Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients.

OBJECTIVES AND PATIENTS: We compared the template bleeding time (BT) and closure time (CT) in the PFA-100 as screening tests in 148 consecutive patients with unequivocal mucocutaneous bleeding and positive family history. EXCLUSION CRITERIA: drug intake, concomitant diseases including minor infections, low platelet count, diseases of secondary hemostasis. RESULTS: Type 1 von Willebrand disease (VWD-1) was diagnosed in 26 patients, primary platelet secretion defect (PSD) in 33, VWD-1 + PSD in nine, whereas 80 patients did not comply with the criteria for known hemostatic disorders (UD, unknown diagnosis). BT and CT were prolonged in 35.8% and 29.7% of all the patients, respectively (P = 0.23). Sensitivity increased to 48% if an abnormality of BT and/or CT was considered. Same comparisons for BT and CT in each diagnostic category were, respectively: 42 vs. 61.5% in VWD-1 (P = 0.18), 42 vs. 24% in platelet secretion defects (P = 0.11), 67 vs. 89% in VWD-1 + PSD (P = 0.50), and 27.5 vs. 15% in UD (P = 0.06). CONCLUSION: Both tests were relatively insensitive and not significantly different in detecting incoming patients with mucocutaneous hemorrhages. In patients with VWD-1, the PFA-100 performed slightly better, whereas the opposite occurred in those patients with platelet secretion defects. In the UD group, both tests lost sensitivity, but the BT detected 1.8 times more patients than the PFA-100. Given the large proportion of undiagnosed bleeders and the overall low sensitivity of these tests, clinical decisions still rely on the medical history and etiological diagnosis of the bleeding disorder.

Round window membrane. Structure function and permeability: a review.

The ultrastructure of the round window membrane of humans, monkeys, felines, and rodents discloses three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium. Interspecies variations are mainly in terms of thickness, being thinnest in rodents and thicker in humans. Morphologic evidence suggests that the layers of the round window participate in absorption and secretion of substances to and from the inner ear, and that the entire membrane could play a role in the defense system of the ear. Different substances, including antibiotics, local anesthetics, and tracers such as cationic ferritin, horseradish peroxidase, and 1 mu latex microspheres, are placed in the middle ear side traverse the membrane. Cationic ferritin and 1 micron microspheres placed in perilymph become incorporated by the inner epithelial cells of the membrane. Permeability is selective; factors include size, concentration, liposolubility, electrical charge, and thickness of the membrane. Passage of substances through the round window membrane is by different pathways, the nature of which is seemingly decided at the outer epithelium of the round window membrane.

Diagnosis of typhoid fever by two serologic methods. Enzyme-linked immunosorbent assay of antilipopolysaccharide of Salmonella typhi antibodies and Widal test.

Serum samples from 85 patients with proven typhoid fever, 11 patients with p-typhoidal fever, 101 patients with febrile non-typhoidal, and 130 healthy subjects were tested for immunoglobulin G (IgG), IgA, and IgM antilipopolysaccharide (LPS) of Salmonella typhi antibodies by enzyme-linked immunosorbent assay (ELISA) and Widal test. The levels of all three classes of immunoglobulin anti-LPS of S. typhi were higher in typhoid patients than in healthy or febrile nontyphoidal groups; we selected various combinations between the three classes of immunoglobulin to obtain the best combination of sensitivity and specificity. The sum of the absorbance values obtained from the ELISA assay for IgG+IgA+IgM (sigma lgs) was the best choice for diagnostic utility for typhoid fever. We selected a positive test at a decision level of sigma lgs > or = 1.2 with a sensitivity of 94% and a specificity of 92% with a frequency of false negative of 5.9%. The frequency of false positives for healthy controls was 7.7% and, for the febrile nontyphoidal group, it was 7.9%. We also compared receiver (or relative) operating characteristic (ROC) curves for the diagnostic usefulness of the ELISA with that of the Widal test, whose merits and limitations, especially in endemic regions, are discussed. The ELISA assay was much more sensitive and specific than any combination of the Widal test, and hence it could be a useful tool for the serologic diagnosis of typhoidal fever with a single blood sample.

