Objectives: To provide information regarding the challenge and refinement of our understanding of perilymphatic fistulae (PLFs) by systematic clinical observations coupled with human temporal bone histopathologic/clinical studies. Materials and Methods: (1) Traditional human temporal bone collection for histologic study (representing subjects having disorders of hearing or balance); (2) special human temporal bone collection for histologic study (from consecutive autopsies representing a cross-section of society); (3) clinical data corresponding to human temporal bone specimens of both types; (4) predictive experimental paradigm (histopathology predicts clinical signs and symptoms and vice versa); (5) clinical study parallel to human temporal bone study using the same medical and surgical variables; (6) outcome analysis of clinical study (5-year follow-up – 173 patients with diagnosis of PLF); (7) temporal bone specimens for histopathologic study of patients from the clinical study having the diagnosis of PLF. Results: (1) The accuracy of the clinical diagnosis for PLF criteria was defined: p < 0.001, sensitivity 59% and specificity 91%. (2) The histologic diagnostic criteria for PLFs were defined. (3) The prevalence of labyrinthine capsule patencies related to PLF was determined with fluid permeability/impermeability of patencies as identified variable. (4) The duration of symptoms before the diagnosis of PLF was determined and a comparison of medical versus surgical management was made (symptoms: complete resolution, improvement, persistence and recurrence). (5) Human temporal bone histopathologic findings from patients with PLF diagnosed during life were consistent with the predictive PLF studies and revealed variables related to surgical methods. Conclusions: (1) Clinical criteria for the diagnosis of PLF can be used to predict patencies of the labyrinth capsule at the fissula ante fenestram, fissure of the round window niche (and sometimes the fossula post fenestram) which are related to disorders of hearing and/or balance. (2) Current treatment methods result in less than ideal success rates – medical management should precede surgical intervention. (3) It appears that no reliable perilymph tracer is yet identified for clinical or surgical use.

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