Chapter 41 Chemical Treatment of the Labyrinth

Edwin M. Monsell, Stephen P. Cass, Leonard P. Rybak, Julian M. Nedzelski

Despite some successes, the medical treatment of inner ear conditions, such as Meniere’s disease and sudden sensorineural hearing loss, is often frustrating to patients and physicians. Molecular studies of inner ear function have revealed some promising approaches to therapy. Chemoprotection strategies for exposure to noise,¹ cisplatin,² and aminoglycosides³ have generated considerable interest. Other than aminoglycoside treatment for vertigo in Meniere’s disease, no intratympanic treatment strategy has gained widespread acceptance as standard therapy. We review the status of this treatment and of intratympanic treatment with corticosteroids.

Most patients with Meniere’s disease can be managed satisfactorily with dietary salt restriction, diuretics, and vestibular suppressants. Only about 10% of patients become disabled in regard to work, domestic activities, travel, and the general enjoyment of life. The goals of treatment of Meniere’s disease are to control the definitive spells of vertigo and to preserve hearing.⁴

From the standpoint of the clinical skills required by the practitioner and the potential morbidity to patients, the administration of aminoglycosides for vertigo by any route of administration should be considered as great an undertaking as surgical treatment. Because not all the problems and pitfalls of any technique can be conveyed in a printed article, we advise that streptomycin treatment be learned under the guidance of a practitioner experienced in its use.

In 1944, streptomycin was isolated from cultures of a soil organism, Streptomyces griseolus.⁵ This drug displayed broad-spectrum antibacterial activity and was the first found to be effective against tuberculosis. Because effective treatment of tuberculosis with streptomycin required prolonged therapy, ototoxicity became evident soon after introduction of the drug. In 1948, streptomycin was used to treat patients with unilateral Meniere’s disease specifically on the basis of its vestibulotoxic effects.⁶

Mechanisms of aminoglycoside ototoxicity have been reviewed more recently.⁷ Aminoglycosides exert toxic effects on the hair cells of the inner ear by several mechanisms. First, aminoglycosides bind to the plasma membrane and displace calcium and magnesium. This event results in acute but reversible interference with calcium-dependent mechanicoelectric transduction channels.⁸ Second, dihydrostreptomycin enters the mouse outer hair cell through the mechanoelectric transduction channel.^9,¹⁰ This channel can act as a one-way valve for aminoglycoside entry, promoting the accumulation of aminoglycoside within the cell. There seems to be a competition between the aminoglycoside and calcium for entry into the outer hair cell. The normal low endolymph concentration of calcium promotes intracellular accumulation of aminoglycosides.¹⁰ Third, aminoglycosides are transported into the cell by an energy-dependent process. Within the cell, the drug binds to phosphatidylinositol. This event is associated with progressive disruption of the plasma membrane and inhibition of the second messenger inositol triphosphate. With progressive disruption of the second messenger system and the plasma membrane, cell death occurs.¹¹^–¹³

The disruption of cell membranes and other intracellular components may be mediated by free radicals. More recent studies have shown that aminoglycosides form a complex with iron, and that this complex catalyzes the production of free radicals. Reactive oxygen species formation in vitro requires iron and polyunsaturated lipids, such as those found in cell membranes, as electron donors. Gentamicin and iron form ternary complexes with phospholipids. Oxidative damage to phospholipids can cause the release of arachidonic acid, which can also form complexes with gentamicin and iron. These complexes can lead to further lipid peroxidation, damaging membranes, proteins, and DNA to disrupt the function of the outer hair cell, leading to programmed cell death (apoptosis).¹⁴ Reactive oxygen species may promote the opening of the mitochondrial permeability pore.¹⁵ The Jun N-terminal kinase (JNK) pathway seems to play a role in the death from gentamicin of auditory and vestibular hair cells.¹⁶

The combination of iron chelators and free radical scavengers in animal experiments provides complete protection from gentamicin ototoxicity.¹⁷ Pretreatment with aspirin protected against amikacin ototoxicity in animals.¹⁸ More recent clinical trials in China showed protection against gentamicin-induced hearing loss in patients pretreated with salicylates.¹⁹

Aminoglycosides do not become concentrated in cochlear fluids, although the elimination half-life increases with long-term administration. These observations support the notion that intracellular sequestration of the drug occurs.^10,²⁰ Aran and associates²¹ confirmed that aminoglycosides undergo rapid uptake by cochlear and vestibular hair cells, and slow clearance from these cells.