Experimental studies on round window structure: function and permeability.

Current research and an overall review of 12 years of round window membrane studies is presented. The approach, rationale, and concepts that have evolved from the studies are described. An ultrastructural study of the round window membrane of rhesus monkeys disclosed three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium. Morphologic evidence in monkeys, cats, and chinchillas suggests that these layers of the round window participate in absorption and secretion of substances to and from the inner ear, and that the entire membrane could play a role in the defense system of the ear. Cationic ferritin, horseradish peroxidase, 1-micron latex spheres, and neomycin-gold spheres placed in the middle ear of these experimental animals were observed to traverse the round window membrane through pinocytotic vesicles. Three-micron latex spheres and anionic ferritin were not incorporated by the membrane. Cationic ferritin and 1-micron latex spheres placed in perilymph were incorporated by the inner epithelial cells, suggesting absorptive capabilities of the round window membrane. Cationic ferritin was observed within the mesothelial cells underlying the scala tympani side of the basilar membrane, suggesting a role for these cells in the inner-ear defense system. A review of the subject and a general perspective from the author's viewpoint are discussed.

Ultrastructural studies of the peripheral extensions (dendrites) of type I ganglion cells in the cat.

An ultrastructural study of peripheral extensions (dendrites) of type I ganglion cells in seven healthy adult cats and one cat that underwent bilateral cochlear injection of neomycin was undertaken. Morphologic evidence revealed that the peripheral process (dendrite) consistently has a smaller diameter than the central process. As the dendrite reaches the cell body, there is a constricted segment with a length that ranges from 10 to 30 microns, and a diameter of 0.5 microns. This region is covered by a continuous myelin sheath that does not thin. The central process (axon) does not have a corresponding constriction, and consists of a myelin covered, smoothly tapered segment that extends to the first axonal node of Ranvier. In the deafened cat, some cell bodies of the surviving ganglion cells appeared to have a residual portion of dendrite. These morphologic characteristics might have physiologic implications both in the mechanisms of normal hearing and in cochlear implantation.

Prevalence of microfissures in the human temporal bone: a report of 1000 temporal bones.

A total of 1000 human temporal bones were studied to determine the prevalence of two microfissures: 1. the one between the facial canal and the vestibule, 2. the microfissure between the round window niche (RWN) and the posterior semicircular canal (PSC). Additionally, this study compares the prevalence according to temporal bone age and sex. The microfissure between the facial canal and the vestibule was observed in 470 (47%) temporal bones, with a bilateral presence of 77.2%. The prevalence of this microfissure increases linearly with age. It was not found in any bone within the 0 to 2 age group. It was present in 3 (7.3%) bones from the 2 to 9 age group, as opposed to 374 (54.8%) bones from the 40 and over group. The microfissure between the RWN and the PSC was detected in 915 (91.5%) temporal bones. This second microfissure was found to be an overwhelmingly bilateral entity. The prevalence of this other microfissure also increases with age. This microfissure was also not present in any temporal bone within the 0 to 2 age group. It was found in 28 (68.3%) bones from the 2 to 9 age group, in contrast to 678 (99.4%) temporal bones from the 40+ group.

Experimental grafting of the round window membrane: Part I.

The histology and permeability of cats' round window membranes were described following surgical grafting with gelatin foam or fascia. An increase in the thickness of the round window membrane due to fibrosis, neovascularization, and epithelial metaplasia was observed 2 months following grafting with gelatin foam. Grafting with fascia did not increase the thickness of the round window membrane, but did form a thick layer of granulation tissue adjacent to and overlying the window membrane, with occasional adhesions between. The layer of granulation tissue consisted of cuboidal or columnar ciliated epithelial cells, fibrous tissue, lipid, and undigested grafted material. The granulation tissue did not always completely cover the round window membranes.

Silent otitis media: clinical applications.

