurred there was a build up of endolymph in the inner ear until
the membranes ruptured. This led to the concept of endolymphatic shunt surgery, where a tube or
sialastic sheeting was placed in the endolymphatic sac to facilitate its ability to absorb the fluid. This concept has now been largely discounted. Swedish workers have shown that the endolymphatic sac is a sponge like structure and not a sac which passively accepts endolymph [5]. Endolymph is only attracted into the sac when it secretes and reabsorbs glycoproteins. Salt and his co-workers have demonstrated that there is no constant flow of endolymph to the endolymphatic sac but longitudinal flow only occurs when there is a sudden increase in endolymph volume [6].
Furthermore, audiological studies and electrophysiological studies undertaken by the author and
others have shown no loss of cochlear function during the attacks of vertigo [7]. In a controversial
study the author has shown that removal of the endolymphatic sac rather than shunt surgery
provides a better outcome as it hastens the ‘burn out’ stage of MD [8].
The search is now on to find the real cause of the attacks of vertigo. The Meniere’s Research
Laboratory has been established in Sydney under the care of Dr Daniel Brown. Here work has been
undertaken to increase the volume of endolymph in the inner ear while observing the changes in the
firing of the vestibular and cochlear nerves. Studies suggest that sudden changes in endolymph
volume cause a stretching or collapse of the vestibular hair cells within the cristae of the semicircular canals. The author proposed a ‘drainage theory’ which postulates that the increased volume of endolymph inside the utricle (vestibular portion) is due to reflux of endolymph from the cochlear part of the inner ear during periods of longitudinal drainage [9]. Further studies are presently occurring.
Gibson’s drainage theory proposes that there is an initial increase in endolymph volume due to an
inflammatory reaction inside the inner ear. Once this extra volume of fluid is present minor
fluctuations in the level of excess endolymph could be the trigger for each attack: for example, after
ingestion of salt or when stress causes a hormone (vasopressin) to be released. After a series of
attacks the excess volume decreases and a period of remission from attacks occurs until another
inflammatory event occurs causing another cluster of attacks.
What causes the initial increase in endolymph volume and the recurrent attacks of vertigo?
Many researchers consider that Meniere’s Disease is multifactorial and there are many different
causes which lead to the situation which results in Meniere’s disease.
It is known that the bony vestibular duct which contains the membranous duct leading to the
endolymphatic sac is narrow in Meniere’s disease sufferers although it is also narrow in some people
who do not suffer with Meniere’s disease. Furthermore, there is a genetic abnormality associated
with Meniere’s disease.
Possible causes include congenital disorders such as viral illness during the pregnancy including
rubella (German measles) and toxoplasmosis. Diseases of the bone surrounding the ear such as
otosclerosis or Padgets disease, tumours of the endolymphatic sac or vestibular nerve, allergies
especially to food substances, various infections caused by syphilis, yaws or viruses, autoimmune
problems and failure of the immunodefence mechanism.
If the cause of the increased endolymph is due to an inflammatory reaction inside the inner ear,
then steroids should limit this inflammation. There has been a vogue towards using oral or
intratympanic steroids to stop clusters of attacks of vertigo. The validity of this approach has yet to
be clearly shown although clinical evidence does seem to suggest it is an effective treatment.
Is a virus the most common cause of Meniere’s disease?
Over fifty years ago Lempert and his co-workers suggested that Meniere’s disease was caused in the
majority of ears by a herpes virus [10]. The herpes family of viruses consist of at least 8 members
including HSV1 (causes cold sores), HSV2 (causes genital herpes), VCV (causes chicken pox and
shingles), EBV (causes glandular fever) and CMV (causes birth defects).
The herpes virus has been found in autopsy specimens obtained from Meniere’s disease sufferers in
both the endolymphatic sac and in the ganglion of the vestibular and cochlear nerves. However ears
from non Meniere’s disease sufferers often also contain the virus.
The idea of a herpes virus causing the initial inflammatory response in the inner ear is compelling.
For example, herpes simplex virus causes cold sores which erupt on the lip and then the virus lies
latent or hides in the nerve for a while and then can erupt again causing more cold sores. It is
postulated that a similar virus causes an initial inflammatory response in the ear and results in
inflammation which causes excess endolymphatic fluid (endolymphatic hydrops). As the virus lies
latent within the ear, it can erupt again causing another cluster of attacks.
Unfortunately there is no medical treatment which can kill the virus when it goes into its latent
state. Anti-virals may be effective in stopping eruptions of the virus but would have to be taken
continually.
The need for research into a viral cause
The first step in the research will be to find out which Meniere’s disease sufferers have a viral cause
for their condition. A prolonged, double blind trial needs to be undertaken to determine if antiviral
drugs can prevent clusters of attacks occurring. A double blind trial means that a placebo which
looks exactly like the antiviral agent is used in some subjects and the actual antiviral medication is
used in others. Neither the doctor nor the patient will know which is being used. If a subject has
another cluster of attacks, the secret is revealed and if that person is on the placebo, they will be
offered the active medication.
Why do some ears have the virus present but do not develop Meniere’s disease?
While the virus lies latent (hidden) within the inner ear structures, the function of the ear is
unaffected. When the virus erupts it causes the inflammatory response resulting in the production
of excess endolymph. If the ear can mount an adequate defence mechanism, the virus can be
destroyed before it causes an excessive inflammatory reaction. Some ears can mount this defence
mechanism, whereas ears affected by Meniere’s disease cannot.
The immune system clears viruses and other pathogens from the body using special cells called
lymphocytes. Lymphocytes are developed in the bone marrow (B lymphocytes) and in the thymus (T lymphocytes or T cells). Viruses are cleared by a specific lymphocyte known as Th1 and the ear needs lots of these Th1 lymphocytes to prevent the virus from causing the inflammatory reaction.
T cells are made specifically for certain tasks. T cells develop from immature T cells in the thymus
and these can differentiate into specific types with highly specialised tasks. Some may develop into
T1 cells and these can be measured with a blood test using a special marker called CD8+. Other
immature T cells develop into Th2 cells which communicate with B lymphocytes (which produce
anti-bodies to combat bacterial infections and parasites). Th2 cells have a CD4+ marker.
Furthermore, other T cells are produced that limit the immune system so the body does not attack
its own tissues, a process known as autoimmunity.
Perhaps if a person with Meniere’s disease has insufficient or inefficient specialised immune cells,
they may be unable to prevent the virus erupting and causing inflammation in the inner ear. This
may be the reason why some ears which contain the virus do not suffer from Meniere’s disease.
Stephen Spring, himself a Meniere’s disease sufferer, has discovered a possible means of altering the
T1/T2 balance which may provide long term relief and we hope to be able to properly evaluate his
ideas at the University, but such is the fickle nature of Meniere’s disease that isolated cures cannot
be taken as definite proof of efficacy.
Our hopes for the future
It is our aim at the University of Sydney to be able to explain the mechanism which causes Meniere’s and to find an eventual cure. We feel that some definite strides towards this goal have already been made. We are desperately keen to be able to complete the tasks and hope that there will be sufficient funding to make this possible. The Meniere’s Research Fund under the superb leadership of Bruce Kirkpatrick has been the lifeline and we urge all Meniere’s disease sufferers and their families to continue to support this cause.
We need to recruit Meniere’s disease sufferers who are willing to become part of our research
programme. Specifically we need sufferers who are experiencing clusters of attacks of vertigo so that
we can discover if antiviral medication can be effective.
If a reader wishes to help us, please contact me (Professor Gibson at 02 9844 6801).
References
1. Passe ERG, Seymour JS (1948) Meniere’s syndrome: successful treatment by surgery on the sympathetic. Brit Med J, 2,
812-816
2. Furstenberg AC, Lashmet FH, Lathrop F (1934) Ann ORL, 43, 1035-1046
3. Harrison MS, Naftalin L (1968) Meniere’s disease: Mechanism and management, Springfield: Charles C Thomas
4. Schuknecht H. Correlation of pathology with symptoms of Meniere’s disease. Otolaryngol Clin N Amer 1968; 1:433-438
5. Bagger-Sjöbäck, Friberg U, Rask-Andersen H: The human endolymphatic sac: an ultrastructural study. Arch Otoalryngol
Head Neck Surg 112: 398-409 1986
6. Salt AN: Fluid homeostasis in the inner ear. In Harris JP (ed) Meniere’s Disease. The Hague, Kugler Publications 93-101 1999
7. McNeil C, Cohen M, Gibson WPR (2009) Changes in audiometric thresholds before, during and after attacks of vertigo
associated with Meniere’s syndrome Acta Otolaryngol. 129, 1404-1409.
8. Gibson WPR (2005) The effect of removal of the extra-osseous portion of the endolymphatic sac in ears affected by
Meniere’s disease. In ‘Meniere’s Disease & Inner ear homeostasis disorders’ Ed Lim DJ. Pages 239-240. House Ear Institute
publication, Los Angeles (ISBN 0-9776204-0-9)
9. Gibson WPR (2010) Hypothetical mechanism for vertigo in Meniere’s Disease. Otolaryngol Clin N Am 43: 1019-1027
10. Lempert J, Wolff D, Rambo JHT, Wever EG, Lawrence M. (1952) New theory for the correlation of the pathology and the
symptomatology of Meniere’s disease; a research study of the vestibular endolymphatic labyrinth. Anna ORL.61,717–746
Thursday, June 4, 2015
Evaluating Scientific Claims
As an oncology dietitian, it is an integral part of my job to help my patients navigate nutrition and dietary supplement claims they come across through a variety of resources. While some alternative and complementary therapies have a very low risk of harm and can provide some relief, some can actually be quite dangerous. Differentiating between something that is safe and effective, safe and not effective, and downright risky can be a daunting task, especially for someone without scientific training.
To make matters worse, anecdotal claims or treatments promoted by (dubious) physicians or others with medical or healthcare credentials can sound so promising, especially when conventional medicine isn't meeting the all of the expectations and needs of the sufferer. As those of us with Meniere's know, this phenomenon is not limited to cancer patients.
I will be giving a presentation in August on just this subject and will share my slides with you all then. But in the meantime, consider the following guidelines when evaluating claims regarding treatments and supplements promoted as therapies for Meniere's disease.
It is not lost on me that by promoting cautious evaluation of scientific-sounding claims, that I might be called a hypocrite due to having sought out and chosen to take part in a treatment which is not yet widely known or accepted as standard medical practice in the management of Meniere's disease. However, between my own training and background, that of my husband, and some of our friends and colleagues, we have been able to sufficiently evaluate and extrapolate from the existing data enough information to form a positive opinion of this treatment option. And it's this same standard which I encourage others to apply to claims being made for the use of any other particular treatment or dietary supplement.
Be aware of ‘pseudoscience’ (‘false-science’). Pseudoscientists make claims that may appear scientific, but don’t follow scientific principles. Distinguishing between science and pseudoscience can be difficult. When trying to discern whether something is scientific, check the following:
INTEREST
Who is funding the research and who may profit from it?
Biased organizations may give themselves neutral-sounding names. An organization will often have an interest in the outcome of a study they are funding.
AUTHOR and PUBLISHER
Who conducted the research? Where was it done? Where was it published?
Look at the background of the people involved in the research, if possible. What kind of training have they had? Have they done extensive research in the field? Have they published other papers on the topic? Do others frequently cite them? Was the work conducted at an established facility, which could provide the support necessary to conduct thorough research?
Scientists publish their results in peer-reviewed journals so that others in the same field can critically evaluate their work. View with suspicion any discoveries that are ‘secret’ or rely on ‘secret formulas’. Results that have been originally published in journals such as Science, Nature, the New England Journal of Medicine, etc. will have been examined more closely, and are therefore are more reliable, than those that are directly announced to the media.
HYPOTHESES
Are hypotheses testable and capable of being falsified?
Hypotheses and theories (even those which cannot be tested directly) should be able to be used to make predictions and allow the collection of evidence to test those predictions. Often pseudoscientific claims can’t be proven wrong by any possible evidence. For example, there is no way to disprove the claim that only someone with special powers can sense a certain phenomenon.
There is a large body of knowledge in science that is not influenced by trends in public opinion and is not likely to change. However, scientific ideas should be capable of changing should new evidence arise. In contrast, ideas in pseudoscience either stay the same (if there is an unchanging idea behind them) or change randomly (if criteria for accepting ideas and rejecting others do not exist).
PROCEDURE
1. Are experiments repeatable? Have they been repeated?
Experimental procedures are reported so that others may repeat them. Valid results can be reproduced by others. Check to see that there has been more than one study, and that the studies support past research. One single study may produce results that other studies can’t repeat. The more independent studies that exist which can support a claim, the more likely it is to be true.
2. Are specific, well-defined predictions made?
Scientists use careful, precise language and make quantitative predictions if possible. Pseudoscientists use vague and imprecise terms that can be interpreted in many different ways, such as the language used in many horoscopes.
3. Are appropriate controls used?
If a drug is being tested, for example, scientists compare an experimental group (getting the treatment) with a control group (not receiving the treatment).
Controls (which should be identical to the experimental group except for the factor being tested) ensure that results are due to the drug itself and not some other factor. Test subjects should be randomly assigned to either group (‘randomized’). Blind studies (subjects don’t know which group they are in) and double-blind studies (neither subjects nor researchers know which group subjects are in) provide additional safeguards.
4. Was a representative sample used? Was it large enough? Were enough trials done?
Scientists use samples that represent larger groups. If only men were used in a study, claims about how the study applies to women would be suspect.
Pseudoscientific or unproven claims will rely on case histories, anecdotal evidence, or personal testimonials (Jane lost 30 lbs. in two weeks with Slim-X!) While case studies might be a starting point for future research, scientists require many trials combined with statistical analysis in order to evaluate their claims. Furthermore, ethical scientists wouldn’t reveal the names of people involved in tests.
Sometimes, a statistical claim may be made without reference to the sample size (‘3 out of 4 dentists surveyed’…but how many were surveyed?) The larger the sample size, and the longer the study lasted, the more confident scientists are about their results
RESULTS
1. Were the results statistically significant?
‘Statistical significance’ measures how often a particular result would occur due to chance alone, assuming that the experiment were repeated many times. The convention is to say that results are statistically significant if there is a 5% probability or less that the results were due to chance alone.
2. Are logic and statistical analysis used to help distinguish between coincidence (chance), correlation (association), and causation?
