Jan E. Veldman

Cisplatin-induced ototoxicity: morphological evidence of spontaneous outer hair cell recovery in albino guinea pigs?

Cisplatin is frequently used in the treatment of various forms of malignancies. Its therapeutic efficacy, however, is limited by the occurrence of sensorineural hearing loss. Little is known about the course of hearing loss over longer time intervals after cessation of cisplatin administration. Infrequently, recovery of hearing has been described in animals and humans. Stengs et al. (1997) treated guinea pigs with cisplatin at a daily dose of 1.5 mg/kg for 8 consecutive days and subsequently studied cochlear function after survival times varying from 1 day to 16 weeks. Spontaneous improvement of the hair cell-related potentials (cochlear microphonics and summating potentials) was observed starting 2 weeks after cessation of treatment. In the present study we examined light microscopically the cochleas used in the study of Stengs et al. (1997). One day after cessation of cisplatin administration outer hair cell (OHC) loss in the basal cochlear turn averaged 66%. In the 1-week survival group, OHC counts were similar to those of the 1-day survival group. In the 4-week survival group, however, a relatively small loss of OHCs was found in the basal cochlear turn; OHC loss averaged only 15%. A similar loss was found after 8 weeks. In the 16-week survival group, OHC loss in the basal turn increased to 48%, but this was not statistically significant. Our histological observations are in line with the electrophysiological data from the same animals. Our findings suggest that OHCs recover from cisplatin-induced damage 1-4 weeks after treatment. However, the results do not allow a conclusion as to whether the observed recovery is due to the formation of new OHCs or to (self-)repair of damaged OHCs.

Diagnostic and Therapeutic Dilemmas in Rapidly Progressive Sensorineural Hearing Loss and Sudden Deafness a Reappraisal of Immune Reactivity in Inner Ear Disorders

Sera from 76 patients with a clinical diagnosis of idiopathic rapidly progressive sensorineural hearing loss (SNHL) (n = 15), sudden deafness (n = 31) and with other etiologies of their hearing loss (n = 30) were analysed by western blot assay. Seventy-three percent of the cases with rapidly progressive SNHL had cross-reacting antibodies (27, 45, 50, 68 kD). The overall response to immunoprogressive therapy was effective in only 50% of cases. Sixty-five percent of the patients with sudden deafness also had cross-reacting antibodies (27, 45, 50, 80 kD). In these cases steroid therapy was more effective in re-establishing the hearing than no treatment, regardless of the western blot outcome. Spontaneous recovery occurred in approx. 50% of cases, but only in those with a positive assay. The antigenic epitopes detected with immunoblotting were not cochlea specific; they were also found in protein extracts of other organs (cranial nerves, kidney, brain).

Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of factors. Many parameters, such as dose, mode of administration, dosage schedule and concomitant administration of protective additives, vary among the published studies. Therefore, we performed a basic dose-effect study on cisplatin ototoxicity in the guinea pig. Albino guinea pigs were treated with cisplatin at daily doses of either 0.7, 1.0, 1.25, 1.5 or 2.0 mg/kg for 8 consecutive days. Electrocochleography was performed on day 10 after which the cochleas were removed and processed for histological examination. The electrophysiological results showed a marked transition from almost no ototoxic effect to a large effect between a daily dose of 1.25 and 1.5 mg/kg (Stengs et al., 1998). Outer hair cell (OHC) counts corresponded well with the electrophysiological results. At daily doses of 0.7, 1.0 and 1.25 mg/kg no statistically significant OHC loss was observed, whereas OHC loss averaged 60% and 65% in the basal turns at daily doses of 1. 5 and 2.0 mg/kg, respectively. Morphological changes in the stria vascularis were present only in cochleas from animals treated with cisplatin doses of 1.0, 1.25 and 1.5 mg/kg/day. Cochleas from animals treated with a daily cisplatin dose of 2.0 mg/kg for 8 consecutive days showed an endolymphatic hydrops. The present study shows that cisplatin, administered at a daily dose of 1.5 mg/kg for 8 consecutive days, provides a degree of OHC loss that is well suited to study the effects of putative protective agents and possible hair cell recovery.

Ultrastructural localization of gentamicin in the cochlea

The ultrastructural distribution of gentamicin in the cochlea was investigated immunocytochemically. Specific labeling was restricted to the organ of Corti, in particular to the outer and inner hair cells, the Deiters cells, Hensens cells and the tympanic layer cells of the basilar membrane. Other cochlear tissues did not demonstrate any labeling. At the subcellular level, gentamicin was found in lysosomes, multivesicular bodies and small tubules and vesicles. A model is proposed in which it is hypothesized that gentamicin is internalized by endocytotic vesicles and is transferred to the lysosomal compartment as well as to the endoplasmic reticulum and Golgi complex.

