Clin Exp Otorhinolaryngol.  2021 Nov;14(4):367-373. 10.21053/ceo.2019.02040.

Effects of Intratympanic Injection of Isosorbide on the Vestibular Function of Animal Models of Endolymphatic Hydrops

• Kim M
• Yoon SY
• Hong H
• Hong HJ

• KMID: 2522427
• DOI: http://doi.org/10.21053/ceo.2019.02040

Abstract

Objectives
. The aims of this study were to investigate the effects of intratympanic injections of isosorbide on vestibular function in animal models of endolymphatic hydrops and to find a new treatment option for the acute onset of vertigo in Ménière disease (MD).
Methods
. Seventy male guinea pigs received intratympanic injection of isosorbide (IT-ISB). The animals were divided into three study groups: control, a chronic hydrops model, and an acute hydrops model. Intracochlear drug concentrations were measured using high-performance liquid chromatography. Vestibular function was analyzed using an animal rotator test with bidirectional sinusoidal harmonic acceleration before and after IT-ISB administration. Histological changes were also investigated.
Results
. ISB successfully permeated the perilymph through the round window membrane (RWM) at all three concentrations (25%, 50%, and 100%). In the chronic hydrops model, while IT-ISB histologically induced a reduction of endolymphatic hydrops, vestibular function was unchanged. In the acute hydrops model, no endolymphatic hydrops was histologically observed, and vestibular symmetry was also preserved after IT-ISB.
Conclusion
. ISB passed through the RWM into the perilymphatic space even at lower concentrations. IT-ISB histologically reduced hydrops in the chronic model and preserved symmetrical vestibular function in the acute model. IT-ISB could be a treatment candidate for acute attacks of vertigo in MD.

Keyword

Isosorbide; Endolymphatic Hydrops; Meniere Disease

Figure

• 

  Fig. 1 Experimental groups. Group 1, the control group, was injected with three different isosorbide concentrations (IT-ISB). Group 2, the chronic hydrops model, was treated with IT-ISB at 12–16 weeks after endolymphatic sac (ES) ablation surgery. Group 3, the acute hydrops model, was treated with (3a) desmopressin (VP) injected at 2–4 weeks after ES surgery for the induction of hydrops aggravation and (3b) IT-ISB along with VP. IT-ISB, intratympanic injection of isosorbide.

• 

  Fig. 2 Intracochlear concentrations of isosorbide after injections at different concentrations. Whiskers show the standard deviations. IT-ISB, intratympanic injection of isosorbide. *P<0.05.

• 

  Fig. 3 Intratympanic injection of isosorbide (IT-ISB) in the chronic hydrops model. (A) No significant change of symmetrical vestibular function was observed after IT-ISB. (B) Endolymphatic hydrops decreased after IT-ISB (arrowheads) (H&E, ×40).

• 

  Fig. 4 Intratympanic injection of isosorbide (IT-ISB) in the acute hydrops model. (A) Acute vestibular dysfunction after the induction with desmopressin (VP) and preserved vestibular symmetry after IT-ISB along with VP. Whiskers show the standard deviations. *P<0.05. (B) Acute endolymphatic hydrops after VP, however, preserved normal endolymphatic space after IT-ISB along VP (arrowheads) (H&E, ×40).

Reference

1. Foster CA. Optimal management of Meniere’s disease. Ther Clin Risk Manag. 2015; Feb. 11:301–7.

2. Nevoux J, Barbara M, Dornhoffer J, Gibson W, Kitahara T, Darrouzet V. International consensus (ICON) on treatment of Meniere’s disease. Eur Ann Otorhinolaryngol Head Neck Dis. 2018; Feb. 135(1S):S29–32.

3. Kitahara M, Takeda T, Yazawa Y, Matsubara H, Kitano H. Treatment of Meniere’s disease with isosorbide. ORL J Otorhinolaryngol Relat Spec. 1982; 44(4):232–8.

4. Juhn SK, Prado S, Pearce J. Osmolality changes in perilymph after systemic administration of glycerin. Arch Otolaryngol. 1976; Nov. 102(11):683–5.

5. Kakigi A, Takeda T, Saito H, Kataoka H. Effect of isosorbide on hearing loss due to endolymphatic hydrops. Acta Otolaryngol Suppl. 1995; 519:223–6.

6. Takeda T, Takeuchi S, Saito H. Effect of glycerol on pressure difference between perilymph and endolymph. Acta Otolaryngol. 1990; Jul–Aug. 110(1–2):68–72.

7. Kakigi A, Takeda S, Takeda T, Sawada S, Azuma H, Higashiyama K, et al. Time course of dehydrating effects of isosorbide on experimentally induced endolymphatic hydrops in guinea pigs. ORL J Otorhinolaryngol Relat Spec. 2004; 66(6):291–6.

8. Padoan S. Oral versus i.v. administration of the glycerol test: side-effects and usefulness. Acta Otolaryngol. 2003; May. 123(4):482–7.

9. Matsubara H, Kitahara M, Takeda T, Yazawa Y. Rebound phenomenon in glycerol test. Acta Otolaryngol Suppl. 1984; 419:115–22.

10. Larsen HC, Angelborg C, Klockoff I, Stahle J. The effect of isosorbide and urea on hearing in patients with Meniere’s disease. Acta Otolaryngol (Stockh). 1984; 412:113–4.

11. Yamazaki T, Imoto T, Hayashi N, Watanabe S, Kozaki H, Abe T. Meniere’s disease and isosorbide as an oral hyperosmotic agent. Arch Otorhinolaryngol. 1982; 234(1):97–104.

12. Nozawa I, Nakayama H, Hashimoto K, Imamura S, Hisamatu K, Murakami Y. Efficacy of long-term administration of isosorbide for Meniere’s disease. ORL J Otorhinolaryngol Relat Spec. 1995; May–Jun. 57(3):135–40.

13. Kim M, Do KH, Kim KS. Isosorbide concentration in perilymph of the guinea pig after oral administration versus that after round window perfusion. Clin Exp Otorhinolaryngol. 2014; Dec. 7(4):281–5.

14. Kakigi A, Takeda T, Sawada S, Taguchi D. Antidiuretic hormone and osmolality in isosorbide therapy and glycerol test. ORL J Otorhinolaryngol Relat Spec. 2006; Aug. 68(5):279–82.

15. Klockhoff I. Diagnosis of Meniere’s disease. Arch Otorhinolaryngol. 1976; Sep. 212(4):309–14.

16. Egami N, Kakigi A, Sakamoto T, Takeda T, Hyodo M, Yamasoba T. Morphological and functional changes in a new animal model of Meniere’s disease. Lab Invest. 2013; Sep. 93(9):1001–11.

17. Kim M, Kim KS. Vestibular function change in a vasopressin-induced hydrops model. Otol Neurotol. 2017; Dec. 38(10):e495–500.

18. Salt AN, Plontke SK. Endolymphatic hydrops: pathophysiology and experimental models. Otolaryngol Clin North Am. 2010; Oct. 43(5):971–83.

19. Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandala M, et al. Diagnostic criteria for Meniere’s disease. J Vestib Res. 2015; 25(1):1–7.

20. Sajjadi H, Paparella MM. Meniere’s disease. Lancet. 2008; Aug. 372(9636):406–14.

21. Shigeno K, Egami T, Sasano T. Experimental study of nystagmus induced by injecting various solutions into the middle ear cavity. Acta Otolaryngol. 1989; Jul–Aug. 108(1–2):31–7.