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

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

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.

The Weird and Seemingly Secret Symptoms of Meniere's

I have weird symptoms that I am convinced are absolutely related to my Meniere's disease.  Over the years, I have asked all of my doctors about them and in almost every case, I get no more than a weird look and a shrug of the shoulders from them.  I have also asked fellow sufferers the same questions and, in many cases, I get a yeah-me-too, response.

Let's start by reviewing the standard definition of Meniere's disease.  In a nutshell, once all other causes, such as a brain tumor, have been ruled out, there are four "official" symptoms which will put you in the Meniere's disease camp: episodic hearing loss, usually in the lower frequencies, aural pressure, tinnitus, and vertigo.  When I go back and read about Meniere's disease on just about any medically-valid website, the description and prognosis are so sterile and practically benign that it's almost laughable.  For me, Meniere's has been so much more than these four symptoms.  Things have come and gone, but over the years I have also experienced the following:

Frequent Urination
I don't seem to get this anymore, but I used to get it every time the aural pressure would build up in the hours leading up to a vertigo attack.  After doing some research, I concluded that a possible explanations is that as the endolymphatic sac (ES) becomes swollen with fluid, the aquaporins on its surface will send signals to the brain to decrease the production of antidiuretic hormone.  This causes diuresis and I guess is the body's way of responding to the SOS being sent out by the ear that it's fluid overloaded.  This would often persist through most of a vertigo attack, as well.  As if it's not bad enough to be spinning so violently that I cannot possibly stand up, much less walk to the bathroom, I now had to pee like a racehorse every 30 minutes!

Sinus Pressure and Inflammation
There is some validating evidence in the literature that people with Meniere's disease are more likely to experience environmental and food allergies.  The leading expert on this phenomenon happens to be one of my doctors, M. Jennifer Derebery at House Ear Clinic in Los Angeles.  She is adamant that she doesn't believe that allergies cause Meniere's disease, only that there is a correlation.  Now she didn't personally tell me this, but if you've read my previous post, you know that there is some evidence to suggest that Meniere's disease is in fact one of immune dysfunction.  So, could it be that this dysfunctional immune response lends itself to the development of allergies or allergy-like symptoms?  Anyway, for the first few years, I kept telling any doctor who would listen that my sinuses often felt swollen and inflamed, at times even tingling, the sensation extending into my ears.  Each doctor agreed that they could visualize this inflammation when they looked in my nose and they threw different drugs at it, namely nasal steroids and a host of allergy medications.  The nasal steroids often temporarily helped and Claritin seemed to take the edge off, but nothing really made much of a difference until I started allergy shots.  The weird thing is that the first allergist I saw tested me for well over 30 allergens and could not find one thing I would react to.  He was as frustrated as I was because, like all the others, he could see that my nasal membranes were really inflamed.  Ultimately he named it 'nonallergic rhinitis' and sent me on my way.  It was shortly after this that I was referred to Dr. Derebery.  Rather than the standard scratch tests most allergists use, she injects small amounts of allergen solution under the skin, just like a TB test, in varying concentrations in an effort to elicit a reaction.  Testing in this way, she was able to identify 5 or 6 things that I seemed to react to, including mold, and from there I began allergy shots.  With time, they significantly alleviated my sinus inflammation.  I mention the mold specifically because I believe all of my problems began with a persistent exposure to mold about six years ago.  Other sufferers have reported a similar experience with a large mold exposure in the months leading up to the onset of their Meniere's.

The Absence of Infectious Illnesses
The literature has shown that people with Meniere's disease have an increased incidence of having one or more autoimmune diseases, such as rheumatoid arthritis, lupus, multiple sclerosis, Hashimoto's disease, Sjogren's, and others.  Meniere's disease itself is not an autoimmune disease.  While, knock on wood, I don't seem to have any other chronic conditions, I have made an odd observation in the past five years: I have not had one single cold, flu, or other known viral infection!  This is amazing because during this time, all three of my kids were in elementary school and constantly passing around the germ du jour.  Most recently it was hand, food, and mouth disease.  Ugh.  Even my husband catches a cold once or twice a year.  But not me.  I might feel like I'm fighting something off for a day, but it has never developed into full-blown illness.  Before Meniere's, I got the usual number of colds, tummy bugs, and even a couple of sinus infections, but that all seems to have changed.  My theory is that the type and degree of immune dysfunction causing my Meniere's symptoms has somehow protected me from viral infections.

