The Vestibular System and Its Diseases: Transactions of the International Vestibular Symposium of the Graduate School of Medicine of the University of Pennsylvania [Reprint 2016 ed.] 9781512808698

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The Vestibular System and Its Diseases

The Vestibular System and Its Diseases Transactions of the International Vestibular Symposium of the Graduate School of Medicine of the University of Pennsylvania

Edited

by

Robert J. Wolfson, M.D.

1

Philadelphia University of Pennsylvania Press

© 1966 by the Trustees of the University of Pennsylvania Library of Congress Catalogue Card Number: 65-16915 Second Printing, 1968

7492 Printed in the United States of America

Preface

Although vertigo is a complaint commonly encountered by practioners of medicine, considerable difficulty frequently exists in establishing an accurate diagnosis. This is, no doubt, due to the fact that a great deal of information concerning the function of the Vestibular System is still lacking or incomplete. In an attempt to solve these diagnostic problems, considerable investigation has been directed toward the Vestibular System in both its basic functioning and its clinical manifestations. In order to further clarify and correlate the available knowledge of the Vestibular System and the vertigo produced by its pathology, the International Symposium was organized. The Symposium was sponsored by the Department of Otolaryngology of the Graduate School of Medicine, University of Pennsylvania, and held on September 10th, 11th, and 12th, 1964, at the University of Pennsylvania in Philadelphia. The faculty of the Symposium consisted of twenty-nine American and European authorities in the field of vertigo and vestibular research. The audience consisted of three hundred physicians, primarily specialists in the field of Otolaryngology, Neurology and Neurosurgery. The topics presented at the Symposium and included in this book dealt with the following aspects of the Vestibular System: ( 1 ) Anatomy of the Labyrinth, Both Its Gross and Microscopic Details. ( 2 ) The Vestibular Pathways. ( 3 ) The Physiology and Biochemistry of the Labyrinth. ( 4 ) Vestibular Tests and Evaluation. ( 5 ) Vestibular Disorders, Their Manifestations and Pathology. ( 6 ) The Treatment of Vestibular Diseases, Both Medical and Surgical. The research, theoretical, and clinical data presented at the Symposium has fulfilled three major purposes. First, it served as a review of established facts concerning the Vestibular System and the vertigo 5

6

THE VESTIBULAR SYSTEM AND ITS DISEASES

produced by its pathology. Secondly, it brought us abreast of the most recent developments in this field. Finally, it brought to light the need for still further investigation and provided a perspective of advance yet to come. I want to thank Dr. Paul Nemir, Jr., Dean of the Graduate School of Medicine, University of Pennsylvania, and David Myers, M.D., Chairman of the Department of Otolaryngology, Graduate School of Medicine, University of Pennsylvania, for their cooperation and support in helping to establish this Symposium. I also want to thank the organizing committee for their aid in preparing the program. I would like to express my gratitude to Mrs. Ruth Davis and Mrs. David Myers for their untiring efforts in attending to the multitude of details which were so essential for the success of the International Symposium. Robert J. Wolfson, M.D. Philadelphia, 1964

Organizing Committee DAVID MYERS, M.D. WOODROW D. SCHLOSSER, M.D. HAROLD F. SCHUKNECHT, M.D. ALFRED D. WEISS, M.D. ROBERT J. WOLFSON, M.D.

7

Contributors Franz Altmann, M.D. Clinical Professor of Otolaryngology College of Physicians and Surgeons, Columbia University New York City, New York Barry J. Anson, Ph.D. Research Professor, Department of Otolaryngology and Maxillofacial Surgery, College of Medicine State University of Iowa, Iowa City, Iowa Michele Arslan, M.D. Professor and Chairman, Department of Otolaryngology, University of Padova Padova, Italy Morris B. Bender, M.D. Director, Department of Neurology Mt. Sinai Hospital New York City, New York Bernard Cohen, M.D. Assistant Attending Neurologist, Department of Neurology, Mt. Sinai Hospital, New York City, New York 9

THE VESTIBULAR SYSTEM AND ITS DISEASES

Malcolm B. Carpenter, M.D. Professor of Anatomy College of Physicians and Surgeons Columbia University New York City, New York David A. Dolowitz, M.D. Associate Professor of Surgery and Chairman of Otolaryngology, University of Utah, Salt Lake City, Utah William S. Fields, M.D. Professor and Chairman, Department of Neurology Baylor University College of Medicine Houston, Texas Francis M. Fodor, M.D. Director of Otoneurologic Clinic New York Eye and Ear Infirmary New York City, New York Richard R. Gacek, M.D. Assistant in Otolaryngology Harvard Medical School Boston, Massachusetts Ashton Graybiel, M.D. Director of Research U.S. Naval School of Aviation Medicine Pensacola, Florida Fred E. Guedry, Jr., Ph.D. Head, Experimental Psychology Branch, Psychological Sciences Division, Research Department, U.S. Naval School of Aviation Medicine Pensacola, Florida Fred R. Guilford. M.D. Clinical Professor of Otology Baylor University College of Medicine Houston, Texas

CONTRIBUTORS

C. S. Hallpike, M D., F.R.C.S., F.R.C.P., Aural Physician and Director of Otological Research Unit, Medical Research Council, National Hospital of Nervous Diseases Queen Square, London, England M. Spencer Harrison, M.D., F.R.C.S., F.R.C.P. Lincoln, England Jerome A. Hilger, M.D. Professor of Otolaryngology University of Minnesota Minneapolis, Minnesota William F. House, M.D. Assistant Clinical Professor of Surgery (Otology, Rhinology & Laryngology) University of Southern California Los Angeles, California L. B. W. Jongkees, M.D. Chairman, Department of Otolaryngology, University of Amsterdam Amsterdam, Netherlands Raymond E. Jordan, M.D. Chairman, Department of Otolaryngology Eye and Ear Hospital University of Pittsburgh Pittsburgh, Pennsylvania John R. Lindsay, M.D. Professor and Head, Department of Otolaryngology University of Chicago Chicago, Illinois Earl F. Miller, Ph.D. Head, Physiological Optics Branch U.S. Naval School of Aviation Medicine Pensacola, Florida

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THE VESTIBULAR SYSTEM AND ITS DISEASES

Brian F. McCabe, M.D. Professor and Chairman, Department of Otolaryngology and Maxillo-facial Surgery State University of Iowa Medical School Iowa City, Iowa T. Manford McGee, M.D. Clinical Associate Professor of Otolaryngology Wayne State University Detroit, Michigan Harold F. Schuknecht, M.D. Professor of Otology and Laryngology Harvard Medical School Boston, Massachusetts Heinrich H. Spoendlin, M.D. Department of Otolaryngology University of Zurich Zurich, Switzerland Jan Stahle, M.D. Associate Professor of Otolaryngology, University of Uppsala Uppsala, Sweden Alfred D. Weiss, M.D. Assistant in Otolaryngology Harvard Medical School Boston, Massachusetts Richard A. Winchester, Ph.D. Assistant Professor of Audiology Graduate School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Robert J. Wolfson, M.D. Associate, Department of Otolaryngology Graduate School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Contents Preface Contributors 1. Developmental and Adult Anatomy of the Membranous Labyrinth, by Barry J. Anson, Ph.D. 2. Ultrastructure of the Vestibular Sense Organ, by Heinrich H. Spoendlin, M.D. 3. The Ascending Vestibular System and Its Relationship to Conjugate Horizontal Eye Movements, by Malcolm B. Carpenter, M.D. 4. The Efferent Vestibular Pathway, by Richard R. Gacek, M.D. 5. Further Observations on the Mechanism of Vestibular Suppression, by Brian F. McCabe, M.D. 6. The Relationship of the Semicircular Canals to Induced Head and Eye Movements in Mammals, by Morris B. Bender, M.D., and Bernard Cohen, M.D. Discussion 7. Biochemistry of the Labyrinthine Fluids, by L. Naftalin and M. Spencer Harrison, M.D., F.R.C.P., F.R.C. S. 8. Experimental Menière's Disease, by Michele Arslan, M.D. 9. The Caloric Test: A Review of Its Principles and Practice with Especial Reference to the Phenomenon of Directional Preponderance, by C. S. Hallpike, M.D., F.R.C.S., F.R.C.P. 10. Parallel Swing Test, by L. B. W. Jongkees, M.D. 11. Ocular Counterrolling, by Earl F. Miller, Ph.D. 12. Modification of Vestibular Responses Produced by Unnatural Patterns of Vestibular Stimulation, by Fred E. Guedry, Ph.D. Discussion 13. Electronystagmography — Its Value as a Diagnostic Tool, by Jan Stahle, M. D. 13

5 9 19 39

69 99 117

131 156

159 180

207 218 229

242 265 267

14

THE VESTIBULAR SYSTEM AND ITS DISEASES

14. Laterotorsion, by David A. Dolowitz, M.D. Discussion 15. Calorization in Relation to Otoneurologic Diagnosis, by Alfred D. Weiss, M.D. Discussion 16. Electronystagmography: Its Perspective, Advantages, and Limitations in Routine Vestibular Testing, by Francis Fodor, M.D. Discussion 17. The Evaluation of the Vestibular Caloric Test, by L. B. W. Jongkees, M.D. 18. Audiologic Patterns in Vestibular Disorders, by Richard A. Winchester, Ph.D. 19. Diagnostic Significance of Vertigo, by Franz A It mann, M.D. Discussion 20. Menière's Disease: Pathology and Manifestations, by John R. Lindsay, M.D. 21. Some Observations on the Character and Mechanism of Spontaneous Nystagmus in Subjects with Tumors of the VIII Nerve, by C. S. Hallpike, M.D., F.R.C.S., F.R.C.P. 22. Benign Positional Vertigo, by M. Spencer Harrison, M.D., F.R.C.S., F.R.C.P. 23. Pathophysiology of Angle Tumors, by Harold F. Schuknecht, M.D. 24. Surgery of Eighth Nerve Tumors, by William F. House, M.D. Discussion 25. Vestibular Problems in Relation to Space Travel, by Ashton Graybiel, M.D. 26. Vestibular Neuritis, by Jan Stahle, M.D. Discussion 27. Vertigo Related to Alteration in Arterial Blood Flow, by William S. Fields, M.D. Discussion 28. Medical Treatment of Menière's Disease, by Jerome A. Hilger, M.D. 29. Surgical Treatment of Menière's Disease, by Raymond E. Jordan, M.D. 30. Experimental Use of Ultrasonic Sound, by T. Manford McGee, M.D.

281 296 298 307

309 322 323 334 353 372 375

390 404 429 439 440 443 459 471 412 484 486 493 502

CONTENTS

Ultrasonic Destruction of the Vestibular Receptors, by Michele A rslan, M.D. 32. Labyrinthine Surgery for Vertigo, by Robert J. Wolf son, M.D. Discussion 33. Summary of Vestibular Symposium, by Fred R. Guilford, M.D.

15

31.

515 527 545 550

The Vestibular System and Its Diseases

Developmental and Adult Anatomy of the Membranous Labyrinth in Man* Barry J. Anson, Ph.D., David G. Harper, M.D., and Thomas R. Winch, B.S.

INTRODUCTION

In the course of this three-day symposium on the vestibular apparatus we are to hear about the ultrastructure of the sensory and supporting elements, the chemistry of contained fluids and the functions of neural pathways to higher cerebral and cerebellar centers, in their normal and abnormal manifestations; we shall learn about present trends in medical and surgical treatment. The present assignment is one of tracing, by simple means, the steps by which an epithelial vesicle and its surrounding mesenchymal bed become lybryinthine spaces (respectively epithelial and osseous), the one circumambient to the other, with windows to the world about * From the Department of Otolaryngology and Maxillofacial Surgery, College of Medicine of the State University of Iowa and the Department of Anatomy of the University of Wisconsin. Carried out with the support of the Central Bureau of Research of the American Otological Society, Inc. and the National Institutes of Health of the United States Public Health Service (Grant No. N.B. 03855-02). Drawings by George Buckley and Jean McConnell. Photomicrographs by Homer Montague, labelling by Jane Gordon. The illustrations were prepared from the following series in the Wisconsin Collection: Figures la to 1 c, from series 178, 180 and 92, respectively; figures 2a to 2d, series 87, 86, 22 and 70, resp.; figures 3a to 3c, series 87, 86 and 54, resp.; figures 4a, series 29, 4b, series 121; figures 6a to 6c, series 29; figures 7 and 8, series 121; figures 9a and 9b, series 25, 9c, series 13; figures 11a to 11 d, series 121; figure 12, series 83.

19

20

THE VESTIBULAR SYSTEM AND ITS DISEASES

us — either of which may be closed through unbridled growth of pathological tissue in its own wall. The author's study thus represents a facet in a mosaic which should ultimately attain an inclusive and harmonious pattern.

