Appendix 4: The Crisis in Otopathology

Michael M. Paparella, M.D.
Minnesota Ear, Head and Neck Clinic
701 25th Av So
Minneapolis MN 55454
Director, Otopathology Laboratory
Clinical Professor and Chairman Emeritus, Department of Otolaryngology
University of Minnesota, Minneapolis MN 55455
International Hearing Foundation, Minneapolis MN 55454

Workshop
This work supported in part by NIH-NIDCD Grant # P30DC04660

Introduction

On behalf of all of us here and all who care, I sincerely thank Drs. Beatty and Gulya and the NIDCD for sponsoring this meeting. As we shall soon be reminded, otopathology is in a deep state of crisis, and its survival is threatened. We know that pathology, which exists in every hospital as a clinical service, is the fundamental backbone of every field of medicine. Understanding anatomical pathology and pathogenesis has, more than anything, led to advancements of diagnosis and treatment of disease. This is especially true of otopathology.

Unfortunately, the pathology of human temporal bones since its inception has necessarily been relegated to an endeavor of research because of complexities of cost, skills, acquisition, processing, and interpretation of data. My comments here, and this symposium, will highlight the many new horizons of research for archival human temporal bones now and in the future. However, if otopathology is to survive, let alone thrive, the greatest emergent need is to find a means of NIH support for routine acquisition, processing, and interpretation of pathological specimens of human temporal bones. The rationale for this statement follows.

The renaissance of otopathology occurred at the turn and in the early period of the 20th century through meticulous drawings and descriptions of otopathology by such great names as Wittmaach, Siebenmann, Fraser, and Nager. The legacy of otopathology in the United States was established first by Stacy Guild at Johns Hopkins University, then by John Lindsay at the University of Chicago, and finally by Harold Schuknecht at Henry Ford Hospital and Harvard Medical School. I, along with others here, was fortunate to have Dr. Schuknecht as my mentor and senior associate in Boston. Having reviewed the world's literature by editing the Year Book of Otolaryngology/Head and Neck Surgery for 30 years, I am always on the lookout for good otopathological publications, but have found relatively few in the past decade or two.

Allow me to quote from a publication by Harold F. Schuknecht in the American Journal of Otology in 1984 in which he discusses temporal bone banks and laboratories in the U.S.A.¹:

There are 36 active temporal bone laboratories in the United States. These laboratories are not only a source for new knowledge concerning otologic disease, but also a great didactic asset to an otolaryngology training program. Chairmen of otolaryngology departments should be willing to commit department resources to maintain these laboratories, and granting agencies should he aware of their importance in the search for the prevention and control of ear disease.

That abstract is as true today as it was in 1984. Unfortunately, every department chairman is strapped for funds, and I do not know of any department chairman who has funds to support an otopathology laboratory in the United States. Also as we shall see, there are only three active human temporal bone laboratories in the United States at the present time.²

The Relevance of Otopathology

Unlike many other diseases, otological problems including hearing loss often cannot be seen, and their seriousness is often ignored. Helen Keller, who was blind and deaf, said that of all of her afflictions her loss of hearing was her greatest handicap. A most important quality of humans is our ability to communicate. Millions, young and old, suffer from diseases of the ear. Indeed, there are literally hundreds of such diseases resulting in discomfort, pain, disability, and even, through complications, death.

Approximately 30 million Americans have a significant hearing loss or deafness, and 90 million Americans suffer from dizziness or imbalance, while 30 to 40 million Americans have tinnitus, a constant ringing, buzzing, or roaring in the ear. According to the National Institute on Deafness and Other Communication Disorders (NIDCD), one in three people older than 60, and half of those over 85, have a hearing loss. Almost all children will have at least one episode of infection in the middle ear (otitis media) by the time they are a year old, while ten percent of children have chronic ear infection resulting in hearing loss and other problems. If left untreated, hearing disorders in the young can interfere with fundamental development of language as well as lead to other serious otological sequelae.