GI Issues
Since the very beginning, I have felt like my body is fighting off a chronic infection.  This is evidenced by the chronic episodes of exhaustion and fatigue, but also the fact that I often have "unusual" bowel movements.  Sorry for the grossness factor.  I happen to talk about poop in great detail on a daily basis with my patients at work, but I appreciate that it's a sensitive subject for many.  I don't have diarrhea, per se, but it's not normal like it used to be either.  Most days it's just once first thing in the morning, but when my ear is acting up, it is rather urgent in nature and really just not anywhere near normal.  Like so many other things, this symptom lends itself to the theory of a disrupted immune system, specifically at the level of the mucous-associated lymph tissue (MALT) which lines everything between our ears and rectum.

Ear, Jaw, Neck, and Tooth Pain and Swollen Lymph Nodes
To me, this seems to be a huge oversight on the part of doctors and researchers and no one seems to have anything to say about it.  I know I am not alone in experiencing these symptoms.  I have had so many dental exams, going so far as to have my crowns replaced and having antibiotics injected under my gum line, because at times my teeth on the right side of my jaw ache and become sensitive to hot and cold.  It comes and goes, but always correlates with an earache such that if I even touch the aural area in front of the ear, I will feel almost-excruciating pain.  During these episodes, my ear canal also narrows, indicating some kind of inflammation, which I suspect is caused by swelling of the aural lymph node.  These episodes also coincide with a sore throat and a sensation of a swollen node in my throat, along with aches and pains down the side of my neck correlating with other lymph nodes.  Sometimes I can feel them by palpating them with my fingers, sometimes I can't.  I knew my ear canal was swollen and painful when I used to wear my hearing aid as during these episodes it would be very difficult to put in my ear.  Now I can tell simply by inserting a cotton swab in my ear.  Some days there is plenty of room and it's painless, other times I can barely get the swab in there and it's quite painful.

Facial Tingling
I really get weird looks from doctors when I mention this one.  This may, or may not, be related to the Meniere's.  But I get these weird, very brief tingling sensations across one or the other of my cheekbones or across the bridge of my nose.  It feels like a spiderweb or feather brushing the skin and lasts for just a second or two.  It never happens all at once, just in one of the three locations.  I think it's been quite some time since I have felt this one, though, and I don't recall that it would correlate with any other symptoms.

Balance Problems other than Vertigo
In the summers of 2012 and 2013, we took road trips.  After each, trip I developed Mal de Barquement syndrome, with the symptoms lasting about six months!  What that meant for me was that after any time spent driving or in the car, even 5 minutes, I would feel like I was moving for anywhere from 30 minutes to a couple of hours.  At times, driving was very difficult because my eyes couldn't track all the motion around me.  And, as everyone with Meniere's disease knows, we experience a very wide range of vestibular disturbances aside from vertigo.  Some wax and wane and others persist.  I don't think doctors like to bring it up because there's not much to be done about it.  There is vestibular therapy or rehabilitation, but as far as I can tell, it works best for people with a static and permanent loss.  For those of us with fluctuating symptoms, I'm not sure how much vestibular exercises can help to retrain the brain.  Just as soon as our brain adapts to a change, something else gives and we're back to square one.  Many of us also experience a kind of slow nystagmus, or eye darting, another really annoying and distracting symptom.  Fun stuff!

Cognitive Dysfunction and Fatigue
In my experience, doctors and researchers like to pin brain fog and exhaustion on the brain working so hard to keep us balanced.  But I think it's far more complex than that.  I've again come to the conclusion that it is somehow related to some kind of chronic infection and underlying immune response.  I also believe it is complicated by hearing loss and tinnitus.  Despite these symptoms having a huge impact on our quality of life, no one likes to talk about them - maybe because they are poorly understood and there is no known treatment.