OBSERVATIONS

1. Comparative Anatomy In this instance, as in so many others where physiogeny offers a connecting link among living creatures — even of seemingly diverse sorts — comparative embryology serves to explain otherwise baffling aspects of human adult anatomy. In an aquatic creature, for example the shark (squalus acanthias), the epithelium of the receptive organ for the equilibratory sense is derived from the ectoderm — just as it is in man. In both man and shark the placodes thicken and become auditory pits; enlarging and sinking below the surface layer, they assume ovoid form. These are the auditory vesicles, or otocysts. Where the otocyst joined the ectoderm, a tubular process pushes out as a new growth, the endolymphatic duct. In selachian fishes the duct, retained as a stalk of the otocyst, opens permanently to the exterior. Here the function is static only. In man, they lose their connection with the ectoderm. The internal ear is obliged to reestablish an aqueous environment, and to become an acoustic as well as an equilibratory organ. This entails the formation of two closed labyrinths: an inner one derived from the otocyst (therefore, having an epithelial wall); an outer, immediately surrounding and generally matching the shape of the inner one (and having an osseous wall). Each labyrinth must acquire a fluid content, and maintain it in optimal physiological state. Once more, it must become a fluid-containing system. The canalicular side of the organ retains to a degree the fundamentally simple matter of the otocyst of the selachian fishes. To this subject we shall return, after a comment on the opposite side. On the cochlear side, a mechanism must be built to bring the membranous labyrinth (or, more particularly, its specialized sense

ANATOMY OF THE

MEMBRANOUS

LABYRINTH

21

organs ) into physical relationship with the outside world. The sensory epithelium, separated from the parental ectoderm, must not be divorced from happenings in the body's environment. With no new source of anatomical material for the putting together of a mechanism for hearing in a terrestrial environment, the human embryo must remodel a system for which it will have no use, namely, the visceral arches of a respiratory system serviceable only in aquatic and amphibious creatures. To the original elements of the simpler vertebrate, namely the epithelial duct-system, are added by a most impressive kind of phylogenetic salvage, the following structures: from the ectoderm of the first pharyngeal groove, the external acoustic meatus and the epidermal layer of the tympanic membrane; from the entoderm of the corresponding pouch, the auditory tube, the tympanic cavity, the pneumatic extensions therefrom and the mucosal (inner) layer of the tympanic membrane. The branchial arches (mandibular and hyoid) contribute the auditory ossicles. The mesenchyme surrounding the membranous labyrinth is converted into otic capsule and the sparse tissue in the perilymphatic space. Concurrently, the vestibular side of the stato-acoustic organ undergoes far less dramatic conversion.

2. Developmental Anatomy a. Membranous laybrinth; general. By way of introduction to our consideration of the equilibratory side of the membranous labyrinth, we shall review the general developmental steps which bring the entire duct-system to maturity. (Fig. 1.) In the 5 th week the ovoid otocyst undergoes elongation in both dorsal and ventral directions. The slender, ventral part represents the future cochlear duct. In the dorsal portion we see early evidence of the developing semicircular ducts. The intermediate region is destined to subdivide into the utricle and the saccule. Less than a week later the semicircular ducts are outlined as two flattened pouches. The superior and posterior duct (at S and P ) arise from a single pouch along the dorsal border of the otocyst. The lateral semicircular duct comes from a horizontal outpocketing. The cochlear region of the otocyst, further elongated, has assumed J-

5+ wk.

- End oly mphatic duct 6 wk.

Areas of epithelial xuöion Vestibular pouch

/ /

i

N

.U.

^ J .

/

t

absorption Cochlear p o u c h 8+wk

r c

·

Saccule Cochlea

Semicircular ductS' Superior Posterior Lateral

Cristae of

(endolymphatic sac)

Utricle saccule

Cochlear duct ($cala media)

Crista o£ ampulla Cul de sac of cochlear duct

Fig. 1. The development of the human membranous (otic) labyrinth. Three fetal stages.

Fig. 2. T h e development of an ampulla and its crista, and of surrounding perilymphatic space and the bone of the otic capsule. Four fetal stages. Transverse sections. X 3, 73, 33, and 40 respectively.

24

THE VESTIBULAR SYSTEM AND ITS DISEASES

shaped form. Centrally the walls of the pouches, after flattening and fusing into epithelial plates, break down to set the semicircular ducts free, except at their ends. Thereby, they become tubes whose lumens retain communication with the parent division of the otocyst, namely, the utricle. In the 8th week the endolymphatic and semicircular ducts are well represented. The main sac has divided into utricle and saccule. The cochlear duct has coiled like a snail's shell. Early in the 9th fetal month the general adult form of the internal ear is nearly attained. The illustrated changes take place in 3 fetal weeks. b. Cristae of ampullae. In keeping with the scheme of precocious differentiation common to the several parts of the ear, the cristae assume the histological appearance of adulthood in a developmental period of approximately two fetal months (Fig. 2.) These steps will be traced in photomicrographs from specimens of 8, 10, 15 and 23 fetal weeks. In passing it should be mentioned that on the opposite, acoustic side, the spiral organ of Corti follows an even more precocious developmental course. All structures are present in definitive form about six weeks after the sensory area is evident as a thickened neuroepithelium. c. Maculae of utricle and saccule. Comparably, the neuroepithelium of the maculae of two fetal months attains adult histological character in a brief period. A favorable section of an 8-week specimen includes both maculae and the crista of a semicircular duct, in their primordial form (Fig. 3a). Less than 3 weeks later the sensory layer of the utricle has acquired an otolithic membrane (Fig. 3 b). At the end of another short period (of about 4 weeks), the sensory organ of the saccule is approaching mature structure. A very definite otolithic membrane overlies an epithelium; the latter rests upon a connective tissue substratum (Fig. 3c). 3. Adult Anatomy a. Ampullae and cristae. Our next concern is with the adult anatomy of the ducts and their sensory elements.

ANATOMY OF THE MEMBRANOUS

LABYRINTH

25

Utricle

Utricle MACULA

'' Crista of ampulla

QßKkhf after L E· B L A I R

Fig. 5. The form and the position of the cristae and maculae. Reconstruction from a newborn infant. (After Bast and Anson, "The Temporal Bone and the Ear," Charles C. Thomas, Springfield, 1949; figure 40.)

saccule. At this transverse (horizontal) level, the section passes through the fundus of the internal acoustic meatus and the anterior portion of the vestibule (Fig. 6c). The vestibular division of the VIII nerve passes from the internal acoustic meatus to the macula of the saccule. Nerve-bundles, upon reaching the inferior area (below the transverse crest), pass through

Fig. 6. The maculae of the utricle and the saccule. Adult 10 years of age. Transverse sections.

Internal sucoustic

Cochlea, (basal t u r n ) Fig. 6a. General topography of the utricle and saccule, and of related structures. The area blocked is shown in detail in the following figure. Fig. 6b. Detailed histology of the macula of the utricle and of the pattern of innervation (area blocked in Fig 6a). Fig. 6c. Detailed histology of the macula of the saccule, and the course of the saccular division of the vestibular nerve. X 7, 43 and 40, respectively.

30

T H E VESTIBULAR SYSTEM

AND ITS

DISEASES

small perforations to reach the recessus sphaericus, the shallow excavation on the wall of the vestibule for lodgement of the saccule. The perforations, or foramina, make up the macula cribrosa media of this spherical recess. Therefrom the fibers pass to the sensory organ, the macula acustica sacculi. The macula is an ovoid plaque on the lateral surface of the utricle measuring 2.3 mm. in height, and 2.1 mm. in width (Fig. 7 ) . The macula of the saccule is similarly ovoid. Its dimensions are 2.6 mm. by 2.2 mm. (Fig. 1 l a ) .

Gñ&ut ampulla Macula οΓ límele

Semicircular duete :

Ductus reimwrre

Cochlear d u « ficaia meal»' Culdesac of' cochlear duct

ETidolymplvitK' sac Crista ampuilaris posterior

Fig. 7. T h e form and position of the cristae ampullares and the macula utriculi. Compare Fig. 11a. Reconstruction from an infant of 6 months. Original reconstruction X 37.

ANATOMY

OF

THE

MEMBRANOUS

LABYRINTH

31

The maculae are similar but their chambers are strikingly different in shape and in the pattern of their communication with adjacent parts of the duct-system. The utricle is elongate and broadly continuous, L-shaped fashion, with the equally capacious common arm of the two semicircular ducts; together they make up a widely open right-angled compartment. Unlike the utricle, the saccule, somewhat the smaller of the two, is offset from the ducts which lead to and depart from its lower portion. The utricle, therefore, might be regarded as an expansive kind of ampulla, wherein the fluid is allowed to move freely through the vestibular and canalicular subdivisions of the endolymphatic system. Viewed in this simple, hydrostatic way, we would be obliged to place the saccule in a different category. Endolymph, in excursion toward the cochlear side, must pass first through the narrow slit beneath the utriculo-endolymphatic fold into a saccular duct that quickly tapers into the even more tenuous ductus reuniens. This last-named passage, of excessively minute calibre, is continued as a chamber leading finally into the cochlear duct.

Fig. 8. The form and the vestibular location of the saccule and utricle, and their relation to the base (footplate) of the stapes. Compare Fig. 12. Infant of 6 months. Transverse section. X 12.

32

THE VESTIBULAR SYSTEM AND ITS DISEASES

The utricle and saccule, situated between the semicircular duccts and the endolymphatic duct, lie in close proximity to the vestibullar (oval) window. At one point, a distance of only .28 mm. separattes the stapedial base (footplate) from the utricle (Fig. 8 ) . c. Endolymphatic duct and sac. The course of the m e m b r a n o u s labyrinth will now be followed in the opposite direction, that is, frcom the internal aperture of the vestibular aqueduct, toward the posteriior surface of the petrous pyramid on the wall of the middle fossa of tthe cranial cavity. The endolymphatic duct traverses this channel throujgh the bone to the external aperture, there to be lodged in the craniial layer of the dura mater. While still in intraosseous course, the epithelial wall assumes, a rugose form (Figs. 9a and 9b). It is important to recall that the stereotyped concept of form of tithe membranous labyrinth requires modernization. The endolymphatic duct is not a simple quill-like tube, expanded at one end, bifid at tkhe other — in the latter position, suggesting the arms of an inverted Λ Y. Each segment differs from that of the standard form: the utricle comrimunicates with a sinus-like dilation of the endolymphatic duct, bbeneath a fold produced by the combined layers of the two vesiculilar spaces; the duct narrows, next, finally becomes a rugose, intradurral expansion. In the other direction, an expanded portion, the sinuus, similarly narrows (in reaching the saccule). Therefrom, the reunitiring duct continues into the cochlear duct. The duct-system will first be traced toward the external apertuure of the vestibular aqueduct, then toward the tympanic scala. The rugose segment of the endolymphatic sac begins within thhe vestibular aqueduct; it then is prolonged beyond the external apertunre, where, imbedded in the tissue of the cranial dura mater, it occupiiies a shallow fovea on the posterior surface of the pyramid (Fig. 9 c ) . It seems probable that there is physiological significance in the nnature of the connective tissue of its intraosseous segment; this tissue ; is vascular, the vessels being derived from those in the surrounding bonne. As the vestibular aqueduct approaches the cranial cavity, the eexternal aperture becomes a funnel-shaped expansion (Fig. 10). Thertreby is produced a space whose capacity is greatly in excess of thhat needed to house the endolymphatic sac. The width of the largest eexternal aperture is almost twenty times the diameter of the smalleiest internal aperture.

Fig. 9. T h e vestibular and intraosseous course and relations of the endolymphatic duct and sac. Fig. 9a, demonstrating portions of the membranous labyrinth. Fig. 9b, showing the vestibule at the internal orifice of the vestibular aqueduct, and the distal portion of the latter with the contained duct and surrounding connective tissue. Periotic strands are indicated by arrow. Adult, 17 years of age. Transverse sections. X 18.

Fig. 9c. T h e endolymphatic sac and dural tissue at and near the external aperture of the vestibular aqueduct. Adult, 62 years of age. Transverse section. X 40.

34

THE VESTIBULAR SYSTEM AND ITS DISEASES

VESTIBULAR AQUEDUCT (external aperture)

Internal acoustic meatus

COCHLEAR CANALICULUS (external aperture)

Fig. 10. A left temporal bone, viewed from the medial aspect. Inset. Enlargement of the area of the external aperture of the vestibular aqueduct, demonstrating the relative capaciousness of the latter. T h e large arrow traces the former course of the saccus; an arrow encircles a bridge of bone that remains to mark the inlet of the funnel-shaped aqueduct. T h e overlying bone has been removed, as indicated by the small arrows.

d. Saccular, reuniting and continuing ducts. A s the duct-system continues from the utricle to the cochlea, the opening into the sinuslike enlargement of the endolymphatic duct is "guarded" by a fold formed by the approximated walls of the two spaces (Fig. 11 d\ compare figures 11 a and 11 b ). The labyrinth is continued as the saccular and reuniting ducts

ANATOMY OF THE

MEMBRANOUS

LABYRINTH

35

(Figs. 116, l i e and 11 d). Distal thereto, the ductus reuniens is brought into communication with the cochlear duct through the intermediation of an offset, or cul de sac (Fig. 11c). Proximity in this instance may have functional significance in hearing. The cul de sac is not a neural element. However, the constituent layers are continuous with those of the spiral of Corti: the epithelial wall toward the vestibule is the vestibular (Reissner's) membrane; that facing the tympanic side (scala tympani) is the basilar membrane. e. Vestibule and scalae. Little attention has been paid to the anatomy of the cochlear ( r o u n d ) window, the secondary tympanic membrane and the related parts of the membranous duct-system (labyrinth). Some of these have just been reviewed for the vestibular side. On the tympanic aspect they are generally unfamiliar, yet equally important (Fig. 12). From the orifice of the fossula to the secondary tympanic membrane the distance is 1.4 mm. From the secondary tympanic to Reissner's membrane of the cochlear duct, the distance is only 1.0 mm., just slightly greater than the distance intervening between the secondary tympanic membrane and the utricle. Here, differing from the arrangement at the vestibular (oval) window, the structures named are protected by the depth of the fossula (of the round window) — on the wall of which the membrane is likewise out of harms's way (in the progress of too venturesome exploration).