Correlation and causation are commonly confused with each other. For example, ‘people who exercise have a lower risk of heart attack’ is a statement of correlation, but ‘exercise lowers the risk of heart attack’’ is a statement of causation.
It is very hard to prove causation (that A causes B). In order to do so, one needs to show that A must always be present for B to occur, and that B will always occur when A is present (‘A is both necessary and sufficient cause of B’). An example of how this can be done in science is the use of Koch’s postulates for determining whether a microorganism causes a particular disease:
The organism must be associated with every case of the disease
A pure culture of the organism must be able to be grown outside the body
When introduced into a healthy subject, the pure culture of the organism must cause the disease to occur.
The organism must be recovered from the subject and cultured again.
Because of limits on time, funding, or because of ethical considerations, often the best that can be done is to evaluate a relationship using logic and laws of probability.
When looking for a cause of an illness, scientists would look for large differences between people who had and didn’t have exposure to a suspected cause. They would check to see that those differences are present between groups that would otherwise be at similar risk for developing an illness. Scientists would also check that a logical reason for a suspected relationship exists.
3. Are new ideas or results viewed critically and with skepticism?
Scientists should ideally presume a new idea wrong until it is well supported with evidence.
Pseudoscientists aren’t skeptical of their own results, but are skeptical of the results of others.
Types of Arguments and Persuasive Devices
Certain techniques are commonly used to attempt to convince the reader of the validity of an argument. Be aware of some of these techniques when you are evaluating a source.
The following types of arguments are discussed in What Science is and How it Works, by Gordon Derry:
1. Straw Man
An argument directed not at someone’s actual position, but at a weaker version (the ‘straw man’) created by the opponent. This weaker version would seem, for example, illogical or irrelevant.
2. Ad Hominem (‘to the man’)
An argument directed at an individual, rather than the individual’s position. The person themselves is attacked, rather than the evidence or the logic of their argument.
3. False Dilemma
Two choices are proposed, and one of these is more easily attacked. This leaves the other choice as the only obvious possibility. However, in reality there may be many other alternatives or complexities which are not addressed.
4. Begging the Question
This type of argument (also called ‘circular reasoning’) assumes the truth of its conclusions as part of the reasoning leading up to the conclusion.
5. Slippery Slope
An argument in which the position argued against is depicted to result in something terrible. The terrible result is then argued against, rather than the position itself.
The following types of persuasive devices are described in Forests: Identifying Propaganda Techniques, by Anderson and Buggey:
6. Bandwagon
‘Everyone else is doing it.’ This technique takes advantage of the desire of many people to feel as though they belong to a group. The argument is that if most people believe a certain way, then the reader should also feel that way.
7. Slanted Words or Phrases
In this technique, emotionally charged or biased words are used to convince the reader of a certain position (contrast ‘mature citizen’ with ‘old fogy’).
8. Scare Tactics
This technique tries to scare the reader into siding with a particular position. The argument is evaluated on the basis of emotion (fear) rather than logic and reason.
REFERENCES
Aaseng, Nathan. Science vs. Pseudoscience. New York: Franklin Watts, 1994.
American Cancer Society: ACS Newsstand, Interpreting the Science in Scientific Studies (1997), http://www.cancer.org/media/1mar4.html (accessed 7/5/97).
Anderson, Robert, and JoAnne Buggey. Forests: Identifying Propaganda Techniques. San Diego, CA: Greenhaven Press, Inc., 1992.
Arthritis: Unproven Remedies, Arthritis Foundation, Atlanta, Georgia, 1987.
Derry, Gregory. What Science is and How it Works. Princeton, NJ: Princeton University Press, 1999.
Park, Robert. "Voodoo Science: the road from foolishness to fraud," Oxford University Press, 2000.
Weiss, Noel S. "Distinguishing Cause From Coincidence", Alaska Airlines/Horizon Air Magazines July 1993.
Special thanks to:
Cynthia McClellan, Steve Collins, Nancy Hutchison,
Karen Peterson, Diane Rosman, and Dave Vannet.
To make matters worse, anecdotal claims or treatments promoted by (dubious) physicians or others with medical or healthcare credentials can sound so promising, especially when conventional medicine isn't meeting the all of the expectations and needs of the sufferer. As those of us with Meniere's know, this phenomenon is not limited to cancer patients.
I will be giving a presentation in August on just this subject and will share my slides with you all then. But in the meantime, consider the following guidelines when evaluating claims regarding treatments and supplements promoted as therapies for Meniere's disease.
It is not lost on me that by promoting cautious evaluation of scientific-sounding claims, that I might be called a hypocrite due to having sought out and chosen to take part in a treatment which is not yet widely known or accepted as standard medical practice in the management of Meniere's disease. However, between my own training and background, that of my husband, and some of our friends and colleagues, we have been able to sufficiently evaluate and extrapolate from the existing data enough information to form a positive opinion of this treatment option. And it's this same standard which I encourage others to apply to claims being made for the use of any other particular treatment or dietary supplement.
Sorting out Sources: Guidelines for EvaluatingScientific Information
The goal of this page is to help you evaluate information, specifically scientific information. This skill is critical not only when conducting research using the internet or traditional print media, but also in helping you sort out claims you may encounter in your daily life.Be aware of ‘pseudoscience’ (‘false-science’). Pseudoscientists make claims that may appear scientific, but don’t follow scientific principles. Distinguishing between science and pseudoscience can be difficult. When trying to discern whether something is scientific, check the following:
INTEREST
Who is funding the research and who may profit from it?
Biased organizations may give themselves neutral-sounding names. An organization will often have an interest in the outcome of a study they are funding.
AUTHOR and PUBLISHER
Who conducted the research? Where was it done? Where was it published?
Look at the background of the people involved in the research, if possible. What kind of training have they had? Have they done extensive research in the field? Have they published other papers on the topic? Do others frequently cite them? Was the work conducted at an established facility, which could provide the support necessary to conduct thorough research?
Scientists publish their results in peer-reviewed journals so that others in the same field can critically evaluate their work. View with suspicion any discoveries that are ‘secret’ or rely on ‘secret formulas’. Results that have been originally published in journals such as Science, Nature, the New England Journal of Medicine, etc. will have been examined more closely, and are therefore are more reliable, than those that are directly announced to the media.
HYPOTHESES
Are hypotheses testable and capable of being falsified?
Hypotheses and theories (even those which cannot be tested directly) should be able to be used to make predictions and allow the collection of evidence to test those predictions. Often pseudoscientific claims can’t be proven wrong by any possible evidence. For example, there is no way to disprove the claim that only someone with special powers can sense a certain phenomenon.
There is a large body of knowledge in science that is not influenced by trends in public opinion and is not likely to change. However, scientific ideas should be capable of changing should new evidence arise. In contrast, ideas in pseudoscience either stay the same (if there is an unchanging idea behind them) or change randomly (if criteria for accepting ideas and rejecting others do not exist).
PROCEDURE
1. Are experiments repeatable? Have they been repeated?
Experimental procedures are reported so that others may repeat them. Valid results can be reproduced by others. Check to see that there has been more than one study, and that the studies support past research. One single study may produce results that other studies can’t repeat. The more independent studies that exist which can support a claim, the more likely it is to be true.
2. Are specific, well-defined predictions made?
Scientists use careful, precise language and make quantitative predictions if possible. Pseudoscientists use vague and imprecise terms that can be interpreted in many different ways, such as the language used in many horoscopes.
3. Are appropriate controls used?
If a drug is being tested, for example, scientists compare an experimental group (getting the treatment) with a control group (not receiving the treatment).
Controls (which should be identical to the experimental group except for the factor being tested) ensure that results are due to the drug itself and not some other factor. Test subjects should be randomly assigned to either group (‘randomized’). Blind studies (subjects don’t know which group they are in) and double-blind studies (neither subjects nor researchers know which group subjects are in) provide additional safeguards.
4. Was a representative sample used? Was it large enough? Were enough trials done?
Scientists use samples that represent larger groups. If only men were used in a study, claims about how the study applies to women would be suspect.
Pseudoscientific or unproven claims will rely on case histories, anecdotal evidence, or personal testimonials (Jane lost 30 lbs. in two weeks with Slim-X!) While case studies might be a starting point for future research, scientists require many trials combined with statistical analysis in order to evaluate their claims. Furthermore, ethical scientists wouldn’t reveal the names of people involved in tests.
Sometimes, a statistical claim may be made without reference to the sample size (‘3 out of 4 dentists surveyed’…but how many were surveyed?) The larger the sample size, and the longer the study lasted, the more confident scientists are about their results
RESULTS
1. Were the results statistically significant?
‘Statistical significance’ measures how often a particular result would occur due to chance alone, assuming that the experiment were repeated many times. The convention is to say that results are statistically significant if there is a 5% probability or less that the results were due to chance alone.
2. Are logic and statistical analysis used to help distinguish between coincidence (chance), correlation (association), and causation?
Correlation and causation are commonly confused with each other. For example, ‘people who exercise have a lower risk of heart attack’ is a statement of correlation, but ‘exercise lowers the risk of heart attack’’ is a statement of causation.
It is very hard to prove causation (that A causes B). In order to do so, one needs to show that A must always be present for B to occur, and that B will always occur when A is present (‘A is both necessary and sufficient cause of B’). An example of how this can be done in science is the use of Koch’s postulates for determining whether a microorganism causes a particular disease:
The organism must be associated with every case of the disease
A pure culture of the organism must be able to be grown outside the body
When introduced into a healthy subject, the pure culture of the organism must cause the disease to occur.
The organism must be recovered from the subject and cultured again.
Because of limits on time, funding, or because of ethical considerations, often the best that can be done is to evaluate a relationship using logic and laws of probability.
When looking for a cause of an illness, scientists would look for large differences between people who had and didn’t have exposure to a suspected cause. They would check to see that those differences are present between groups that would otherwise be at similar risk for developing an illness. Scientists would also check that a logical reason for a suspected relationship exists.
3. Are new ideas or results viewed critically and with skepticism?
Scientists should ideally presume a new idea wrong until it is well supported with evidence.
Pseudoscientists aren’t skeptical of their own results, but are skeptical of the results of others.
Types of Arguments and Persuasive Devices
Certain techniques are commonly used to attempt to convince the reader of the validity of an argument. Be aware of some of these techniques when you are evaluating a source.
The following types of arguments are discussed in What Science is and How it Works, by Gordon Derry:
1. Straw Man
An argument directed not at someone’s actual position, but at a weaker version (the ‘straw man’) created by the opponent. This weaker version would seem, for example, illogical or irrelevant.
2. Ad Hominem (‘to the man’)
An argument directed at an individual, rather than the individual’s position. The person themselves is attacked, rather than the evidence or the logic of their argument.
3. False Dilemma
Two choices are proposed, and one of these is more easily attacked. This leaves the other choice as the only obvious possibility. However, in reality there may be many other alternatives or complexities which are not addressed.
4. Begging the Question
This type of argument (also called ‘circular reasoning’) assumes the truth of its conclusions as part of the reasoning leading up to the conclusion.
5. Slippery Slope
An argument in which the position argued against is depicted to result in something terrible. The terrible result is then argued against, rather than the position itself.
The following types of persuasive devices are described in Forests: Identifying Propaganda Techniques, by Anderson and Buggey:
6. Bandwagon
‘Everyone else is doing it.’ This technique takes advantage of the desire of many people to feel as though they belong to a group. The argument is that if most people believe a certain way, then the reader should also feel that way.
7. Slanted Words or Phrases
In this technique, emotionally charged or biased words are used to convince the reader of a certain position (contrast ‘mature citizen’ with ‘old fogy’).
8. Scare Tactics
This technique tries to scare the reader into siding with a particular position. The argument is evaluated on the basis of emotion (fear) rather than logic and reason.
REFERENCES
Aaseng, Nathan. Science vs. Pseudoscience. New York: Franklin Watts, 1994.
American Cancer Society: ACS Newsstand, Interpreting the Science in Scientific Studies (1997), http://www.cancer.org/media/1mar4.html (accessed 7/5/97).
Anderson, Robert, and JoAnne Buggey. Forests: Identifying Propaganda Techniques. San Diego, CA: Greenhaven Press, Inc., 1992.
Arthritis: Unproven Remedies, Arthritis Foundation, Atlanta, Georgia, 1987.
Derry, Gregory. What Science is and How it Works. Princeton, NJ: Princeton University Press, 1999.
Park, Robert. "Voodoo Science: the road from foolishness to fraud," Oxford University Press, 2000.
Weiss, Noel S. "Distinguishing Cause From Coincidence", Alaska Airlines/Horizon Air Magazines July 1993.
Special thanks to:
Cynthia McClellan, Steve Collins, Nancy Hutchison,
Karen Peterson, Diane Rosman, and Dave Vannet.
Money and Meniere's
Glenn over at Mind Over Meniere's has outdone himself with this post. He has put together a pretty creative list of ways people disabled with MD might be able to bring in some cash. For ease of reading, I've copied and pasted the article below. But please considering going directly to the page and subscribing to up-dates.
Chronic illness can take so much from so many of us.
We march along enjoying our lives, families, hobbies, passions, and work, until one day, the unthinkable happens. Disaster strikes and you quickly find yourself in an entirely new reality. One where you are suddenly dependent on others and you must be willing to ask for help. The simple chores of daily life become mountains to climb.
But often, the most challenging obstacle is losing the ability to work and provide for yourself and your family. We spend so much of our lives working that it can come to define you. Sometimes, it’s not just a loss of income, but the loss of purpose as well. I know how devastating this can be.
But when your world is turned upside down, it’s important to never lose hope. There are ALWAYS opportunities available; you just have to know where to look.
Regardless of your limitations, there are many ways to generate income, even when you’re stuck at home. With a little bit of effort and creativity, you can find fulfilling work and start making money again.
Here are 10 ways you can start earning money today:
1) Rent out a room in your home:
If you have an extra bedroom in your house, you can rent it out to travelers on Airbnb.com. If you have never heard of it, Airbnb is a website that connects travelers who are looking for a place to stay with people who want to rent out their entire home or just an extra room. It’s a great way to generate extra income and meet some interesting people. Through Airbnb, people can reserve your extra bedroom, just like they would book a hotel room. You can sign up and start today!
2) Rent out your car:
If you are stuck at home and unable to drive, you can easily rent out your car with Relayrides.com. It works just like Airbnb, except you are renting out your car. The service is available in every state across the US except for New York. Plus they offer a $1 million liability insurance policy to keep you covered in case of an accident. You set the price and availability, and Relayrides takes care of the rest.