I hope this post validates some of the symptoms you've been having , too.  Did I forget anything?  Let me know what weird symptoms you have that no one talks about being related to Meniere's disease.

The Tides are Changing

If the idea that Meniere's disease could be caused through a pathogenic process which goes on to produce immune dysfunction is new to you, you might find this article about the practice of rheumatology very interesting.  Wouldn't it be great if the mystery surrounding these diseases of unknown origin could finally be solved and each of us went on to be treated by the appropriate medical specialist?

Is this the end of rheumatology as we know it?
JONATHAN S. HAUSMANN, MD | CONDITIONS | MAY 21, 2014

Recently, an international research team led by Xavier Rodó published a fascinating study in PNAS suggesting that Kawasaki disease is caused by an agent transported by wind from farms in Northeast China.  This agent, possibly a fungal toxin, is responsible for triggering an exuberant immune response in children, causing the typical manifestation of the disease: fevers, rash, conjunctivitis, “strawberry tongue,” enlarged lymph nodes, and swelling of the extremities.  Untreated, Kawasaki disease can cause aneurysms of the coronary arteries, premature heart disease, and even death.


What I find so fascinating about this article is that it sheds light on the possible etiology of a rheumatic illness.  As rheumatologists, one of the biggest challenges we face is not knowing the causes of most of the diseases we treat (that’s our dirty little secret!).  Even though we use state-of-the-art medicines, our understanding of disease is still in the Dark Ages.

Fortunately, we’ve had some progress.  Rheumatic fever, for example, was found to be caused by Streptococcus, the same bug that causes Strep throat.  We learned that treating Strep throat with antibiotics prevents rheumatic fever, likely the reason why rheumatic fever is now extremely rare in the United States.

In the 1970′s, an epidemic of arthritis struck Connecticut, affecting many children.  Detailed research showed that it was due to a bacteria, Borrelia burgdorferi, carried by a tick.  To prevent disease, we advise people to use repellents and avoid tick-infested areas.  If they develop Lyme, we offer effective treatments with antibiotics.

We have also made progress in understanding of some types of vasculitis (diseases that cause inflammation of blood vessels).  Polyarteritis nodosa is often caused by hepatitis B virus, and cryoglobulinemic vasculitis is due to hepatitis C virus.  Cures for these types of vasculitides can be achieved by eradicating the virus.

Is it a coincidence that several diseases that we considered to be “rheumatic” are now known to be caused by bacterial, viral (and perhaps) fungal elements?  Not really, especially if we understand evolutionary medicine.  This often-overlooked field of study helps explain why humans, despite millions of years of evolution, are still vulnerable to disease.   Two common reasons include pathogens (which are able to evolve faster than we can), and the mismatch between our bodies and our new environment (likely responsible for the obesity epidemic).

Unfortunately, most rheumatology research is conducted without an awareness of evolution.  It seeks to find abnormalities of the immune system that cause disease, without first asking why any abnormality would exist in the first place.  It tries to identify genes that make people susceptible for a disease, without asking how deleterious genes could be passed down through generations.

Fortunately, the winds of change may be near.  Interest in P. gingivalis as a cause for rheumatoid arthritis continues to grow, and the role of the microbiome in the development of rheumatic diseases shows promise.  With a better understanding of why we get sick, we may uncover other environmental triggers responsible for the rest of the rheumatic diseases that we treat.

Gary Hoffman, a rheumatologist who studies vasculitis at the Cleveland Clinic, has said that understanding the cause of a disease is the “most crucial element.”  He writes: “How empowering that knowledge is, especially when the etiological agent persists and perpetuates the process.  In that setting, given adequate therapeutic interventions, we can even affect cures.”

Scientific progress is said to occur through “paradigm shifts,” or radical changes in our way of thinking, which abruptly transforms the field.  Will a fungal toxin mark this change for rheumatology?

Jonathan S. Hausmann is a rheumatology fellow who blogs at Autoinflammatory diseases.

Gut Health Equals Immune Health

As you may have heard by now, the bacteria living in our MALT play a critical role in the function of the immune system. These bacteria either produce or stimulate our own bodies to produce specific types of substances that are absorbed into the bloodstream and go on to communicate directly with immune cells. 