SUMMARY

We have accounted for the developmental steps taken by the membranous labyrinth to bring it to maturity in man, as a duct-system of complex double function, acoustic and equilibratory. Adult size and general form are attained early on both sides of the system: enlargement of the cristae and cochlear duct is completed at about midterm. Precociousness in growth of the labyrinth is matched by that of the surrounding otic capsule and the auditory ossicles. Toward the canalicular side, the utricle is broadly continuous with the semicircular ducts. In the opposite direction, the communication with the cochlear duct consists of segments differing in form and capacity, in the following succession: a chink-like opening into an

36

a

Semicircular ducts Superior Postenor Common arm •

Isthmus ν mus Rugose portion Crista om-pullaris posterior

Saccular duct Cu. ite sac of cochlear dhict Ductus retimene Cochlear diaci (scala :··.

Fig. 1 la. F o r m and position o f the macula sacculi. Same reconstruction as shown in Figure 7. T h e levels of the sections in the t h r e e a c c o m p a n y i n g figures are m a r k e d I, I I , and I I I ; transverse sections.

Ütrial

/

Inferior vestibular area.

,v I

.. . Utricle

λ

\

\ \

/ π ENDOLYMPH \

S

PERILYMPH

Endolymphatic Saccular duct

duct •

D u c t u s reu mens. Cul de

1 If I

k,

^ t i i u U

II·' s S a c c u l a r

duct

Dν uctus reuniens Hk ' C u l d e S a c of \ .V c o c h l e a r d u c t I

«zCondary lembranaj JCala. ¿E , , .η c o c h l e a r ' vmparnK ρ r lu f e n e s t r a

Figs. 11 b, e, and d. Sections (indicated levels in Fig. I l o ) selected to demonstrate the lesser ducts which bring the endolymphatic sac, utricle, saccule and cochlear duct into communication. Arrows in Fig. lib trace the course of ducts pictured in Figs. 11c and lid.

38

THE VESTIBULAR SYSTEM AND ITS DISEASES

VgStiirule

-I\eunitind duct

Cul de sac of cochlear duct A

Internal acoustic meatus Ä » ^

Cochlear

( r o u n d

fenestra,

window)

closed hy

S e c o n d a r y t y m p a n i c

m e m b r a n e

^

\ J

Fig. 12. T h e location of the cochlear duct in the basal turn of the cochlea and its relation to the secondary tympanic membrane and the cochlear ( r o u n d ) window. I n f a n t of 10 weeks. Transverse section. X 35.

expanded part of the endolymphatic duct; narrowing continuation through a saccular duct, ductus reuniens and cul de sac of the cochlear duct — the last-named subdivision being separated f r o m the secondary tympanic m e m b r a n e ( a n d thereby also f r o m the middle e a r ) by a prolongation of the scala tympani of the perilymphatic labyrinth. T h e membranous labyrinth is largely supported by the perilymph of this more capacious, circumambient space — little anchorage being provided by the strands of periotic tissue. A s mentioned at the outset, the formation of this enveloping medium, produced as a secondary mechanism in acoustic service, is a phenomenon of structural adaptation to terrestrial life. Speaking solely f r o m an anatomical viewpoint, the vestibular side of the stato-acoustic organ retains m u c h of its earlier simplicity. It is certainly not suggested that this statement be extended to function.

Ultrastructure of the Vestibular Sense Organ H. Spoendlin,

M.D.

Since the application of Electron-Microscopy to the histology of the inner ear, the significance of the ultrastructural organization of the vestibular sensory epithelia was generally recognized. Initially it was Wersall ( 1 9 5 6 ) who studied those structures in the electron-microscope. More information was obtained by other workers such as Engstrom and Wersall ( 1 9 5 8 ) Smith and Dempsey ( 1 9 5 7 ) Bairati ( 1 9 6 0 ) and Friedmann ( 1961 ) . Engstrom, Ades & Hawkins ( 1 9 6 2 ) and Flock & Wersall ( 1 9 6 2 ) , studied particularly the sensory hairs. Our own investigations have been carried out on monkeys, guinea-pigs and cats. This report however will concentrate on the more recent findings. All sensory epithelia of the vestibular labyrinth show basically the same structure. T h e main elements of the sensory epithelia are: the sensory cells of two different types, the supporting cells, the nerve fibres and nerve endings and finally a specific suprastructure such as the cupula in the cristae and the otolithic membrane on the maculae. W e will discuss those structural elements in the view of their presumable functional significance. SUPRASTRUCTURE

The suprastructure (Cupula of the cristae and otolithic membrane of the m a c u l a e ) can be considered as a mechanical device to transform a particular form of energy into the stimulating mechanism of the sensory elements. This stimulating mechanism most probably is a common one for all sensory epithelia in the inner ear. In the cochlea it has been demonstrated to be a shearing motion (Bekesy 1 9 5 2 ) and 39

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there is anatomical and physiological evidence (Loewenstein 1956) for a similar stimulating mechanism in the vestibular epithelia as well. On one hand the cupula transforms endolymph movements, which occur during angular acceleration in the semicircular canals, into shearing forces at the surfaces of the sensory epithelia. The maculae on the other hand respond to rectilinear accelerations by means of inertial forces due to the high specific weight of the otolithic membrane. The electron-microscopy however does not add very much to our knowledge of those suprastructures which consist mainly of a gelatineous mass rich in mucopolysaccarides. In the electron-microscope they reveal, after osmium fixation, an extremely fine fibrilar texture. The fibrils frequently are condensated to bundles and groups of bundles. In addition we find in the otolithic membrane the otoliths on top of and imbedded in this gelatineous mass as hexagonal calcite cristals of different size. The sensory hairs penetrate for a certain distance into the cupula or the otolithic membrane. SENSORY

CELLS

The sensory cells, the central structure of the receptor organ are the sites of transformation of mechanical energy of the stimulus into bioelectrical energy which leads finally to the initiation of nerve impulses. We like to distinguish different zones of the sensory cells which might have a different functional significance: a) the main cell body with the nucleus b) the sensory hairs and the apical part of the sensory cell c) the base of the cell with synaptic connections between sensory cell and nerve endings Two types of hair cells can clearly be distinguished. The type I haircell has the shape of a bottle and is with the exception of the apical part surrounded by a nerve chalice (Figs. 1 , 2 ) . The type II haircell shows, however, an irregular cylindrical shape and is in contact with serverai small nerve endings (Figs. 1 , 3 ) . Both cell types are found over the entire surface of the maculae and the cristae. The type I haircells are however particularly concentrated in the central part of the maculae and on the vertex of the cristae. The zone of concentrated type I haircells in the maculae seems to correspond to the "striola" which was described by earlier investigators as a band going slightly curved through the middle of maculae, where the sensory

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Fig. 1. Schematic drawing of an area from a vestibular sensory epithelium, with haircell of type I (HC 1) and type II (HC I I ) . Typical arrangement of the stereocilia (St) and kinocilia ( K C ) modified kinocilia (kc) with their basal bodies and roots (b) in the supporting cells ( S ) — Nerve fibres ( N ) , Nerve-chalice (NC) and Nerve endings ( N E ) , Synaptic structures (Sy), Golgimembranes ( G ) , Multivesicular bodies ( V ) and endoplasmic reticulum ( E ) . Reticular membrane ( R M ) Microvilli ( M V ) .

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Fig. 2. Survey-picture of a haircell of type I (HC I) which is entirely surrounded by a nerve-chalice ( C ) and embedded between supporting cells ( S ) . Between the apex with the sensory hairs ( H ) and the main cell-body is a narrow "bottle neck" ( N ) . Reticular membrane ( R ) . Part of a hair-cell type II (HC I I ) .

cells are especially large and all supporting cells close to the bottom of the epithelium (Werner 1 9 4 0 ) . Hitherto it was not possible to make a functional differentation between the two types of sensory cells. A tempting assumption that one type would correspond to the spontaneous active and the other to the spontaneous inactive sensory units, as described by Loewenstein ( 1 9 5 6 ) , must be rejected. In certain animals such as the ray,

Fig. 3. Survey-picture of a hair cell of type II (HC II) with a very dense catoplasme and several independent nerve endings ( E ) . Supporting cells (S) with one kinocilium ( K ) . Part of a hair cell type I and a intraepithelial nerve fibre ( N ) .

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the sensory epithelia of the inner ear reveal only type II haircells, although spontaneous active and inactive units are found in electrophysiological studies. The type II haircells are, according to Wersall and Hawkins ( 1 9 6 2 ) , more sensitive to chronic streptomycin intoxication than the cells of type I. The main cell body with the nucleus is the least specific part of the sensory cell resembling very much any other cell in the organism. It contains numerous unspecific cytoplasmic structures such as mitochondria, Golgi membranes, multivesicular bodies, endoplasmic reticulum, ribosomes and lysosomes (Fig. 1); all together responsible for the unspecific metabolism which provides the energy for the specific function of the cell. In the infranuclear part there is again a higher structural specificity of the cell which is expressed in different types of synapses between the sensory cell and the adjacent nerve endings. In the type I haircell the main cell body is linked with the apical part of the cell by a narrow bottle neck which in many cells is several microns long. This "bottleneck" contains almost no cytoplasmic structures other than fine fibrils and tubules, very similar to those found in the axon of neurons (Fig. 4 ) . This is particularly obvious in cross sections through the "bottleneck." It illustrates the concept that sensory cells belong to the same family as neurons (Davis 1961) and it might indicate that this part of the cell has a similar conductive function for electrical potentials as neurons have. Potential changes originating within the apical part of the cell would be transferred through this neck down to the main cell body and the base of the cell where there is synaptic connection with nerve endings. The most specific and morphologically outstanding zone of the cell certainly is the apical part with the cilia. It probably represents a functional unit. Held ( 1 9 2 6 ) and Kolmer ( 1 9 2 7 ) already recognized two types of sensory hairs in the inner ear sensory epithelia. It was however only recently when Wersall in 1956 was able to show in the electron-microscope that each sensory cell of the crista contained a large number of stereocilia and one kinociliumlike process very similar to motile cilia of the respiratory tract. The same findings were reported in all vestibular sensory cells of different animals by Smith 1957, Engstrom and Wersall 1958, Loewenstein und Wersall 1959, Friedmann 1961 and others.

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Fig. 4. On top there is a horizontal section through the "bottle neck" ( N K ) of a type I hair cell, surrounded by the nerve chalice ( C ) between supporting cells ( SC ) . At the bottom is a transverse section through the axon of a nerve fibre ( N ) with many mitochondria ( M ) . Both, the "bottle-neck" of the sensory cell and the axon contain the same type of neuro tubules ( N t ) .

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Fig. 5. Rigid club like stereocilia (St) with small rootlets ( R ) in the cuticular plate (C) of the sensor cells. One kinocilium ( k ) appears somewhat bent. Between t w o sensory cells a extension of a supporting cell with a microvillus ( M ) .

Each vestibular sensory cell of a macula or crista carries 60-100 stereocilia and one kinocilium. The stereocilia are morphologically defined as homogeneous clublike rods with dense roots extending downward deep into the cuticular plate and reaching only a short distance upward into the cilium (Fig. 5 ) . They show a strictly geometrical arrangement in form of a hexagonal packing (Spoendlin 1964) on top of the hair cell. Their length is increasing from one side of the cell surface to the other comparable to organ pipes, measuring from one micron to approximately 12

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microns in the maculae and much more in the cristae where the exact length could not be established. The stereocilia appear to be rather rigid structures as it was shown by Engstrom et al. ( 1 9 6 2 ) not only in fixed but also in fresh material. The kinocilium usually is the longest of the sensory hairs. It seems to be much more flexible than the stereocilia and it always is next to the longest of the stereocilia. It originates from a specific basal b o d y in a cuticula-free area of the cell surface. In transverse sections the typical pattern with nine peripherally arranged double-tubular fila-

Fig. 6. Horizontal transverse section through some stereocilia (St) and one kinocilium ( K ) which shows the typical pattern with nine peripheral double-tubularfilaments and two central single tubular filaments.

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ments and two centrally located single-tubular filaments is evident (Fig. 6 ) . This typical nine plus two pattern is found in all kinocilia wherever they exist in all types of tissues and animals such as for instance in the respiratory epithelia, in the oviduct or in unicellular flagallates. T h e filaments of the kinocilium extend into the basal body where they assume a triple tubular shape and appear in a spiral arrangement (Spoendlin 1 9 6 4 ) . T h e basal bodies of the kinocilia reveal an almost identical structure as the centrioles in any cells. It is therefore accepted by many authors that basal bodies may develop f r o m centrioles. Frequently a second centriole of the same structure is found somewhere in the cytoplasm of the cell. It also happens that a centriole is situated in the lower part of the cell and that a kinocilium is differentiated from it at the base of the sensory cell instead of at the top as is usual. On several occasions we found such kinocilia extending downward from the base of the sensory cell between the supporting cells (Fig. 7 ) . This seems to illustrate that the kinocilium really originates from a centriole which then takes the role of a basal body. Such displaced centrioles and kinocilia are considered as a slight disorganisation in the differentation of the sensory cell. T h e great importance of the centrioles in the organization of the cell and the concept that the basal bodies of kinocilia and centrioles are homologeous structures, certainly justifies the assumption that the kinociliar basal bodies in the inner ear still represent important centers of the cell (Engstrom and Coll 1 9 6 2 ) . This might be related to a functional polarization of the cell. T h e kinocilium is, as mentioned above, a very elementary structure found in almost identical forms in many different tissues of all animals. Its primary role seems to consist of motility as is expressed in its name. In certain situations however its motility is very unlikely and it may have quite a different functional significance. T h u s kinocilia are not only found in many types of parenchymateous tissues but also in many types of sensory cells such as the rod cells of the retina (Sjostrand 1953) the olfactory sensory epithelium or sensory organelles in primitive unicellular animals (Wolken 1 9 5 6 ) . This certainly suggests that kinocilia might play an active role in sensory systems. T h e assumption that the kincilium with its basal body indicates a functional polarization of the sensory cells gets further support f r o m the spatial arrangement of the kinocilia in relation to the stereocilia

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Fig. 7. T h e bottom of a haircell type II. T h e cytoplasm is rich in Golgi membranes ( G ) , vesicles ( V ) and mitochondria ( M ) . T h e r e is a centriole ( C e ) visible and a displaced basal body ( B ) from which a kinocilium ( K ) extends downward between the supporting cells. T h e inset in the left lower corner shows a transverse section through a typical kinociliar basal body ( B ) at high magnification. T h e spirally arranged nine tripletubular filaments ( F ) are also found in centrioles.