3) Hire your friends to drive your car with Uber:
Another way to make money with your car is to hire your friends to drive your car for Uber.com. Uber is an innovative company that enables people to make money by driving their car as a taxi. Drivers sign up, and can work anytime they want, simply by launching the Uber app (Android) (IPhone) on their smartphone. Uber connects their drivers with people nearby who need a ride and handles the entire transaction. If you can’t drive yourself, you can hire a friend to drive for Uber with your car and split the earnings. (You will need to add your friend/family member to the insurance policy for your car)
4) Make money watching other people’s pets:
If you still have some degree of mobility, you can make money by dog sitting from your home. Rover.com and Dogvacay.com are two great websites that connect you with people who need pet sitters. If you love animals, this can be an entertaining way to make extra money. Like all of the other companies listed above, both Rover.com and Dogvacay.com handle the entire transaction. Simply sign up, list your availability and you’re all set.
5) Rent out your driveway as a parking spot:
If you live in a big city, near an airport or train station, or near a tourist attraction, you can make money by renting out your garage, driveway, or parking spot to travelers who need a place to park. You won’t make as much money as the other methods listed here, but if you have the space it may worth it. Remember every little bit adds up. You can list your parking spot for rent on JustPark.com and ParkingSpotter.com.
6) Make money buying and selling on Craigslist:
Craigslist.com is an online classifieds page and a great way to buy and sell things locally. If you happen to be a collector or know a lot about a specific type of product, you can make money through craigslist. By finding undervalued products and getting a great deal, you can turn around and resell those products for a profit. Think of your hobbies. Are there things you know a lot about? Maybe you know a lot about baseball cards or vintage record albums. The more you know about a specific type of product, the better you will be at spotting these deals. Sometimes, people even give stuff away for free on Craigslist. It takes time but if you have a good eye for spotting deals, you can make a lot of money on Craigslist.com.
7) Become a paid consultant:
If you were successful in business and think you can help others in the same line of work be successful too, you can make money as a paid consultant. Clarity.fm is a relatively new platform that connects experts with business owners and entrepreneurs who need advice. When you sign up, you set a per-minute price, and through the app, people will be able to call you and consult with you. If you are knowledgeable, it can be a lucrative opportunity.
8) Become a Freelancer and sell your skills online:
If you have ever held a job at any point in your life, odds are you were being paid to put a skill to work. Through websites like Upwork.com, and Fiverr.com, you can sell your skills as a service. All three of these websites connect people who need work completed with the people who have the skills to do the work.
Can you write well? Maybe you are good at editing and proofreading. Maybe you can build websites or do graphic design. If you can do something well, you will most likely be able to offer it as a service to someone else. Some other common examples are creating PowerPoint presentations, translating documents, computer programming, and much more. You can also become a virtual assistant and help people complete various tasks.
9) Write an EBook and sell it through Amazon
Have you ever thought to yourself that you should write a book? Well, it’s easier now than ever before! Thanks to Amazon, you can now self-publish an EBook quickly and easily through Amazon’s Kindle Direct Publishing website. Within 24 hours of publishing your manuscript, you can have your book for sale in the Amazon Kindle store and start earning royalties.
You can even offer a paperback version through another Amazon owned company called Createspace. After you upload your manuscript to Createspace, people will be able to buy a paperback version of your book on Amazon as well. After each order, a copy of your book is printed on demand, shipped to the customer and you get paid a royalty!
You don’t need to write a long book either. A 10,000 – 15,000 word EBook (this translates to a 30-50 page book) can sell amazingly well on Amazon. To put it in perspective, this article is 1,428 words long. The trick is to plan out your idea and write a little bit each day. If you can write 300 words every day, you can finish your book in a month or two.
10) Teach a course online:
You can make a lot of money by creating a class and teaching students all over the world through websites like Udemy.com and Skillshare.com. If you are good at something and think you can teach it to others, this can be a fun and exciting way to generate money. Not to mention, if you can build a great course and a following of students, you can easily sell your students other courses in the future. Take a few minutes and browse the courses offered for sale. It will give you some ideas for courses you may be able to offer yourself!
Conclusion:
If you have been forced out of your job by your chronic illness, it’s a devastating blow, but you still have options. These 10 ideas are a good way to start making money again, but by no means an all-inclusive list. There are more opportunities to make money than ever before and the gatekeepers are gone.
So give these ideas a try! Even if you are still able to work, these opportunities are a great way to generate some extra income on the side.
There is always so much hope. Your chronic illness cannot and will not ever be bigger than your dreams. I wish you the best of luck!
10 Ways to Make Money From Home with a Chronic Illness
Posted by Glenn
Chronic illness can take so much from so many of us.
We march along enjoying our lives, families, hobbies, passions, and work, until one day, the unthinkable happens. Disaster strikes and you quickly find yourself in an entirely new reality. One where you are suddenly dependent on others and you must be willing to ask for help. The simple chores of daily life become mountains to climb.
But often, the most challenging obstacle is losing the ability to work and provide for yourself and your family. We spend so much of our lives working that it can come to define you. Sometimes, it’s not just a loss of income, but the loss of purpose as well. I know how devastating this can be.
But when your world is turned upside down, it’s important to never lose hope. There are ALWAYS opportunities available; you just have to know where to look.
Regardless of your limitations, there are many ways to generate income, even when you’re stuck at home. With a little bit of effort and creativity, you can find fulfilling work and start making money again.
Here are 10 ways you can start earning money today:
1) Rent out a room in your home:
If you have an extra bedroom in your house, you can rent it out to travelers on Airbnb.com. If you have never heard of it, Airbnb is a website that connects travelers who are looking for a place to stay with people who want to rent out their entire home or just an extra room. It’s a great way to generate extra income and meet some interesting people. Through Airbnb, people can reserve your extra bedroom, just like they would book a hotel room. You can sign up and start today!
2) Rent out your car:
If you are stuck at home and unable to drive, you can easily rent out your car with Relayrides.com. It works just like Airbnb, except you are renting out your car. The service is available in every state across the US except for New York. Plus they offer a $1 million liability insurance policy to keep you covered in case of an accident. You set the price and availability, and Relayrides takes care of the rest.
3) Hire your friends to drive your car with Uber:
Another way to make money with your car is to hire your friends to drive your car for Uber.com. Uber is an innovative company that enables people to make money by driving their car as a taxi. Drivers sign up, and can work anytime they want, simply by launching the Uber app (Android) (IPhone) on their smartphone. Uber connects their drivers with people nearby who need a ride and handles the entire transaction. If you can’t drive yourself, you can hire a friend to drive for Uber with your car and split the earnings. (You will need to add your friend/family member to the insurance policy for your car)
4) Make money watching other people’s pets:
If you still have some degree of mobility, you can make money by dog sitting from your home. Rover.com and Dogvacay.com are two great websites that connect you with people who need pet sitters. If you love animals, this can be an entertaining way to make extra money. Like all of the other companies listed above, both Rover.com and Dogvacay.com handle the entire transaction. Simply sign up, list your availability and you’re all set.
5) Rent out your driveway as a parking spot:
If you live in a big city, near an airport or train station, or near a tourist attraction, you can make money by renting out your garage, driveway, or parking spot to travelers who need a place to park. You won’t make as much money as the other methods listed here, but if you have the space it may worth it. Remember every little bit adds up. You can list your parking spot for rent on JustPark.com and ParkingSpotter.com.
6) Make money buying and selling on Craigslist:
Craigslist.com is an online classifieds page and a great way to buy and sell things locally. If you happen to be a collector or know a lot about a specific type of product, you can make money through craigslist. By finding undervalued products and getting a great deal, you can turn around and resell those products for a profit. Think of your hobbies. Are there things you know a lot about? Maybe you know a lot about baseball cards or vintage record albums. The more you know about a specific type of product, the better you will be at spotting these deals. Sometimes, people even give stuff away for free on Craigslist. It takes time but if you have a good eye for spotting deals, you can make a lot of money on Craigslist.com.
7) Become a paid consultant:
If you were successful in business and think you can help others in the same line of work be successful too, you can make money as a paid consultant. Clarity.fm is a relatively new platform that connects experts with business owners and entrepreneurs who need advice. When you sign up, you set a per-minute price, and through the app, people will be able to call you and consult with you. If you are knowledgeable, it can be a lucrative opportunity.
8) Become a Freelancer and sell your skills online:
If you have ever held a job at any point in your life, odds are you were being paid to put a skill to work. Through websites like Upwork.com, and Fiverr.com, you can sell your skills as a service. All three of these websites connect people who need work completed with the people who have the skills to do the work.
Can you write well? Maybe you are good at editing and proofreading. Maybe you can build websites or do graphic design. If you can do something well, you will most likely be able to offer it as a service to someone else. Some other common examples are creating PowerPoint presentations, translating documents, computer programming, and much more. You can also become a virtual assistant and help people complete various tasks.
9) Write an EBook and sell it through Amazon
Have you ever thought to yourself that you should write a book? Well, it’s easier now than ever before! Thanks to Amazon, you can now self-publish an EBook quickly and easily through Amazon’s Kindle Direct Publishing website. Within 24 hours of publishing your manuscript, you can have your book for sale in the Amazon Kindle store and start earning royalties.
You can even offer a paperback version through another Amazon owned company called Createspace. After you upload your manuscript to Createspace, people will be able to buy a paperback version of your book on Amazon as well. After each order, a copy of your book is printed on demand, shipped to the customer and you get paid a royalty!
You don’t need to write a long book either. A 10,000 – 15,000 word EBook (this translates to a 30-50 page book) can sell amazingly well on Amazon. To put it in perspective, this article is 1,428 words long. The trick is to plan out your idea and write a little bit each day. If you can write 300 words every day, you can finish your book in a month or two.
10) Teach a course online:
You can make a lot of money by creating a class and teaching students all over the world through websites like Udemy.com and Skillshare.com. If you are good at something and think you can teach it to others, this can be a fun and exciting way to generate money. Not to mention, if you can build a great course and a following of students, you can easily sell your students other courses in the future. Take a few minutes and browse the courses offered for sale. It will give you some ideas for courses you may be able to offer yourself!
Conclusion:
If you have been forced out of your job by your chronic illness, it’s a devastating blow, but you still have options. These 10 ideas are a good way to start making money again, but by no means an all-inclusive list. There are more opportunities to make money than ever before and the gatekeepers are gone.
So give these ideas a try! Even if you are still able to work, these opportunities are a great way to generate some extra income on the side.
There is always so much hope. Your chronic illness cannot and will not ever be bigger than your dreams. I wish you the best of luck!
Monday, June 1, 2015
Status Up-Date: Still Well!
I've had a few requests lately for an up-date on my health since starting the Stephen Spring Treatment Protocol (SSTP*). As of June 11, 2015, I will have been on the treatment for exactly 21 months.
The first 3 months of this treatment were significant only for faster than usual cycling between my usual episodes. Symptoms during this time were otherwise the same as they had been in the years before I started this, which included severe brain fog, frequent intense disequilibrium, chronic intense fatigue, roaring tinnitus, and vertigo or near-vertigo depending on my limited response to various treatments I had tried up to that point (IT dex, IT gent, antivirals, and allergy shots to name a few).
Between months 3 and 6, I began to notice periods of feeling well which lasted weeks rather than the usual few days. Symptoms during my episodes were also becoming less intense and shorter. Amazingly, the episodes started resolving without the occurrence of vertigo or near-vertigo attacks. That was a first-ever after almost 5 years of vertigo or near-vertigo punctuating my attacks.
During this time, my hearing also improved significantly. To better illustrate what I mean, my speech discrimination had been consistently declining and hovered between 55%-65% between January 2011 and October 2012. In January, 2013 it had fallen to 20%! It had crept back up to 40% a couple of months later and again hovered there. I started this treatment in September, 2013 and one month later I happened to have a hearing test scheduled and found the results of the speech discrim then were 75% . Three months later they bounced up to 95%, a level I had not had since the first months after diagnosis in 2009. Today I still use my hearing aid because in real world settings the tinnitus interferes with my speech discrim. I would guess that currently, if I had a professional audiogram, that my speech discrim would probably be consistently greater than 80-85%. I want to say that not everyone I have spoken to on this treatment has had nearly the improvements in hearing that I have had. I don't know why, but it seems most people are not reporting such drastic hearing improvements. Though some have observed more conservative improvement.
By the 6th month of treatment, I had developed a whole new symptom which were these short, intense bursts of dizziness. They were not preceded by aural pressure, changes in tinnitus, brain fog, or generalized fatigue as my dizziness and vertigo had been before. They would just happen out of the blue maybe 3 to 6 times per day. Once I realized they would not turn into full-blown vertigo episodes, I learned to live with them The best explanation for these was they were probably a result of the changing shape of my endolymphatic sac and the resetting of the valve of Bast. By about the 9th month, they disappeared as quickly as they started.
One year into treatment, I continued to have longer periods, maybe 4-6 weeks, of feeling 95% normal. These would be sandwiched between symptoms of increased tinnitus, mild-ish brain fog, and fatigue lasting 12-72 hours. As of now, I would say this is pretty much where I remain.
Today I continue to take the vaccine, albeit at a lower dose in the last few months to see if I can sustain the effects. I work 20-30 hours per week and am able to do all the things I did before Meniere's without fear of an attack. I make plans and am able to keep them. Even when I am experiencing symptoms, they are not so severe that I cannot carry out whatever it is I need to do that day. Yes, some days are still a little rough, but NOTHING like they used to be.
Overall, I don't take any of this for granted. I don't believe I am cured, only that this treatment has perhaps corrected, or rehabilitated, my immune system enough to minimize the effects that Meniere's disease has on me.
*SSTP is not for everyone. It requires commitment, dedication, and for some people a leap of faith. Also, each person's circumstances, length and extent of disease are unique, so the treatment course may vary from person to person. Some may require additional medical intervention with prescription medications prescribed by their physician. I neither encourage nor discourage others from seeking more information about it. It is a deeply personal decision that should be made with the support of your family and your physician. It is probably wise to attempt to exhaust all conventional treatments and to consider just how disabling your symptoms are for you. On the other hand, it would seem reasonable to believe that earlier intervention might mean better, more durable results. Until there can be large, well-designed studies, we won't know the answers to many questions. While I am happy to answer general questions, it is best to reach out directly to Stephen Spring at stephen_spring@me.com for specific details of the treatment and to determine if it is right for you.