Yet the medical community has only scratched the surface in terms of understanding, diagnosing, treating, and preventing the many diseases that exist in the field of otology. As elaborated further below, the need for more research is especially urgent given the dwindling number of active laboratories collecting, processing, and studying temporal bones, a function critical to advances in this field. Recent breakthroughs in genomics and in cellular and molecular biology have profound potential for future research and progress relating to otopathology, and for understanding ear disease. Yet at this very promising moment in time, otopathological research is in danger. The number of active otopathology laboratories has dwindled to a very small number, and for all practical purposes there are no funds available for routine collection, processing, and study of human temporal bone materials, since NIH grants are based on prospective hypotheses.

Every discipline in medicine has pathology as its basis. Whether it is tissue removed from surgery, or frozen biopsy, or postmortem autopsy studies, pathology is a vital path to knowledge about disease. All hospitals have pathology departments; they are the backbone of medicine. Unfortunately, no hospital in the world has an otopathology laboratory or department. Therefore, it is of paramount importance to continue the efforts of otopathology laboratories to maintain and expand this rare resource. With sufficient resources, otopathology laboratories will be able to build on their inherent strengths and forge a path to leadership on research of ear-disease that will result in a better quality of life for all the millions impacted each year by hearing and related ear-diseases. More than ever, our ability to diagnose and treat otological diseases depends on our understanding of pathogenesis and otopathology. We are in a period of crisis where otopathology needs to survive if our ability to help diagnose and treat diseases in our patients is to progress into the future.

The Origin of the NIDCD—National Temporal Bone Bank Registry

In the United States, the National Temporal Bone Bank program (NTBB) was established in 1960 with the support of the National Institutes of Health and the Deafness Research Foundation (DRF). The principal purpose of the NTBB was the decentralization of temporal bone donors into four regional centers. In 1960, the directors of the DRF initiated the temporal bone banks (TBB) program, the principal objective of which was to identify prospective donors of temporal bones with ear-disease and to acquire their pledges to donate their ear tissues for pathological studies. In 1979, the DRF appointed an advisory committee to make recommendations concerning the future of the TBB program. This committee consisted of Harold Schuknecht, M.D., Chairman; Michael Paparella, M.D., Bobby Alford, M.D., Paul Ward, M.D., David Lim, M.D., George Nager, M.D., Mansfeld Smith, M.D., James Snow, M.D., and Harry Rosenwasser, M.D., and the committee was to meet at least annually. This advisory committee recommended that the NTBB program again be decentralized into four regional centers, an Eastern TBB center, Massachusetts Eye and Ear Infirmary, Boston MA, Director Harold F. Schuknecht; Southern TBB center, Baylor College of Medicine, Houston TX, Director Bob Alford, M.D.; Western TBB center, UCLA Medical Center, Los Angeles CA, Director Paul H. Ward, M.D.; and Midwestern TBB center, University of Minnesota, Minneapolis MN, Director Michael M. Paparella, M.D. Medical records of the pledged donors were distributed regionally to the four regional centers, who then began their work on January 1, 1980.

In July, 1988, a workshop cosponsored by the National lnstitute of Neurological and Communicative Disorders and Stroke (NINCDS) and the DRF reaffirmed the importance of collection of temporal bones. A decline in the number of active collections of temporal bone as well as a decline in the number of active investigators in the area of human otopathological research was identified, however, and on September 30, 1992, the National Temporal Bone, Hearing, and Balance Pathology Resource Registry was established by the National lnstitute on Deafness and Other Communication Disorders (NIDCD). The registry was soon the responsibility of the previous NTBB and most importantly it was to add ambitiously to the objectives in order to provide a more effective network on temporal bones. Drs. Saumil Merchant and Joe Nadol have provided admirable leadership for this program to date. Unfortunately, all of the above programs were set up so as not to provide any resources whatever for routine acquisition, processing, and interpretation of pathological specimens of human temporal bones.