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over the entire sensory epithelium. In horizontal sections through sensory epithelia, just above the surface of the cells all the bundles of sensory hairs are transversely cut and their spatial arrangement can be studied. In most of the sensory cells in one area the kinocilia are always found on one and the same side of the stereocilia bundles (Fig. 8 ) . They originate always from the same pole of the cellular surface. Such a morphological polarization of the sensory hairs has already been described by Loewenstein and Wersall 1959 and Flock and Wersall 1962 in the cristae and lateral line organ of fishes where they discussed its possible relation with the function of those sensory epithelia. We investigated the polarization of the vestibular sensory hairs over the entire cristae and maculae in mammals such as guinea pigs, cats and monkeys. For electron microscopic use it is impossible to get horizontal sections of the entire surface of a crista or macula. The sensory epithelium must be devided in smaller blocks, which then are cut in such a way that the sections are always oriented according to their original position in the macula. The possibility of errors in orientation is relatively high with such a method and somewhat confusing results made us look for another way to study this question. Since the arrangement and the morphology of the hairs is well known from electron-microscopic investigations, the kinocilia can be recognized and differentiated from the stereocilia in about one micron thick sections in phase contrast microscopy (Fig. 8, 9 ) . This however is only possible in horizontal sections at the level of the cellular surface or slightly above it where either the basal body of the kinocilium is visible or where the kinocilium as such is conspicious being much thicker at this level than the neighbouring stereocilia. One micron thick sections of the entire flat surface of the sensory epithelia can be obtained and used for phase contrast microscopy. Since the macula utriculi has two planes at an angle of about 45 degrees to each other, each of those surfaces has to be sectioned independently. The macula sacculi can be sectioned in one piece and the cristae in two halves. With this method the pattern of polarization of the sensory hairs over the entire surface of cristae or maculae can be studied. From physiological studies in the cristae we know that their function is dependent upon the direction of the stimulus. Utriculopetal and utriculofugal deviations of the cupula have different effects. This was first expressed in the second law of Ewald according to which

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Fig. 8. Horizontal section through several sensory hair bundles just above the cell surface. Each bundle belongs to one sensory cell and consists of 60-100 stereocilia (St) and one kinocilium ( K ) , which always is on the same side of the stereocilia bundles. Modified kinocilia from supporting cells ( k ) and microvilli ( M ) . T h e inset at the upper left corner shows a sensory cell surface in phase-contrast, where the kinocilium ( K ) can be differentiated from the stereocilia ( S t ) .

Fig. 9. Phase-contrast picture of the surface of a macular sensory epithelium with the sensory hair bundles ( H ) and the uniformally polarized kinocilia ( K ) , visible as black spots.

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utriculopetal deviation of the cupula in the horizontal ampulla evokes a stronger reaction than utriculofugal deviation, whereas in the vertical ampullae the utriculofugal deviations of the cupula represent a stronger stimulus. In electro-physiological experiments Loewenstein and Coll ( 1940, 1 9 5 5 ) were able to confirm this law to a certain extent. They f o u n d essentially that there are two types of sensory units, ones with and others without spontaneous activity in rest. T h e spontaneously active receptors represent the majority. Utriculopetal stimulation increases not only the activity of the spontaneous firing units but also activates the spontaneously silent units. Utriculofugal stimulation reduces only the activity of the spontaneously active or bidirectional receptors and has no effect on the spontaneously silent receptors. T h u s the total deviation f r o m the resting activity is stronger on utriculopetal stimulation. In the vertical ampullae the pattern is reversed in accordance with the second law of Ewald (Fig. 1 0 ) .

Fig. 10. Schematic representation of the essential electrophysiological characteristics of the cristae. Upper part: Resting potential changes in relation to cupula deviation (Trincker). Lower part: changes in action potentials in relation to cupula deviation ( Lowenstein and coll. ).

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A similar directional functional behaviour of the cristae was found by Trincker ( 1 9 5 7 ) who studied the resting potentials in the ampullae of guinea pigs. He found that a utriculopetal cupula deviation in the horizontal ampulla always results in a depression of the resting potential whereas an utriculofugal deviation increased this potential. Here again the pattern was reversed in the vertical ampullae (Fig. 10). This functional directivity of the cristae finds its expression and has possibly its cause within the arrangement of the sensory hairs. In the cristae the kinocilia of all sensory cells are found on one and the same side of the hair bundles or cellular surface. The sensory hairs are therefore morphologically uniformally polarized. In the crista of the horizontal canal the kinocilia always are at the utricular pole of the surface of the sensory cell, in the crista of the vertical canals (superior and posterior semicircular canal) they are however always at the distal pole of the cell-surface (Fig. 11). This is in agreement with the findings of Loewenstein and Wersall in fishes. The reversed functional pattern of horizontal and vertical cristae is therefore related to a reversed morphological polarization of the sensory hairs. Such a direct relation between the arrangement of the kinocilia and the function of the sensory cell suggests that the kinocilium as such is an important structure for the sensory cell stimulation. A deviation of the hairs in the direction of the kinociliar pole would, according to Trinckers interpretation of his own findings, produce a depolarization of the sensory epithelium and therefore an increased nervous activity as found by Loewenstein and Sand. A deviation of the sensory hairs away from the kinociliar pole on the other hand would create a hyperpolarization of the sensory epithelium and a decreased nervous activity. In the maculae the situation appears to be more complex. The sensory hairs are somewhat shorter than in the cristae but have otherwise an identical structure. The kinocilia are also polarized in the same direction over wide areas (Fig. 9 ) . However, the direction of polarization differs for different parts of the maculae. Since the macular surface is not entirely flat, a single horizontal section hits the epithelial surface only in certain zones and a reconstruction of the entire surface of the macula is only possible with the aid of serial horizontal sections. Such a reconstruction reveals a typical pattern of sensory hair polarization.

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U TRI CUL O PE TAL

Fig. 11. Schematic representation of the polarization of the kinocilia in the cristae of the semicircular canals. In the horizontals crista all kinocilia are on the utricular pole of the sensory cells, whereas in the vertical cristae they are on the opposite side of the cells. On the right hand side of the surface of one sensory cell of a harizontal and a vertical cristae is shown. In the m a c u l a of the u t r i c u l e the d i r e c t i o n o f p o l a r i z a t i o n s p r e a d s fanlike f r o m the m e d i a l a n d a n t e r i o r p a r t o f the m a c u l a u p to

a

c u r v e d b o u n d a r y line b e y o n d w h i c h t h e p o l a r i z a t i o n o f the s e n s o r y hairs is r e v e r s e d . T h e k i n o c i l i a o n e i t h e r side of this dividing line

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are facing each other (Fig. 12). Although the great majority of sensory hairs in one area of the macula is polarized in the same direction there is always a certain number of sensory cells with a different polarization of their sensory hairs as illustrated in the following table.

direction of polarization

' anterior 1 lateral I posterior L medial

I 1 6 35 3

Section II 1 15 2 0

III 14 3 1 1

Each column represents the number of sensory cells in one section which have been counted and sampled according to the direction of their kinocilia. Each section shows a different direction of polarization. On rare occasions we see sensory cells, where the kinocilium is not polarized at all being in the middle of the stereociliar bundle.

All possible directions of polarization are represented in one macula utriculi. There seems however to be a preponderance of laterally polarized sensory cells over the medially polarized ones, whereas the

LATERAL ANTERIOR

\ POSTERIOR

MEDIAL

N

Fig. 12. Schematic representation of the directions of polarization of the sensory hairs in the macula utriculi. The main part of the macula is on the horizontal plane. The boundary line between the opposite polarizations correspond with the striola.

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number of anterior and posterior polarized cells appears to be approximately equal. A very similar pattern of polarization is observed in the m a c u l a sacculi. Here too we find a curved dividing line going through the entire sensory epithelium on either side of which the polarization of the sensory hairs is opposite. Here however the kincilia are not facing each other as in the macula utriculi but they are facing away f r o m each other (Fig. 1 3 ) . Not all directions of polarization are represented in the macula sacculi. T h e sensory cells are mainly polarized to approximately equal parts in an antero inferior and a posterosuperior direction.

SUPERIOR

POSTERIO

ANTERIOR

Fig. 13. Schematic representation of the polarization of the sensory hairs in the macula sacculi. T h e boundary line of the divergent polarization corresponds to the striola.

It is very striking that the site of the dividing line of sensory hair polarization in the macula utriculi and sacculi seems to correspond fairly well with the site of the striola, that special zone in the center of the maculae. It might well be that we deal here with a particularly sensitive and well developed zone in the sensory epithelium. Further-

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m o r e we find a similar structural pattern within the otolithic m e m b r a n e in so f a r as larger otoliths in the distal p a r t of the m a c u l a utriculi can be distinguished f r o m smaller ones in the proximal and medial part of the macula. T h e b o u n d a r y line between the two sorts of otoliths corresponds again roughly with the curved line of the reversed polarization or the striola of W e r n e r . Similar differences in the otoliths have been discribed by L o r e n t o de N o ( 1 9 2 6 ) a n d Werner ( 1 9 4 0 ) . A t this point the studies of Mygind ( 1 9 4 8 ) should be mentioned. He divided on the bases of phylogenetic aspects the m a c u l a in two different functional zones where he also considered the direction of innervation of the macula as essential. If we assume that in the macula the same mechanism of hair cell stimulation is taking place as in the cristae, a positive stimulation with increased nervous activity would always arise when the sensory hairs are deviated towards the kinociliar pole of the sensory cell. Since all four directions of polarization are represented in one macula utriculi we would conclude that one macula is able to respond to rectilinear accelerations in all directions. This is in perfect agreement with the electrophysiological findings of Loewenstein and Roberts ( 1 9 5 1 ) . According to their results one single macula utriculi responds to tilting from normal position around all horizontal axes. A single functional unit however will have its m a x i m u m positive and negative response to tilting around one specific horizontal axis, exactly as we would expect it from its morphological polarization. Units, which respond to any deviation f r o m the normal with the same change in their activity might correspond to the sensory cells with no polarization of the kinocilium. The p r e p o n d e r a n c e of laterally polarized sensory cells might be in accordance with the functional findings of Bos, Jongkees and Philipszoon ( 1 9 6 3 ) who found in rabbits after unilateral labyrinthectomy a great difference of nystagmic response in right or left lateral position. Although f r o m the structural point of view it would seem very likely that the macula sacculi has a similar function as the macula utriculi, there is physiological evidence that it might act as a vibration receptor (Frisch and Stetter 1 9 3 2 ) . There is however m u c h controversy about its functional significance. T h e r e is certainly much morphological evidence that the kinocilium plays an important role in the receptor mechanism of the

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vestibular sensory cells. T h e basic structural identity with motile kinocilia as for instance in the respiratoy epithelium has to be kept in mind. T h e active movements of motile kinocilia are strictly directional going always in the same direction. Those movements are evoked by a stimulation which spreads throughout the cilium. It is possible that in the case of the sensory epithelia we deal with a reversed mechanism. T h e passive movement of the kinocilium in a proper direction would cause a stimulation as already suggested by Loewenstein and Wersall ( 1 9 5 8 ) . Even the assymmetric intrinsic structure of the kinocilium speaks for a directional function. The odd number of nine peripheral tubular filaments in the kinocilium might be the base and the condition f o r a direction-specific action. NERVE

ENDINGS

AND

NERVE

FIBRES

If the apical part of the sensory hairs is most likely concerned with the first step in the transformation of mechanical energy into electrical energy by producing potential differences, it is the basal part of the cell with the synaptic areas between the sensory cell and the nerve endings which is of great interest for the second step of the receptor action by initiating the nerve impulses. It is generally believed that in most cases the impulse transmission f r o m the sensory cell to the nerve ending occurs only at certain places with specific synaptic structures (Fig. 1 4 ) . It is questionable whether bare approximation of nerve ending and sensory cell c a n be taken as evidence for a synaptic function. T h e morphological multitude of such synaptic structures within the maculae of monkeys is striking (Spoendlin, Schuknecht and Graybiel 1 9 6 4 ) . T h e most basic and regularly observed features of possible synaptic structures is the absolute parallelity of axon and cell m e m b r a n e with a narrowing of the intercellular space to a constant width of 150 A . T h e axon m e m b r a n e is thickened in such synaptic regions and the cytoplasm of the sensory cell frequently shows a condensation sometimes extending into the synaptic cleft, similar to desmosomes between epithelial cells. Next to such "synaptic" areas the intercellular space is often considerably widened (Fig. 1 5 ) . In addition however there is a variety of accessory synaptic structures in the cytoplasm of sensory cells. (Figs. 15, 1 6 ) . They consist usually of a very dense osmophilic structure frequently surrounded by

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Fig. 14. Survey-picture of the lower part of a vestibular sensory epithelium. A hair cell type I ( H C I) shows pronounced synaptic structures (Sy) adjacent to the nerve chalice ( C ) . T h e r e are many large ( N ) and small ( n ) nerve fibres, some of which end at a haircell type II. T h e supporting cells (S) sit in a thin basement-membrane (BM).

small vesicles of the dimensions of synaptic vesicles ( D e Robertis, 1 9 5 6 ) . The most c o m m o n of those formations are synaptic bars similar to what has been described by Smith ( 1 9 6 1 ) in the organ of Corti (Fig. 1 5 ) . Instead of bars there are also found small round masses, spherical structures which in the section appear as rings or long straight or bent laminas extending far into the cytoplasm of the sensory cell (Fig. 1 6 ) . T h e latter structures could only be found in the haircells of type I. All the others appear in both types of sensory

Fig. 15. T h e upper part shows some nerve endings ( N E ) at the base of a hair cell type II with synaptic bars ( S b ) . Nerve fibres ( N ) . T h e inset represents a high magnification of a synaptic area (Sy) between a nerve ending ( N E ) and a hair cell type II ( H C I I ) . Vesicles are found as well around the synaptic bar (Sb) as in the nerve ending. T h e lower part shows among other nerve endings ( N E ) a highly vesiculated probably efferent nerve ending ( V ) on a haircell type II. Synaptic areas ( S y ) .