The first 3 months of this treatment were significant only for faster than usual cycling between my usual episodes. Symptoms during this time were otherwise the same as they had been in the years before I started this, which included severe brain fog, frequent intense disequilibrium, chronic intense fatigue, roaring tinnitus, and vertigo or near-vertigo depending on my limited response to various treatments I had tried up to that point (IT dex, IT gent, antivirals, and allergy shots to name a few).
Between months 3 and 6, I began to notice periods of feeling well which lasted weeks rather than the usual few days. Symptoms during my episodes were also becoming less intense and shorter. Amazingly, the episodes started resolving without the occurrence of vertigo or near-vertigo attacks. That was a first-ever after almost 5 years of vertigo or near-vertigo punctuating my attacks.
During this time, my hearing also improved significantly. To better illustrate what I mean, my speech discrimination had been consistently declining and hovered between 55%-65% between January 2011 and October 2012. In January, 2013 it had fallen to 20%! It had crept back up to 40% a couple of months later and again hovered there. I started this treatment in September, 2013 and one month later I happened to have a hearing test scheduled and found the results of the speech discrim then were 75% . Three months later they bounced up to 95%, a level I had not had since the first months after diagnosis in 2009. Today I still use my hearing aid because in real world settings the tinnitus interferes with my speech discrim. I would guess that currently, if I had a professional audiogram, that my speech discrim would probably be consistently greater than 80-85%. I want to say that not everyone I have spoken to on this treatment has had nearly the improvements in hearing that I have had. I don't know why, but it seems most people are not reporting such drastic hearing improvements. Though some have observed more conservative improvement.
By the 6th month of treatment, I had developed a whole new symptom which were these short, intense bursts of dizziness. They were not preceded by aural pressure, changes in tinnitus, brain fog, or generalized fatigue as my dizziness and vertigo had been before. They would just happen out of the blue maybe 3 to 6 times per day. Once I realized they would not turn into full-blown vertigo episodes, I learned to live with them The best explanation for these was they were probably a result of the changing shape of my endolymphatic sac and the resetting of the valve of Bast. By about the 9th month, they disappeared as quickly as they started.
One year into treatment, I continued to have longer periods, maybe 4-6 weeks, of feeling 95% normal. These would be sandwiched between symptoms of increased tinnitus, mild-ish brain fog, and fatigue lasting 12-72 hours. As of now, I would say this is pretty much where I remain.
Today I continue to take the vaccine, albeit at a lower dose in the last few months to see if I can sustain the effects. I work 20-30 hours per week and am able to do all the things I did before Meniere's without fear of an attack. I make plans and am able to keep them. Even when I am experiencing symptoms, they are not so severe that I cannot carry out whatever it is I need to do that day. Yes, some days are still a little rough, but NOTHING like they used to be.
Overall, I don't take any of this for granted. I don't believe I am cured, only that this treatment has perhaps corrected, or rehabilitated, my immune system enough to minimize the effects that Meniere's disease has on me.
*SSTP is not for everyone. It requires commitment, dedication, and for some people a leap of faith. Also, each person's circumstances, length and extent of disease are unique, so the treatment course may vary from person to person. Some may require additional medical intervention with prescription medications prescribed by their physician. I neither encourage nor discourage others from seeking more information about it. It is a deeply personal decision that should be made with the support of your family and your physician. It is probably wise to attempt to exhaust all conventional treatments and to consider just how disabling your symptoms are for you. On the other hand, it would seem reasonable to believe that earlier intervention might mean better, more durable results. Until there can be large, well-designed studies, we won't know the answers to many questions. While I am happy to answer general questions, it is best to reach out directly to Stephen Spring at stephen_spring@me.com for specific details of the treatment and to determine if it is right for you.
Sunday, May 31, 2015
A Couple of Cool New Tools
Wanted to take a minute to share a couple of neat tools that showed up in this week.
The first is a thought-provoking questionnaire to help assess dizziness which can be found here. Check it out!
The second is a super-neat, comprehensive, fillable form for tracking Meniere's developed bn blogger, Glenn, over at Mind Over Menieres. I could post the pdf, but I imagine Glenn would like to generate some traffic to his site and it's well-worth putting an email address in to get this cool tool.
The first is a thought-provoking questionnaire to help assess dizziness which can be found here. Check it out!
The second is a super-neat, comprehensive, fillable form for tracking Meniere's developed bn blogger, Glenn, over at Mind Over Menieres. I could post the pdf, but I imagine Glenn would like to generate some traffic to his site and it's well-worth putting an email address in to get this cool tool.
Monday, April 13, 2015
Is the use of dietary supplements safe?
I have written here at least once before about dietary supplements. As an oncology dietitian, I hear about and research a variety of supplements people use to treat a variety of conditions, including cancer. They generally turn to these substances because of something they've heard about from someone they know or read on the internet.
Those of us with Meniere's disease are no different in our desperation to find relief from our symptoms and hope for better health. However, as is so well-described by Catherine Price in her book Vitamania, dietary supplements are the product of a highly unregulated industry and treated by the FDA in near-opposite fashion as compared to pharmaceuticals and over-the-counter drugs. Namely, anything classified as a medication, the law states, must undergo years of safety and efficacy testing in real humans before being released for sale to the public. However dietary supplements are in fact allowed to be sold to the public first, without any safety or efficacy data, and can only be pulled from shelves by the FDA after sufficient evidence, usually in the form of consumer complaints, has revealed that they have caused significant harm or death. Even in such cases, it is up to the FDA to decide whether or not to pursue a recall and that decision is based in no small part on how much it will cost to launch and pursue an investigation, often running into the millions of dollars and many months or years of legal wrangling.
Harm from supplements may occur immediately upon taking a substance, as was the case with ma huang, aka ephedra, before it was banned for sale in the U.S. in 2004 after its use was linked with heart attacks, strokes, and more than 22 deaths. But use of other supplements, previously believed to promote good health and longevity, as well as protect from diseases such as cancer, have turned out to also be correlated with potential for serious risk, as in the case of beta carotene and lung cancer, vitamin E and selenium and prostate cancer, and folic acid in the case of prostate cancer.
Now here is an article about a newly published study that has found a strong link between the use of common muscle-building supplements and testicular cancer. Nice.
- See more at: http://www.stonehearthnewsletters.com/muscle-building-supplements-linked-to-testicular-cancer-brown-university-study/cancer-testicular/#sthash.oJoDC5Z6.XNWWYLtY.dpuf
PROVIDENCE, R.I. [Brown University] — Men who reported taking muscle-building supplements, such as pills and powders with creatine or androstenedione, reported a significantly higher likelihood of having developed testicular cancer than men who did not use such supplements, according to a new study in the British Journal of Cancer.
Moreover, said study senior author Tongzhang Zheng, the associated testicular germ cell cancer risk was especially high among men who started using supplements before age 25, those who used multiple supplements and those who used them for years.
“The observed relationship was strong,” said Zheng, who led the study at Yale University before joining the Brown University School of Public Health as a professor of epidemiology. “If you used at earlier age, you had a higher risk. If you used them longer, you had a higher risk. If you used multiple types, you had a higher risk.”
Testicular cancer incidence rose to 5.9 cases per 100,000 men in 2011, from 3.7 cases in 100,000 in 1975, Zheng said. Researchers aren’t sure why.
“Testicular cancer is a very mysterious cancer,” he said. “None of the factors we’ve suspected can explain the increase.”
The study is the first analytical epidemiological study of the possible link between supplements and testicular cancer, the authors wrote in the journal. The work was inspired by mounting evidence that that at least some supplement ingredients may damage the testes.
“Our study found that supplement use was related to a higher risk of developing testicular cancer. These results are important because there are few identified modifiable risk factors for testicular cancer,” said Russ Hauser, professor of environmental health science at Harvard T.H. Chan School of Public Health and a main collaborator of the research.
Testing the odds
To conduct the study, Zheng’s research team conducted detailed interviews of nearly 900 men from Massachusetts and Connecticut — 356 of whom had been diagnosed with testicular germ cell cancer, and 513 who had not. In the interviews, researchers asked the men not only about their supplement use but also about a wide variety of other possible factors such as smoking, drinking, exercise habits, family history of testicular cancer, and prior injury to their testes or groin.
After tallying their data and accounting for all those possible confounders, as well as age, race, and other demographics, the researchers found that the men who used supplements had a 1.65 odds ratio (a 65 percent greater risk) of having developed testicular cancer compared to the men who did not use supplements.
The researchers defined “use” as consuming one or more supplements at least once a week for four consecutive weeks or more.
The odds ratios increased to 2.77 (a 177 percent greater risk) among men who used more than one kind of supplement, and to 2.56 among men who used supplements three years or longer. Men who started using supplements at age 25 or younger also had an elevated associated odds ratio of 2.21, the researchers calculated.
“Considering the magnitude of the association and the observed dose-response trends, muscle-building supplements use may be an important and modifiable exposure that could have important scientific and clinical importance for preventing testicular germ cell cancer development if this association is confirmed by future studies,” the authors conclude in the study.
Future large epidemiologic studies and lab experiments would be necessary to establish a causal link between supplements and testicular cancer.
The study’s lead author is Ni Li of Yale University and the Chinese Academy of Medical Sciences. Other authors are Pat Morey of Harvard T.H. Chan School of Public Health; Theodore R. Holford, Yong Zhu, Yawei Zhang, Bryan A. Bassig, Stan Honig, and Helen Sayward of Yale; Chu Chen and Stephen Schwarz of the Fred Hutchinson Cancer Research Center; Peter Boyle of the International Prevention and Research Institute in Lyon, France; Zhibin Hu and Hongbin Shen of Nanjing Medical University; and Pable Gomery of Massachusetts General Hospital.
The U.S. National Institutes of Health, the National Natural Science Foundation of China, The Beijing Natural Science Foundation, and the Beijing Nova Program supported the research.
- See more at: http://www.stonehearthnewsletters.com/muscle-building-supplements-linked-to-testicular-cancer-brown-university-study/cancer-testicular/#sthash.oJoDC5Z6.XNWWYLtY.dpuf
Those of us with Meniere's disease are no different in our desperation to find relief from our symptoms and hope for better health. However, as is so well-described by Catherine Price in her book Vitamania, dietary supplements are the product of a highly unregulated industry and treated by the FDA in near-opposite fashion as compared to pharmaceuticals and over-the-counter drugs. Namely, anything classified as a medication, the law states, must undergo years of safety and efficacy testing in real humans before being released for sale to the public. However dietary supplements are in fact allowed to be sold to the public first, without any safety or efficacy data, and can only be pulled from shelves by the FDA after sufficient evidence, usually in the form of consumer complaints, has revealed that they have caused significant harm or death. Even in such cases, it is up to the FDA to decide whether or not to pursue a recall and that decision is based in no small part on how much it will cost to launch and pursue an investigation, often running into the millions of dollars and many months or years of legal wrangling.
Harm from supplements may occur immediately upon taking a substance, as was the case with ma huang, aka ephedra, before it was banned for sale in the U.S. in 2004 after its use was linked with heart attacks, strokes, and more than 22 deaths. But use of other supplements, previously believed to promote good health and longevity, as well as protect from diseases such as cancer, have turned out to also be correlated with potential for serious risk, as in the case of beta carotene and lung cancer, vitamin E and selenium and prostate cancer, and folic acid in the case of prostate cancer.
Now here is an article about a newly published study that has found a strong link between the use of common muscle-building supplements and testicular cancer. Nice.
Muscle-building supplements linked to testicular cancer: Brown University study
Posted on April 13, 2015 by Stone Hearth News- See more at: http://www.stonehearthnewsletters.com/muscle-building-supplements-linked-to-testicular-cancer-brown-university-study/cancer-testicular/#sthash.oJoDC5Z6.XNWWYLtY.dpuf
PROVIDENCE, R.I. [Brown University] — Men who reported taking muscle-building supplements, such as pills and powders with creatine or androstenedione, reported a significantly higher likelihood of having developed testicular cancer than men who did not use such supplements, according to a new study in the British Journal of Cancer.
Moreover, said study senior author Tongzhang Zheng, the associated testicular germ cell cancer risk was especially high among men who started using supplements before age 25, those who used multiple supplements and those who used them for years.
“The observed relationship was strong,” said Zheng, who led the study at Yale University before joining the Brown University School of Public Health as a professor of epidemiology. “If you used at earlier age, you had a higher risk. If you used them longer, you had a higher risk. If you used multiple types, you had a higher risk.”
Testicular cancer incidence rose to 5.9 cases per 100,000 men in 2011, from 3.7 cases in 100,000 in 1975, Zheng said. Researchers aren’t sure why.
“Testicular cancer is a very mysterious cancer,” he said. “None of the factors we’ve suspected can explain the increase.”
The study is the first analytical epidemiological study of the possible link between supplements and testicular cancer, the authors wrote in the journal. The work was inspired by mounting evidence that that at least some supplement ingredients may damage the testes.
“Our study found that supplement use was related to a higher risk of developing testicular cancer. These results are important because there are few identified modifiable risk factors for testicular cancer,” said Russ Hauser, professor of environmental health science at Harvard T.H. Chan School of Public Health and a main collaborator of the research.
Testing the odds
To conduct the study, Zheng’s research team conducted detailed interviews of nearly 900 men from Massachusetts and Connecticut — 356 of whom had been diagnosed with testicular germ cell cancer, and 513 who had not. In the interviews, researchers asked the men not only about their supplement use but also about a wide variety of other possible factors such as smoking, drinking, exercise habits, family history of testicular cancer, and prior injury to their testes or groin.
After tallying their data and accounting for all those possible confounders, as well as age, race, and other demographics, the researchers found that the men who used supplements had a 1.65 odds ratio (a 65 percent greater risk) of having developed testicular cancer compared to the men who did not use supplements.
The researchers defined “use” as consuming one or more supplements at least once a week for four consecutive weeks or more.
The odds ratios increased to 2.77 (a 177 percent greater risk) among men who used more than one kind of supplement, and to 2.56 among men who used supplements three years or longer. Men who started using supplements at age 25 or younger also had an elevated associated odds ratio of 2.21, the researchers calculated.
“Considering the magnitude of the association and the observed dose-response trends, muscle-building supplements use may be an important and modifiable exposure that could have important scientific and clinical importance for preventing testicular germ cell cancer development if this association is confirmed by future studies,” the authors conclude in the study.
Future large epidemiologic studies and lab experiments would be necessary to establish a causal link between supplements and testicular cancer.
