Transtympanic Gentamicin Treatment For Meniere's Disease

(AKA) Intratympanic Gentamicin Treatment

(c) Timothy C. Hain, MD

Last edited: 2/03. Please read our disclaimer.

TTG defined Results Variant procedures Where to get it done Education Index

 

Transtympanic gentamicin (TTG) or Intratympanic gentamicin treatment (IGT) defined

Figure 1. Gentamicin (a medication intended to purposefully damage the vestibular part of the inner ear) is injected through the eardrum using a narrow needle. The drug is left in the middle ear for about 30 minutes, and then allowed to drain out.

In extremely severe cases of episodic vertigo, such as due to Meniere's disease, treatments that deaden the inner ear such as gentamicin injections may be considered. This is a last resort treatment for persons who have severe attacks of vertigo. Injections of gentamicin are given through the ear drum, by way of a small needle. This may either be called "transtympanic gentamicin treatment" or "intratympanic gentamicin treatment". This procedure allows one to treat one side, without affecting the other. Typically four injections are given in total, administered on a once/week basis. The procedure is not painful -- a local anesthetic is used to numb the ear drum. The treatment is stopped when vertigo ensues, indicating that the gentamicin is affecting the inner ear. Rarely, even after 6 injections, vertigo cannot be induced and vestibular function remains normal. At this point, treatment is stopped and another method of eliminating vestibular function is used (such as labyrinthectomy).

 

Figure 2: The goal of transtympanic gentamicin treatment is to reduce or eliminate vestibular function from one ear. This causes an imbalance between the two ears, and a spontaneous nystagmus or jumping of the eyes. This figure illustrates a video-eng tracing. Normally, the eyes are still (the trace would be flat)

 

After treatment is stopped, vertigo usually lasts from 7-10 days, but may take as long as a month to resolve. Symptoms are controlled with vestibular suppressants and medications for nausea. Good family support or admission to the hospital is required at this point. Unsteadiness usually resolves after several months, but in older individuals, some unsteadiness may be permanent (although vertigo spells are stopped).

The main risk is that hearing may worsen. While as protocols evolve, the percentage of treatments associated with hearing reduction continues to gradually be reduced (see table below), there is still some risk of hearing loss. A risk of 30% for a mild reduction appears to be "ballpark" at this writing. We believe, based on pharmacokinetic considerations, that protocols where the gentamicin is administered gradually, on a once/week schedule (or less frequently), are less risky to hearing than protocols where a large amount of medication is administered over a week or less. If a patient has already lost usable hearing on the "bad" side, then the risk is eliminated, and either a slow or quick protocol can be used.

Results, in terms of relief from vertigo, are typically very good (see table). Hearing is generally unaffected or worsened, and may continue to worsen even after vertigo spells are stopped. Tinnitus is also generally unaffected but some recent studies report reduction in tinnitus. Some patients get relief from Meniere's symptoms in spite of a subtotal ablation of vestibular function. This is attributed to selective damage of gentamicin to the dark cells of the labyrinth (Atlas, 1999; Pender, 1985). In support of this idea is the observation that TTG reduces the size of the summating potential of ECOG , which is a diagnostic test for Meniere's disease (Adamonis et al, 2000).

Results

Authors number patients treated response (vertigo) % hearing reduced Comment
Schuknecht, 1957 5 100 100 Treatment with Streptomycin, not Gentamicin
Beck and Schmidt, 1978 118 90 58  
Rauch and Oas, 1997 21 95.2 24-38 30% relapse rate at 1 year
Nedzelski,1993 30 100 27  
Hirsch, 1997 28 91 33  
Sala T, 1997. 21 86 19% 19% hearing better
Micco, 1997 10 90 30 Weekly Injections
Pfleiderer, 1998 16 87 6 Catheter system used, TID for 4 days.
Eklund S, et al, 1999 93 not reported, but presumably very high 10% deafened. Tinnitus improved. as many as 10 injections were used
Minor, 1999 34 91% 3% deafness 22% recurred
Atlas and Parnes, 1999 68 84-90 17% worse, 26% better Weekly injections
Bauer PW, MacDonald CB, Cox LC, 2000 6 "all" Not relevant In non-servicable ears
Abou-Halawa and Poe, 2002 44 80% 14% One patient deafened

Disability is lessened in patients with Menieres after TTG treatment (Pfleiderer, 1998; Perez et al, 1999) but subjective quality of life is unchanged (Soderman et al, 2001). Dizziness may reoccur one year later, requiring another series of injections. Several authors have reported that tinnitus or fullness may improve substantially after TTG (e.g. Sala, 1997)

A substantial advantage of TTG treatment is low cost, compared to alternative destructive treatments (i.e. vestibular nerve section or labyrinthectomy) Most authors find that the control of vertigo is comparable to vestibular nerve section (about 90%). TTG treatment is also intrinsically of very low risk, especially compared to nerve section. Compared to labyrinthectomy, TTG treatment is also lower in risk because there is no need for general anesthesia.

Variant transtympanic gentamicin procedures

Many variants of this protocol have been reported. Streptomycin injection (the dihydro form) has been tried in two published studies (e.g. Schuknecht, 1951), with much worse hearing results than Gentamicin. This may be caused by the relative selectivity of gentamicin for the vestibular hair cell, compared to dihydro-streptomycin. It would seem, however, that streptomycin sulfate might be equally effective as gentamicin. Recently an article analyzing the kinetics of Gentamicin in the fluids of the inner ear was published by Plontke et al (2002). While the content of this article is beyond the scope of this page, the duration that gentamicin is in contact with the round window is an important variable. Methods that deliver a low dose of gentamicin over a prolonged time are likely to have a more uniform effect on the ear than brief, concentrated administrations (Pender, 2003).

