2013 Ménière’s Research Plan
Dr. Brown’s Laboratory Work
Now that we have demonstrated that:
- Acute Endolymph Injection provides a good Model for a Ménière’s Attack
- Hydrops can cause Ménière’s-Like Symptoms (i.e. sudden loss of balance function)
- Cochlear & Vestibular function can both be Measured in Experimental Animals
- Hydrops causes the Inner Ear Volume to Swell, but then Collapse
- A Vertigo Attack is probably Not due to a Rupture of the Labyrinth (see video)
We aim to:
- Investigate what Mechanisms Regulate Endolymph Volume
- Introduce Pharmacological Blockers of Ion Channels and Receptors
- Specifically, we will alter Sodium Absorption in the Labyrinth
- We will also alter Purinergic Mediated Ion Channels
It has long been suggested that abnormally large volumes of endolymph can cause Ménière’s Disease, but some previous studies have placed a cloud over this idea with the finding that a percentage of people (~20%) have hydrops but not Ménière’s. Our recent research demonstrated how and why hydrops can cause the symptoms of Ménière’s, and why some people may have hydrops but not experience vertigo attacks.
Now we have to work out what causes hydrops in the first place…..
Numerous pathologies have been suggested to cause Ménière’s Disease (virus, hormone imbalance, allergy, autoimmune disorder, immune disorder, genetic disorder etc…), and many researchers believe that Ménière’s may indeed be the result of any one of these underlying pathologies. The thinking is that one of these pathologies “scars” the inner ear, impairing its ability to regulate endolymph volume. This leads to the question:
How is the volume of the endolymphatic labyrinth regulated normally?
Think of the endolymphatic labyrinth as a leaky balloon which is constantly being filled with water. In the case of the endolymphatic labyrinth, research has shown that normally it is being filled very, very slowly. The labyrinth may swell if it is filled faster (let’s say, due to an immune mediated inflammation), or if it leaked less (let’s say, due to the endolymphatic sac – thought to be an outlet for endolymph, becoming damaged). Many researchers have focused on the endolymphatic sac being damaged, reducing the fluid leakage from the labyrinth. The problem I have with this idea is that, as with almost all forms of physiology, if the leakage is reduced there is probably some sort of feedback mechanism that alters the production of endolymph to compensate.
But how could the inner ear detect the volume of endolymph?
To my mind, there must be some sort of ‘stretch’ sensor in the inner ear, and moreover, this stretch sensor must be able to modify the production (or absorption) of endolymph. At the very least, such a mechanism must be present in the inner ear to ‘setup’ endolymph volume when we are born, but also to maintain a healthy endolymph volume throughout our lives. If I was going to ‘engineer’ an inner ear that had to carefully control endolymph volume so as to avoid the symptoms of Ménière’s Disease, I would put a stretch sensor on a region of the balloon which was most easily stretched (the most compliant part), and I would have the stretch sensor directly open or close the leakage of either water, or alternatively, dissolved salts (because water will inherently follow salt, provided water can flow between compartments).
It so happens that such channels do exist in the inner ear, furthermore, these channels are located on very compliant membranes, and they can alter the flux of salt through them when physically stretched. They have also already been implicated in a number of inner ear pathologies. Specifically, there are stretch-sensitive Sodium Channels, and cation-permeable Purinergic Channels (P2Y and P2X channels). We are only just starting to recognise the role these channels play in the inner ear, despite the fact that their role in regulating extracellular volumes in other parts of the body had been studied for decades.
The difficulties with studying the activity of stretch-sensitive channels are 1) how to stretch them in a way which would be expected physiologically, and 2) how to measure the effects of stretching them. Fortunately for us, we are now in the position that we have a way of activating these putative stretch-sensitive mechanisms in the inner ear, and we also have a way of monitoring their effects on the regulation of fluid volume in the inner ear.
In 2013, Dr Brown’s laboratory aims to pharmacologically manipulate the activity of these stretch-sensitive mechanisms in the inner ear, in an attempt to demonstrate 1) that pathologies which alter the number or function of these channels can lead to hydrops, and 2) that there are drugs which may be able to correct the expression of these channels in the inner ear, as a means for providing a treatment or cure for Ménière’s Disease.
It so happens that a large number of pathologies are known to alter the expression of these channels in the inner ear, so they are a prime target in the hunt for the underlying cause of Ménière’s Disease, and an ideal target for therapeutic intervention.