Current Scientific Advancements of Temporal Bone Research

Let us assess some of the current scientific advancements for the study of human temporal bones at the present time with extraordinary potential for future study. Scientific study of the human temporal bone is a time-consuming, expensive, and challenging process. Laboratories dedicated to the study of pathological aspects of ear-disorders are highly specialized. The accomplishments of studies of temporal bone in terms of acquisition of clinically relevant new knowledge are impressive, and the potential for future achievement is great. Today's technology must be of sufficiently high quality to permit quantitative evaluations of pathologic changes in the sensory and neural elements of both auditory and vestibular systems and if possible brain tissue. We have moved into a new era, that of cytologic quantification, morphologic studies, immunohistochemistry, and the elucidation of ultrastructural detail.

Adaptation of the techniques of immunohistochemistry, immunoelectron microscopy, PCR (polymerase chain reaction), RT-PCR (reverse-transcription polymerase chain reaction), laser-capture microdissection, proteomics, and in situ hybridization histochemistry to the study of temporal bone have afforded investigators the tools necessary to study the normal function and pathology of the inner ear and facial nerve. In 1993, Dr. Wackym was the first to describe a method to isolate DNA from archival tissues from human temporal bone that introduced a new horizon to the field of research in temporal bones.³ Polymerase chain reaction is an ingenious new tool for molecular biology that is an in vitro method of synthesis of nucleic acid by which a particular segment of DNA can be replicated specifically. Now, nucleic acids can be retrieved from specimens of temporal bone embedded in celloidin or paraffin or from frozen specimens, and then subjected to amplification by PCR, followed by further analysis using sequencing, electrophoresis, or other techniques.

With such tools, investigators have been able to identify viral DNA or RNA within the inner ear in specimens of temporal bone in a number of disorders. For example, the herpes zoster virus has been identified in Ramsay Hunt syndrome, the herpes simplex virus in Bell's palsy, cytomegalovirus (CMV) in some specimens with labyrinthitis, and the measles virus in otosclerosis. The technique has also enabled the identification of genomic mutations of DNA: mutations in the connexin-26 gene and deletion of the gene responsible for cystic fibrosis have been identified in archival temporal bones. Several investigations have also retrieved mitochondrial DNA from archival specimens.

Because of these recent scientific developments, archival temporal bone studies have become much more relevant from a clinical and molecular biological point of view. It is paradoxical therefore, and ever more tragic, that we are least able to grow our national archival collections due to lack of funds.

Fundamental Objectives (Principles) of a Human Temporal Bone Laboratory—(The Greatest Need)

The above describes exciting new opportunities for additional research for archival studies of human temporal bones. Some have said that study of otopathology has already been accomplished, negating the need for further acquisition and study. Nothing could be further from the truth. I quote Dr. Ralph Naunton, a good friend and colleague who was a Director in the then National lnstitute of Neurological and Communicative Disorders and Stroke, in the Acta journal of 1985; his words might be of interest. He was writing a preface to European Programs in Otopathology as published in that supplement of Acta⁴:

The study of human inner ear pathology, necessarily tied to autopsy studies in general, is influenced in the United States at the present time by a number of factors. Virchow would turn in his grave were we even to suggest that the study of human tissue pathology and its comparison with the normal is a practice that has outlived its usefulness. Nevertheless there are those in our field or in closely related fields who believe that light microscopic studies of human temporal bone pathology represent a pasture whose previous yield in the '30s, '40s, and '50s was rich but which has by now been so thoroughly plowed that productivity has diminished to the point of cost ineffectiveness. Certainly many spectacular, effective, and clinically valuable studies were carried out in those decades, but the list of otological problems whose etiology and treatment continue to defy us and whose solutions could come from further studies of the human temporal bone is even more impressive.

His comments are more accurate and relevant today than in 1985. He then goes on to mention the serious problem of the falling autopsy rate, which of course has also become more of a problem at the present time. A recent Festschrift was published in honor of the 95th birthday of lmrich Friedmann, the last great otopathologist of Europe.⁵ Unfortunately, he died a few months after the Festschrift. Sadly, there are no active funds nor human temporal bone laboratories in Europe currently.⁶

I wish to emphasize the basic routine function, value, and requirements of a temporal bone laboratory. What are the purposes and rationale of an otopathology laboratory?