The study’s lead author is Ni Li of Yale University and the Chinese Academy of Medical Sciences. Other authors are Pat Morey of Harvard T.H. Chan School of Public Health; Theodore R. Holford, Yong Zhu, Yawei Zhang, Bryan A. Bassig, Stan Honig, and Helen Sayward of Yale; Chu Chen and Stephen Schwarz of the Fred Hutchinson Cancer Research Center; Peter Boyle of the International Prevention and Research Institute in Lyon, France; Zhibin Hu and Hongbin Shen of Nanjing Medical University; and Pable Gomery of Massachusetts General Hospital.
The U.S. National Institutes of Health, the National Natural Science Foundation of China, The Beijing Natural Science Foundation, and the Beijing Nova Program supported the research.
- See more at: http://www.stonehearthnewsletters.com/muscle-building-supplements-linked-to-testicular-cancer-brown-university-study/cancer-testicular/#sthash.oJoDC5Z6.XNWWYLtY.dpuf
Sunday, April 12, 2015
Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss
This article was published in September, 2014 in Frontiers of Pharmacology. I found it a nice summary of different immune approaches that have been tried for sensorineural hearing loss (SNHL), the type of hearing loss experienced by those of us with MD, and the limitations with available agents so far. (Go directly to the link for references and citations.) Might it be safe to say that if a successful treatment for SNHL were to be found that it would also address the other symptoms of MD? It seems a logical conclusion.
Front Pharmacol. 2014; 5: 205.
Published online 2014 Sep 2. doi: 10.3389/fphar.2014.00205
PMCID: PMC4151383
Abstract
Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.
Keywords: resident macrophages, autoimmunity, corticosteroids, cell therapy, molecular targeted drugs
INTRODUCTION
Sensorineural hearing loss (SNHL) is a collection of common auditory disorders resulting from dysfunction of the inner ear, auditory nerve, or the auditory processing pathway in the central nervous system. SNHL comprises a wide variety of auditory disorders including sudden deafness, age-related hearing loss, noise-induced hearing loss, and Meniere’s disease. To date, very little of the SNHL pathophysiology is known because biopsy of the human inner ear is not feasible. Among the purposed mechanisms, immune-mediated SNHL has been introduced and accepted in the last three decades.
The inner ear has been thought of as an immune privileged organ for a long time. The cochlea has no lymphatic drainage, and the blood-labyrinth barrier is tightly controlled to separate the cochlear microenvironment from the circulation. In addition, the concentration of immunoglobulin in the cochlear fluid is 1/1,000 of the concentration in the cerebrospinal fluid (Harris and Ryan, 1984). McCabe (1979) introduced the clinical definition of autoimmune inner ear disease as rapidly progressive bilateral hearing loss that responds to corticosteroid and immunosuppressive therapy. Corticosteroids have been widely used as the first and only regimen to treat virtually all types of SNHL with sudden onset or rapid progression even before McCabe’s report. The anti-inflammatory and immune suppressive functions of corticosteroids led to their common use for hearing loss, especially when inflammation or an immunological disorder is suspected. Despite the common use of corticosteroids for inner ear disorders, our understanding of their role in the pathogenesis of reversible hearing loss remains limited. Steroid-responsive hearing loss does not always indicate an underlying inflammation or immune disorder in the inner ear (Trune and Canlon, 2012). Topical application of corticosteroids in the tympanic cavity has also been reported in patients unable to tolerate systemic treatment due to global adverse effects (Kakehata et al., 2006; Han et al., 2009), and the functional mechanisms of systemic and topical corticosteroid application supposedly differ. Therefore, a better understanding of the inner ear immunology and mechanisms of corticosteroids in the inner ear would enable development of a more sophisticated therapy for SNHL, including immune-mediated inner ear disease. In addition, alternative strategies of modulating immune activity without corticosteroids are desirable for treating certain types of SNHL.
In this review, we will discuss the characteristics and suspected pathophysiology of clinical hearing loss mediated by the immune system. Second, we will describe the current understanding of the inner ear immune system and will explore recent advances in both basic and clinical research of the mechanism of corticosteroid therapy in the inner ear. Finally, we will discuss current and potential SNHL therapies, including treatments targeting immune-mediated inner ear disease.
PATHOPHYSIOLOGY OF SNHL FROM AN IMMUNOLOGICAL VIEWPOINT
The pathophysiology of organ-specific autoimmune disease is believed to be initiated by three primary mechanisms: (i) production of autoantibodies against tissue antigens, (ii) deposition of antigen–antibody complexes in tissue, and (iii) infiltration and destruction of tissue by specific cytotoxic T-cells. To date, the mechanisms of hearing loss in immune-mediated inner ear disease has yet to be determined, and none of the three described pathophysiology mechanisms have been reported in the human inner ear.
Immune-mediated inner ear disease was originally defined by McCabe (1979), who stated that idiopathic bilateral SNHL progresses to deafness over weeks or months, not hours, days, or years, and responds to corticosteroid and immunosuppressive therapy. The term of autoimmune inner ear disease refers to a pathology restricted to the inner ear. The time course of hearing loss distinguishes immune-mediated inner ear disease from sudden deafness or age-related hearing loss. Although this clinical entity is probably immune-mediated as immunosuppressive agents are effective, there is no direct evidence that the condition is autoimmune in etiology because diagnostic biopsy of the human inner ear is not feasible. Moreover, there are no uniformly accepted diagnostic criteria of immune-mediated inner ear disease. The presence of bilateral SNHL of at least 30 dB with evidence of progression in at least one ear on two serial audiograms performed less than 3 months apart is often used as case criteria (Moscicki et al., 1994). Fluctuations in hearing may occur, and immune-mediated disease is one of the few reversible causes of SNHL. Further study is still required to determine the pathophysiologic mechanisms underlying immune-mediated inner ear disease.
The pathology of Meniere’s disease has historically been defined as an inner ear disorder presenting with endolymphatic hydrops. It is well known that some patients with Meniere’s disease show remarkable recovery from fluctuating and refractory SNHL or vertigo following systemic corticosteroid treatment; therefore, an immune-mediated mechanism has been implicated in the pathology of Meniere’s disease (Hughes et al., 1983; Derebery et al., 1991). In a study of patients with Meniere’s disease, immunohistochemistry showed IgG deposition in the endolymphatic sac obtained by surgical biopsy in 10 of 23 patients (Dornhoffer et al., 1993). Alleman reported that 3 of 30 (10%) patients with Meniere’s disease showed a positive serum reaction against proteins extracted from the endolymphatic sac of autopsy samples, and clinical data have shown an association between immunoreactivity and the disease severity (Alleman et al., 1997), suggesting an autoimmune component in some cases of Meniere’s disease. In contrast, other studies report a relationship between herpes simplex virus and the pathology of Meniere’s disease (Bergstrom et al., 1992; Kumagami, 1996). Although it appears likely that an immune reaction is involved in the pathophysiology of Meniere’s disease, the mechanism of endolymphatic hydrops, whether caused by viral infection, autoimmune reaction, or both, remains to be elucidated.
Multisystemic, organ-nonspecific autoimmune pathology may involve the inner ear, leading to secondary SNHL. A limited number of studies have evaluated human temporal bones from patients with autoimmune disease, such as Wegener granulomatosis, polyarteritis nodosa, Cogan syndrome, and lupus (McCabe, 1989; Moscicki et al., 1994). Some specimens showed fibrosis and osteoneogenesis, consistent with the end stage of inflammation. Other bones demonstrated atrophy of the stria vascularis, the organ of Corti, and the spiral ganglion without evidence of inflammation, findings consistent with ischemia. Dettmer et al. (2011) reported that the temporal bones of Crohn’s disease patients with granulomatous inner ear disease demonstrated mild chronic inflammation, poorly defined granulomas, and infiltration of CD68-positive macrophages.
Cytomegalovirus (CMV) is the leading cause of human non-hereditary congenital hearing loss. Approximately 10–20% of children with congenital CMV infection exhibit varying degrees of hearing loss (Barbi et al., 2003; Numazaki and Fujikawa, 2004). However, the pathology of congenital CMV infection within the inner ear is poorly understood. Various animal models have been employed to study the pathology of SNHL caused by intrauterine CMV infection (Woolf et al., 1989; Juanjuan et al., 2011; Wang et al., 2013). Two studies using mouse CMV infection models reported that CMV DNA was detected in spiral ganglion neurons and the stria vascularis (Juanjuan et al., 2011; Wang et al., 2013), suggesting a potential therapeutic target in CMV-induced SNHL. Multiple studies have focused on developing effective vaccines or antiviral therapy for congenital CMV infection. Unfortunately, there is no clinically effective vaccine for congenital CMV infection or CMV-induced SNHL (Arvin et al., 2004).
Several mechanisms have been postulated as the pathophysiology of sudden deafness, including microcirculatory disturbances caused by thrombosis, microtrauma or rupture of endolymph, viral infection or reactivation, and immune-mediated reaction.
One of the main pathophysiology theories of idiopathic sudden deafness is that viral infection or reactivation in the inner ear damages critical structures in the cochlea. Increased serum concentrations of antibodies against CMV, herpes zoster, herpes simplex type 1, influenza B, and mumps have been reported in patients with idiopathic sudden deafness (Merchant et al., 2008; Pyykko and Zou, 2008). Cochlear enhancement on magnetic resonance imaging (MRI) is a potential sign of inflammation in the inner ear and has been observed in some patients suffering from sudden deafness (Stokroos et al., 1998). The inner ear enhancement on MRI disappeared following resolution of hearing loss in 2 of 12 patients with sudden deafness (Mark et al., 1992). Garcia-Berrocal et al. (1997) reported a decreased concentration of both CD4+ and CD8+ cells in patients compared to healthy control subjects, suggesting an abnormal autoimmune response in lymphocyte subpopulations in patients with sudden deafness. In addition, western blot assay showed a response to recombinant human heat shock protein 70, a non-specific heat shock protein, in 19 of 58 (33%) patients with idiopathic SNHL (Tebo et al., 2006). An analysis of 11 human temporal bones from patients with sudden SNHL showed that the morphology of the stria vascularis and spiral ligament were relatively preserved, supporting a viral etiology rather than a vascular insufficiency (Linthicum et al., 2013). These findings suggest that immune mechanisms, including T cell-mediated and antibody responses, are involved, at least in part, in the onset or progression of idiopathic sudden deafness.
EVIDENCE OF THE IMMUNE SYSTEM IN THE INNER EAR
As previously mentioned, the inner ear was believed to be “immune-privileged” and to exclude all immunocompetent cells, except in the endolymphatic sac, for a long time because chronic degeneration without neutrophilic infiltration in the organ of Corti has been described in patients with presbycusis or hearing loss due to chronic noise exposure. However, Rask-Andersen and Stahle (1979) initiated a new era of inner ear immunology by describing intimate contact between the lymphocytes and macrophages in the endolymphatic sac of guinea pigs. This association suggested that two cell types mediated the antigen-presenting process in the endolymphatic sac. The presence of immunocompetent cells and phagocytized antigen within macrophages was also reported in the endolymphatic sac (Harris et al., 1997). These findings revealed the specific role of the endolymphatic sac in antigen processing and immune activity in the inner ear. However, recent studies have demonstrated the presence of immunoreactive cells in other areas of the inner ear even under normal conditions (Lang et al., 2006; Okano et al., 2008; Sato et al., 2008). Lang et al. (2006) reported that bone marrow-derived cells of hematopoietic origin migrate into the cochlea and reside in the cochlear modiolus and the cochlear lateral wall. They also showed that bone marrow-derived cells in the cochlea express ion transporters such as the sodium/potassium/chloride co-transporter or sodium/potassium-ATPase in the cochlear lateral wall, which contains several types of fibrocytes. In a study using bone marrow-chimeric mice that were transplanted with hematopoietic stem cells after receiving lethal systemic irradiation, Okano et al. (2008) demonstrated that bone marrow-derived cells reside as macrophages in the cochlea. They also reported that Iba-1-positive macrophages were continuously and slowly replaced by bone marrow-derived cells from the systemic circulation over several months. Finally, Sato et al. (2008) reported that bone marrow-derived cells expressing CX3CR1, a fractalkine receptor specific to monocytes, natural killer cells, activated T-cells, and tissue macrophages, reside in the spiral ganglion and spiral ligament. In addition, they showed that CX3CR1-positive cells were repopulated in the cochlea over several months. Collectively, these findings indicate that the inner ear harbors immunocompetent cells of hematopoietic origin normally, with most cells likely to be tissue macrophages phenotypically. Although these tissue macrophages are distributed primarily in the spiral ganglion, spiral limbus, and spiral ligament, macrophage-like melanocytes are also observed in the intermediate layer of the stria vascularis (Zhang et al., 2012). These melanocytes reside adjacent to blood vessels and are believed to be perivascular-resident macrophages that contribute to the formation of the blood-intrastrial fluid barrier (Figure Figure11).
Distribution of cochlear macrophages. Schematic drawing shows the cross section of the cochlear duct. Cochlear macrophages reside in the spiral ligament and spiral limbus where fibrocytes are located to keep ion exchanges. In addition, macrophages are ...
The role of cochlear macrophages and mechanisms of macrophage migration into the cochlea remain largely unknown. Previous studies demonstrated that injury of the auditory sensory epithelium induces inflammation characterized by macrophage infiltration into the chick basilar papilla (Warchol, 1997; Bhave et al., 1998). A large increase in the number of CD45-positive cells has been observed after noise exposure in the mouse cochlea, suggesting inflammation caused by bone marrow-derived cells (Hirose et al., 2005; Tornabene et al., 2006). The number of cochlear macrophages is also increased after aminoglycoside insult in both the spiral ganglion and spiral ligament (Sato et al., 2010). These findings indicate that cochlear macrophages play important roles in the onset and progression of inflammation after damage to the cochlear sensory epithelium. Macrophages in the cochlea are likely involved not only in the degeneration of the organ of Corti, but also the stria vascularis. Jabba et al. (2006) reported that hyperpigmentation of the stria vascularis and reorganization of marginal cells occurs in Slc26a4-null mice, a mouse model of Pendred syndrome, and is associated with the invasion of CD68-positive macrophages. Similar findings regarding hyperpigmentation of the stria vascularis have also been reported in genetically modified mice (Singh and Wangemann, 2008; Lu et al., 2012). The invasion of macrophages is restricted to the degenerated stria vascularis, suggesting contribution from the cochlear macrophages to degeneration or regeneration of the stria vascularis and the cochlear lateral wall.