Silent (masked) otitis media refers to usually chronic pathological conditions behind an intact tympanic membrane which may be clinically "undetected" or "undetectable." Correlations are described for pathological changes in temporal bones and clinical considerations for silent otitis media associated with Hemophilus influenzae meningitis in infants, silent otitis media--the continuum, silent otitis media--sequelae, and chronic silent otitis media.

Current clinical and pathological features of round window diseases.

The round window niche and membrane can be involved in clinical problems including perilymphatic fistulas, sensorineural hearing loss in otitis media, and a variety of others. The background of these problems is documented by a review of the literature and recent experimental evidence on round window grafting and tracer studies. Clinical pathological correlates including recent clinical experience are discussed for perilymphatic fistulas (sudden deafness, chronic progressive fluctuating sensorineural hearing loss, and association with Meniere's disease), sensorineural hearing loss in acute and chronic otitis media, and findings in round window membrane including absent round window reflex in cases of exploratory tympanotomy and otosclerosis. In addition, a new syndrome termed perilymphatic hypertension is described as seen in a subset of patients with sudden sensorineural hearing loss.

Silent otitis media.

There is a traditional view that chronic otitis media and chronic mastoiditis must exist in the presence of a tympanic membrane perforation. Based on a human histopathological study of 123 temporal bones with chronic otitis media out of 333 temporal bones with all forms of otitis media pathology, only 24 patients (36 ears) had symptoms of otological disease recorded on their charts and only 19.5% of these had an associated tympanic membrane perforation. Unsuspected findings of chronic otitis media (active or inactive) are occasionally confirmed at exploratory tympanotomy. Such quiet chronic pathological findings in the middle ear have occurred in association with endolymphatic hydrops and cochlear end organ lesions suggesting the possibility that silent chronic otitis media may help explain sensorineural hearing loss, vertigo, and tinnitus for certain patients. We put forth the hypothesis that clinically undetectable silent otitis media in neonates and infants might help explain why certain children are otitis media prone. Our otopathology laboratory includes 111 ears harvested from neonates and infants (average age 8 months). Histological analysis revealed normal findings in some, whereas significant numbers of others show all forms of otitis media, including purulent otitis media, chronic otitis media, serous otitis media, and mucoid otitis media, with occasional overlap of types. Clinical implications will be discussed with emphasis on silent otitis media and its relationship to the pathogenesis of otitis media and silent chronic otitis media and its possible role in causing insidious labyrinthine changes. A significant outcome of this study was the marked degree of unresolved mesenchyme in the clinically manifest otitis media group or silent otitis media group as compared to a control group. This association and role of mesenchyme is discussed relative to the pathogenesis of infantile otitis media.

Endolymphatic hydrops and otitis media.

Clinical observation of patients with fluctuant sensorineural hearing loss following or occurring with chronic otitis media led to the hypothesis that endolymphatic hydrops can result from chronic otitis media. Illustrative case reports are described. This hypothesis resulted in a temporal bone study of 560 cases in which 109 temporal bones demonstrated the presence of hydrops and 194 evidenced otitis media. Seventy-five cases demonstrated both otitis media and hydrops, of which 20 cases were selected for more detailed histopathological study. An interesting finding was the presence of apical hydrops in every case of the latter group. Statistical interpretation of this data helped rule out a coincidental or chance occurrence. A discussion of this clinical relationship included the significance of subclinical (silent) otitis media as a possible cause of endolymphatic hydrops.

Prevalence of facial canal dehiscence and of persistent stapedial artery in the human middle ear: a report of 1000 temporal bones.

A total of 1000 temporal bones were used to study the prevalence of facial canal dehiscence and of persistent stapedial artery in detail. Of the temporal bones studied, 560 (56%) contained at least one facial canal dehiscence. There was a 76.3% prevalence of bilaterality of this canal wall gap. The most common site of dehiscence was the oval window area. The concept of microdehiscence of the facial canal is introduced. One third of the temporal bones observed had a microdehiscence of the facial canal, usually located at the oval window area (74.9%) and found bilaterally 40% of the time. The authors found a 0.48% prevalence (5 out of 1045) of persistent stapedial artery. This is the first histological study of temporal bones to report a prevalence of this vascular anomaly.

