Timothy C. Hain, MD
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|When a person has bilateral vestibular damage, such as may result from Gentamicin toxicity, they may experience oscillopsia. When the head is moving, objects blur. When driving one may be unable to see signs clearly on a bumpy road.|
Gentamicin is a commonly used antibiotic medication. Gentamicin toxicity is the most common single known cause of bilateral vestibulopathy, accounting for 15-50% of all cases. A review of 1976 patients receiving gentamicin or another similar (aminoglycoside) antibiotic showed that about 3% developed some sort of vestibular injury (Kahlmeter and Dahlager, 1982). Bilateral vestibulopathy, discussed in more detail here, occurs when the balance portions of both inner ears are damaged. The symptoms typically include imbalance and visual symptoms. The imbalance is worse in the dark, or in situations where footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called "oscillopsia", only occur when the head is moving. Quick movements of the head are associated with transient visual blurring. This can cause difficulties with seeing signs while driving, or recognizing peoples faces while walking.
|Typical audiogram of person exposed to gentamicin. Hearing is commonly normal through 4000 hz, and then falls off at higher frequencies. Often persons with significant vestibular damage from gentamicin do not notice any change in their hearing.|
Other than gentamicin, there are numerous other ototoxins, but most affect hearing mainly. (Note that gentamicin is spelled with a terminal "icin", unlike several other drugs in the same aminoglycoside family, that end with "mycin", the difference in spelling from the other aminoglycosides such as streptomycin reflects the different species of origin of this antibiotic (Begg and Barclay, 1995). Hearing ototoxicity reportedly occurs about 5-10% of the time that gentamicin is given intravenously or during peritoneal dialysis. However hearing in humans is generally affected only for high frequencies (e.g. 8 and 12,000 Hz) or not at all. This differs from the situation in most animals where hearing and vestibular function both suffer (Chen et al, 2002).
More importantly, the vestibular system can be damaged with gentamicin. The exact incidence of vestibulotoxicity when gentamicin is administered is humans is presently estimated to be about 3%(Kahlmetera and Dahlager, 1982). However, this statistic is open to question as not only have very few prospective studies of vestibular function been done, but it is also difficult to detect vestibular damage until it is profound. It seems likely that significant vestibular damage does not occur as frequently as the subtle hearing impairment reported above (5-10%). The author's "ball-park" estimate is that about 1% of all 2 week courses of gentamicin result in significant vestibular toxicity.
In pathologic studies, aminoglycoside toxicity is associated with death of inner ear hair cells (Plogar et al, 2001). The auditory ganglion is spared (Tsuji et al, 1999) although there are some dissenters (Hinojosa et al, 2002) suggesting that eventually it is concievable that an inner ear prosthesis similar to a cochlear implant might be designed to remedy this condition.
As discussed above, gentamicin toxicity is certainly not the rule, even for month long courses of gentamicin. Why do some people get toxicity and others don't ? In the following text we will discuss the following factors that may affect toxicity:
Dose: One possibility is that the dose was too small. It is very uncommon for gentamicin otototoxicity to develop with with less than 1 week of treatment. It is possible to develop bilateral vestibular toxicity from gentamicin even when the level of the drug is never too high, given that it is given for a long period. The risk may be especially high if there are other drugs being given (see below), and in certain individuals with genetic predisposition (see below).
Recent studies suggest that gentamicin ototoxicity is most closely related to total dose rather than having inappropriately high levels. Conventionally, gentamicin is given three times per day, with a total dose per day ranging from 3 mg/kg to 5 mg/kg. These doses may need to be modified for special situations such as when kidney function is impaired. For three times/day dosing, ordinarily a peak of 5-10 and a trough of < 2 is aimed for, see Keller et al). R.E. Black et al (1976) showed that high serum levels of amikacin (a related aminoglycoside) were statistically associated with the development of cochlear toxicity. However his patients received higher than recommmended maximum dosages. In another study, F.O. Black et al (2001) did not find a correlation between total dose and ototoxicity. However, their numbers were small and a correlation could have easily been missed. Fee also did not find that area under the curve (related to total dose) correlated with toxicity (Fee, 1980). Fee suggested that there were other, yet unknown factors, operative.
Further data suggesting that a high peak dose is not necessarily harmful is available. A recent trend is to administer gentamicin on a once/day schedule because bacterial killing is a stronger function of concentration than time. Details about how this is done using a nomogram called the "Hartford Nomogram" is found in in a paper written by Nicolau et al. Other algorithms are discussed by Begg and Barclay (1995). Peak levels are expected to be quite high and targets for three time/day dosing as discussed above are inappropriate for once/day dosing. Instead, levels drawn at known times from the administration are used to adjust the interval of dosing using a nomogram. According to Begg (1995), trough levels are not needed for once-daily dosing. Most evidence suggests that ototoxicity is less for once/day dosing than more frequent dosing (Begg and Barclay, 1995). This line of evidence again suggests that high-peak levels are not necessarily ototoxic, but rather it is the total dose or some other factor that is important. It also possible that toxicity might be related to a combination of peak dose and total dose, or that toxicity is a complex function of peak and total dose, potentiating medications and genetic suceptibility. The studies done to date are not powerful enough to clearly distinguish between these possibilities.