The number of cochlear macrophages is also increased by systemic administration of macrophage colony stimulating factor (Csf1), which is one of the primary regulators of mononuclear phagocyte activation. The density of Iba1-positive macrophages is increased in both the spiral ligament and spiral ganglion 1 day after administering Csf1 (Okano et al., 2008), but it is unclear whether the increased macrophage population is due to migration from the circulation or in situ proliferation in the cochlea. Yagihashi et al. (2005) also demonstrated that topical administration of Csf1 ameliorates the degradation of auditory neurons following surgical injury in a rat model. In addition, Csf1 was demonstrated to have neuroprotective properties in an in vitro model of excitotoxicity in hippocampal neurons, suggesting both direct and indirect effects of Csf1 on survival of targeted cells (Vincent et al., 2002). It is unknown whether the activation of tissue macrophages has protective or degenerative effects in the target organ, but control of macrophage activity through Csf1 administration is a potential approach for several inner ear disorders.
Previous reports investigating in situ proliferation of cochlear macrophages are controversial. Using Bromodeoxyuridine labeling, Hirose et al. (2005) reported that cochlear macrophages do not proliferate after acoustic trauma. However, according to the study done by Okano et al. (2008) a subset of macrophages expressed Ki67, suggesting that resident macrophages enter the cell cycle after migration following surgical invasion of the cochlea. Although the precise nature of migrating macrophages is to be determined, cochlear macrophages are most likely responsible for several different inner ear pathologies.
TISSUE MACROPHAGES IN THE INNER EAR
In general, adaptive immune cells play a major role in disease progression, and the innate immune system, primarily monocytes and macrophages, plays a central role in the onset of immune activity. The concept of multiple macrophage activation states is not new, but extending this idea to resident tissue macrophages has garnered increased interest in recent years. Unfortunately, research of peripheral macrophage polarization might not accurately describe their central nervous system counterparts.
Macrophages are derived from monocyte precursors that undergo tissue-specific differentiation and infiltrate the site of infection or injury to produce inflammatory mediators. The cells typically polarize into the pro-inflammatory M1 phenotype and function as an effector of the Th1-mediated immune response. The M1 polarization of macrophages is regulated by several factors including the mineralocorticoid receptor (Lawrence and Natoli, 2011). In the normal course of inflammation, the immune process is controlled, and M1-macrophages undergo apoptosis or switch to the anti-inflammatory M2 phenotype, thereby halting inflammation. However, if the inflammatory response of macrophages is not controlled, it becomes pathogenic, resulting in significant levels of non-specific tissue damage and leading to inflammatory and autoimmune diseases (Wynn et al., 2013). Therefore, macrophage-targeted therapy is extremely relevant in improving the prognosis of inflammatory diseases, particularly inflammation in the inner ear.
Thought provoking observations have been obtained in studies of patients with human immunodeficiency virus (HIV), specifically concerning macrophage function in the inner ear. Monocytes and macrophages are susceptible to HIV infection and are considered a main mechanism responsible for central nervous system infection in areas containing perivascular macrophages and parenchymal microglia (Burdo et al., 2013). Lin et al. (2013) demonstrated that HIV infection is significantly associated with an increased risk of developing sudden deafness in patients aged between 18 and 35 years. In addition, Assuiti et al. (2013) found no direct association between anti-retroviral therapy and hearing loss but stressed the need for future investigation of the causes and association between anti-retroviral therapy and hearing loss. These data suggest that deficiencies in the macrophage and monocyte lineage may lead to dysfunction in the inner ear and highlight the important roles of macrophages in the maintenance of auditory function.
Several surface markers have been used in the animal studies of macrophages to immunohistochemically test their phenotypes and distribution in the tissues. CD68 is a heavily glycosylated transmembrane protein and is a common surface marker expressed in all macrophages (Smith and Koch, 1987; Ramprasad et al., 1996). F4/80 is a member of a gene family that includes the human epidermal growth factor module-containing mucin-like hormone receptor 1 and human CD97, and resides on the surface of a family of cells that includes all well differentiated members of the mononuclear phagocyte system. Although the precise function of F4/80 is not completely understood as F4/80-null mice have no remarkable phenotype, F4/80-positive cells have many common features regardless of their tissue location and are characterized by highly ramified cell shape (Hume et al., 2002). Iba1 is a calcium binding protein specific to macrophages that mediates calcium signals that may control migration and phagocytosis in tissue macrophages (Imai et al., 1996). Reportedly, tissue macrophages in the inner ear express Iba1 in addition to F4/80 (Okano et al., 2008). Csf1r is an alternative surface marker on macrophages and is thought to play key roles in the proliferation, differentiation, and survival of macrophages (Hume et al., 2002). In other categorical systems, the differentiation of monocytes and macrophages is described based on the expression of specific cell markers. If similar markers could be identified in tissue macrophages or cells of monocyte lineage, it may be possible to trace these cells along several different points of the inner ear pathophysiology, including systemically circulating monocytes, migrating monocytes, and resident tissue macrophages.
CORTICOSTEROID THERAPY
Systemic or possibly local administration of corticosteroids is the mainstay of treatment for SNHL, including immune-mediated inner ear disease. However, there are limited prospective data evaluating the appropriate dose, route, and length of corticosteroid treatment. In addition, although many patients experience a short-term response to steroids, the response is generally not sustained (Zeitoun et al., 2005). A prospective, randomized, controlled study in 116 patients with rapidly progressive, bilateral SNHL reported that 57% of patients in the 1 month prednisone challenge showed improved hearing, but adverse effects such as hyperglycemia were observed in 14% of patients (Alexander et al., 2009). A meta-analysis of the management of idiopathic sudden SNHL performed by Spear and Schwartz (2011) reported that intratympanic corticosteroids administered as the primary treatment appeared equivalent to treatment with high-dose oral prednisone. Furthermore, intratympanic administration of corticosteroids potentially recovered some degree of hearing as a salvage therapy. These observations suggest that the local administration of corticosteroids is beneficial through mechanisms distinct from those of systemic corticosteroid therapy.
Despite numerous clinical reports of corticosteroid treatment for SNHL, the spontaneous rate of recovery in acute SNHL complicates conclusions about corticosteroid efficacy. To date, the mechanisms underlying fluctuating SNHL in an immune-mediated inner ear disease are unclear. We know little on how corticosteroids work in the inner ear and which parts of the inner ear are affected during reversible hearing loss. The expression of glucocorticoid receptors in the inner ear is limited to the inner and outer hair cells, the spiral ganglion, and the spiral ligament (Tahera et al., 2006; Meltser et al., 2009). In addition to glucocorticoid receptors, corticosteroids have a strong affinity for mineralocorticoid receptors. The use of systemic mineralocorticoids alone or in combination with glucocorticoids has not been evaluated in humans, but is apparently efficacious in animal models (MacArthur et al., 2008). Because the inner ear requires tight regulation of ion homeostasis in both the perilymph and endolymph, the effect of corticosteroid therapy through mineralocorticoid receptors should be considered in the mechanism of action when treating SNHL. Moreover, there are several questions on the assumptions which clinicians and researchers take for granted. Do corticosteroids only suppress inflammation and immune response in the inner ear? Do corticosteroids affect the inner ear specifically or do the systemic effects of corticosteroids benefit the inner ear disorder? Does immune-mediated hearing loss always respond to corticosteroids? A better understanding of the immune-mediated aspects of hearing loss and specific diagnostic assays would lead to the development of immune-modulating therapy for sudden or progressive SNHL.
McCabe recommended high-dose corticosteroids along with cyclophosphamide therapy for prolonged treatment of immune-mediated inner ear disease (McCabe, 1979). However, the extended follow-up of patients treated with cyclophosphamide revealed potential adverse effects and long-term morbidity and mortality risks of the agent, particularly neoplasm development in younger patients, which limited its use and prompted the search for other immunosuppressive options (Harris et al., 2003; Garcia-Berrocal et al., 2006).
Methotrexate has been used as a sparing treatment to control refractory immune-mediated SNHL. Salley et al. (2001) reported improvement in the majority of 53 patients with immune-mediated inner ear diseases who were treated with low-dose methotrexate. Long-term, low-dose methotrexate therapy appeared to be effective in at least some patients with immune-mediated hearing loss that is refractory to traditional corticosteroid therapy (Matteson et al., 2001). By contrast, a randomized, double-blind, placebo-controlled trial in 2003 of immune-mediated inner ear disease suggested that methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy (Harris et al., 2003).
Azathioprine was also reported as an alternative option in treating immune-mediated inner ear disease, although reports were based on small case series and were inconclusive (Lasak et al., 2001).
According to these findings, systemic immunosuppressives such as methotrexate are effective in some patients with bilateral, progressive, or fluctuating SNHL, which indicates an immune component in the pathophysiology of hearing loss. However, the diagnostic criteria of immune-mediated inner ear disease vary among previous reports. Clinicians and investigators should consider that patients with bilateral fluctuating SNHL do not always have an immune disorder in the inner ear.
RECENT ADVANCES AND FUTURE DIRECTIONS OF SNHL TREATMENT
MOLECULAR-TARGETED DRUGS AND BIOLOGICAL AGENTS
Despite initial optimistic reports suggesting a therapeutic effect of methotrexate, a recent study by Harris et al. (2003) failed to demonstrate its efficacy for long-term management of immune-mediated inner ear diseases as mentioned above. Instead, molecular-targeted drugs have garnered attention of investigators and clinicians in the fields of immunology and audiology due to their specificity against therapeutic targets, resulting in less toxicity and fewer adverse effects.
Etanercept is a fusion protein comprising two recombinant tumor necrosis factor (TNF) receptors linked to the C portion of human IgG1 (Mohler et al., 1993). A retrospective case series by Rahman et al. (2001) examined the response to etanercept in 12 patients with immune-mediated haring loss responsive to high-doses of corticosteroids. Improvement or stabilization of hearing and tinnitus was observed in 91% of patients, suggesting that etanercept therapy is safe and may be efficacious in some patients with immune-mediated hearing loss. By contrast, two studies reported that etanercept has no substantial efficacy in improving hearing loss (Cohen et al., 2005; Matteson et al., 2005). Further studies are needed evaluating alternative regimens that use etanercept or other anti-TNF-alpha agents.
Infliximab is another monoclonal antibody against TNF-alpha that binds TNF-alpha and reduces its activity (Siddiqui and Scott, 2005). A retrospective review of eight patients with suspected immune-mediated hearing loss refractory to conventional treatment examined the efficacy of infliximab on hearing improvement; however, none of the patients exhibited a positive response to infliximab therapy based on objective measurements (Liu et al., 2011). Monoclonal antibody therapy directly targeting cells in the inner ear is unlikely to be effective because the concentration of immunoglobulin is much lower in this region than that in cerebrospinal fluid or blood due to tight regulation by the blood-labyrinthine barrier. Accordingly, transtympanic administration of infliximab was evaluated by Van Wijk et al. (2006) in nine patients with immune-mediated hearing loss. Transtympanic administration of infliximab resulted in hearing improvement and reduced disease relapses, indicating the potential utility of local administration of monoclonal antibody in treating inner ear disease.
Adalimumab was also used to block TNF signaling in patients with immune-mediated hearing loss, but reports were based on a small number of cases (Morovic Vergles et al., 2010).
Rituximab is a genetically engineered chimeric monoclonal antibody against CD20, which resides the surface of B cells. The agent reduces autoantibody production both in circulating and tissue B cells, but does not affect plasma cells. A small pilot study in patients with immune-mediated inner ear diseases was performed evaluating the efficacy of rituximab in treating hearing loss (Cohen et al., 2011). Further evaluation of rituximab is encouraged using a properly designed randomized study.
NUCLEIC ACID THERAPY
Nucleic acid therapy, including delivery of gene constructs to increase or force expression in the targeted tissue, and small interfering RNA to block expression of a specific gene, is a promising approach for treating inner ear disease. However, limited access to the lesion site creates challenges in nucleic acid therapy of the inner ear. Various studies employing animal models utilize viral vectors to introduce the nucleic acid into the inner ear, but there are toxicity and safety concerns associated with this method, including immunogenicity and mutagenesis. Non-viral vectors are advantaged by overcoming these limitations plaguing viral vectors. Although nucleic acid therapy is challenging in the in vivo setting, the development of novel delivery systems could lead to drastic advances in improving the prognosis of patients with SNHL. Obviously, macrophages are a potential target for nucleic acid therapy using novel delivery systems in the inner ear, controlling not only inflammation and degeneration of sensory organs, but also regeneration of the cochlear lateral wall and innervation from the spiral ganglion neurons to hair cells.
DELIVERY OF GENE MODIFIED MACROPHAGES
The last, but not least, the use of genetically modified monocytes or macrophages as vectors should be considered for production of therapeutic molecules or factors that promote regeneration or regrowth of specific structures in the inner ear. This concept is especially well suited for a secreted paracrine or endocrine factor such as a hormone or growth factor. Because the inner ear contains three fluid-filled compartments, secreted factors from genetically modified macrophages could potentially diffuse throughout the inner ear without help from the blood or lymphatic circulation. Although the use of genetically modified cells as vectors of genes or pharmacotherapeutic reagents is in the early stage (Hakuba et al., 2005; Okano et al., 2006; Kesser and Lalwani, 2009), transplantation of genetically engineered cells able to secrete specific metabolic or humoral cues could augment pharmacologic immune modulation in the inner ear. Delivery of genetically modified cells into the inner ear could pose a major challenge because of the anatomical characteristics of the inner ear. Monocytes and macrophages are able to migrate into the inner ear in both pathologic and normal conditions (Hirose et al., 2005; Okano et al., 2008). Thus, the human monocyte lineage could be isolated and cultured ex vivo and genetically manipulated. Intravenous administration of genetically modified monocytes could enable them to reach and migrate into the inner ear, although tissue- or organ specificity could be a potential problem to overcome in clinical applications (Figure Figure22).
Schematic depictions of a concept to utilize genetically modified macrophages for the treatment of inner ear diseases. Autologous monocyte lineage is taken from patient’s peripheral blood, and transfected plasmids of targeted gene. After ex vivo ...
Apart from resident macrophages at the disease site, circulating monocytes are continuously recruited to meet the demands of the inflammatory response and the expression of chemokines, cytokines, and cell adhesion molecules. An alternative approach is to facilitate phagocytosis of loaded delivery vehicles by monocytes, which then passively targets the site of disease due to the mounting immune response. The active targeting approach is most attractive and promising if the surface of the delivery vehicle can be decorated with a ligand that selectively interacts with their target receptors. Further research evaluating the use of monocytes as vehicles is desired.