Prevalence of carotid canal dehiscence in the human middle ear: a report of 1000 temporal bones.

A total of 1000 human temporal bones were used to study the prevalence of carotid canal dehiscence, microdehiscence, and thin bony coverage. Additionally, this study compares the prevalence according to sex and temporal bone age. A carotid canal dehiscence was detected in 77 (7.7%) bones. It was present bilaterally in 23.2% of the paired temporal bones. The prevalence of carotid canal dehiscence decreases with increasing temporal bone age. It was found in 10 (15.9%) bones in the younger than 2 age group, as opposed to 43 (6.3%) bones from the 40 and older group. The concept of microdehiscence of the carotid canal is introduced. A carotid canal microdehiscence was found in 74 (7.4%) bones. Microdehiscences were noted to occur bilaterally in 12.3% of the paired bones. The prevalence of carotid canal microdehiscence also decreases with increasing temporal bone age. It was detected in 7 (11.1%) bones in the younger than 2 age group, in contrast to 51 (7.5%) bones in the 40 and older group. A total of 134 (15.5%) temporal bones were found to have a thin bony coverage, without the presence of a dehiscence or microdehiscence. The prevalence of thin coverage was noted to increase linearly with age. A thin carotid canal was found in 2 (8.3%) bones from the younger than 2 age group, whereas 113 (17.3%) temporal bones from the 40 and older group exhibited this entity. To the best of our knowledge, this is the first systematic study of histologic sections of a large number of temporal bones that looks at these entities.

In search of missing links in otology. I. Development of a collagen-based biomaterial.

Experiments leading to the development and use of a biomaterial based on reconstituted collagen for use in tympanoplasty are presented. A stable, even membrane with optimal strength and an organized matrix of collagen protein strands has been obtained. Biocompatibility was documented by subcutaneous implantation, cytotoxicity with agar overlay, cell contact, and cell-growth inhibition studies. Experimental grafting in chinchillas with perforated tympanic membranes demonstrated that the collagen membrane performed well in all cases. Histopathological studies in chinchillas showed that the collagen membrane compared favorably with fascia grafts. Of significance is that: 1. The membrane has a matrix of microperforations that enhance tissue ingrowth, allow stable anchoring, and permit aeration of the middle ear cavity. 2. The membranes obtained are not exposed to aldehyde cross-linking; therefore, tissue reaction due to aldehydes is avoided.

In search of missing links in otology. II. Development of an implantable middle ear drug delivery system: initial studies of sustained ampicillin release for the treatment of otitis media.

The development of a new device that consists of a biodegradable support incorporating a therapeutically releasable amount of ampicillin is presented. This device is in an insertable shape that allows placement into the middle ear via a myringotomy incision. Once in the middle ear cavity, it expands, contacts the walls, and provides extended release of ampicillin. In vitro studies (3 months) documented the consistent release of therapeutic levels of ampicillin. In vivo efficacy was demonstrated in otitis-induced chinchillas (bacterial inoculation). The device compared favorably with topical and systemic treatment and prophylaxis of otitis media. The device was also efficient in repeated bacterial challenges. Topical extended middle ear drug delivery can become a significant form of treatment for middle ear disease, and has the potential of being useful as a source for inner ear drug delivery.

In search of missing links in otology. III. Development of a new animal model for cholesteatoma.

An experimental study was conducted in chinchillas regarding the pathogenesis of acquired cholesteatoma (keratoma). The placement of a chemically modified gelatin membrane from the external auditory canal to the promontory through a tympanic membrane perforation stimulated squamous epithelial cell migration. Cholesteatoma formation with the presence of keratin debris and inflammatory reactions was observed in the middle ear and anterior bulla in 53.5% of the experimental animals. These experimental findings show for the first time the presence of epithelial migration and true cholesteatoma formation in the middle ear of chinchillas in an experimental model with deliberate perforation of the tympanic membrane. Erosion of the cochlear walls was observed in areas with granulation tissue and cholesteatoma. The importance and significance of the migration of squamous epithelium and of the middle ear inflammatory reaction in the genesis of acquired cholesteatomas are discussed.