Amikacin, dihydrostreptomycin, and kanamycin are primarily cochleotoxic, whereas gentamicin and streptomycin are primarily vestibulotoxic. At high doses, streptomycin is also cochleotoxic. Streptomycin, 25 mg/kg per day, administered systemically to cats resulted in loss of vestibular hair cells only, but at 100 mg/kg/day, vestibular and cochlear hair cells were lost.²²

More recent animal experiments have tried to model the pharmacokinetics of intratympanic administration of gentamicin applied in a sustained-release vehicle of liquid fibrin glue. High levels of gentamicin were measured in perilymph within 8 hours of administration. These high levels persisted for at least 24 hours, then declined rapidly by 72 hours. The elimination rate for gentamicin was 1.04 mg/mL/hr.²³

The hair cells of the cristae, the ampullae, and the cochlea degenerate to different degrees after the administration of aminoglycosides. The primary vestibular neurons, the cochlear nuclei, and the vestibular nuclei are not directly affected, even at high doses.^22,²⁴ The basal turn of the cochlea is the region most susceptible to permanent loss of hair cells, resulting in an initial loss of high-frequency hearing sensitivity. Although the mechanisms of this differential toxicity are incompletely understood, several contributing factors have been identified, including the route of administration, dose variables, and the specific aminoglycoside used. Mutations in the 12S ribosomal RNA gene have been identified in association with maternally inherited susceptibility to deafness from treatment with aminoglycosides.²⁵ Affected individuals can sustain profound deafness from even a single dose administered systemically.

Damage to vestibular dark cells, which are thought to play a role in the production of endolymph, has been reported after administration of doses of aminoglycoside below the threshold for damage to hair cells. It is possible, but unproven, that impaired function of dark cells is beneficial in Meniere’s disease.^26,²⁷

INTRAMUSCULAR APPLICATION OF STREPTOMYCIN

Clinical Studies

Between 1948 and 1980, eight investigators reported a total of 49 patients treated with intramuscular streptomycin for unilateral or bilateral Meniere’s disease. In the first extensive studies of intramuscular streptomycin, Schuknecht ^28,²⁹ administered 0.75 to 1.75 g intramuscularly every 12 hours. Treatment continued until there were no ice water caloric responses in the diseased ears. This treatment end point was assumed to represent total or near-total vestibular ablation. The total doses ranged from 13.5 to 89 g (mean 39 g). All patients became severely ataxic, and most had oscillopsia early in the course of treatment, but none experienced hearing loss; 35% had persistent ataxia, and 15% had persistent oscillopsia. Ninety-five percent of patients had no post-treatment vertigo. Hearing levels did not change or fluctuate in 90% of patients. When a totally ablative dose of intramuscular streptomycin was administered, vertigo was controlled, and hearing was preserved.³⁰ Patients who undergo total vestibular ablation may still be disabled by chronic dysequilibrium, ataxia, and oscillopsia.³¹

To attempt to limit the chronic oscillopsia and ataxia that follow total bilateral vestibular ablation, subtotal or “titration” treatment protocols with streptomycin were developed.^32,³³ Rather than giving an ablative dose, streptomycin was administered until episodic vertigo was controlled.

Treatment Method for Subtotal Vestibulectomy with Intramuscular Streptomycin

Our suggestions have been adapted from established protocols and modified by our own experience.^32,³³

Indications

Intramuscular streptomycin may be considered for patients with disabling episodic vertigo caused by Meniere’s disease in the following situations: (1) simultaneously active Meniere’s disease in both ears, or when it is unclear from which ear the attacks of vertigo are arising; (2) Meniere’s disease in an only hearing ear; or (3) in the second ear after an ablative procedure on the opposite side, such as selective vestibular nerve section. It is essential to determine to what extent a patient may be disabled by the definitive episodic vertigo of Meniere’s disease as defined by the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS).⁴ Patients disabled primarily by continuous dysequilibrium, ataxia, oscillopsia, or motion intolerance are generally not good candidates for vestibular destructive procedures of any type because their symptoms are due to a failure of central compensation, to the perception of dysequilibrium in the presence of normal balance performance, or both.^34,³⁵

It is important to identify patients with Cogan’s syndrome, luetic hydrops, and autoimmune disease of the ear because these patients may respond to nondestructive medical treatment, such as corticosteroids.³⁶ Although reliable data are lacking, it is likely that the recognition of autoimmune inner ear disease and immunosuppressive treatment have resulted in reduction of the number of cases of bilateral Meniere’s disease treated with intramuscular streptomycin. Patients with markedly reduced caloric function before treatment with streptomycin should be managed with additional caution because they may develop permanent dysequilibrium or oscillopsia with the loss of additional vestibular function. Treating such patients with lower doses of streptomycin should be considered.