CONCLUSION
In this review, we discussed the involvement of the immune system in the pathology of SNHL, particularly the innate immune system in the inner ear and the pathology of immune-mediated inner ear disease. Recent advances in basic and clinical audiology and immunology research has been rapid. Although there is still much work to be done, we believe that the future of inner ear immunology and SNHL treatment are bright and promising.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
This study was supported by funds from the Shimizu Foundation of Immunology and Neuroscience Grant for 2012 and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan and Japan Society for Promotion of Science.
Front Pharmacol. 2014; 5: 205.
Published online 2014 Sep 2. doi: 10.3389/fphar.2014.00205
PMCID: PMC4151383
Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss
Takayuki Okano*Abstract
Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.
Keywords: resident macrophages, autoimmunity, corticosteroids, cell therapy, molecular targeted drugs
INTRODUCTION
Sensorineural hearing loss (SNHL) is a collection of common auditory disorders resulting from dysfunction of the inner ear, auditory nerve, or the auditory processing pathway in the central nervous system. SNHL comprises a wide variety of auditory disorders including sudden deafness, age-related hearing loss, noise-induced hearing loss, and Meniere’s disease. To date, very little of the SNHL pathophysiology is known because biopsy of the human inner ear is not feasible. Among the purposed mechanisms, immune-mediated SNHL has been introduced and accepted in the last three decades.
The inner ear has been thought of as an immune privileged organ for a long time. The cochlea has no lymphatic drainage, and the blood-labyrinth barrier is tightly controlled to separate the cochlear microenvironment from the circulation. In addition, the concentration of immunoglobulin in the cochlear fluid is 1/1,000 of the concentration in the cerebrospinal fluid (Harris and Ryan, 1984). McCabe (1979) introduced the clinical definition of autoimmune inner ear disease as rapidly progressive bilateral hearing loss that responds to corticosteroid and immunosuppressive therapy. Corticosteroids have been widely used as the first and only regimen to treat virtually all types of SNHL with sudden onset or rapid progression even before McCabe’s report. The anti-inflammatory and immune suppressive functions of corticosteroids led to their common use for hearing loss, especially when inflammation or an immunological disorder is suspected. Despite the common use of corticosteroids for inner ear disorders, our understanding of their role in the pathogenesis of reversible hearing loss remains limited. Steroid-responsive hearing loss does not always indicate an underlying inflammation or immune disorder in the inner ear (Trune and Canlon, 2012). Topical application of corticosteroids in the tympanic cavity has also been reported in patients unable to tolerate systemic treatment due to global adverse effects (Kakehata et al., 2006; Han et al., 2009), and the functional mechanisms of systemic and topical corticosteroid application supposedly differ. Therefore, a better understanding of the inner ear immunology and mechanisms of corticosteroids in the inner ear would enable development of a more sophisticated therapy for SNHL, including immune-mediated inner ear disease. In addition, alternative strategies of modulating immune activity without corticosteroids are desirable for treating certain types of SNHL.
In this review, we will discuss the characteristics and suspected pathophysiology of clinical hearing loss mediated by the immune system. Second, we will describe the current understanding of the inner ear immune system and will explore recent advances in both basic and clinical research of the mechanism of corticosteroid therapy in the inner ear. Finally, we will discuss current and potential SNHL therapies, including treatments targeting immune-mediated inner ear disease.
PATHOPHYSIOLOGY OF SNHL FROM AN IMMUNOLOGICAL VIEWPOINT
The pathophysiology of organ-specific autoimmune disease is believed to be initiated by three primary mechanisms: (i) production of autoantibodies against tissue antigens, (ii) deposition of antigen–antibody complexes in tissue, and (iii) infiltration and destruction of tissue by specific cytotoxic T-cells. To date, the mechanisms of hearing loss in immune-mediated inner ear disease has yet to be determined, and none of the three described pathophysiology mechanisms have been reported in the human inner ear.
Immune-mediated inner ear disease was originally defined by McCabe (1979), who stated that idiopathic bilateral SNHL progresses to deafness over weeks or months, not hours, days, or years, and responds to corticosteroid and immunosuppressive therapy. The term of autoimmune inner ear disease refers to a pathology restricted to the inner ear. The time course of hearing loss distinguishes immune-mediated inner ear disease from sudden deafness or age-related hearing loss. Although this clinical entity is probably immune-mediated as immunosuppressive agents are effective, there is no direct evidence that the condition is autoimmune in etiology because diagnostic biopsy of the human inner ear is not feasible. Moreover, there are no uniformly accepted diagnostic criteria of immune-mediated inner ear disease. The presence of bilateral SNHL of at least 30 dB with evidence of progression in at least one ear on two serial audiograms performed less than 3 months apart is often used as case criteria (Moscicki et al., 1994). Fluctuations in hearing may occur, and immune-mediated disease is one of the few reversible causes of SNHL. Further study is still required to determine the pathophysiologic mechanisms underlying immune-mediated inner ear disease.
The pathology of Meniere’s disease has historically been defined as an inner ear disorder presenting with endolymphatic hydrops. It is well known that some patients with Meniere’s disease show remarkable recovery from fluctuating and refractory SNHL or vertigo following systemic corticosteroid treatment; therefore, an immune-mediated mechanism has been implicated in the pathology of Meniere’s disease (Hughes et al., 1983; Derebery et al., 1991). In a study of patients with Meniere’s disease, immunohistochemistry showed IgG deposition in the endolymphatic sac obtained by surgical biopsy in 10 of 23 patients (Dornhoffer et al., 1993). Alleman reported that 3 of 30 (10%) patients with Meniere’s disease showed a positive serum reaction against proteins extracted from the endolymphatic sac of autopsy samples, and clinical data have shown an association between immunoreactivity and the disease severity (Alleman et al., 1997), suggesting an autoimmune component in some cases of Meniere’s disease. In contrast, other studies report a relationship between herpes simplex virus and the pathology of Meniere’s disease (Bergstrom et al., 1992; Kumagami, 1996). Although it appears likely that an immune reaction is involved in the pathophysiology of Meniere’s disease, the mechanism of endolymphatic hydrops, whether caused by viral infection, autoimmune reaction, or both, remains to be elucidated.
Multisystemic, organ-nonspecific autoimmune pathology may involve the inner ear, leading to secondary SNHL. A limited number of studies have evaluated human temporal bones from patients with autoimmune disease, such as Wegener granulomatosis, polyarteritis nodosa, Cogan syndrome, and lupus (McCabe, 1989; Moscicki et al., 1994). Some specimens showed fibrosis and osteoneogenesis, consistent with the end stage of inflammation. Other bones demonstrated atrophy of the stria vascularis, the organ of Corti, and the spiral ganglion without evidence of inflammation, findings consistent with ischemia. Dettmer et al. (2011) reported that the temporal bones of Crohn’s disease patients with granulomatous inner ear disease demonstrated mild chronic inflammation, poorly defined granulomas, and infiltration of CD68-positive macrophages.
Cytomegalovirus (CMV) is the leading cause of human non-hereditary congenital hearing loss. Approximately 10–20% of children with congenital CMV infection exhibit varying degrees of hearing loss (Barbi et al., 2003; Numazaki and Fujikawa, 2004). However, the pathology of congenital CMV infection within the inner ear is poorly understood. Various animal models have been employed to study the pathology of SNHL caused by intrauterine CMV infection (Woolf et al., 1989; Juanjuan et al., 2011; Wang et al., 2013). Two studies using mouse CMV infection models reported that CMV DNA was detected in spiral ganglion neurons and the stria vascularis (Juanjuan et al., 2011; Wang et al., 2013), suggesting a potential therapeutic target in CMV-induced SNHL. Multiple studies have focused on developing effective vaccines or antiviral therapy for congenital CMV infection. Unfortunately, there is no clinically effective vaccine for congenital CMV infection or CMV-induced SNHL (Arvin et al., 2004).
Several mechanisms have been postulated as the pathophysiology of sudden deafness, including microcirculatory disturbances caused by thrombosis, microtrauma or rupture of endolymph, viral infection or reactivation, and immune-mediated reaction.
One of the main pathophysiology theories of idiopathic sudden deafness is that viral infection or reactivation in the inner ear damages critical structures in the cochlea. Increased serum concentrations of antibodies against CMV, herpes zoster, herpes simplex type 1, influenza B, and mumps have been reported in patients with idiopathic sudden deafness (Merchant et al., 2008; Pyykko and Zou, 2008). Cochlear enhancement on magnetic resonance imaging (MRI) is a potential sign of inflammation in the inner ear and has been observed in some patients suffering from sudden deafness (Stokroos et al., 1998). The inner ear enhancement on MRI disappeared following resolution of hearing loss in 2 of 12 patients with sudden deafness (Mark et al., 1992). Garcia-Berrocal et al. (1997) reported a decreased concentration of both CD4+ and CD8+ cells in patients compared to healthy control subjects, suggesting an abnormal autoimmune response in lymphocyte subpopulations in patients with sudden deafness. In addition, western blot assay showed a response to recombinant human heat shock protein 70, a non-specific heat shock protein, in 19 of 58 (33%) patients with idiopathic SNHL (Tebo et al., 2006). An analysis of 11 human temporal bones from patients with sudden SNHL showed that the morphology of the stria vascularis and spiral ligament were relatively preserved, supporting a viral etiology rather than a vascular insufficiency (Linthicum et al., 2013). These findings suggest that immune mechanisms, including T cell-mediated and antibody responses, are involved, at least in part, in the onset or progression of idiopathic sudden deafness.
EVIDENCE OF THE IMMUNE SYSTEM IN THE INNER EAR
As previously mentioned, the inner ear was believed to be “immune-privileged” and to exclude all immunocompetent cells, except in the endolymphatic sac, for a long time because chronic degeneration without neutrophilic infiltration in the organ of Corti has been described in patients with presbycusis or hearing loss due to chronic noise exposure. However, Rask-Andersen and Stahle (1979) initiated a new era of inner ear immunology by describing intimate contact between the lymphocytes and macrophages in the endolymphatic sac of guinea pigs. This association suggested that two cell types mediated the antigen-presenting process in the endolymphatic sac. The presence of immunocompetent cells and phagocytized antigen within macrophages was also reported in the endolymphatic sac (Harris et al., 1997). These findings revealed the specific role of the endolymphatic sac in antigen processing and immune activity in the inner ear. However, recent studies have demonstrated the presence of immunoreactive cells in other areas of the inner ear even under normal conditions (Lang et al., 2006; Okano et al., 2008; Sato et al., 2008). Lang et al. (2006) reported that bone marrow-derived cells of hematopoietic origin migrate into the cochlea and reside in the cochlear modiolus and the cochlear lateral wall. They also showed that bone marrow-derived cells in the cochlea express ion transporters such as the sodium/potassium/chloride co-transporter or sodium/potassium-ATPase in the cochlear lateral wall, which contains several types of fibrocytes. In a study using bone marrow-chimeric mice that were transplanted with hematopoietic stem cells after receiving lethal systemic irradiation, Okano et al. (2008) demonstrated that bone marrow-derived cells reside as macrophages in the cochlea. They also reported that Iba-1-positive macrophages were continuously and slowly replaced by bone marrow-derived cells from the systemic circulation over several months. Finally, Sato et al. (2008) reported that bone marrow-derived cells expressing CX3CR1, a fractalkine receptor specific to monocytes, natural killer cells, activated T-cells, and tissue macrophages, reside in the spiral ganglion and spiral ligament. In addition, they showed that CX3CR1-positive cells were repopulated in the cochlea over several months. Collectively, these findings indicate that the inner ear harbors immunocompetent cells of hematopoietic origin normally, with most cells likely to be tissue macrophages phenotypically. Although these tissue macrophages are distributed primarily in the spiral ganglion, spiral limbus, and spiral ligament, macrophage-like melanocytes are also observed in the intermediate layer of the stria vascularis (Zhang et al., 2012). These melanocytes reside adjacent to blood vessels and are believed to be perivascular-resident macrophages that contribute to the formation of the blood-intrastrial fluid barrier (Figure Figure11).
Distribution of cochlear macrophages. Schematic drawing shows the cross section of the cochlear duct. Cochlear macrophages reside in the spiral ligament and spiral limbus where fibrocytes are located to keep ion exchanges. In addition, macrophages are ...
The role of cochlear macrophages and mechanisms of macrophage migration into the cochlea remain largely unknown. Previous studies demonstrated that injury of the auditory sensory epithelium induces inflammation characterized by macrophage infiltration into the chick basilar papilla (Warchol, 1997; Bhave et al., 1998). A large increase in the number of CD45-positive cells has been observed after noise exposure in the mouse cochlea, suggesting inflammation caused by bone marrow-derived cells (Hirose et al., 2005; Tornabene et al., 2006). The number of cochlear macrophages is also increased after aminoglycoside insult in both the spiral ganglion and spiral ligament (Sato et al., 2010). These findings indicate that cochlear macrophages play important roles in the onset and progression of inflammation after damage to the cochlear sensory epithelium. Macrophages in the cochlea are likely involved not only in the degeneration of the organ of Corti, but also the stria vascularis. Jabba et al. (2006) reported that hyperpigmentation of the stria vascularis and reorganization of marginal cells occurs in Slc26a4-null mice, a mouse model of Pendred syndrome, and is associated with the invasion of CD68-positive macrophages. Similar findings regarding hyperpigmentation of the stria vascularis have also been reported in genetically modified mice (Singh and Wangemann, 2008; Lu et al., 2012). The invasion of macrophages is restricted to the degenerated stria vascularis, suggesting contribution from the cochlear macrophages to degeneration or regeneration of the stria vascularis and the cochlear lateral wall.
The number of cochlear macrophages is also increased by systemic administration of macrophage colony stimulating factor (Csf1), which is one of the primary regulators of mononuclear phagocyte activation. The density of Iba1-positive macrophages is increased in both the spiral ligament and spiral ganglion 1 day after administering Csf1 (Okano et al., 2008), but it is unclear whether the increased macrophage population is due to migration from the circulation or in situ proliferation in the cochlea. Yagihashi et al. (2005) also demonstrated that topical administration of Csf1 ameliorates the degradation of auditory neurons following surgical injury in a rat model. In addition, Csf1 was demonstrated to have neuroprotective properties in an in vitro model of excitotoxicity in hippocampal neurons, suggesting both direct and indirect effects of Csf1 on survival of targeted cells (Vincent et al., 2002). It is unknown whether the activation of tissue macrophages has protective or degenerative effects in the target organ, but control of macrophage activity through Csf1 administration is a potential approach for several inner ear disorders.