1. To acquire, process, and study pathological specimens of human temporal bone in a routine manner. For various reasons (declining autopsy rates, cost, lack of public awareness, etc.), these pathological specimens are hard to come by, and every attempt ought to be made to collect as many useful pathological specimens with good clinical data as possible. While grant-support and funding mechanisms under the auspices of NIH are based in hypotheses, with appropriate peer-review, there is to my knowledge not a single NIH dollar available for routine acquisition, processing, and study of pathological material from human temporal bones nationwide.

2. To diagnose accurately the patient's ear-disease and to gain insight into its pathogenesis. This information is helpful to the family, especially since we find that genetic deafness and genetic causes of other otological diseases are much more common than was formerly thought. While current literature and studies are revealing many genomic studies of syndromic and non-syndromic hearing loss, we have no correlative studies in pathology for these thousands of potential diseases and subsets of diseases to be described. Moreover, we routinely find that the pathological diagnosis differs from the clinical diagnosis before death. Thus there is a need for routine collection and processing for all ear diseases.

3. Multiple otopathologies are common and are routinely not diagnosed clinically.⁷

4. To correlate clinical data (for example results of tests using ECoG [electrocochleography], ENG [electronystagmography], ABR [audiologic brainstem response], routine audiology, CT-scans [computerized tomography], MRI [magnetic resonance imaging], etc.) with histopathological findings. It is paradoxical that as advancements in diagnostic technology (tools and equipment) have developed recently, we have fewer studies and means of such corollary studies with the important new clinical data than ever before.

5. By collecting and categorizing (inter- or intra-institutionally) a larger number of human temporal bones with a specific disease or sub-set of a disease, studies can be initiated, and relevant data can be anticipated with greater statistical significance.

6. Experimental studies, including histopathological studies, with animals for most otological diseases can be correlated with human otopathological findings, which lends itself to relevance and enhanced understanding of pathogenesis and clinical pathology. While animal studies can replicate many otopathologies as seen in humans, only pathological studies of human temporal bones can provide direct information regarding human otological disease.

7. To determine anatomical variants as they relate to disease as well as pathological findings.

8. To assess chronological changes of subcomponents of the temporal bone, as many changes occur from birth to old age.

9. To assess light-microscopic histopathological studies and to emphasize fresh collections of specimens that enhance stereometric (quantitative) studies and ultrastructural studies as well as other new, currently available scientific studies.

10. With the falling autopsy rates, to encourage and educate our patients with otological disease to bequeath their temporal bones as specimens after death.

11. To discover new diseases, which helps diagnose and treat diseases in living patients. (For example, in studying the otopathology of the continuum of otitis media, especially in humans, we identified a very common disease, namely so-called "silent" chronic otitis media, which we find commonly in patients and have been able to diagnose and treat such patients with success to date. This would not have been possible without information from human otopathological studies in the laboratory.)⁸

12. To discover new methods of diagnosing and treating diseases, including surgical treatment of disease. (Through a study of the continuum of otitis media, we have developed a flexible, more conservative approach to dealing with all the forms of otitis media. Once again, these surgical approaches have helped thousands of patients and were based on human otopathological studies.)⁹

13. To cooperate and to correlate our otopathological studies with studies from other disciplines. This leads to a team effort, and could encourage more relevance to the program-grant mechanism as it exists under NIH. Dr. Scott Giebink, who succeeded me as principal investigator of the otitis media pathogenesis program grant, and who most tragically has recently left us, has always referred to otopathology as the "gold standard" in our collaborative study.

14. To collect and study temporal bones from patients who have had otological surgery for a variety of diseases. This has assisted, and will greatly assist (especially in the future), our understanding of the methods and rationale for surgery in other, living, patients. Few or no such cases are reported in the recent literature. Particular importance exists in the study of otopathology from patients who have received cochlear implantation or cerebral implantation to assess relevancy and iatrogenic side-effects relative to clinical data.

15. To acquire specimens from recent disease-onsets or during an active phase of ear-disease (for example Meniere's disease) to correlate with recent clinical data. This desirable objective is non-existent in the literature.