A subset of the MALT is the GALT, or gut-associated lymphoid tissue. In my area of practice as a nutrition support dietitian, we have been talking about this for years in relation to our patients who are unable to obtain their nutrition through the gut and instead are dependent on IV nutrition. It had been something of an enigma for years that this population was far more prone to infections, especially bloodstream infections, aka sepsis. We now know that this is due to the growth of undesirable bacteria in the gut and the subsequent increased permeability of the intestinal walls. It is common practice now that we administer a fiber-containing tube feeding formula into the gut as what are known as trickle feeds for the sole purpose of preventing this from happening, which has resulted in fewer bloodstream infections. 

Along these lines, scientists have begun studying the make-up of the intestinal flora of healthy people. While the communities of microbes can vary widely in the healthy population, there are some common themes among them and studies have shown that even small changes in the diet, specifically the presence or absence of certain types of fiber, can have an impact on the profile of the microbial flora. In particular, diets containing prebiotics, in conjunction with probiotics, are believed to be particularly beneficial. Click here for a brief article that explains this in a little more detail. 

It is very important to note that some people have difficulty digesting something called FODMAPs, of which prebiotic fibers are included. Symptoms of this can be gas, bloating, diarrhea, constipation, nausea, and fatigue. Click here to learn more about these symptoms and what to do about them.

Here's a good way to start the day:

Place 1/3 cup of dry, old-fashioned oats and about 2/3 cup of water in a cereal or soup bowl and cook in the microwave for 90 seconds. Stir in 2 heaping tablespoons of whole milk plain Greek yogurt, 1/2 sliced banana, and 1 tsp honey (opt.). Eat with 10-12 dry roasted, unsalted almonds and a small orange.

Alcohol and Immune Suppression

Jessica Tyrrell, PhD, et al, published a study recently linking Meniere's disease with immune dysfunction.  This idea has been on my radar now for the past three years and there is quite a bit of literature out there to support this conclusion if you know what you're looking for.

Based on what I have learned, I don't want to imply that the answer is as simple as "boosting" our immune system through diet and lifestyle changes promoted on the Web.  Not that these things can hurt and, in fact, for some people, and in the early stages of the disease, they might be enough to tilt the immune system just enough to keep symptoms at bay for a while.  However, I can't emphasize enough the complexity of the underlying cause(s) of this immune dysfunction which is thought to lead to Meniere's symptoms and progression.  That being said, why not take some steps to avoid further compromising immune function?  One of the things that can be done to this end is minimize or avoid alcohol consumption.

This is sad news for many of us, myself included.  I do enjoy my red wine and before Meniere's disease,  I used to enjoy a whole lot more of it.  I quit drinking for the first three years after I was diagnosed and while that didn't seem to make any difference in my symptoms at the time, when I did reintroduce the occasional drink I found it often correlated with an uptick in my symptoms for the next few days.

The article entitled Influence of Alcohol and Gender on Immune Response, published by the NIH's National Institute on Alcohol Abuse and Alcoholism,  provides an excellent explanation of how alcohol, in any amount, can compromise immunity.  As a bonus, it provides a basic primer explaining how the immune system works.  It is a long read, but well worth it if you're just becoming familiar with the idea that Meniere's disease is one of immune dysregulation.

For those who are following my progress on the Stephen Spring Treatment Protocol, I continue to feel very, very well.  Quite normal actually.  My hearing is excellent, perhaps only a little lingering loss in the high frequencies as a result of the three gent injections I had several years ago.  For the past several weeks, my only symptoms have been soft, humming tinnitus with only a momentary buzz here and there and a few thirty-second mini-spins most days which are unrelated to any other symptoms, as compared to before when I had a host of symptoms that went along with mini-spins and vertigo.  I am able to just push through these without having to stop what I am doing.  They feel like a burst of nystagmus (eye-darting) in my right eye.  It starts off fast and slows down gradually, then passes.  My energy level and mental clarity remain very good.  I am only requiring 7 hours of sleep each night.  And still no more chronic sore throat.