Vestibular compensation

By Marcello Cherchi, MD PhD

For patients

After a patient suffers vestibular damage, the body has some capacity to heal from that damage.  One of the mechanisms responsible for this healing is known as “vestibular compensation.”  The best studied mechanism to promote vestibular compensation is appropriately targeted vestibular rehabilitation therapy.  Various chemical compounds have also been studied, though mostly only in animal models.  Of the chemicals that have been studied which are available as medications, we tend to favor betahistine because it is readily available, it is generally well-tolerated, and it has few drug-drug interactions.

For practitioners

Overview

Vestibular compensation refers to the adaptive neural plasticity that facilitates recovery from a vestibular insult.  Vestibular compensation is a complex process and thought to involve multiple mechanisms, which may differ from one individual to another and one disease to another.

Many studies have explored whether medications may accelerate vestibular compensation.  The evidence is mixed for most agents studied.  Of the medications currently available in the United States, betahistine (while not currently FDA approved) is obtainable through compounding pharmacies, is generally very well-tolerated, appears to have minimal drug-drug interactions, and is supported by at least some evidence.  Betahistine also has the advantage of already being used for management of other otovestibular diseases (such as Ménière’s disease) and thus many practitioners have some clinical experience with it and are comfortable prescribing it.

Vestibular damage, compensation, and neural plasticity

When peripheral vestibular function is reduced due to damage (such as from vestibular neuritis, labyrinthitis, vestibular schwannoma, etc.), it is possible for the brain to “recalibrate” to this newly abnormal circumstance through a process known as vestibular compensation (Lacour et al. 2016; Vidal et al. 1998), which is believed to occur in the brainstem, probably mediated by multiple structures (Peppard 1986), including the commissural neurons between the vestibular nuclei (Graham and Dutia 2001; Olabi et al. 2009), though the neuroanatomy and neurochemistry of this process remains poorly understood (Vibert et al. 1999).  In humans, dead neurons do not regenerate, so “healing” in neurological terms is mediated by remaining neurons sprouting new synapses, and changing (upregulating or downregulating) the expression of neurotransmitter receptors.  Vestibular compensation is sometimes offered as a paradigm example of neural plasticity (Macdougall and Curthoys 2012; Vibert et al. 1999; Vidal et al. 1998). Balaban and colleagues (Balaban, Hoffer, Gottshall 2012) point out that the observations of Wladimir Michailowitsch Bechterew (Bechterew 1883) comprised the earliest evidence of vestibular compensation.

In many cases vestibular compensation occurs simply through remaining active, and appropriately targeted vestibular rehabilitation therapy appears to play a significant role in accelerating this process.  Non-vestibular inputs likely play a role in this process (Yates and Miller 2009), as well as strategies such as sensory substitution (Curthoys 2000).

The neural plasticity that makes vestibular compensation possible deteriorates with normal aging (Paige 1992), making this “rescue mechanism” progressively less effective over time.

Some researchers have explored whether there are pharmacologic means to coax the compensatory process along.  The pharmacology of vestibular compensation (Flohr et al. 1985) is a complex question for several reasons; first because nearly every known neurotransmitter is found somewhere in the vestibular system (Flohr et al. 1985; Soto et al. 2013); and second because compensation is not a monolithic process but rather appears to proceed through distinct phases (Curthoys and Halmagyi 1995).  The majority of studies about vestibular compensation were undertaken in animal models rather than in humans, and while these may be instructive, their relevance to management of patients is not immediately clear.

Pharmacologic agents for vestibular compensation?

For any given pharmacologic agent, different studies often reveal conflicting results.

For example, alcohol (ethanol) has been reported both to promote vestibular compensation (Petrosini 1982) and to impede it (Berthoz et al. 1977).

Betahistine is a mixed histamine receptor agonist (at H1 receptors) and antagonist (at presynaptic H3 receptors), and has been reported to promote vestibular compensation in several studies (Chen et al. 2019; Dutia 2000; Lacour 2013; Lacour and Tighilet 2000; Tighilet et al. 1995; Tighilet et al. 2007).  One study pointed out that betahistine acts at multiple levels, including vascular, the central nervous system, and the peripheral vestibular system (Lacour 2013).

Flunarizine, a calcium channel antagonist, has been reported to promote vestibular compensation (Gilchrist et al. 1993; Tolu and Mameli 1984).  Flunarizine is not currently FDA approved.

The neurotransmitter dopamine appears to play a role in vestibular compensation.  Studies report that vestibular compensation is accelerated by D2 dopamine receptor agonists such as quinpirole (Drago et al. 1996) and bromocriptine (Petrosini and Dell’Anna 1993), and retarded by the D2 dopamine receptor antagonist sulpiride (Drago et al. 1996; Petrosini and Dell’Anna 1993).

Tanakan, which is the EGb761 extract of ginkgo biloba, has been studied with mixed results for vestibular compensation.  Some studies report it to promote vestibular compensation (Lacour et al. 1991; Zaĭtseva 2014), while others find it has no effect (Schlatter et al. 1999)

N-acetyl-L-leucine was reported to promote vestibular compensation in one study (Günther et al. 2015).

The NMDA (N-methyl-D-aspartate) system appears to be involved in vestibular compensation (Aoki et al. 1996).  Some studies reported that NMDA receptor antagonists MK801 and CPP disrupted vestibular compensation (Darlington and Smith 1989; Smith and Darlington 1988), whereas another study found these to have no effect (Smith and Darlington 1992).  A study of the competitive NMDA receptor antagonist CGS 19755 reduced spontaneous nystagmus but did not affect the rate of vestibular compensation (Sansom et al. 1993).  One study concluded that the NMDA receptor antagonist MK801 may have different effects during different phases of compensation (Flohr and Lüneburg 1993).  Another study reported that the NMDA receptor agonist APV appeared to facilitate early phases of vestibular compensation (Pettorossi et al. 1992).

The effect of various kinds of steroids have been studied with respect to vestibular compensation.  One study of the caloric response in humans who had suffered vestibular neuritis reported steroids to improve outcomes (Kitahara et al. 2003), while an animal study of steroids (dexamethasone and methylprednisolone) found no such benefit (Alice et al. 1998).

Gamma amino butyric acid (GABA) binds to several receptors, GABA_A and GABA_B.  A number of animal studies have examined the difference between pre- and post-lesion expression of GABA receptors (Dutheil et al. 2013; Gliddon et al. 2005a, b; Johnston et al. 2001; Magnusson et al. 2000; Magnusson et al. 2002; Shao et al. 2012; Yamanaka et al. 2000; Yu et al. 2009).  Other studies reported no significant changes (Zhang et al. 2005), with one study concluded that, “There is no compelling evidence that these changes have a causal role in the compensation process” (Gliddon et al. 2005c).  An animal study of baclofen (a GABA receptor agonist) reported improved vestibular compensation (Heskin-Sweezie et al. 2010).

Medications used in the acute symptomatic management of vertiginous episodes generally work through vestibular suppression.  Given this mechanism, it has often been suspected that vestibular suppressants may impair vestibular compensation, though a study of diazepam (a benzodiazepine) did not find evidence for this (Ishikawa and Igarashi 1984).

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