Fig. 16. Different types of accessory synaptic structures between nerve endings ( N E ) and sensory cells of type I (HC I ) and type II ( H C II) such as round masses ( R M ) , bent lamines (L) or ring like formations ( R ) usually surrounded by small vesicles ( V ) comparable to synaptic vesicles. An invagination of a nerve chalice (C) into a hair cell type I is seen at ( D ) . The cytoplasm of the sensory cells contains many ribsomes, whereas they are missing in the nerve chalice. Mitochondria ( M ), Lysosome ( Ly ) .

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cells. Special attention has to be given to invaginations of nerve chalices into the body of sensory cells of type I where the intercellular space is narrow but where no accessory synaptic structure can be seen. The number of synapses per sensory cell and nerve endings varies greatly. By counting the number of synapses in serial sections we found sensory cells with many synapses and others of type I or type II with very few or none. The nerve chalices of the hair cells of type I contain only very few vesicles, neuro-filaments or neuro-tubules. It is striking that the sensory cell contains a great number of ribosomes whereas they are almost completely missing within the nerve chalices (Fig. 16). Some of the bud-like endings at the haircells of type II however are filled with vesicles comparable to the cochlear efferent endings (Fig. 15). However, the morphological distinction between efferent and afferent fibres in the vestibular sensory epithelia is not as clear as in the cochlea. (Engstrom 1958, Spoendlin 1961, 1963, Kimura, Wersall 1962, Smith 1963). Nerve endings with synaptic vesicles are frequently found associated with synaptic bars and agglomerations of synaptic vesicles on the sensory cell side of the synapse as well. Only on very rare occasions we could observe a synapse between a vesiculated nerve ending and another nerve fibre or nerve chalice. It is certainly questionable whether places where vesiculated nerve structures are just adjacent to other nerve fibres can be considered as synaptic areas. Generally spoken there are unquestionally much more vesiculated nerve-endings in synaptic contact with the hair cells of type II than with the nerve chalices of the type I hair cells. In accordance with those findings Gacek, Schuknecht and Nomura (personal communication) found with histochemical methods much less acetylcholinesterase-activity in the area of the striola, where we have a particular concentration of type I hair cells. It is most likely that the vesiculated endings correspond to acetylcholinesterase-active structures and that the terminals of the efferent vestibular fibre as described by Gacek ( 1960 ) and Ireland & Fakashidy ( 1 9 6 1 ) . Cytoplasma condensations at certain spots between sensory cells and nerve endings still do not prove the presence of a synapse. The fact that the same or similar structures are also found as desmosomes between supporting cells (Brightman and Palade 1964) could indicate that those desmosome-like synaptic-structures have only the

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f u n c t i o n of desmosomes to hold the areas of neural junction close together (Robertson 1 9 5 6 ) . Accessory synaptic structures such as synaptic bars, accessory m e m b r a n e s or synaptic vesicles are however restricted to neural junction and they can be considered as part of a real synapse. T h e enormeous variety and big number of synaptic structures in the vestibular sensory epithelia of the squirrel monkey has not yet been described in other animals. It might be in relation to the great functional importance of the gravity receptors in those squirrel monkeys where acrobatic skill is important for survival. Uninterrupted synaptic transmission must be provided in order to guarantee a steady function. T h e special importance of the vestibular system in monkeys as c o m p a r e d with other animals is also expressed by the relative numbers of nerve fibres in the vestibular nerve. According to G a c e k and Rasmussen ( 1 9 6 1 ) the vestibular nerve in monkeys consists of more than double as many nerve fibres in guinea pigs. T h e question remains whether those morphologically different types of synapses are correlated with qualitatively different functions or whether they correspond to different functional states of the synapses. T h e observation that some sensory cells show only very few or no synaptic structures while others have a large n u m b e r makes it more likely that functional synapses are not permanent structures but that they are built up and wear out in a functional cycle. According to such a concept the various forms of synaptic structures would correspond to different functional states or degrees of maturity of the synapses. Sensory cells with very few synapses would be considered as being in a relative resting state whereas the others with many synapses would be in an active state. T h e r e are other signs such as different density of ribosomes and vesicles within the cytoplasm of the sensory cells which suggest that not all sensory cells are in the same functional state at a given time. Since there is no correlation between the spontaneous active and spontaneously silent sensory units of Leowenstein with the two types of sensory cells the difference in functional behaviour of sensory units might be in relation to the number and state of the synapses in the different sensory cells. The spontaneously silent receptors, which are considered to be less sensitive, would correspond to sensory cells with few functional synapses. T h e nerve fibres show great differences in diameter. Large fibres of

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more than five micron diameter end usually in the nerve chalices around the hair cells of type I. One single fibre forms not more than two or three chalices around neighbouring sensory cells. The smaller fibres end with independent endings on many haircells of type II over wider areas (Wersall). After leaving the myelin sheath at the basement membrane the bare axons penetrate the sensory epithelium. They are intimately surrounded and imbedded in deep groves of the supporting cells (Fig. 14). In the subepithelial stroma which is a very loose type of mesenchymal tissue most of the fibres are myelinated. There are however a few large fibres which have lost their myelin sheath already before penetrating the basement membrane of the sensory epithelium and therefore run for a certain distance as bare axons. There are other very small fibres of the diameter of about one micron running in the subepithelial space surrounded only by some extensions of stroma cells. Such fibres have never been seen to penetrate the epithelium. They might correspond to the unmyelinated fibres in the vestibular nerve which are thought to belong to the vegetative nervous system. SUPPORTING

CELLS

The supporting cells form with their cell bodies a coherent basal layer sitting on a basement membrane where only the nerve fibres penetrate. Their slender extensions reach to the epithelial surface filling the space between the sensory cells and closely embedding all intraepithelial nerve fibres. Their cytoplasma contains the usual unspecific structures with a great number of vacuoles and Golgi-membranes. In the apical part they form a reticular membrane obviously as a supporting frame work which surround closely each sensory cell apex. In the monkey each supporting cell has one modified kinocilium at its free surface among a number of microvilli (Spoendlin). This kinocilium is short (only a few microns) and contains a reduced number of fibrils arranged without a special order (Fig. 17). Its basal body shows the typical structure of a centriole and is connected with one or more striated roots. The basal body usually is associated with a second centriole, which always lies in a perpendicular position to the basal body (Fig. 17). This corresponds to the typical position of the distal and proximal centriole in a diplosome as is found for example in

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Fig. 17. At the left hand side is the basal body (B) of a kinocilium ( K ) in a supporting cell. A large root ( R ) shows clear periodicity. At the right hand side is the basal body (B) of a kinocilium ( K ) in a supporting cell with an associated centriole (Ce) in a perpendicular position.

dividing cells such as spermatids ( F a w c e t t 1 9 6 1 ) . It might indicate that supporting cells in the vestibular sensory epithelia retain the capacity of multiplication. There is evidence that the supporting and sensory cells originate from the same pluripotential cell. It remains

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however an open question whether the supporting cells even in later life could eventually differentiate into sensory cells. CONCLUSION

The ultrastructural organization of the vestibular sensory epithelia reveals a correlation to their function. The polarization of the "kinocilia" of the sensory cells seem to represent the morphological basis of a functional polarization of the sensory-epithelium. This morophological and functional polarization appears to be unidirectional in the cristae and pluridirectional in the maculae. The structural findings correspond very well with the results of electrophysiological investigations (Loewenstein, Loewenstein and Roberts, Loewenstein and Sand, Loewenstein and Wersall). The variety and large number of synaptic structure between the sensory cells and the nerve endings is in accordance with a permanent functional activity of the sensory epithelium. The great differences in number and sizes of the accessory synaptic structures from one sensory cell to another might illustrate different functional states of the sensory cells, which possibly correspond to the electrophysiologically different sensory units as described by Loewenstein and coll. There is morphological evidence for a efferent innervation of the vestibular sensory epithelia similar to the organ of Corti but less extensive. The vesiculated nerve endings most likely belong to the efferent system, although the morphological differentation of afferent and efferent elements in the vestibular sensory epithelia is less clear than in the organ of Corti. REFERENCES

Bairati, Α., Jr.: Acta Otolar. suppl. 163 (1960). Barnes, B. S.: J. Ultrastruct. Res. 5, 453-467 (1961). Békésy, G. v.: J. Acoust. Soc. Amer. 24, 72-76 (1952). Bos, J. H., L. B. W. Jongkees, H. J. Philipszoon: Acta Otolar. 56, 477-489 (1963). Brightman, W. M., S. L. Palay: J. of Cell Biology 19, 415-439 (1963). Dahl, Η.: Ζ. Zellforschung 60, 369-386 (1963). Davis, H.: Phys. Rev. 41, 391-416 (1961).

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De Robertis, E.: Triangel. Sandoz-Zeitschrift 5, 76-88 (1961). De Robertis, E.: Int. Rev. Cytol. 2, 503 (1959). Engström, H.: Acta Otolar. 49, 109 (1958). Engström, H., J. Wersäll: Intern. Review of Cytology 7, 535-585 ( 1 9 5 8 ) . Engström, H., J. Wersäll: Exp. Cell Res. Suppl. 5, 460 ( 1 9 5 8 ) . Engström, H., Ades H., J. Hawkins: J. of Acoust. Soc. Amer. 34, 13561363 (1962). Fawcett, D. W.: The Cell 2, 217-297 (1961). Flock, Α., Wersäll, J.: J. Cell. Biol. 15, 19-27 (1962). Friedmann I.: Triangle, J. Sandoz 6, 74 (1963). Frisch, Κ., Stetter: Ζ. vergi. Physiol. 17, 686 (1932). Gacek, R. R., Grant L. Rasmussen: Anat. Ree. 139, 455-463 ( 1 9 6 1 ) . Held, Η.: A. Bettre, Handbuch d. norm. u. pathol. Physiol. Band II, 467541 (1926). Hilding, D. P. Ireland, J. Farkashidy: Ann. of ORL 70, 420-563 (1961). Kimura, R„ J. Wersäll: Acta Otolar. 55, 11-32 (1962). Kolmer, W.: Handbuch d. mikr. Anatomie v. Möllendorf S. 315. Lorento de No. R.: Trav. recherches biol. Univ. Madrid 24, 53 (1926). Löwenstein O.: J. Physiol. 127, 104-117 (1955). Löwenstein O., A. Sand: Proc. of the Royal Soc. Series Β. Biol. Sciences 129, (1940). Löwenstein O., Roberts: J. Physiol. 110, 392 (1949) 114, 471 (1951). Löwenstein O., J. Wersäll: Nature 184, 1807-1808 (1959). Löwenstein O., J. Wersäll: Nature 184, 4701, 1807 (1959). Mygind, S. H.: Acta Otolar. 70, (1948). Robertson, J. D.: J. Biophys. Cytol. 2, 38, 381 (1956). Smith, C. : Ann. of ORL 70, 504-527 ( 1961 ). Smith, C„ F. S. Sjöstrand: J. Ultrastruct. Res. 5, 184 (1961). Spoendlin, H.: Z. f. Zellforschung 62, 701-716 (1964). Spoendlin H., H. F. Schuknecht, A. Graybiel: in press. Trincker D.: Pflügers Archiv für die ges. Physiol. 264, 351-382 (1957). Werner, C. F. : Georg Thieme, Leipzig 1940. Wersäll, J.: Acta Otolar. 126 (1956). Wersäll, J., J. Hawkins: Acta Otolar. 54, 1 (1962). Wolken, J. J.: J. Protozool 3, 211-225 (1956).