THE FUND’S CUREPLAN – 1ST QUARTER 2011
TO CURE MENIERE’S DISEASE, WE MUST FIRST UNDERSTAND ITS CAUSE.
Our mission is to finance researchers to arrive at a cause and cure for Meniere’s Disease. (“MD”) We believe that the fastest way to a cure derives from knowing the specific cause or causes of MD to allow researchers to focus on therapeutic interventions. Our programme of research to discover the cause(s) of MD in the shortest possible time allows for cost, development and implementation. We call it the “cureplan”. Our cureplan explains the difficulties and processes of the Fund’s medical research in non-technical, and hopefully easy to understand language without resorting to complex diagrams and essays on inner ear anatomy.
MD IS A COMPLEX DISORDER WITH MULTIPLE APPARENT ROOT CAUSES AND DIAGNOSIS IS ONE OF EXCLUSION.
All diseases are caused by one or more root causes. These can be characterised as:-
- Genetic – a dysfunction caused by abnormal genes or genetic function, possibly passing through generations;
- Pathogens – bacteria, viruses and other infections;
- Toxins – poisonous substances;
- Systemic – improper balance or lack of critical nutrients and hormones;
- Trauma – physical injury, mental stress or environmental factors;
- Morphological – structural changes from tissue damage, tumour, immunological attack etc.
Many diseases are caused by a single or obvious factor – the cause is readily identifiable and the cure progresses in a straightforward manner. MD is unfortunately one of the many complex diseases that may have multiple causes with separate factors acting together to produce the symptoms. MD is simply a name given to a set of symptoms when all other causes have been ruled out. It may be the end stage of the condition, not the beginning. One common pathway many researchers appear to end up with is that MD symptoms are due to endolymphatic “hydrops” or a swelling of inner ear fluid. This condition is more fully detailed below.
Importantly for any MD research, currently there is no tried and tested way to completely diagnose and measure the progress of MD. Despite over 100 years of research, the standard methods to provide a marker or isolate a single root cause have proved inconclusive. It appears that there is evidence of elements of genetic predisposition and perhaps allergy and virus complications and others, but because these elements are complex, it takes longer to discover a cause and makes it even more critical for research to proceed according to a logical and comprehensive plan.
THE CUREPLAN STRATEGY IS BASED ON SYSTEMATICALLY LISTING AND INVESTIGATING THE POSSIBLE CAUSES OF MD.
It would be ideal if we had a list of causes from which we could simply pick and choose together with a method of determining if each cause played a role in MD. Obviously, there is no list. The cureplan has categorised the known research and potential root causes of the symptoms. Its seems probable that the symptoms named MD can be caused by a number of factors, each one resulting in inner ear dysfunction leading to similar clinical features. Perhaps at some time in the future, endolymphatic hydrops without a specific identifiable cause will no longer be the term behind MD, but a clinician will identify and treat the specific biochemical or cellular abnormality.
It’s true that many theories about the cause of MD are taught as fact, but MD is not one pathological entity but a symptom complex. By its very nature of frequent remissions, this disease is a boon to those who propound remedies outside conventional medicine because a high percentage of those diagnosed with MD will improve whilst having any form of therapy. The Fund’s researchers can only consider evidence based material.
The basic approach of our researchers has been to analyse previous research, be trained and skilled in performing basic inner ear research and animal modelling and build upon the experience of the research team who have practised in this field for many years. We have developed a strategy for further research in the most promising areas where we have noticed patterns and relationships as well as gaps in the knowledge base. Our research programme will expand as knowledge and resources become available. Our current programme is set out below:-
1. HUMAN EVOKED RESPONSE TESTING
Our researchers are developing tools for objectively measuring abnormal physiological responses in MD sufferers. These tools will help determine the effectiveness of various treatments, without relying on the subjective views of a sufferer who may be in true a remission period or diminution of the primary symptoms yet still experience other subjective and individual problems such as brain fog, disequilibrium, visual disturbances etc. The tools will also help understand the cause of the disease. Our team recently developed a measurement technique, currently being used in Italy, using echo responses (DPOAEs) from people’s ears which were uniquely abnormal in MD sufferers. We have also begun investigating the use of vestibular evoked responses (VOR and VEMPs) in MD sufferers, to see if they are also uniquely abnormal. Ultimately, we would like a hand-held device that allows us to monitor inner ear function in a MD sufferer over an extended period, with or without treatment. We are hoping to develop this sort of take-home device and study over 2011-2013.