Pretreatment Evaluation and Patient Counseling

The pretreatment evaluation requires a complete history and physical examination, including a neurologic examination, observation of eye movements, and vestibulospinal examination. The vestibulospinal examination consists of observation of gait, tandem gait, and Romberg and sharpened Romberg maneuvers. A simple, effective assessment of postural stability can be performed in the examination room or bedside by having a patient stand on 4 to 6 inches of dense foam with eyes closed. The foam reduces the reliability of proprioceptive input to postural control mechanisms, so the subjects must depend on vestibular inputs when eyes are closed. Normal individuals have no difficulty standing on the foam, but patients with bilateral loss of vestibular function or an acute vestibular loss fall when forced to rely solely on vestibular cues to maintain posture. Baseline audiometric and laboratory vestibular function tests are performed, including electronystagmography, rotational testing, and posturography. Renal function tests are performed as indicated.

It is essential to distinguish clearly between two phenomena in patients with Meniere’s disease who are undergoing intramuscular treatment with aminoglycosides: (1) vertigo owing to the disease, and (2) the syndrome of acute bilateral vestibular loss caused by vestibulotoxicity. Vertigo is the hallucination of motion—the perception of motion when none is occurring. The vertigo of Meniere’s disease occurs without provocation, consists of a spinning or rotating sensation always with spontaneous nystagmus, lasts 15 minutes to several hours, and is accompanied by dysequilibrium and nausea that may last for hours.⁴

The syndrome of acute bilateral vestibular loss may include rotational vertigo, but the vertigo is related to treatment rather than being spontaneous. Commonly, patients experience discomfort associated with rapid head movements, a sense of disorientation in space, and ataxia. Patients may also manifest oscillopsia, a disturbing sensation of the visual field bobbling as the patient walks about or rides in a car. This phenomenon is due to impairment or loss of the vestibulo-ocular reflex, which helps to maintain a stable image on the retina during head movement. Oscillopsia may be temporary or permanent after bilateral loss of vestibular function.^30,^31,³⁷

These distinctions are important because symptoms resulting from Meniere’s disease are indications to resume treatment, whereas symptoms resulting from vestibulotoxicity are indications to halt treatment. Occasionally, the physician may find it difficult to make this distinction from a patient’s history. In such cases, caution would dictate that treatment should be discontinued until the situation is clarified by repeated observations over time.

Patient counseling is crucial. Patients are counseled that the purpose of the titration of streptomycin is to control the recurrent episodes of vertigo typical of Meniere’s disease, and that disability secondary to dysequilibrium may replace disability from episodic vertigo. Patients need to understand that treatment may be protracted, and that additional courses of streptomycin may be needed in the future. Other risks and complications include hearing loss, tenderness from the deep intramuscular injections, nausea, perioral or peripheral numbness or tingling, rash, and fever. Renal, visual, and hematologic effects have also been reported with prolonged treatment with aminoglycosides.

Special discussion is required for patients with abnormal renal function because renal toxicity is a potential complication of aminoglycosides. Careful monitoring of renal function and consultation with a nephrologist are recommended to ensure safe treatment of a patient with impaired renal function.

Occasionally, a patient reports allergy to aminoglycosides. In this case, the nature of the allergy is explored, and an intradermal test dose is considered.

Treatment Technique

Therapy may start with streptomycin sulfate injected intramuscularly, 1 g twice a day for 5 days (10 g total cumulative dose). After this initial course, clinical reassessment is performed by interview, vestibulospinal physical examination, audiometry, and vestibular function tests. If studies remain unchanged, there is no clinical indication of decreased vestibular function, and the patient continues to experience vertigo, additional streptomycin may be given. A second course could consist of additional streptomycin sulfate injected intramuscularly, 1 g twice a day for 5 days (10 g in the second course and a total cumulative dose of 20 g). After administration of the first 20 g of total cumulative dose, we suggest that additional doses be smaller, such as streptomycin sulfate injected intramuscularly, 1 g once per day for 5 days (5 g per increment).