Potentiating medications: There may be increased risk of ototoxicity from gentamicin if other ototoxic drugs such as cisplatin (a chemotherapy agent) and vancomycin (another antibiotic), are given at the same time. There also appears to be a synergistic effect of loop diuretics such as furosemide or ethacrynic acid (Ding, 2001), and also loud noise (Aran et al, 1992), when combined with gentamicin. The potentiating effect of loop diuretics is likely related to a more rapid entry of gentamicin into the ear. Gentamicin is probably also toxic to the ear of the developing fetus as related drugs (e.g. streptomycin) have been shown to have this problem (see Boradori et al, 1997). Ear drops containing gentamicin as well as related substances may be ototoxic if given over a prolonged time to individuals with perforated ear drums. Click HERE for more information about this.
Tainted drug ? Other types of toxicity from gentamicin have been suggested. One particular supplier of gentamicin, Long March Pharmaceuticals, and a US distributor, Fujisawa USA, was under investigation by the FDA according to a recent newspaper article (Pound and Sternberg, 2000). Of course, investigation does not prove that damage occured or establish guilt, but this investigation may bear watching.
Genetic susceptibility: It been recently found that in some individuals there is unusual susceptability to gentamicin or streptomycin ototoxicity related to a mutation of mitochondrial RNA (Fishel-Ghodsian et al, 1997;Gardner et al, 1997). It is called the "A1555G" mitochondrial mutation. This susceptability is passed on genetically through the mother and occurs in as many as 17% of individuals with hearing loss after aminoglycoside exposure (note that this paper was concerned with hearing, not vestibular loss). A patient with idiopathic loss of vestibular function has also been reported with mitochondrial abnormalities (Baloh et al, 1997), and some pedigrees have been reported with both sensorineural deafness and aminoglycoside sensitivity (El-Schahawi et al, 1997). Other sites in the cell other than the mitochondria such as the golgi apparatus might also be the locus for additional susceptibility mutations (Blackburn and Avery, 2003). Hearing loss is also common in Kearns-Sayre, a disorder with mitochondrial disturbances as well as other mitochondrial disorders. The A1555G test is now easily available through most hospitals as a send out to Mayo medical laboratories.
Age: In general, older people are more susceptible than younger people to gentamicin toxicity. This may relate to a steady attrition of vestibular neurons during life, so that by the age of 80, approximately 50% of vestibular ganglion cells have died, even in normal persons. Little is known about toxicity in children. Aust (2001) suggested that children are less prone to develop vestibulotoxicity from gentamicin than adults.
In general the message is not very encouraging. People do recover, but the process is slow and usually incomplete. The majority of the improvement occurs at high-frequencies on rotatory chair testing -- high-frequency gain usually returns to normal after several years, but remains depressed for lower frequencies. Generally a person who is working at a "desk job" prior to gentamicin toxicity, is ultimately able to return to that job. Person's whose occupations require extra-good balance such as persons in the construction industry may be unable to function in their previous capacity. A discussion of prognosis in 35 patients was recently reported by Gillespie and Minor (1999).
Progression of vestibulotoxicity can occur for months after the last dose, and recovery can be measured out to a year or even longer (Black et al, 2001). Recovery likely is related to a combination of several factors:
1) Some "sick" inner ear hair cells get better. Nobody knows exactly how many inner ear hair cells are sick rather than being dead, but it seems reasonable to assume that they are not all dead, but that some remain but are not functioning at top-efficiency. In experimental animals (rats), hair cells may lose their motion sensitive processes (stereocilia), but still survive (Zheng et al, 1999). This may also happen in humans. As gentamicin persists in the ear for somewhere between 80 days and a year, recovery from this process might reasonably stretch over the same time frame.
2). The brain adapts to the missing inner ear information. Certainly people adapt to missing sensory input using plasticity, substitution of other senses, anticipation and behavioral changes. It has recently been suggested that the typical recovery seen on rotatory chair testing at high-frequency is usually due to sensory substitution rather than vestibular recovery.
3). There may be regeneration occuring. Birds can regenerate their hair cells, and although it was felt for a long time that people can't do this, there is a small amount of evidence that some regeneration does occur. At present, it is not felt that regeneration is a significant factor in recovery in humans.
4). Nerve axons sprout and innervate surviving hair cells.
Please see our Bilateral Vestibulopathy Page for further information regarding diagnosis, treatment, prognosis, and research efforts related to otoxicity in general and gentamicin toxicity in particular.