2. VESTIBULAR MEASUREMENTS IN ANIMALS
The Fund’s researchers are developing methods for measuring functional changes in the vestibular system in experimental animals (we already have a host of cochlear measurement techniques). There are currently too few methods for investigating vestibular function in animals, which we need for our MD research. We believe that the combination of cochlear and vestibular measurements in animal models of MD is a far more effective method for researching MD. The team has demonstrated that the vestibular responses we initially set out to obtain can be obtained in animals, and our researchers are the first to record these types of responses in mammals. It’s not currently clear precisely how or if they can be used to indicate mechanical changes in the vestibular system because the responses are very complex, but the Fund’s researchers hope to utilise these responses in a meaningful way in 2011.
3. DEVELOP ANIMAL MODELS OF MENIERE’S
Beginning with systemic treatments of the anti-diuretic hormone vasopressin, which induces hydrops over a 2 week treatment period, we are currently investigating ways of producing MD in animals. At the moment, we are more focused on producing animals with endolymphatic hydrops than MD per se, although we anticipate incorporating steps that induce attacks of vertigo. With a good animal model, we can work more effectively on our understanding and towards a cure for MD (particularly if the methods we use involves the pathology that underlies some forms of MD). It is expect an animal model of MD will emerge by 2013.
4. FUNDAMENTAL INNER EAR RESEARCH
As the Fund’s team research systemic hormones and develop new research tools, it will concurrently learn more about how the inner ear functions normally. Specifically, the team is interested in how the inner ear regulates fluid volumes and concentrations. This is a long running question in the world of inner ear research, and will involve both animal research and mathematical modelling of inner ear physiology, both of which our team is currently set to do. The animal research involves experimentally altering the various structures of the inner ear and monitoring the effects. Researchers then use this information to test mathematical models of inner ear function. With a working model, we can work on computer based simulations of possible causes of MD.
5. SURVEY MENIERE’S SUFFERERS
There have been many surveys of MD sufferers and their symptoms and sufferers often share their experiences publicly. However, we believe some critical aspects of MD may have been overlooked. We will undertake a unique, global physiologically based online survey with a large sample set that may help us more fully understand the aetiology and true cause of the symptoms and timeline of events of MD sufferers.
6. OTHER RESEARCH
Whilst the development of a diagnostic tool is a valuable step in any research investigating MD, we are currently heading toward investigating the role of systemic hormones. The Fund would clearly like to embark on other streams of investigation such as genetic factors, viral issues (a definite possibility), or trauma (less likely to be involved) in order to build upon what has already been researched and to gain deeper insights. Unfortunately resources at this stage prevent such a broad spread of inquiry. Inherent in any medical research, there is a risk that systemic hormone research and a link to MD’s cause may prove fruitless. Thus the next avenue would be to concentrate efforts on viral infections of the inner ear, specifically those which alter the expression or function of ion channels in the inner ear. This may involve research using genetically modified animals (an expensive and lengthy process), or alternatively treating animals with pharmaceuticals that mimic the effects of various viruses. There is also interest among our researchers to analyse the tissues extracted from MD sufferer’s ears during various surgeries, to further investigate the role of viral infections in MD
ENDOLYMPHATIC HYDROPS AND MENIERE’S DISEASE
Centre: from (Katayama et al., 2010) MRI showing enlarged endolymph compartment in the cochlea (dashed outline) in Ménière’s Disease sufferer.
Centre; (from Salt et al., 2009). Endolymphatic hydrops (right panel) in an animal following surgical ablation of the endolymphatic sac.
Most well informed MD sufferers know something about endolymphatic hydrops. Hydrops is a bloating of one of the endolymph filled inner ear fluid chambers, visible in MRI scans or in post-mortem examinations. Almost all MD sufferers end up with hydrops, leading many researchers to believe it may be the cause of the hearing and balance symptoms. With advancing MRI imaging technology, more and more research studies on MD sufferers are emerging and it’s beginning to look like the type of hydrops is correlated with the types of symptoms.
However, studies also demonstrate that almost 1/3rd of people with normal hearing and balance have hydrops. But if they also have hydrops then why don’t they have MD symptoms? The easy answer is that hydrops may not be responsible for the symptoms of MD – it may simply be a hallmark/indicator/ epiphenomenon/side-effect of the underlying pathology. Also, hydrops seems to be present continuously in MD sufferers, but the primary symptoms, especially vertigo, fluctuate over time. How can hydrops be there constantly, but cause transient attacks of vertigo? Is it that the volume of hydrops suddenly changes, causing a transient attack of vertigo?
Some clinicians believe that the volume of hydrops varies over several days, but we currently lack a complete understanding of how hydrops might result in vertigo attacks. Some past researchers have suggested hydrops may cause a rupture or leak of the bloated endolymph chamber, causing different fluids in the ear to mix, resulting in a sudden change in hearing and balance function. However, this “rupture” theory has lost popularity over the years because there is evidence of little hearing loss during an attack in most sufferers, discrediting the rupture model.
The interesting question, (at least to the Fund’s researchers), is why does bloating of the endolymphatic chamber change inner ear function? One theory is that hydrops causes a large increase in endolymph fluid pressure and displaces the cochlear and vestibular hair cells resting on one of the walls of the endolymphatic chamber. A displacement of these hair cells would most likely cause hearing and balance dysfunction. The problem with this idea is the compliant endolymph chamber is very “stretchy” and it’s difficult to increase endolymph pressure to the extent that the hair cells become displaced.
In animals, when endolymphatic volume is artificially increased, there is little increase in endolymphatic pressure (apart from transient effects). Therefore, there is little change in hearing function (nobody truly knows what happens to vestibular function under these conditions as far as we are aware). Furthermore, when endolymphatic hydrops is induced in animals chronically (long-term), there appears little pressure increase, at least not that is measurable (a quite difficult thing to do). If endolymph simply increases in volume without a pressure increase, why would that affect the cochlear and vestibular hair cells given that they would be oblivious to the volume of fluid above them (teleologically speaking)?
One answer could be that with the bloating of the endolymphatic chamber, the cochlear and vestibular hair cells become displaced due to the mechanical stretch of the surrounding chamber walls rather than a pressure increase. That is, it is possible a volume increase, with very little pressure change could be enough to affect the cochlear and vestibular hair cells, leading to hearing and balance problems. Of course, that still doesn’t answer why there is a transient change in function to produce an attack of vertigo, or the underlying cause the volume increase. Professor Bill Gibson has long been working up a theory that describes a sudden reduction in endolymph volume following a slow build-up, and this sudden reduction in endolymph volume causes substantial, transient changes in hearing and in particular, balance function, leading to the attacks of vertigo in MD sufferers.
A great deal of research has focused on what causes endolymphatic hydrops, and for that matter, how the ear regulates the volume of endolymph. Hydrops might result from an over production of, or alternatively a reduced absorption of, the endolymph fluid, or both. Where this fluid secretion/absorption takes place has been debated, with some researchers suggesting it takes place in a side-arm structure in the ear called the ‘endolymphatic sac’, and other researchers suggesting that endolymph fluid is secreted and absorbed throughout the ear locally. When one surgically removes or damages the endolymphatic sac in animals, they end up with hydrops. Debris in the inner ear also tends to end up in the sac, suggesting there might be a flow of endolymph toward the sac, although this idea has been somewhat disproven. The important point to realise is the fluid itself isn’t really secreted or absorbed, water just flows through the various tissues into the most concentrated areas, following the movement of salts in the ear (i.e. the fluids are concentrated with salts, and the tissues regulate where the salts flow, with water more or less just following passively). It’s the distribution of ions and molecules (salts) in the inner ear fluid determining where the water goes. The cellular tissues in the ear largely determine where the salts are directed to.
The ear is basically filled with fluid, although there are two main types. There is the endolymph fluid mentioned above, and then there is perilymph fluid, which surrounds endolymph and a thin membrane separates the two compartments. There are also fluids in the cells and blood vessels that line the bony walls of the inner ear. Perilymph and endolymph are both made of water, but what makes them different to each other is the concentration of salts in either one. Endolymph is high in potassium and chloride, whereas perilymph is high in sodium. The fluids also have different electrical charges, due to the fact that the salts are charged and flow though tissues which have an electrical resistance.