16. Finally, to use histopathological studies in the teaching of otology to medical students, residents, Fellows, and associates. Understanding of otopathology provides a great insight into the diagnosis and treatment of clinical disease, and of course such studies, in the aggregate, have led to new information to assist our ability to practice clinical otology.

Another individual who has made many significant contributions to our understanding of human otopathology is Tauno Palva of the University of Helsinki in Finland. May I quote from a recent article in the lnternational Journal of Pediatric Otorhinolaryngology in this current year,¹⁰ in which he states in a letter to the editor that "histopathology is neglected in teaching of otology," and then follows with examples of why this is true. With fewer active laboratories, the teaching of otopathology has also become a dwindling resource and activity.

Using our otopathological laboratory as a basis for study, I have had the privilege of helping train more than 250 specialists including more than 25 professors and chairmen and many other faculty members throughout the United States and other countries, especially through our research Fellowship training program. They, in turn, have developed other scientific disciplines and have taught many others, as did my very first Fellow in 1964, Dr. David Lim. These talented individuals, in turn, have trained many more scientists, which enhances the research-mission of NIDCD.

The Great Future Need for Routine Otopathologlcal Studies (as Well as Special Studies)

For those who believe we have completed our understanding of otopathology, once again I strongly reiterate that we have barely scratched the surface, and much needs to be done. Every specialty of medicine or surgery counts upon pathology, not only as a current but a future necessity in order to understand disease and its pathogenesis. This is ever more true for otopathology, since we have such dwindling active laboratories and resources. There is a need for otopathological study which is then the basis for an understanding of pathogenesis. You and I could identify a need for otopathological research for every ear disease. To accomplish this, as mentioned, we must collect as many cases of temporal bone pathology as possible, recognizing that pathological diagnosis often differs from the clinical diagnosis with corollary clinical data.

Allow me just to mention some examples of the need for a better understanding of otopathology for certain selected diseases associated with corollary clinical data:

1. Otitis media

   1. The continuum of otitis media including OME (otitis media with effusion) and leading to the various sequelae of otitis media including granulation tissue, cholesterol granuloma, and cholesteatoma. Such studies have been and will be ever more useful when combined with prospective studies of animal models.
   2. The pathology of the tympanic membrane, epithelium of the middle ear, and the subepithelial space in the continuum of otitis media.
   3. The pathology and pathogenesis of tympanosclerosis.

2. Meniere's disease

   1. Vestibular
   2. Cochlear
   3. Very few cases in the literature; we need many more cases with good clinical data.
   4. Active versus inactive Meniere's disease
   5. Meniere's disease in children
   6. Tumarkin's falling attacks
   7. Positional vertigo
   8. Correlations with animal studies and anatomical pathology of Meniere's disease including Trautmann's triangle and various aspects of the temporal bone.

3. Middle ear/inner ear interactions

   1. Viral
   2. Middle ear/inner ear interactions relating to otitis media
   3. Vascular
   4. Recovery
   5. The anatomical pathology of the round window membrane and niche

4. Tumors of the temporal bone

   1. Primary
   2. Metastatic
   3. lncluding glomus, meningioma, adenocarcinoma, etc.

5. Congenital atresia

6. Pathology of sensorineural hearing loss, congenital or acquired, genetic (syndromal or non-syndromal) or nongenetic

   1. The pathological correlates and pathogenesis of autoimmune disease of the inner ear
   2. Congenital hearing loss: the role of mesenchyme

7. Multiple pathological diseases

8. Labyrinthitis

   1. Vestibular neuronitis
   2. Viral
   3. Toxic
   4. Suppurative
   5. Fungal, etc.

9. Trauma

   1. Acoustic
   2. Physical (concussion, fracture, damage to the middle ear and ossicles)

10. Presbycusis

    1. Genetic-strial atrophy
    2. Types and causes, including multiple causes

11. Surgery and histopathology of the middle ear and inner ear

    1. Ossiculoplasty, including TORPs and PORPs
    2. Effects in the middle ear
    3. Effects in the inner ear
    4. Tympanoplastic grafts
    5. Stapedectomy, erosion of the incus, granuloma of the oval window, fistulae, complications in the inner ear, etc.
    6. Cochlear implantation
    7. Iatrogenic causes