Oval and round window changes in otitis media. Potential pathways between middle and inner ear.

A longitudinal sequential study of oval and round window changes in otitis media in an experimental animal (cat) using Eustachian tube obstruction was done. Thirty-two animals were used. In this first sequential study of the oval and round windows in otitis media, the continuum of round window membrane changes from 1 day to 6 months after obstruction revealed changes to be gradual and similar to those of the mucoperiostium. These changes are suitable for changes in permeability and suggest that this membrane is a very likely pathway from the middle to the inner ear. Bony fistulas were not observed and the oval window remained essentially unchanged in time, thus they were not considered routes into the inner ear. Other possible routes are discussed.

Otitis media with perforation of the tympanic membrane: a longitudinal experimental study.

Despite the high incidence and prevalence of otitis media, its pathogenesis is not thoroughly understood. In an effort to provide a better understanding of this disease, experimental animal models have been developed which corroborate the changes observed in humans. In this study a new factor was added: tympanic membrane perforation 1 week after Eustachian tube obstruction. Twelve cats were divided in 4 even groups, and sacrificed at 1 and 2 weeks, 1 and 3 months after perforation, and their temporal bones were studied. Findings revealed an early massive reaction of the mucoperiosteum with granulation and polypoidal tissue formation which filled a considerable portion of the middle ear cavity. Polypoidal changes involved the stapediovestibular joint, possibly explaining the cases of stapes fixation found at tympanomastoidectomy procedures for chronic otitis media. Cholesterol granulomas with the classic characteristics as described in humans were observed in all animals at 3 month periods. These were preceded by clefts in the effusions, at 1 month, containing red blood cells. These clefts were considered as probable precursors of cholesterol granuloma formation. The association of endolymphatic hydrops, round window membrane changes, and otitis media without purulent labyrinthitis was observed; however, it was felt that the paucity of animals precluded any definite conclusions.

The round window membrane following application of staphylococcal exotoxin: an electron microscopic study.

The round window membrane has been considered as a pathway for the passage of toxic substances from the middle ear cavity to the vestibular labyrinth in cases of otitis media. To determine the role of the round window membrane in this passage, chinchillas were given intrabullar inoculations with staphylococcal exotoxin and the round window membranes were examined electron microscopically. We observed cytoplasmic vacuolization, intercellular edema, cellular and nuclear swelling of the surface epithelia and polymorphonuclear leukocyte (PMN) infiltration of the fibrous layer. Light microscopic observation of the labyrinth revealed PMN infiltration of the most basal portion of the scala tympani. These findings demonstrate a chemotactic effect of the toxin for PMNs and support the concept of the round window membrane as an important avenue of entry.

Anatomical perspective, approach, and experience with multichannel intracochlear implantation.

An overall review of the authors' anatomical perspective, approach, and experience with multichannel intracochlear implantation is presented. This report includes pertinent anatomical observations and experimental surgical procedures on fresh temporal bones. Although the scala tympani in the basal turn of the cochlea has an adequate space laterally for the insertion of electrodes, in the upper turns the adequate space is located medially. This is, in practice, the single-most limiting factor for an electrode, inserted via the round window, to reach the apical turns without damaging the basilar membrane. An experimental surgical procedure is described in which a second electrode is inserted in the middle turn via a mastoidotomy-tympanotomy approach and reaches a point near the apex. Studies of horizontal sections of human temporal bones include a review of potential structures that could be stimulated by the electrical currents generated by electrodes. The wall of the carotid artery, located at 750 microns from the basal turn at the level of the round window niche, is considered a potential structure to be affected by long-term stimulation. Anatomical principles and surgical considerations for the mastoidotomy-tympanotomy approach are described as an alternative to the facial recess approach. In the authors' experience, this procedure is technically easier, eliminates the possibility of postauricular flap complications, provides a better angle for insertion of electrodes, requires shorter hospitalization, and permits faster recovery than the facial recess approach. The authors' clinical approach, results, and observations are reviewed. Of note is a successful home-based rehabilitation program.