Because the endolymph-filled chamber is surrounded by the perilymph, in order for the endolymph chamber to bloat, perilymph must be displaced out of the perilymph chamber (either into the blood or into the endolymph). That is, it is possible that water enters the endolymph from the perilymph chamber through tiny pores on the membranes that surround it, which only allow water (not salts) to flow through them. These pores are called “aquaporins”, and they exist almost everywhere throughout the ear. One possibility is that the water from the perilymph simply flows through these pores into the endolymph space, causing the endolymph space to swell. Alternatively, water flows into the endolymph from the blood vessels and other tissues of the ear, again through aquaporin pores. One of our current research projects summarised above in paragraph C.4 focuses on systemic hormones that regulate the number of aquaporins in the ear.
VASOPRESSIN IN MENIERE’S DISEASE
Where does water causing the endolymphatic space to bloat and create hydrops, come from? As discussed above, one answer is through “aquaporins”, where water is free move from one chamber of the inner ear to the next. It’s possible then that water from the perilymph-filled chamber simply flows through these pores into the endolymph space, causing the endolymph space to swell. Alternatively, water might flow into the endolymph from the blood vessels and other tissues of the ear, again through aquaporin pores.
Why would abnormal levels of water flow into the endolymph space through these pores? One reason could be the tissues responsible for directing the flow of ions (potassium for example) into the endolymph space stop working properly, possibly making the endolymph very concentrated. Water will generally flow into very concentrated areas (concentrated fluids have more fluid “pressure” than less concentrated fluids). Water flowing from concentrated areas to less concentrated areas and tissues regulating the secretion/transport of ions is a basic aspect of human physiology, and it happens throughout the body (e.g. – that’s how we pee!).
Certain hormones in the body regulate the number of aquaporins in our tissues, and in turn, may be able to regulate the dynamics of how much fluid flows across various tissues. Vasopressin is one such hormone (it’s an anti-diuretic hormone). Vasopressin has a number of functions in the body, such as regulating how much we urinate, regulating blood pressure and regulating a number of central nervous system functions. Given that vasopressin regulates the number of aquaporins in our tissues, it’s reasonable to ask, “Does hydrops develop because there is too much vasopressin in my ear and too much water flowing into my endolymphatic chamber?” Of course, simply increasing the number of aquaporins in the ear alone would not lead to an increased flow of water into the endolymph – the endolymph would have to be more concentrated than the other fluids in the ear – which it doesn’t normally appear to be. So simply increasing vasopressin and aquaporins is probably only part of the story, if at all.
Having said that, research has shown that if we experimentally increase the levels of vasopressin in animals (or desmopressin, which is similar), endolymphatic hydrops is induced. There is also some evidence that people with endolymphatic hydrops have abnormal levels of vasopressin in their blood, although this is being debated by researchers. Nonetheless, the fact that vasopressin can induce hydrops in animals gives us:
- A simple way of inducing hydrops to investigate what it does to hearing and balance mechanics;
- An insight into how the ear regulates its fluid volumes, and
- A possible lead on what may be causing MD.
Researchers at the Fund are not the only ones investigating possible links between vasopressin and MD. At present, we are researching the effects that vasopressin treatment has on the function of the inner ear, partly to help us to understand how the ear regulates the volumes of fluid (to prevent bloating and a displacement of the hair cells), and partly to simply understand what fluid bloating in the ear does mechanically to hearing and balance function. In other words, we need to find out one way or the other if vasopressin is truly involved in MD. Even if it isn’t, we still need to clarify what abnormal inner ear fluid volumes does to inner ear function. The Funds research involves treating animals with vasopressin systemically (via the blood) over several weeks while monitoring the animal’s hearing and balance function using our special non-invasive measurement techniques (i.e. using tests like we use on humans).
Several problems with vasopressin/MD theory are that:
- Vasopressin doesn’t induce vertigo (although Japanese researchers recently demonstrated that it does when combined with other treatments –very encouraging).
- It isn’t clear if the level of vasopressin in the body is actually elevated in MD sufferers, and even if it is, it may be a result of and not the cause of the disease.
- If vasopressin is the cause, we then need to find the root of the problem, possibly in other body systems.
This document is for information purposes only and is not medical advice. Readers or those diagnosed with MD should not rely on it and/or alter any medical treatments or act upon any or part of the information without first seeking professional medical advice. Our researchers do not directly correspond with the public or those diagnosed with MD on any aspect of the research programme. All inquiries and professional correspondence should be addressed to firstname.lastname@example.org.