Revision surgery for chronic otitis media : A learning experience report on 389 cases with a long-term follow-up

The objective of this study was to evaluate, during a long-term follow-up period, the results of revision surgery for chronic otitis media with or without cholesteatoma. Intact canal wall and canal wall down procedures were performed. The surgical history of every patient was assessed before the operation. A dry, relatively safe, and disease-free ear was created in 90% of the reoperated ears (N = 389). The recurrence rate of cholesteatoma was 5% for the total group. Reperforations of the tympanic membrane occurred in 10%, and persistent or recurrent otorrhea was present in 10% of cases. The functional hearing results were quite satisfactory. A residual air-bone gap of ≤30 dB was reached in 70.3% of the cases after revision tympanoplasty only (N = 41). Revision mastoidectomy with revision tympanoplasty as a one-stage procedure led subsequently, in 76% of intact canal wall procedures (N = 113) and 55% of canal wall down procedures (N = 98), to a residual air-bone gap of ≤30 dB.

Genetic aspects of nonchromaffin paraganglioma

SummaryThis paper surveys the literature on familial nonchromaffin paragangliomas and presents the results of a study of a family with 295 living members.

An improved fixation method for guinea pig cochlear tissues

The influence of different fixation methods and of various primary fixatives on the ultrastructural preservation of guinea pig cochlear tissues was investigated. No differences in fixation quality were observed between cochleas fixed by intravascular perfusion and cochleas fixed by intralabyrinthine perfusion. Tri-aldehyde primary fixation resulted, in contrast to other formulae investigated, in an excellent, uniform preservation of all cochlear tissues without obvious fixation artefacts. The influence of OSO4/K4Ru(CN)6- and OSO4/K4Fe(CN)6 postfixation was also tested. Cochlear tissues postfixed with OSO4/K4Ru(CN)6 or OSO4/K4Fe(CN)6 exhibited more cellular detail (e.g., membrane- and glycogen contrast) as compared to tissues postfixed with OSO4 alone. Tri-aldehyde primary fixation followed by OSO4/K4Ru(CN)6- or OSO4/K4Fe(CN)6 postfixation therefore is recommended as a multipurpose procedure for optimal preservation of labyrinthine tissues.

Early Hair Cell Loss in Experimental Hydrops

One, 2, and 4 months after surgical obliteration of the endolymphatic sac, the sequence of degenerative changes in the organ of Corti of the guinea pig was studied. The block surface technique with interference differential (Nomarski) microscopy was used for this investigation to study the morphological changes in the organ of Corti. The hair cell loss was calculated and mapped in cytocochleograms. One month postoperatively a minimal loss of only outer hair cells was observed in the apical cochlear turn. At 2 months a progression of outer hair cell loss was seen, which proceeded in the 4-month group. At 4 months the inner hair cells showed a slight tendency to degenerate, again beginning in the most apical part of the cochlea.

Ultrastructure of the stria vascularis and Reissner's membrane in experimental hydrops

A time-sequence study was made of the early ultrastructural changes of the stria vascularis and Reissners membrane in the guinea pig after obliteration of the endolymphatic sac and duct. Pathological alterations of both the stria vascularis and Reissners membrane were found to start in the apex of the cochlea. The morphological changes of the stria vascularis were characterized by an increase of vesicles in the marginal cells and by intercellular edema, followed by vacuolization and atrophy of marginal and intermediate cells. In Reissners membrane extensive gaps in the mesothelial cell layer were observed together with intracellular pathology of the epithelial cells. The significance of these ultrastructural changes in the stria vascularis and Reissners membrane with regard to the pathophysiology of the endolymphatic hydrops is discussed.

Immune-mediated sensorineural hearing loss

A review is given on the way our knowledge of pathways of immune responses inside and in the immediate vicinity of the inner ear has gradually developed over the past two decades. Immune reactivity plays a more important role in the etiopathogenesis and natural course of various inner ear disorders than was thought originally. They comprise certain forms of fluctuating or rapidly progressive sensorineural hearing loss (SNHL) with or without endolymphatic hydrops. Patients may present themselves clinically with symptoms resembling Ménières disease or even with sudden deafness. Immune-mediated audio-vestibular dysfunctioning is either a separate disease entity or part of a more generalized (auto-) immune process. The various attempts which have been made to develop methods or tests to confirm the diagnosis of immune-mediated SNHL are critically reviewed, including the treatment responses to immunosuppressive therapy. Various animal models are furthermore presented.