Intratympanic steroid administration is increasingly preferred for the treatment of sudden sensorineural hearing loss (SSNHL), either as initial therapy or salvage therapy after failure of systemic administration [1]. This route can provide organ-specific treatment, with two theoretical advantages: direct steroid uptake through the round window membrane, resulting in higher perilymph levels, and reduced or absent systemic steroid absorption and toxicity [2]. Hence, the permeability of the round-window membrane and the affinity of the utilized steroid to the corticoid receptors of the inner ear represent issues potentially affecting the therapeutic efficacy of intratympanic administration.

The round-window permeability appears radiologically poor in 13% and totally absent in 5% of ears, whereas its membrane macroscopically appears partially or completely obstructed in 12% and 17% of examined middle ears, respectively, in the native state [3]. Yet, on the basis of non-superiority of round-window membrane perfusion over injection in patients receiving steroid treatment for SSNHL [2], coupled with the successful treatment of Meniere’s disease by local administration of gentamicin into the middle ear, albeit being highly polar and hydrophilic (i.e., low molecular permeability), we can surmise that pseudo-membranes in the round-window niche cannot completely block the diffusion of drugs into the human inner ear. Therefore, the respective membrane permeability is not a core impact factor in intratympanic treatment.

Regarding the steroids used as therapeutic agents, dexamethasone and methylprednisolone are mainly preferred for intratympanic administration, typically in their commercially available phosphate (DEX-p) and succinate (MTP-s) soluble forms, respectively. Both DEX-p and MTP-s have comparable round-window permeability, and the decision regarding their use is essentially based on physician preference. On a biochemical basis, given that glucocorticoids exert their beneficial effects through the glucocorticoid receptor (GCR) (although some effects within the inner ear may also be mediated through the mineralocorticoid receptor), DEX-p demonstrates more avid receptor uptake than MTP-s. However, DEX-p becomes undetectable 24 hours after administration, whereas MTP-s maintains higher concentration and longer duration in the perilymph and endolymph. The implication of this finding, in the context of the longer DEX-p half-life and the absence of albumin-binding in the cochlear fluids (i.e., the complete receptiveness of the available drug), provides DEX-p with a small theoretical edge over MTP-s regarding treatment efficacy. Nevertheless, twice-daily intratympanic administration, based on their perilymph pharmacokinetic profiles, has been solidly proposed for both solutions [4].

Considering the potential anti-inflammatory glucocorticoid action in the cochlea, the respective therapeutic effect could also be associated with stimulation of the synthesis and release of annexin A1 (ANXA1), a cellular protein which inhibits leukocyte migration towards the scala media, regulating the clearance of apoptotic cells, when activated by the GCR. It seems that DEX-p, exerting higher glucocorticoid action, may again be preferred in this respect, for the stronger promotion of ANXA1 [5].

Future orientation includes comparative pharmacokinetic studies of DEX-p and MTP-s regarding middle and inner ear absorption and elimination processes for drawing more definite respective conclusions, along with diagnostic protocols (i.e., serum markers), which will define and segregate patients on the basis of pathology more precisely, thus improving the reliability of treatment outcomes.