The Ascending Vestibular System and Its Relationship to Conjugate Horizontal Eye Movements* Malcolm B. Carpenter, M.D.**

The labyrinths, the vestibular nuclei, and secondary vestibular pathways projecting to the nuclei of the extraocular muscles appear to play a major role in the control of conjugate eye movements. Anatomical evidence indicating that the vestibular nuclei are concerned with conjugate eye movements appears to have a secure foundation, since secondary vestibular fibers ascending in the medial longitudinal fasciculus project to all of the nuclei of the extraocular muscles (Szentagothai, '43; Brodai and Pompeiano, '57; Carpenter, '60; Carpenter and McMasters, '63; McMasters, Weiss and Carpenter, '64). Physiological studies (Szentagothai, '52; Fluur, '59; Cohen, Suzuki and Bender, '64) provide clear evidence of a precise functional correlation between specific semicircular canals and eye movements in particular directions. The investigations of Szentagothai ( ' 5 0 ) leave little doubt that the most important impulses mediating ocular movements in response to stimulation of the semicircular canals ascend in the medial longitudinal fasciculus (hereafter abbreviated M L F ) . These results suggest that impulses from the individual semicircular canals ultimately must be transmitted differentially in a specific manner to all of the nuclei of the extraocular muscles, including the functionally distinct subdivisions of the oculomotor nuclear complex. * Supported by research grants (NB-01538-06 and -07) from the Institute of Neurological Diseases and Blindness of the National Institutes of Health, Bethesda 14, Maryland. ** Department of Anatomy, College of Physicians and Surgeons, Columbia University, N e w York, N e w York.

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The above concepts appear well supported even though anatomical details are incomplete concerning: (1) the exact regions of termination of primary vestibular fibers from different parts of the receptor organ (Lorente de No, '26, '31, '33), and (2) the differential projection and termination of secondary vestibular fibers from the individual vestibular nuclei upon the nuclei of the extraocular muscles. The present report represents a synthesis and summation of several recent studies of the vestibular system in the rhesus monkey (Carpenter and McMasters, '63; Carpenter, McMasters and Hanna, '63; Carpenter and Strominger, '64b; McMasters, Weiss and Carpenter, '64) in which attempts have been made to correlate physiological disturbances and anatomical findings resulting from discrete lesions in portions of the vestibular system considered to play a role in controlling conjugate horizontal eye movements. MATERIAL

AND

METHODS

In a series of 95 rhesus monkeys attempts were made to produce discrete localized lesions in: (1) the MLF at various locations, (2) the abducens nucleus, and (3) all individual vestibular nuclei. Lesions in these locations were produced by stereotaxic methods (Carpenter and Whittier, '52) in which electrodes were introduced by a suboccipital approach at a slight angle with respect to the brain stem. Following surgery physiological disturbances were carefully evaluated and disturbances of eye movements were photographed on several occasions. After observation periods ranging from one to 13 weeks, animals were anesthetized and sacrificed by perfusion technics. Brains and spinal cords were removed, fixed further in neutral formalin, and sectioned perpendicular to the axis of the brain stem. Blocks of tissue were cut at 20μ on a freezing microtome and all sections were preserved in multiunit plastic containers. Sections through the lesions were stained by the Weil and Nissl technics to facilitate evaluation of the spatial disposition and extent of the lesions. Selected representative sections from all parts of the brain stem were stained according to the Laidlaw modification of the Nauta-Gygax ('54) technic in order to study axona! and preterminal fiber degeneration. The nomenclature for the subdivisions of the oculomotor complex used in this study was that of Warwick ('53a). The cell column

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medial to the dorsal nucleus and the intermediate cell column, which gives rise to crossed fibers innervating the superior rectus muscle, was not named by Warwick. For convenience of description this nucleus has been referred to as the medial nucleus (Carpenter and Strominger, '64a; McMasters, Weiss and Carpenter, ' 6 4 ) . (See Fig. 1.)

OCULOMOTOR

COMPLEX

- D o r s a l nucleus ROSTRAL •Ventral nucleus

MIDDLE

M e d i a n nucleus

C a u d a l central nuc. CAUDAL Intermediate eel I column

INF. RECTUS 1 • Β

I INF. OBLIQUE

SUP RECTUS LEVATOR PALP.

MED. RECTUS

Fig. 1. Schematic representation of the localization of the extraocular muscles within the oculomotor complex based upon studies in the rhesus monkey ( W a r wick, 53a). T h e visceral nuclei and rostal pole of the complex are not shown. Nerve fibers innervating the medial rectus, inferior rectus and inferior oblique muscles are uncrossed; fibers supplying the superior rectus muscles ( f r o m the medial nucleus) are crossed. Cells of the caudal central nucleus give rise to crossed and uncrossed fibers innervating the levator palpebrae muscle.

OBSERVATIONS

Lesions of the Medial Longitudinal Fasciculus In 41 monkeys attempts were made to produce discrete lesions in the MLF: ( 1 ) adjacent to the abducens nucleus, ( 2 ) immediately

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rostral to the abducens nucleus, and (3) at levels near the trochlear nerve decussation (i.e., isthmus region). Lesions adjacent and immediately rostral to the abducens nucleus were unilateral and bilateral, while those at isthmus levels were unilateral. Bilateral lesions near the abducens nuclei. Bilateral lesions of the MLF near the abducens nuclei were produced in seven monkeys. Lesions varied in size, location, rostrocaudal extent, and were not always symmetrical. In four animals lesions involved fibers of the MLF maximally medial to the abducens nuclei, while lesions in two other animals were maximal rostral to the abducens nuclei. The lesion in one animal (C-618) destroyed only the most medial fibers of the MLF; this lesion began at the level of the abducens nucleus and extended rostrally. Although all lesions of the MLF in these animals were bilateral, resulting disturbances of eye movements were not identical. Lesions destroying fibers of the MLF rostral to the abducens nuclei produced different disturbances of eye movements than lesions interrupting MLF fibers between the abducens nuclei. All disturbances involved conjugate horizontal eye movements only. Vertical eye movements were normal and ocular convergence was not impaired. Lesions destroying fibers of the MLF rostral to the abducens nuclei produced bilateral impairment of ocular adduction on attempted lateral gaze to either side. When the animal attempted to look to the right: (1) the left eye remained in a straight neutral position and failed to adduct, (2) the right eye abducted fully, and (3) large amplitude monocular horizontal nystagmus was seen in the right abducting eye. Similar, but opposite, dissociated eye movements were observed on attempted left lateral gaze. Almost identical impairment of ocular adduction and monocular horizontal nystagmus were seen in one animal (C-618) with a small slit-like lesion destroying only the most medial fibers of the MLF bilaterally; this lesion began at the level of the abducens nuclei, but extended rostrally. Paresis of ocular adduction in two of these animals persisted with minimal attenuation until they were sacrificed — 35 and 49 days after operation. Monocular horizontal nystagmus in the abducting eye persisted for about three weeks; thereafter it became intermittent and disappeared. Lesions destroying fibers of the MLF maximally at the level of the abducens nuclei resulted in impairment of all horizontal eye movements. The eyes were directed straight ahead and no lateral move-

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ments of the eyes were seen. This pronounced restriction of all lateral eye movements appeared to be due to paresis or weakness of both ocular adduction and abduction. None of these animals had detectable nystagmus or impairment of ocular convergence. Eye movements in a vertical plane were normal and frequent. These animals tended to develop a curious reptilian-like stare due to the restriction of horizontal eye movements. During the first or second week after surgery very fleeting and limited lateral movements of the eyes were seen. Paresis of ocular abduction tended to diminish in three of these animals, while paresis of ocular adduction remained. The greater weakness of ocular adduction frequently resulted in a dissociation of horizontal eye movements. In only one of these four animals did the disturbances of conjugate horizontal eye movements disappear. Fiber degeneration resulting from these lesions was similar. Relatively profuse preterminal degeneration passed laterally into the abducens nuclei on both sides. Fiber degeneration closely surrounded some individual cells in the abducens nuclei, particularly in ventromedial regions. Degeneration in the abducens nuclei was most abundant in animals with large lesions between the abducens nuclei; lesions of the M L F rostral to the abducens nuclei produced less degeneration, especially in caudal parts of the abducens nuclei. Additional degeneration seen at the level of the lesion in different animals was seen in: ( 1 ) crossed fibers of the olivo-cochlear bundle (all animals), ( 2 ) a few root fibers of the abducens nerve on one side (one animal), and ( 3 ) a small number of facial nerve fibers (two animals). Moderate numbers of degenerated fibers were seen in different parts of the vestibular nuclear complex, presumably due mainly to passage of the electrode through portions of the cerebellum. Ascending degeneration resulting from these lesions was confined to the medial longitudinal fasciculi, except for variable amounts of degeneration seen in the auditory pathways as a consequence of interrupting dorsally decussating fibers in the acoustic striae. Within the M L F the principal ascending degeneration was confined to ventromedial locations, and did not change at higher levels. No degeneration was seen in the lateral process of the M L F at isthmus levels. Abundant preterminal degeneration projected into the trochlear nucleus bilaterally. Fiber degeneration in the oculomotor nuclear complex in these animals was quantitatively different, but exhibited important similari-

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ties in distribution. In sections through the caudal third of the oculom o t o r complex profuse degeneration was scattered throughout the lateral somatic cell columns bilaterally, though it was most concentrated in the ventral nucleus. Small islands of localized degeneration were present in lateral portions of the dorsal nucleus in some animals. T h r o u g h u t the middle and rostral thirds of the oculomotor complex preterminal degeneration was most abundantly distributed to the ventral nucleus, a cell group innervating the medial rectus muscle. In animals in which paresis of ocular adduction resulted f r o m small lesions of the M L F rostral to the abducens nuclei, degeneration was distributed selectively to the ventral nucleus, and other cell columns were virtually free of degenerated fibers. In animals with larger lesions of the M L F between the abducens nuclei, the principal degeneration was in the ventral nucleus, but scattered degeneration was present in other cell groups, especially those adjacent to the M L F . In rostral portions of the oculomotor complex, a conspicuous reduction in degeneration was evident though a moderate n u m b e r of degenerated fibers remained in the M L F . Sparse degeneration was present in the caudal central nucleus in some animals, but no degeneration was seen in the midline visceral nuclei. Degenerated fibers bypassing the oculomotor complex entered the interstitial nucleus of Cajal bilaterally and arborized about individual cells. A smaller n u m b e r of fibers from the M L F projected bilaterally into: ( 1 ) the nucleus of Darkschewitsch, ( 2 ) the nucleus of the posterior commissure, and ( 3 ) the periaqueductal gray. Unilateral lesions adjacent to the abducens nucleus. Small localized lesions destroying fibers of the right M L F medial to the abducens nucleus were produced in two monkeys. In both of these animals the lesions in the M L F began caudal to the abducens nucleus and extended rostrally beyond its oral pole. T h e lesion in rhesus C - 6 3 9 encroached slightly upon the ventromedial part of the abducens nucleus. Following surgery both of these animals gazed exclusively to the left or straight ahead. Left lateral gaze appeared conjugate and was not forced as seen with lesions of the abducens nucleus. In one of these animals ( C - 7 6 4 ) the preferential gaze to the left gradually diminished and all eye movements appeared normal and conjugate four weeks after surgery. N o nystagmus was seen. In the other animal ( C - 6 3 9 ) there was a suggestion of slight weakness of the right lateral rectus muscle. Examination of this animal in a restraining chair during the

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second postoperative week revealed a moderate bilateral paresis of ocular adduction which was greatest on the left side. Caloric stimulation served to exaggerate the weakness of ocular adduction. These physiological findings suggest that unilateral lesions of the M L F medial to the abducens nucleus may impair ipsilateral lateral gaze to some degree and can impair ocular adduction bilaterally. From the area of the lesion degenerated fibers passed laterally into portions of the abducens nuclei on both sides; degeneration was greatest in the ipsilateral nucleus. At the level of the lesion a large number of degenerated fibers crossed the median raphe and entered the contralateral M L F . Ascending degeneration in the MLF, localized in ventromedial regions, was bilateral, but slightly more profuse on the left side. Abundant degeneration passing into the trochlear nuclei was greatest on the left side. In the animal exhibiting only preferential gaze to the left, degeneration in the oculomotor complex was distributed symmetrically mainly to the intermediate cell columns (Warwick, ' 5 3 a ) ; only sparse degeneration was seen in the ventral nuclei. In the animal ( C - 6 3 9 ) with bilateral paresis of ocular adduction preterminal degeneration in the oculomotor complex was distributed selectively to the ventral nuclei and to small lateral portions of the dorsal nuclei adjacent to the MLF. Degeneration was bilateral and most profuse in the ventral nuclei in the middle third of the oculomotor complex. Unilateral lesions rostral to the abducens nucleus. Small unilateral lesions in the right M L F rostral to the abducens nucleus were produced in four animals. Circular lesions in two animals were localized in the most medial part of the MLF. In other animals the lesions involved more lateral parts of the MLF, including the wing-like process in one animal ( C - 6 3 3 ) . None of these lesions involved any part of the abducens nucleus, and all were strictly confined to the right side. Lesions destroying the most medial fibers of the right M L F rostral to the abducens nucleus produced: ( 1 ) marked paresis of right ocular adduction on attempted left lateral gaze, and ( 2 ) monocular horizontal nystagmus in the left abducting eye. Monocular nystagmus in one animal lasted for only three days. In the other animal monocular horizontal nystagmus persisted throughout the postoperative period of 2 6 days. This animal also had intermittent vertical and rotatory nystagmus bilaterally. N o definite disturbances of conjugate horizontal eye movements

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were seen in the two animals with unilateral lesions involving lateral portions of the M L F rostral to the abducens nucleus. A small amount of preterminal degeneration was seen in the rostral part of the ipsilateral abducens nucleus in all animals of this group. In only one animal (C-633) were degenerated fibers seen in the opposite abducens nucleus. No degenerated fibers were present in the abducens root fibers on either side. Ascending degeneration was confined to the right M L F in all animals of this group. Degeneration in this bundle was localized in the medial part of the right M L F in the two animals with lesions in the medial part of this bundle. In other animals ascending degeneration in the M L F was localized in more lateral parts of the bundle. No degenerated fibers crossed to the opposite MLF. Profuse preterminal degeneration projected into the ipsilateral trochlear nucleus. No degenerated fibers were seen in the left trochlear nucleus. In the oculomotor complex preterminal degeneration projected only into the right lateral somatic cell columns. Degeneration in the caudal parts of the oculomotor complex was scattered among all cell columns. This degeneration was less abundant in animals with lesions in the lateral parts of the MLF. In animals with lesions in the medial parts of the M L F degeneration in the caudal third of the oculomotor complex was greatest in the dorsal and ventral nuclei. Sections through the middle third of the oculomotor complex revealed that degeneration was distributed differentially in the ventral nucleus in animals with paresis of ocular adduction. A similar selective distribution of degeneration in the ventral nucleus was not seen in other animals of this group. While the amount of degeneration conspicuously diminished in the rostral third of the oculomotor nuclear complex in all animals, the differential distribution of preterminal degeneration in the ventral nucleus was maintained in animals that had paresis of ocular adduction. N o degeneration was found in the visceral nuclei of the oculomotor complex. Examination of the somatic cell columns of the oculomotor complex on the opposite side revealed only an occasional degenerated fiber in many stained sections. Very sparse degeneration was seen in the caudal central nucleus, usually on the right side. Abundant degeneration closely surrounded cells of the interstitial nucleus of Cajal ipsilateral to the lesion, suggesting that this nucleus is one of the principal sites of termination of ascending fibers of the M L F bypassing the oculomotor complex.