Streptomycin injections should be stopped when any one of the following occurs: (1) episodic vertigo ceases or seems to abate; (2) the syndrome of acute vestibular loss appears or worsens; (3) worsening of balance performance on the vestibulospinal examination; (4) laboratory tests of vestibular function show loss of vestibular function, such as reduction of caloric responses, increase in phase or decrease in gain of the vestibulo-ocular reflex on rotational testing, and a fall on posturography when forced to rely solely on vestibular cues; or (5) decline in hearing. It is important to proceed with treatment slowly and cautiously. The effects of streptomycin can be delayed. If the reduction of vestibular function continues to complete ablation, ataxia and oscillopsia may persist chronically. If episodic vertigo recurs, additional courses of streptomycin can be given as indicated.

Results

The long-term results of intramuscular subtotal streptomycin therapy for bilateral Meniere’s disease are known from only one report.³⁷ Nineteen patients were reviewed with follow-up from 2 to 9 years. Recurrent vertigo was controlled in 95% of patients within the first 6 to 18 months after treatment. At last follow-up, 63% of patients reported having had no recurrence of vertigo. Persistent mild dysequilibrium occurred in 60% of patients without recurrent vertigo, and oscillopsia persisted in 16% of patients.³⁷

APPLICATION OF STREPTOMYCIN TO LATERAL SEMICIRCULAR CANAL

Experimental Studies

Kimura and colleagues ³⁸ reported that the application of gentamicin to the lateral semicircular canal of normal guinea pigs produced a selective vestibular lesion. There was sensory cell degeneration in the utricular maculae and all but one of the cristae of the superior, lateral, and posterior canals of 27 ears. The saccular maculae were less affected. All cochleas were normal except one that had a small lesion of outer hair cells at the basal turn. Fenestrated control inner ears were normal throughout. Kimura and colleagues³⁹ repeated some of their experiments with streptomycin after producing experimental endolymphatic hydrops by occlusion of the endolymphatic duct. Hydropic ears sustained substantial cochlear and vestibular lesions when streptomycin was applied to the lateral semicircular canal. Fenestration of the lateral canal without drug application produced a significant cochlear lesion, but not a vestibular lesion.

Clinical Studies

The application of streptomycin to the labyrinth through the lateral semicircular canal (labyrinthotomy with streptomycin infusion [LSI]) was introduced by Shea.^40,⁴¹ The rationale of this procedure was that application to the vestibular labyrinth might cause more drug to reach the vestibular hair cells than cochlear hair cells, and produce a more selective lesion with a single treatment. Use of this route of administration requires the performance of a mastoidectomy and opening the bony otic capsule.

Surgical Method

Shea and Norris ⁴⁰ described the technique of LSI. A simple mastoidectomy is performed, and the lateral semicircular canal is identified. The bone of the dome of the semicircular canal is gradually thinned with a diamond burr. A “double blue-line” technique is used to create a fenestration of the lateral semicircular canal.

A small amount of fluid containing streptomycin is slowly infused into the perilymphatic space of the lateral semicircular canal. Opening the lateral semicircular canal in Meniere’s disease results in enhancement of the ratio of the summating potential to the action potential of the electrocochleographic recording, primarily by reduction in the amplitude of the action potential. The ratio does not change during infusion of streptomycin, but sometimes declines slightly after the fenestration is closed.⁴²

The volume of fluid, the composition of the diluent (lactated Ringer solution or other physiologic solution), the amount of streptomycin in the solution delivered, the amount of time during which the fluid is introduced, and whether the streptomycin solution is followed by a “rinse” of a physiologic solution without streptomycin are important technical variables that could affect the amount of streptomycin administered and the amount of trauma to the inner ear. After the drug is infused, the fenestration is closed with a thick piece of temporalis muscle and fascia. The postauricular wound is closed in the usual manner. On the basis of animal experiments, Shea ^40,⁴¹ initially recommended puncturing the lateral membranous canal in hydropic ears to release endolymph, possibly decompressing endolymphatic hydrops acutely, but later withdrew that recommendation.