Previous reports investigating in situ proliferation of cochlear macrophages are controversial. Using Bromodeoxyuridine labeling, Hirose et al. (2005) reported that cochlear macrophages do not proliferate after acoustic trauma. However, according to the study done by Okano et al. (2008) a subset of macrophages expressed Ki67, suggesting that resident macrophages enter the cell cycle after migration following surgical invasion of the cochlea. Although the precise nature of migrating macrophages is to be determined, cochlear macrophages are most likely responsible for several different inner ear pathologies.
TISSUE MACROPHAGES IN THE INNER EAR
In general, adaptive immune cells play a major role in disease progression, and the innate immune system, primarily monocytes and macrophages, plays a central role in the onset of immune activity. The concept of multiple macrophage activation states is not new, but extending this idea to resident tissue macrophages has garnered increased interest in recent years. Unfortunately, research of peripheral macrophage polarization might not accurately describe their central nervous system counterparts.
Macrophages are derived from monocyte precursors that undergo tissue-specific differentiation and infiltrate the site of infection or injury to produce inflammatory mediators. The cells typically polarize into the pro-inflammatory M1 phenotype and function as an effector of the Th1-mediated immune response. The M1 polarization of macrophages is regulated by several factors including the mineralocorticoid receptor (Lawrence and Natoli, 2011). In the normal course of inflammation, the immune process is controlled, and M1-macrophages undergo apoptosis or switch to the anti-inflammatory M2 phenotype, thereby halting inflammation. However, if the inflammatory response of macrophages is not controlled, it becomes pathogenic, resulting in significant levels of non-specific tissue damage and leading to inflammatory and autoimmune diseases (Wynn et al., 2013). Therefore, macrophage-targeted therapy is extremely relevant in improving the prognosis of inflammatory diseases, particularly inflammation in the inner ear.
Thought provoking observations have been obtained in studies of patients with human immunodeficiency virus (HIV), specifically concerning macrophage function in the inner ear. Monocytes and macrophages are susceptible to HIV infection and are considered a main mechanism responsible for central nervous system infection in areas containing perivascular macrophages and parenchymal microglia (Burdo et al., 2013). Lin et al. (2013) demonstrated that HIV infection is significantly associated with an increased risk of developing sudden deafness in patients aged between 18 and 35 years. In addition, Assuiti et al. (2013) found no direct association between anti-retroviral therapy and hearing loss but stressed the need for future investigation of the causes and association between anti-retroviral therapy and hearing loss. These data suggest that deficiencies in the macrophage and monocyte lineage may lead to dysfunction in the inner ear and highlight the important roles of macrophages in the maintenance of auditory function.
Several surface markers have been used in the animal studies of macrophages to immunohistochemically test their phenotypes and distribution in the tissues. CD68 is a heavily glycosylated transmembrane protein and is a common surface marker expressed in all macrophages (Smith and Koch, 1987; Ramprasad et al., 1996). F4/80 is a member of a gene family that includes the human epidermal growth factor module-containing mucin-like hormone receptor 1 and human CD97, and resides on the surface of a family of cells that includes all well differentiated members of the mononuclear phagocyte system. Although the precise function of F4/80 is not completely understood as F4/80-null mice have no remarkable phenotype, F4/80-positive cells have many common features regardless of their tissue location and are characterized by highly ramified cell shape (Hume et al., 2002). Iba1 is a calcium binding protein specific to macrophages that mediates calcium signals that may control migration and phagocytosis in tissue macrophages (Imai et al., 1996). Reportedly, tissue macrophages in the inner ear express Iba1 in addition to F4/80 (Okano et al., 2008). Csf1r is an alternative surface marker on macrophages and is thought to play key roles in the proliferation, differentiation, and survival of macrophages (Hume et al., 2002). In other categorical systems, the differentiation of monocytes and macrophages is described based on the expression of specific cell markers. If similar markers could be identified in tissue macrophages or cells of monocyte lineage, it may be possible to trace these cells along several different points of the inner ear pathophysiology, including systemically circulating monocytes, migrating monocytes, and resident tissue macrophages.
CORTICOSTEROID THERAPY
Systemic or possibly local administration of corticosteroids is the mainstay of treatment for SNHL, including immune-mediated inner ear disease. However, there are limited prospective data evaluating the appropriate dose, route, and length of corticosteroid treatment. In addition, although many patients experience a short-term response to steroids, the response is generally not sustained (Zeitoun et al., 2005). A prospective, randomized, controlled study in 116 patients with rapidly progressive, bilateral SNHL reported that 57% of patients in the 1 month prednisone challenge showed improved hearing, but adverse effects such as hyperglycemia were observed in 14% of patients (Alexander et al., 2009). A meta-analysis of the management of idiopathic sudden SNHL performed by Spear and Schwartz (2011) reported that intratympanic corticosteroids administered as the primary treatment appeared equivalent to treatment with high-dose oral prednisone. Furthermore, intratympanic administration of corticosteroids potentially recovered some degree of hearing as a salvage therapy. These observations suggest that the local administration of corticosteroids is beneficial through mechanisms distinct from those of systemic corticosteroid therapy.
Despite numerous clinical reports of corticosteroid treatment for SNHL, the spontaneous rate of recovery in acute SNHL complicates conclusions about corticosteroid efficacy. To date, the mechanisms underlying fluctuating SNHL in an immune-mediated inner ear disease are unclear. We know little on how corticosteroids work in the inner ear and which parts of the inner ear are affected during reversible hearing loss. The expression of glucocorticoid receptors in the inner ear is limited to the inner and outer hair cells, the spiral ganglion, and the spiral ligament (Tahera et al., 2006; Meltser et al., 2009). In addition to glucocorticoid receptors, corticosteroids have a strong affinity for mineralocorticoid receptors. The use of systemic mineralocorticoids alone or in combination with glucocorticoids has not been evaluated in humans, but is apparently efficacious in animal models (MacArthur et al., 2008). Because the inner ear requires tight regulation of ion homeostasis in both the perilymph and endolymph, the effect of corticosteroid therapy through mineralocorticoid receptors should be considered in the mechanism of action when treating SNHL. Moreover, there are several questions on the assumptions which clinicians and researchers take for granted. Do corticosteroids only suppress inflammation and immune response in the inner ear? Do corticosteroids affect the inner ear specifically or do the systemic effects of corticosteroids benefit the inner ear disorder? Does immune-mediated hearing loss always respond to corticosteroids? A better understanding of the immune-mediated aspects of hearing loss and specific diagnostic assays would lead to the development of immune-modulating therapy for sudden or progressive SNHL.
McCabe recommended high-dose corticosteroids along with cyclophosphamide therapy for prolonged treatment of immune-mediated inner ear disease (McCabe, 1979). However, the extended follow-up of patients treated with cyclophosphamide revealed potential adverse effects and long-term morbidity and mortality risks of the agent, particularly neoplasm development in younger patients, which limited its use and prompted the search for other immunosuppressive options (Harris et al., 2003; Garcia-Berrocal et al., 2006).
Methotrexate has been used as a sparing treatment to control refractory immune-mediated SNHL. Salley et al. (2001) reported improvement in the majority of 53 patients with immune-mediated inner ear diseases who were treated with low-dose methotrexate. Long-term, low-dose methotrexate therapy appeared to be effective in at least some patients with immune-mediated hearing loss that is refractory to traditional corticosteroid therapy (Matteson et al., 2001). By contrast, a randomized, double-blind, placebo-controlled trial in 2003 of immune-mediated inner ear disease suggested that methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy (Harris et al., 2003).
Azathioprine was also reported as an alternative option in treating immune-mediated inner ear disease, although reports were based on small case series and were inconclusive (Lasak et al., 2001).
According to these findings, systemic immunosuppressives such as methotrexate are effective in some patients with bilateral, progressive, or fluctuating SNHL, which indicates an immune component in the pathophysiology of hearing loss. However, the diagnostic criteria of immune-mediated inner ear disease vary among previous reports. Clinicians and investigators should consider that patients with bilateral fluctuating SNHL do not always have an immune disorder in the inner ear.
RECENT ADVANCES AND FUTURE DIRECTIONS OF SNHL TREATMENT
MOLECULAR-TARGETED DRUGS AND BIOLOGICAL AGENTS
Despite initial optimistic reports suggesting a therapeutic effect of methotrexate, a recent study by Harris et al. (2003) failed to demonstrate its efficacy for long-term management of immune-mediated inner ear diseases as mentioned above. Instead, molecular-targeted drugs have garnered attention of investigators and clinicians in the fields of immunology and audiology due to their specificity against therapeutic targets, resulting in less toxicity and fewer adverse effects.
Etanercept is a fusion protein comprising two recombinant tumor necrosis factor (TNF) receptors linked to the C portion of human IgG1 (Mohler et al., 1993). A retrospective case series by Rahman et al. (2001) examined the response to etanercept in 12 patients with immune-mediated haring loss responsive to high-doses of corticosteroids. Improvement or stabilization of hearing and tinnitus was observed in 91% of patients, suggesting that etanercept therapy is safe and may be efficacious in some patients with immune-mediated hearing loss. By contrast, two studies reported that etanercept has no substantial efficacy in improving hearing loss (Cohen et al., 2005; Matteson et al., 2005). Further studies are needed evaluating alternative regimens that use etanercept or other anti-TNF-alpha agents.
Infliximab is another monoclonal antibody against TNF-alpha that binds TNF-alpha and reduces its activity (Siddiqui and Scott, 2005). A retrospective review of eight patients with suspected immune-mediated hearing loss refractory to conventional treatment examined the efficacy of infliximab on hearing improvement; however, none of the patients exhibited a positive response to infliximab therapy based on objective measurements (Liu et al., 2011). Monoclonal antibody therapy directly targeting cells in the inner ear is unlikely to be effective because the concentration of immunoglobulin is much lower in this region than that in cerebrospinal fluid or blood due to tight regulation by the blood-labyrinthine barrier. Accordingly, transtympanic administration of infliximab was evaluated by Van Wijk et al. (2006) in nine patients with immune-mediated hearing loss. Transtympanic administration of infliximab resulted in hearing improvement and reduced disease relapses, indicating the potential utility of local administration of monoclonal antibody in treating inner ear disease.
Adalimumab was also used to block TNF signaling in patients with immune-mediated hearing loss, but reports were based on a small number of cases (Morovic Vergles et al., 2010).
Rituximab is a genetically engineered chimeric monoclonal antibody against CD20, which resides the surface of B cells. The agent reduces autoantibody production both in circulating and tissue B cells, but does not affect plasma cells. A small pilot study in patients with immune-mediated inner ear diseases was performed evaluating the efficacy of rituximab in treating hearing loss (Cohen et al., 2011). Further evaluation of rituximab is encouraged using a properly designed randomized study.
NUCLEIC ACID THERAPY
Nucleic acid therapy, including delivery of gene constructs to increase or force expression in the targeted tissue, and small interfering RNA to block expression of a specific gene, is a promising approach for treating inner ear disease. However, limited access to the lesion site creates challenges in nucleic acid therapy of the inner ear. Various studies employing animal models utilize viral vectors to introduce the nucleic acid into the inner ear, but there are toxicity and safety concerns associated with this method, including immunogenicity and mutagenesis. Non-viral vectors are advantaged by overcoming these limitations plaguing viral vectors. Although nucleic acid therapy is challenging in the in vivo setting, the development of novel delivery systems could lead to drastic advances in improving the prognosis of patients with SNHL. Obviously, macrophages are a potential target for nucleic acid therapy using novel delivery systems in the inner ear, controlling not only inflammation and degeneration of sensory organs, but also regeneration of the cochlear lateral wall and innervation from the spiral ganglion neurons to hair cells.
DELIVERY OF GENE MODIFIED MACROPHAGES
The last, but not least, the use of genetically modified monocytes or macrophages as vectors should be considered for production of therapeutic molecules or factors that promote regeneration or regrowth of specific structures in the inner ear. This concept is especially well suited for a secreted paracrine or endocrine factor such as a hormone or growth factor. Because the inner ear contains three fluid-filled compartments, secreted factors from genetically modified macrophages could potentially diffuse throughout the inner ear without help from the blood or lymphatic circulation. Although the use of genetically modified cells as vectors of genes or pharmacotherapeutic reagents is in the early stage (Hakuba et al., 2005; Okano et al., 2006; Kesser and Lalwani, 2009), transplantation of genetically engineered cells able to secrete specific metabolic or humoral cues could augment pharmacologic immune modulation in the inner ear. Delivery of genetically modified cells into the inner ear could pose a major challenge because of the anatomical characteristics of the inner ear. Monocytes and macrophages are able to migrate into the inner ear in both pathologic and normal conditions (Hirose et al., 2005; Okano et al., 2008). Thus, the human monocyte lineage could be isolated and cultured ex vivo and genetically manipulated. Intravenous administration of genetically modified monocytes could enable them to reach and migrate into the inner ear, although tissue- or organ specificity could be a potential problem to overcome in clinical applications (Figure Figure22).
Schematic depictions of a concept to utilize genetically modified macrophages for the treatment of inner ear diseases. Autologous monocyte lineage is taken from patient’s peripheral blood, and transfected plasmids of targeted gene. After ex vivo ...
Apart from resident macrophages at the disease site, circulating monocytes are continuously recruited to meet the demands of the inflammatory response and the expression of chemokines, cytokines, and cell adhesion molecules. An alternative approach is to facilitate phagocytosis of loaded delivery vehicles by monocytes, which then passively targets the site of disease due to the mounting immune response. The active targeting approach is most attractive and promising if the surface of the delivery vehicle can be decorated with a ligand that selectively interacts with their target receptors. Further research evaluating the use of monocytes as vehicles is desired.
CONCLUSION
In this review, we discussed the involvement of the immune system in the pathology of SNHL, particularly the innate immune system in the inner ear and the pathology of immune-mediated inner ear disease. Recent advances in basic and clinical audiology and immunology research has been rapid. Although there is still much work to be done, we believe that the future of inner ear immunology and SNHL treatment are bright and promising.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
This study was supported by funds from the Shimizu Foundation of Immunology and Neuroscience Grant for 2012 and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan and Japan Society for Promotion of Science.
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