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Unilateral lesions at isthmus levels. Stereotaxic lesions destroyed portions of the M L F unilaterally near the trochlear nucleus in six animals. Similar lesions in four animals destroyed fibers in the medial part of the M L F caudal to the trochlear nucleus. None of these lesions damaged the trochlear nucleus, but a few decussating fibers of the trochlear nerve were injured in one animal (C-634). Lesions in two other animals destroyed fibers in medial (C-615) and lateral (C-652) parts of the M L F and encroached upon ventral portions of the trochlear nucleus. All of these lesions were strictly unilateral, except one (C-626) which extended across the median raphe to touch the opposite M L F . Lesions were on the right side in five animals and on the left side in one ( C - 6 1 5 ) . After surgery five animals of this group appeared to have a slight abnormal adduction of the eye contralateral to the lesion. Detectable, but slight, elevation of the contralateral eye was noted in four of these animals. These findings were most noticeable when the animal's gaze was directed straight ahead. Rapid improvement of this mild extraocular disturbance occurred, though some degree of contralateral ocular adduction persisted. Lateral gaze to both sides appeared conjugate, convergence was unimpaired, and no nystagmus was seen in any of these animals. Head tilt towards the side opposite the lesion, seen in four of these animals, subsided gradually. Fiber degeneration resulting from these lesions was remarkably similar and can be presented in a single description. Abundant preterminal degeneration in the trochlear nucleus was confiined to the lesion side. Ascending degeneration in the M L F was strictly unilateral; no degenerated fibers were observed to cross the midline at any level. Profuse preterminal degeneration was distributed fairly evenly in all cell groups of the lateral somatic cell columns of the oculomotor complex on the side of the lesion. Degeneration was most abundant in caudal regions and diminished progressively in more rostral areas. A few degenerated fibers were found consistently in the caudal central nucleus, mostly on the lesion side. Although degeneration in the middle and rostral thirds of the oculomotor complex was present in all somatic cell columns, relatively more degeneration was seen in the dorsal and ventral nuclei in some animals. No degeneration was seen in the contralateral somatic cell columns or in the midline visceral nuclei. Preterminal degeneration from the M L F passed into the interstitial nucleus of Cajal, the nucleus of Dark-

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schewitsch and the nucleus of the posterior commissure only on the side of the lesion. Descending fiber degeneration confined to the ipsilateral M L F projected to portions of the ipsilateral medial vestibular nucleus and to parts of the inferior olivary complex, especially the rostral pole of the medial accessory olive. Scant degeneration, seen in the ipsilateral abducens nucleus, seemed to be mainly fibers of passage. Lesions of the Abducens Nucleus Discrete lesions destroying portions of the right abducens nucleus were produced in six monkeys. Lesions in two monkeys (C-611 and C-612) destroyed virtually all cells of the nucleus and terminated slightly beyond the rostral pole of the nucleus. These lesions encroached slightly upon fibers in the lateral part of the ipsilateral M L F . In two other animals large portions of the right abducens nucleus were destroyed, but small areas contained normal-appearing cells. In one of these animals (C-622) no fibers of the M L F were destroyed by the lesion. Small lesions in two other animals destroyed localized ventral (C-638) and dorsomedial (C-628) parts of the nucleus. Five of these six monkeys with lesions in the right abducens nucleus exhibited a paralysis of conjugate lateral gaze to the right. Although paralysis of right lateral gaze was the principal finding, certain differences were detectable in individual animals. In one animal (C-612) both eyes were strongly and constantly directed in conjugate fashion to the left. Five days after surgery, the eyes could be directed fleetingly straight ahead, but most of the time they were deviated to the left. The eyes were never directed into the right field of gaze. Four other animals had a similar paralysis of right lateral gaze but eye movements were not always conjugate. In two animals (C-611 and C-622) the right eye was always strongly adducted, but the left eye sometimes moved independently to a straight ahead neutral position. In time the forced abduction of the left eye diminished, but impairment of ocular adduction beyond the neutral position persisted. No significant change in the paresis of ocular abduction in the right eye was noted. Neither of these animals was ever observed to gaze conjugately to the right. Monocular horizontal nystagmus was observed in the left abducted eye only in rhesus C-611. A small partial

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lesion in the abducens nucleus in rhesus C-638 produced a similar paralysis of right lateral gaze, except that it was not enduring. Paralysis of right lateral gaze in one animal (C-625) differed from that seen in other animals in that paresis of left ocular adduction was greater than the paresis of right ocular abduction. The right eye could be brought to a straight ahead neutral position, but the left eye always remained abduced. One animal (C-628) of this group with a lesion in the dorsomedial part of the abducens nucleus did not have a paralysis of conjugate gaze to the right. This animal had a slight weakness of the right lateral rectus muscle which disappeared during the second postoperative week. Fiber degeneration resulting from these lesions was similar. At the level of the lesion degenerated fibers passed: ( 1 ) ventrally into the reticular formation, ( 2 ) laterally toward the vestibular nuclei, and ( 3 ) medially across the median raphe. On the side of the lesion, root fibers of the abducens nerve were degenerated proportional to the extent of destruction in the abducens nucleus. Degenerated fibers crossing the midline entered the contralateral M L F and the abducens nucleus. Within the opposite abducens nucleus abundant degenerated fibers arborized about some of the motor neurons. Ascending degeneration resulting from these lesions was confined principally to the MLF. Most of the degenerated fibers entering the left M L F crossed at the level of the lesion. In the left M L F more numerous degenerated fibers were concentrated in ventromedial parts of the bundle; a smaller number of degenerated fibers in the right M L F were somewhat scattered in more lateral parts of the bundle. At more rostral levels, no degenerated fibers were present in the lateral wing-like process of the M L F on either side and no degenerated fibers crossed the median raphe. On both sides degenerated fibers passed into the trochlear nuclei; these fibers appeared fairly symmetrical in amount and distribution. Abundant degeneration entered the oculomotor complex bilaterally, but none of these fibers entered the midline visceral nuclei or the caudal central nucleus. In the somatic cell columns degeneration appeared scattered bilaterally except for localized areas of especially concentrated degeneration in the dorsal and ventral nuclei. In the ventral nuclei degeneration was most profuse on the left side in the middle third of the oculomotor complex. Predeterminal degeneration in rhesus C-622 seemed particularly signi-

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fìcant because the lesion in the abducens nucleus in this animal did not destroy fibers of the ipsilateral M L F . Although ascending degeneration in the M L F was bilateral, it was overwhelmingly greatest contralateral^. Degeneration in the contralateral nuclei of the extraocular muscles was especially marked. In the left trochlear nucleus the amount of degeneration was several times greater than that in the ipsilateral nucleus. Degenerated fibers in the oculomotor nucleus showed a definite differential distribution. In caudal portions of the oculomotor complex, preterminal degeneration appeared scattered, except for concentrated degeneration bilaterally in the dorsal nuclei. In middle and rostral thirds of the complex, profuse fiber degeneration was present only in the ventral nucleus on the left side. This abundant degeneration, passing selectively to the cell group innervating the contralateral medial rectus muscle, seemed particularly significant. Because of the widely acknowledged theoretical existence of the so-called parabducens nucleus (Strong and Elwyn, '43; Crosby, '50, '53; Peele, '61) and the lack of a definitive description of this entity in the literature (Carpenter, McMasters and Hanna, ' 6 3 ) , attempts were made to determine whether all cells of the abducens nucleus would undergo retrograde cell changes or dissolution following: ( 1 ) excision of the lateral rectus muscle, ( 2 ) avulsion of the abducens nerve, or ( 3 ) intracranial section of this nerve. Although all of these procedures produced impressive retrograde cell changes a n d / o r cell loss in the abducens nucleus, not all cells of the nucleus were affected. These results were inconclusive and failed to confirm the findings of Van Gehuchten (1898, Ό 4 ) , Holmes ( ' 2 1 ) and Warwick ( ' 5 3 b ) . In spite of these differences, we feel that the existence and location of the parabducens nucleus is unresolved. Lesions of Individual Vestibular Nuclei The preceding studies suggested that the disturbances of conjugate horizontal eye movements resulting from discrete lesions in the M L F and the abducens nucleus had certain common features and that these common features probably were a consequence of interrupting ascending secondary vestibular fibers. Paresis of ocular adduction is the principal and most enduring disturbance resulting from localized lesions of the M L F adjacent, or rostral, to the abducens nucleus. The

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syndrome of lateral gaze paralysis resulting from lesions in the abducens nucleus appears to consist of two separate elements: ( 1 ) paralysis of the ipsilateral rectus muscle, and ( 2 ) paresis of contralateral ocular adduction on attempted conjugate horizontal gaze to the side of the lesion. Lesions in both of these locations result in chromatolytic cell changes in parts of the medial, lateral and inferior vestibular nuclei. Paresis of ocular adduction, constituting a part of each of these syndromes, is invariably associated with profuse preterminal degeneration distributed differentially to the ventral nucleus of the oculomotor complex on the side of the paresis of ocular adduction. These findings suggested that a systematic study of the vestibulo-oculomotor fibers originating from the individual vestibular nuclei might contribute to the understanding of the neural mechanisms involved in these disturbances. In a series of 35 monkeys attempts were made to produce discrete lesions in individual vestibular nuclei on the right side. Lesions worthy of detailed analysis were produced in 20 animals. Because of the spatial disposition of these nuclei it was not possible to produce lesions confined strictly to each anatomical subdivision of this complex. However, it was possible to produce localized lesions in the inferior, medial and superior vestibular nuclei which did not involve other subdivisions of this complex. Lesions of the lateral vestibular nucleus always involved portions of either the inferior or superior vestibular nuclei. Findings in this study will be summarized briefly, but interested readers can consult the original publication (McMasters, Weiss and Carpenter, ' 6 4 ) . Medial vestibular nucleus. In three monkeys localized stereotaxic lesions destroyed parts of the medial vestibular nucleus without involving other vestibular nuclei or the adjacent reticular formation. None of these lesions involved the abducens nucleus or destroyed the most ventral border of the medial vestibular nucleus. The principal ascending degeneration was distributed differentially to the nuclei of the extraocular muscles. Moderate preterminal degeneration distributed to the abducens nuclei was bilateral and asymmetrical. In the left abducens nucleus degeneration was greatest in medial regions, while degeneration on the right tended to be localized in lateral parts of the nucleus. N o degeneration was present in root fibers of the abducens nerve. Degenerated fibers entered the M L F in the region of the abducens nucleus and in areas immediately rostral and caudal

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to it. The greatest number of these fibers crossed the median raphe, entered the opposite MLF, and ascended in the ventromedial part of the bundle. A smaller number of fibers entering the ipsilateral M L F tended to occupy more dorsal and lateral positions within the bundle. Preterminal degeneration was profuse in the contralateral trochlear nucleus, but sparse ipsilaterally. In the oculomotor complex degeneration was bilateral and in general more profuse on the left in caudal parts of the nucleus. Fiber degeneration within the oculomotor complex was distributed differentially. In the caudal third of the complex, moderately profuse degeneration on the left was present in the intermediate cell column and in the ventral nucleus. On the right side caudally, degeneration was localized in the dorsal nucleus and a tiny part of the ventral nucleus. Throughout the middle and rostral thirds of the oculomotor complex, degeneration on the left was seen in the dorsal nucleus and the dorsal part of the intermediate cell column. In corresponding regions on the right side, degeneration was abundant only in the ventral nucleus. Rostral portions of the complex contained less degeneration on both sides. Although degeneration was seen bilaterally in the interstitial nucleus of Cajal, it was most numerous on the left side. No degeneration was present in the caudal central nucleus or in the midline visceral nuclei. (See Fig. 2.) Superior vestibular nucleus. Stereotaxic lesions in four animals destroyed significant portions of the superior vestibular nucleus without encroaching upon other vestibular nuclei. However, these lesions concomitantly destroyed parts of the brachium conjunctivum and variable numbers of fastigial efferent fibers as they entered the brain stem. Scattered, sparse degeneration was seen only in the rostral part of the right abducens nucleus. Ascending degeneration resulting from these lesions was limited primarily to two structures, the M L F and the brachium conjunctivum. Degenerated fibers from the superior vestibular nucleus entered the lateral wing-like process of the ipsilateral M L F rostral to the abducens nucleus, and ascended without change of position in this part of the fasciculus. These fibers were distributed ipsilaterally to the trochlear nucleus and to specific parts of the oculomotor nucleus. None of these fibers appeared to cross within the oculomotor complex. Caudally these fibers were distributed among cells in the lateral part of the intermediate cell column. In