A single dose treatment was reported by Driscoll et al (1997) at the Mayo clinic, with 84% response rate in terms of vertigo, and no change in hearing. These results are attributed to claims that gentamicin destroys the endolymph secreting dark cells before destroying the sensory vestibular epithelium (Beck, 1978). We are frankly dubious, but are becoming more convinced that this is a reasonable procedure as time goes on. Variant procedures where gentamicin is administered less frequently (e.g. once/month), or in a more dilute solution than is conventional also seem well worth considering.Abou-Halawa and Poe (2002) recently reported that a slightly less dilute solution (40 mg) has similar results as buffered gentamicin (30 mg). We do not think that this is an appropriate direction to go however, as stronger solutions seem intrinsicially less controllabl. We would rather see a study using a more dilute dose.

When to stop treatment is also an issue. Stopping too late might be more toxic to hearing. Minor (1999) suggested stopping treatment on appearence of spontaneous nystagmus, head-shaking nystagmus or head-thrust sign. While this protocol appears reasonable to us, it is complex, and stopping simply on a significant change in intensity or direction of spontaneous nystagmus, or till a total of 6 treatments have been delivered might be an adequete substitute. Abou-Halawa and Poe stopped treatment or slowed down treatment when a high-frequency hearing loss appeared.

Numerous methods have been used to deliver gentamicin including direct injection, delivery via a tympanostomy tube, and surgical catheters. Either the needle method or tympanostomy tube method seems quite reasonable. We generally favor methods that allow for a protocol of administration over weeks or greater intervals, and also protocols that involve use of dilute solutions of gentamicin (the standard dilution is 30 mg/cc, a dilute solution might be 10 mg/cc). There is some animal evidence that variability in gentamicin levels is less for sustained release methods (Hoffer et al, 2001). Nonetheless, procedures that require surgical placement of a catheter, at this writing, seem unreasonable as they add risk (the surgery) without proof of better results. Procedures that involve placement of a "wick" in the tympanostomy tube (i.e. the "Silverstein MicroWick(tm)"), do not seem very different than simple use of the tympanostomy tube by itself. We do not doubt that it works, but we are not sure that the additional effort needed to place the special tympanostomy tube and wick as well as it's subsequent removal, is warranted.

Some groups advocate endoscopic exploration of the middle ear and "clearing of adhesions" from the round window niche. It is claimed that adhesions are present in about 20% of round windows. We are dubious that this can be done without additional morbidity to the tympanic membrane (from the endoscope). This procedure also adds a requirement for specialized equipment and skill to an otherwise rather straightforward procedure.

The simplest procedure reported so far is that of Rutka and colleagues (Rutka, 2002). They had simply had the patient administer topical gentamicin themselves through a ventilation tube. A tube is placed in the posterioinferior quadrant of the TM. Patients are instructed to lie on their side and place 5-6 drops into the affected ear 3 times/day. They were told to administer the drops until they became constantly vertiginous for 2 days and then stop. In our opinion, this procedure is less precise than most of the other procedures noted above, and the lack of precision is probably associated with greater hearing risk. Nevertheless, it seems reasonable in situations where hearing is unusable, as an alternative to a surgical labyrinthectomy.

With respect to timing, protocols that involve rapid administrations of large amounts of drug (here we define rapid as over one week), seem to be prone to produce worse hearing results, possibly because gentamicin has a delayed and prolonged effect, extending over weeks-months, and it is difficult to know if you have given enough or too much, over a week. However, if hearing is already unusable on the side to be treated, shorter protocols seem quite reasonable.

Finally, some groups suggest transtympanic dexamethasone treatment -- Dexamethasone is a steroid, and not related to gentamicin. At this writing (9/2001), the benefit of this procedure has not been clearly shown -- it may be worth a try in situations where all else has been tried and there is little to lose. For example, it's use might be considered in when the remaining ear affected by Meniere's is the only-hearing ear. Silverstein et al found it to be no better than placebo (1998)

What if TTG fails ?

There are a number of reasons why TTG might fail. First, the diagnosis might be wrong. The patient might have a central disorder (such as Migraine), the patient might have a nerve disorder (such as microvascular compression), or might have bilateral Meniere's.

A second group of reasons depend on the drug not being effective. In theory, it might be ineffective because it isn't delivered to the inner ear (perhaps due to adhesions over the round window), the individual being treated might have an idiosyncratic resistance to gentamicin (idiosyncratic susceptibility has been documented, perhaps there is also resistance), or there might be recovery. Another reason is that initially, gentamicin may do reversible damage to the hair cells. It is common for Meniere's attacks to return 1 or 2 years after the first TTG treatment (Waele et al, 2002).

Patients with otolithic crises of Tumarkin (a variant of Meniere's) might be particularly likely to fail as this is an otolithic disorder, and gentamicin is known to be less toxic to the otoliths than to the canals. Little data is available on this. Abou-Halawa and Poe (2002) reported that of 4 patients with Tumarkin crises, 2 had no further attacks, 1 did not respond, and 1 had a recurrence of attacks requiring additional gentamicin.

When TTG fails, careful consideration should be made to exclude failures in the first group (wrong diagnosis). If the diagnosis still appears to be sustainable, then one may wish to consider more radical procedures such as vestibular nerve section or labyrinthectomy.

Where to get transtympanic gentamicin treatment

Nearly all major medical centers now offer transtympanic gentamicin treatment through their otolaryngology service. However, recall that the treatment series, for persons with usable hearing on the side to be treated, requires 4-6 weeks to complete. Before having transtympanic gentamicin treatment, we also think that it is prudent to try all reasonable medical avenues of treatment.

References related to transtympanic gentamicin treatment: