CURRENT RESEARCH IN MENIERE'S and PROSPER MENIERE

The Newsletter of The Meniere's Network
September 1998
Current Research in Meniere's Disease

Dr. Mark Severtson, MD

Prosper Meniere, lecturing before the Paris Academy of Medicine in 1861, first attributed the sudden onset of vertigo, tints, hearing loss, nausea and vomiting to an abnormality within the inner ear. Prior to Meniere's report, these symptoms were thought to arise from generalized cerebral congestion. To relive this congestion, patients underwent numerous ineffectual, even harmful treatments (e.g. bloodletting).(1)

Pathophysiology: A New Theory

Although Prosper Meniere argued that an abnormal inner ear was responsible for MD in 1861, 77 years passed before he was proven correct. Early research focused on endolymph which is an inner ear fluid produced by the cochlea and resorbed in by the endolymphatic sac and endolymphatic duct. MD patients were found to have overdistension of the inner ear chambers that contained the endolymph. A similar observation was made independently by Hallpike & Cairns and Yamakawa in 1938, and it was termed endolymphatic hydrops. The dynamic process of production, circulation and resorption of the endolymph has been documented using radioactive markers.(2)

How and why this system goes awry in MD remains the subject of investigation. A compelling new theory focuses on glycoproteins and a natriuretic hormone called saccin which have been found recently in the endolymph sac. (3) Patients with anatomically narrow vestibular aqueducts (i.e. bony channel surrounding the endolymphatic duct, are predisposed to underperfusion of the endolymphatic sac. Metabolic debris subsequently accumulates within the endolymphatic sac. In response, the endolymphatic sac attempts to unclog the system by secreting saccin to increase the production of endolymph and also glycoproteins to increase its rate of flow. The sudden restoration of endolymphatic fluid flow results in the vertiginous symptoms. Eventually, the endolymphatic sac is overwhelmed by the overproduction of endolymph. It becomes overdistended resulting in endolymphatic hydrops, the histolopathological manifestation of MD.

Allergy and the Immune System

In addition to regulating the amount of endolymphatic fluid within the inner ear, the endolymphatic sac appears to direct the immune system within the inner ear. Multiple components of the immune system have been identified within the endolymphatic sac including antibodies, mast cells and eosinophils. The fluctuating nature of MD is reminiscent of an allergic disorder. In fact, a recent survey of unselected MD patients found a 50% incidence of inhalant and/or food allergy.(4)

Three allergic mechanisms have been proposed. First, as the seat of the immune system within the inner ear, the endolymphatic sac, itself, may be a 'target organ' of inhalant or food allergies. Second, MD patients have been shown to have increased levels of circulating immune complexes (CICs) which are allergy derived. When deposited in the endolymphatic sac, the CICs clog its filtering system, forcing metabolic debris to accumulate. Finally, viral infections have become the focus of research, both as a potential cause of MD and as a catalyst of allergic mechanisms which contribute to the symptoms experienced by MD patients. Histopathological findings include perisaccular fibrosis, near absence of a microvascular system, thickened basement membrane, and loss of epithelial integrity. Cytomegalovirus DNA was recently identified in the endolymphatic sacs of 7 of 9 MD patients who underwent surgery for their MD. These findings along with radiologic and epidermiologic evidence give credence to the viral theory of the etiopathogenesis of MD introduced by Shambaugh and Kaufman in 1969.(6)

Medical Management of MD

No fundamental changes in traditional medical management of MD have occurred since 1994. However, several new treatment modalities have been studied in research trials, and these will be emphasized below.

The mainstay of therapy for MD remains nonsurgical and is thought to be effective in approximately 80% of patients. Its cornerstone is a strict low salt (maximum 1500 mg/day), the effectiveness of which was first established by A.C. Furstenberg in 1943. Eliminating caffeine, and alcohol from the diet is also recommended. Diuretic medications are often used in conjunction with a low salt diet to lower the endolymph's pressure within the inner ear, correcting the endolymphatic hydrops. Vestibular suppressants (usually benzodiazepines) are used to combat the acute vertiginous symptoms of MD, and various antiemetic agents are added (e.g. Robinul, Meclizine, or Phenergan as needed. Severe attacks may require hospitalizations for intravenous medications and fluid resuscitation.

Regarding new treatment modalities, the application of steroids to the inner ear via the round-window membrane has been advocated to treat a viral etiology of MD. In order to protect neural tissue from virally initiated inflammation which can cause irreversible damage, nerve growth factor can be added to this regimen. Systemic antiviral medicines such as Acyclovir have shown some early promise in mitigating the severity of the initial episode of viral labyrinthitis that might lead to frank MD.(6)

In addition, Atrail Natriuretic Peptide (ANP) received new attention at a recent symposium on the inner ear in Colorado. ANA is a hormone produced by the atrium of the heart that has been shown to regulate serum osmolaity. Molecular studies on guinea pigs identified specific receptors for ANP in the inner ear. Armed with this new finding, Lamprecht theorized that ANP may play a role in controlling the inner ear's fluid composition and volume. Encouragingly, he was able to show, in a small clinical trial of ANP, that MD patients experienced some short-term hearing improvement.(7)

Finally, treatment for allergic disease has shown encouraging results, particulary for patients suffering from bilateral symptoms of their MD. 113 patients who underwent desensitization and dietary treatment for allergy reported significant improvement in both their allergy and MD symptoms.(5)

Surgical Management of MD

Surgical Treatment of MD is indicated when a patient's symptoms become recalcitrant to maximal medical therapy. Several conventional operations are available and they are reviewed briefly. A recent modification of endolymphatic sac surgery is highlighted. Lastly, chemical labyrinthectomy has received a great deal of attention in recent years. This treatment modality will be examined in some detail.

Traditional operations for MD can be divided into hearing conserving and hearing sacrificing procedures. Conservative procedures are recommended when serviceable hearing is present and include endolymphatic sac surgery and vestibular nerve section.

Endolymphatic sac surgery is a controversial operation as success rates for control of vertigo have varied significantly from 33% to 94%. Most surgeons report initial success rates of 70%-80% with a drop to about 50% over time.

A new study modifying the traditional endolymphatic sac operation has recently been published. Its authors argue for wide decompression of the endolymphatic sac and surrounding structures including the posterior fossa dura and sigmoid sinus. Their results, at 2 years, are encouraging (92% patients with no or mild vertigo). A five year follow-up study is planned.(8)

Vestibular nerve section is the most effective surgical procedure for MD with long-term success rates in excess of 90%. This operation does require a craniotomy and presents its attendants risks and potential complications.

Surgical labyrinthectomy is a descructive procedure. The otologist removes part of the inner ear and thereby sacrifices any residual hearing. It offers excellent control of vertigo, but it is reserved for patients without any serviceable hearing.

The final component of otologist's armamentarium in the treatment of MD is the chemical ablation of the inner ear. The antibiotic, streptomycin, was first used in the treatment of vertigo in 1949. This medicine was found to be more toxic to the vestibular functions as compared to the auditory functions of the inner ear. Streptomycin was first instilled into the middle ear by Schknecht in 1957. Getamicin, another aminoglcoside, has also been instilled into the inner ear for the treatment of vertigo.

Blakley recently published an extensive 40-year review on intratympanic therapy for the treatment of MD. The term intratympanic refers to the middle ear space (i.e. tympanic cavity). Based on his review of the literature, several recommendations are made.(9)

First, he argues the the gentamicin should be used preferentially over streptomycin because of its large 'therapeutic window'. Gentamicin appears to have greater difference between its therapeutic affect in controlling vertigo and its cochleotoxic affect in causing hearing loss, making it safer to use than streptomycin. Second, he suggests a dosage of 30 mg/mL, buffered with sodium bicarbonate to reduce inflammation of the middle ear which can result from the injection of gentamicin. Third, he recommends, that gentamicin be delivered to the middle ear by injecting it with a small needle. this allows treatment on an outpatient basis as this mode of delivery is accomplished in the office. Fourth, he disapproves of acute treatment protocols where patients receive injections over three consecutive days. He advocates weekly injections of the chronic toxicity of gentamicin, enhancing the etiologists's ability to 'fine tune' the therapy. Fifth, he believes that good results can be obtained without ablating all of the patient's vestibular function. Therapy should be stopped when signs of symptoms of vestibular toxicity occur (e.g. oscillopsia, ataxia, nystagmus) or hearing deteriorates. Lastly,he argues against the use of intratympanic steroids because insufficient research is available demonstrating the safety and effectiveness of this surgical procedure.

The major problem with chemical labyrinthectomy is the small but undeniable risk of hearing loss. A potential solution to this problem entails the use of a sustained release vehicle which would allow more precise dosing of the medicine to control the patient's vertigo without loss of hearing. Such devises are actively being developed and offer a promising treatment modality when more conservative measures fail.(10)

Summary

Current research has advanced our understanding of the pathophysiology of MD. New treatment options are emerging based on these findings and should offer hope and encouragement to MD patients and their families. This article represents a sample of these endeavors.

References

The following 'references' may be found by searching 'Medline'

(1)	Lustig LR, Lalwani A: The History of Meniere's Disease: Otolaryngologic Clinics North America 1997: 30:917-946
(2)	Lundquist PG: Aspects On Endolymphatic Sac Morphology and Functions: Arch Otorhinolaryngol 1976: 212:231-240
(3)	Gibson WPR, Arenberg IK: Pathophysiologic theories in the Etiology of Meniere's Disease: Otolaryngologic clinics North America 1997: 30:961-667
(4)	Derebery MJ, Rao VS, Siglock RJ: Meniere's Disease: An Immune Complexmediated Illness? Laryngoscope 1991: 101:225
(5)	Derebery MJ: The Role of Allergy in Meniere's Disease: Otolaryngologic clinics of North American 1997: 30-1007-1016
(6)	Arenberg IK, Lemke C, Shambaugh GE: Viral Theory for Meniere's Disease and Endolymphatic Hydrops: Overview and New Therapeutic Options for Viral Labyrinthitis
(7)	Ann NY Academy of Science 1997: 830-313. Claes J. Van de Heyning PH: Medical Treatment of Meniere's Disease: A Review of Literature: Acta Otolaryngology Supply (Stockh) 1997: 526:37-42
(8)	Gianolo GJ, Laroucre MJ, Kartush JM, Wayman J: Sac-Vein Decompressionfor Intractable Meniere's Disease: Two-year Treatment Results. Otolaryngology Head Neck Surgry 1998: 118:22-29
(9)	Blakely BW: Clinical Forum: A Review of Intratympanic Therapy. American Journal Otolaryngology 1997: 18:520-526
(10)	Hirch, BE, Kamerer DB: Role of Chemical Labyrinthectomy in the Treatment of Meniere's Disease. Otolaryngologic Clinics North America 1997: 30:1039-1050