12. Syndromes and histopathology

    There are too many syndromes to mention here, for example Down's syndrome, wherein one of our studies indicates Mondini's deformity to be somewhat prevalent

13. Genetic deafness

    1. Congenital (syndromal or non-syndromal)
    2. (especially) Acquired (syndromal or non-syndromal)

14. Malignant lymphoma, leukemia, multiple myeloma, and temporal bone studies

15. Temporal bones and intracranial interphase

    1. Cerebrospinal fluid drainage
    2. Herniated brain (mastoiditis cerebri)

16. Otosclerosis

    1. Middle ear effects
    2. Cochlear effects
    3. Vestibular effects and pathogenesis

17. Age-related changes in human temporal bone in the

    1. External ear
    2. Middle ear
    3. lnner ear

18. Aneurysms of the temporal bone

19. Facial nerve

    1. Anomalies
    2. Pathology
    3. Bell's palsy

20. Microfissures of the human temporal bone

21. Ototoxicity including damage from cis-platinum radiation and other toxic agents

22. Systemic diseases and involvement of human temporal bone such as

    1. Lupus erythematosus
    2. Diabetes
    3. Cystic fibrosis, etc.

The above are merely a few examples of where we need to go, and I am certain that you and I could add many, many more unknown areas where study of the pathology and pathogenesis of disorders in human temporal bones would be of great benefit in dealing with clinical otological problems.

Summary

The NIH has a long history of concern and support for the viability of human otopathological research in the United States. With new developments in otopathological science and in diagnostic and therapeutic tools, some of which are described herein, it is unfortunate that these laboratories are under threat of extinction. The NIH has excellent peer-review mechanisms for research based in hypotheses, but these mechanisms do not lend themselves to support of routine, basic, and fundamental functions of a human temporal bone laboratory, including acquisition, processing, interpretation, and training.

With recent advances in molecular biology, otopathology laboratories have greater potential than ever for archival scientific studies. Human temporal bone studies have had and will have the greatest potential for direct clinical application (lab to the bedside) for the diagnosis and treatment of ear diseases. This is especially important for many syndromal and especially non-syndromal ear diseases, prevalently increasing in the literature through NIH-supported studies. It is hoped that this workshop will not only address this crisis situation but that it will make specific recommendations to NIDCD that will result in reasonable set-aside funding to support the survival of these national resources and to provide the opportunity for ultimate growth and development of this national research resource.

References

1. Schuknecht HF. Temporal bone banks and laboratories in the U.S.A. Am J Otol 5(6): 431-3, 1984.

2. Personal quote, National Temporal Bone Bank Registry, 2003.

3. Wackym PA, Chen CT, Kerner MM, Bell TS. Characterization of DNA extracted from archival celloidin-embedded human temporal bone sections. Am J Otol 16(1): 14-20, 1995.

4. Naunton RF. Studies of human temporal bone pathologies: The NIH perspective. Acta Otolaryngol (Stockh) Suppl 423: 5-8, 1985.

5. Arnold W, Ferlito A (eds). Festschrift on the occasion of the 95th birthday of lmrich Friedmann. ORL 64(2): 63-168, 2002.

6. Personal quote, Dr. Tauno Palva, 2003.

7. Paparella MM, Schachem P, Goycoolea MV. Multiple otopathological disorders. Ann Otol Rhinol Laryngol 97(1): 14-18, 1988.

8. Paparella MM, Goycoolea MV, Bassiouni M, Koutroupas S. Silent otitis media: Clinical applications. Laryngoscope 96(9): 978-85, 1986.

9. Alleva M, Paparella MM, Morris MS, daCosta SS. The flexible/intact-bridge tympanomastoidectomy technique. Otolaryngol Clin N Amer 22(1): 41-9, 1989.

10. Palva T. Histopathology is neglected in teaching of otology. Int J Pediatr Otorhinolaryngol 67: 681-3, 2003.

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