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SYSTEM

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ROSTKAL

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VESTIBULAR NUCLEI SUPERIOR LATERAL

ABDUCENS NUCLEI INFERIOR MEDIAL

Fig. 2. Schematic diagram of the distribution of secondary vestibular fibers passing to the nuclei of the extraocular muscles from a lesion in the medial vestibular nucleus. In this and succeeding figures axonal and preterminal degeneration is represented by black dots. T h e vestibular nuclei are represented as seen in horizontal sections of the brain stem. T h e area of the lesion is shown in black.

the middle and rostral thirds of the oculomotor complex, degeneration was localized in the dorsal nucleus. (See Fig. 3 ) . No descending degeneration was present in the M L F or the vestibulospinal tract. Variable numbers of degenerated fibers entering the left somatic cell columns of the oculomotor complex originated from the cerebellum and were interrupted by concomitant injury to the brachium conjunctivum. After decussating, small groups of these fibers passed dorsally, medial to the red nucleus, and entered the caudal and middle

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OCULOMOTOR COMPLEX

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Q

" ^ J

VESTIBULAR NUCLEI SUPERIOR LATERAL

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Q INFERIOR MEDIAL

Fig. 3. Schematic diagram of the distribution of secondary vestibular fibers passing to the nuclei of the extraocular muscles from a lesion in the superior vestibular nucleus. These fibers are entirely uncrossed and ascend in the lateral process of the medial longitudinal fasciculus. The lesion is shown in black.

thirds of the oculomotor complex by traversing the undegenerated fascicles of the. left M L F at right angles. These crossed cerebellooculomotor fibers were distributed mainly to the caudal two-thirds of the medial nucleus of the complex, a cell group described as providing root fibers innervating the opposite superior rectus muscle. A systematic study of cerebello-oculomotor fibers has been published elsewhere (Carpenter and Strominger, ' 6 4 a ) . In three additional animals similar lesions in the superior vestibular nucleus concomitantly destroyed dorsal and rostral parts of the lateral

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vestibular nucleus as well as ventral portions of the brachium conjunctivum. Ascending degeneration in the M L F and nuclei of the extraocular muscles was the same as that found in animals with lesions involving only the superior vestibular nucleus and the brachium conjunctivum. Descending degeneration was present in the ipsilateral vestibulospinal tract. These findings indicate that the dorsal half of Deiters' nucleus gives rise to: ( 1 ) few, if any, ascending fibers in the MLF, and ( 2 ) no fibers that descend in the MLF. A lesion in one other animal destroyed part of the superior vestibular nucleus and dorsal parts of Deiters' nucleus without encroaching upon the brachium conjunctivum. Ascending degeneration, present only in the ipsilateral M L F , was distributed only to ipsilateral nuclei of the extraocular muscles. The differential distribution of preterminal degeneration in the ipsilateral somatic cell columns of the oculomotor nucleus was the same as described above. No degeneration was seen in the left half of the oculomotor complex. Descending degeneration was present only in the ipsilateral vestibulospinal tract. Inferior vestibular nucleus. In three animals relatively small lesions were produced in parts of the right inferior vestibular nucleus without destroying portions of other vestibular nuclei. Rostral portions of this nucleus were destroyed in two animals, while a large part of the nucleus was destroyed caudally in a third animal. In all animals of this group a large number of vestibular arcuate fibers coursed ventromedially through the reticular formation, crossed the median raphe, and swept dorsolateral^ into parts of the opposite inferior vestibular nucleus. Within the opposite inferior vestibular nucleus degeneration was most profuse in rostral regions; a few degenerated fibers appeared to enter ventral portions of the lateral vestibular nucleus. Ascending degeneration from these lesions in the inferior vestibular nucleus resulted only from lesions in rostral portions of the nucleus and was much less numerous than that associated with lesions in other subdivisions of the vestibular complex. Relatively sparse degeneration was seen bilaterally in rostral parts of the abducens nuclei. Rostral to the abducens nuclei, a small amount of degeneration was seen in the central part of the right MLF. Although few degenerated fibers could be detected in the left MLF, preterminal degeneration was seen clearly in the left trochlear nucleus. No fibers from the right M L F could be traced into the right trochlear nucleus.

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Preterminal degeneration entering the oculomotor complex was bilateral, sparse and asymmetrical. On the right side most of the degenerated fibers were found in the ventral nucleus, though a small number of fibers were seen in the dorsal nucleus caudally. On the left side sparse degeneration passed into the caudal part of the intermediate cell column. No degeneration was seen in the interstitial nucleus of Cajal on either side. Lateral and inferior vestibular nuclei. In six monkeys well localized lesions destroyed portions of the right lateral and inferior vestibular nuclei selectively. Electrodes used to produce these lesions traversed oral parts of the inferior vestibular nucleus in an oblique manner and entered central or ventral parts of Deiters' nucleus. Destruction within the inferior vestibular nucleus was limited to the rostral third of the nucleus. Lesions in Deiters' nucleus destroyed virtually the entire nucleus, except for small groups of cells in dorsocaudal locations. Fiber degeneration resulting from these lesions was remarkably constant. Profuse preterminal degeneration from the lesion passed into the lateral two-thirds of the adjacent medial vestibular nucleus and into dorsomedial parts of the reticular formation. At levels of the abducens nuclei bundles of degenerated fibers coursed medially ventral to this nucleus; some of these fibers entered the ipsilateral abducens nucleus while a larger number entered the contralateral nucleus. The principal ascending vestibular fibers entered the M L F in the vicinity of the abducens nuclei. Degeneration within the M L F was bilateral with the greatest number of fibers in the left fasciculus. In the left M L F degenerated fibers were localized in a ventromedial zone, while in the right M L F they were located more dorsally and further from the medial border of the bundle. Although the configuration of the M L F changes at higher brain stem levels, degenerated ascending fibers in these fasciculi retained their respective positions. No degenerated ascending fibers in the M L F crossed the median raphe in the upper pons or isthmus region. Relatively profuse preterminal degeneration was confined to the left trochlear nucleus in five of the six animals of this group. In one animal no degeneration was seen in the trochlear nucleus on either side. In the oculomotor complex degeneration was distributed differentially in the lateral somatic cell columns. Degeneration in these cell columns was most profuse in the caudal two-thirds of the complex.

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On the left degenerated fibers were distributed to the intermediate cell column and parts of the medial and dorsal nuclei. Ipsilateral degeneration in the oculomotor complex was found in the ventral nucleus throughout its extent and in the caudal third of the dorsal nucleus. Other somatic cell columns were free of degeneration. N o degenerated fibers entered the caudal central nucleus or the midline visceral nuclei. Preterminal degeneration passing into the interstitial nucleus of Cajal was found exclusively or predominantly contralateral to the lesion. The only descending degeneration extending to spinal levels was that found in the ipsilateral vestibulospinal tract. (See Fig. 4.) Physiological observations made in these animals were of great interest, though the disturbances were mild and tended to disappear rapidly. Ten of these animals with verified unilateral lesions of the vestibular nuclei had transient nystagmus. All animals with lesions of the inferior vestibular nucleus had nystagmus; in two of the three animals it was predominantly rotatory. Clockwise rotatory nystagmus was seen also in animals with lesions in the medial vestibular nucleus. Nystagmus associated with lesions of the lateral and inferior vestibular nuclei usually was compound, involving rotatory and horizontal components. Only one of the eight animals with lesions involving the superior vestibular nucleus had detectable nystagmus. Most of these animals exhibited a mild, but definite, gaze preference to the side opposite the lesion in the immediate postoperative period; this gaze preference was never forced or persistent as seen with lesions of the abducens nucleus. DISCUSSION

While it is well established clinically (Spiller, '24; Cogan, Kubik and Smith, '50; Sahlgren and Hofman-Bang, '50; Case Records M G H , '53; Smith and Cogan, '59; Christoff, Anderson, Nathanson and Bender, '60) and experimentally (Klossowsky and Levikowa, '31; Bender and Weinstein, '44, '50; Shanzer, Wagman and Bender, '59) that lesions in the M L F produce disturbances of conjugate horizontal eye movements, relatively few anatomical studies of this syndrome have been made. Data derived from the current study indicate that bilateral lesions of the M L F at the level of the abducens nucleus, or immediately

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OCULOMOTOR COMPLEX

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MIDDLE

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TROCHLEAR NUCLEI

M LF

(g)

Q

VESTIBULAR NUCLEI SUPERIOR

LATERAL ABDUCENS NUCLEI

Fig. 4. Schematic diagram of the distribution of secondary vestibular fibers passing to the nuclei of the extraocular muscles from a lesion involving the lateral vestibular nucleus and the rostral pole of the inferior vestibular nucleus. Lesions in this location appear to be only lesions that produce degeneration passing to the medial nucleus. Ascending fibers from the lateral vestibular nucleus arise only from ventral portions of the nucleus. T h e lesion is shown in black.

rostral to it, may produce: ( 1 ) bilateral paresis of ocular adduction on attempted lateral gaze to either side, and monocular horizontal nystagmus in the abducting eye, or ( 2 ) bilateral paresis or restriction of both adducting and abducting eye movements without impairment of vertical eye movements. None of these lesions impaired ocular convergence. The location and extent of the lesion in the M L F appears to determine which of these disturbances occurs. Lesions

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destroying only the most medial fibers of the M L F at the level of the abducens nucleus, or immediately rostral to it, appear to produce weakness of ocular adduction on attempted lateral gaze. More extensive lesions of the M L F between the abducens nuclei are associated with impairment of all horizontal eye movements. Paresis of ocular abduction usually is not as severe as the paresis of ocular adduction and tends to undergo attenuation with time. Because paresis of ocular abduction seems to occur only with lesions of the M L F between the abducens nuclei, and preterminal degeneration with the abducens nuclei is particularly profuse, it seems likely that these lesions are interrupting afferent fibers passing to the abducens nuclei. Evidence from this study supports the thesis that paresis of ocular adduction occurring as a consequence of a lesion in the M L F invariably is associated with ascending degeneration in the M L F which projects selectively to the ventral nucleus of the oculomotor complex, a cell group that innervates the medial rectus muscle (Warwick, ' 5 3 a ) . Degeneration within the ventral nucleus is found on the same side as the paresis of ocular adduction. Results of our studies indicate that paresis of ocular adduction is associated only with lesions of the M L F in the vicinity of the abducens nucleus, since lesions of the M L F near the trochlear level do not produce this syndrome. The explanation for this apparent discrepancy remains unknown. It would seem that interruption of what appears to be the same fiber system at different levels would produce the same physiological disturbances. Among the most important observations in the current study were those concerning unilateral lesions of the M L F rostral to the abducens nucleus. Lesions in medial parts of this bundle at this location provoke: (1) paresis of ipsilateral ocular adduction on attempted lateral gaze and ( 2 ) monocular horizontal nystagmus in the contralateral abducting eye. Ocular convergence is unimpaired but bilateral vertical nystagmus can occur. Ascending degeneration resulting from these unilateral lesions is confined to the ipsilateral M L F and distributed only to the ipsilateral nuclei of the extraocular muscles. Degeneration in the ipsilateral abducens nucleus is modest, while that in the trochlear nucleus is profuse. Degenerated fibers projecting to the oculomotor complex are distributed differentially in the ipsilateral ventral nucleus. The absence of degeneration in any of the nuclei of the extraocular muscles contralateral^ indicates that

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monocular horizontal nystagmus seen contralateral to the lesions in these animals was not due to interruption of secondary vestibular fibers passing to the opposite abducens nucleus. Although monocular horizontal nystagmus previously was considered as a manifestation of weakness of the lateral rectus muscle due to interruption of secondary vestibular fibers projecting to it, this hypothesis would not seem to apply here. Current anatomical findings indicate that the monocular horizontal nystagmus seen in the contralateral abducting eye in association with M L F lesions rostral to the abducens nuclei, may be due to concomitant interruption of descending fibers in this bundle. These descending fibers may arise from the interstitial nucleus of Cajal, a cell group known to project to the ipsilateral medial vestibular nucleus (Pompeiano and Walberg, ' 5 7 ) . Our own data demonstrate an asymmetrical projection from the medial vestibular nucleus to both abducens nuclei. This postulated mechanism concerning monocular horizontal nystagmus does not invalidate our previous concept based upon the interruption of secondary vestibular fibers passing to the abducens nucleus. Lesions of the M L F at different levels contribute information concerning the course of ascending fibers. Although unilateral lesions of the M L F adjacent to the abducens nucleus produce bilateral ascending degeneration in the MLF, unilateral lesions in this fasciculus at more rostral sites provoke only ipsilateral ascending degeneration. These observations indicate that crossed ascending fibers in the M L F decussate only in the immediate vicinity of the abducens nucleus. It is of interest that in this and all previous studies of lesions in the M L F in the monkey (Bender and Weinstein, '44, '50; Shanzer, Wagman and Bender, '59; Bender and Shanzer, '64) dissociation of eye movements has occurred only in a horizontal plane. Since lesions of the M L F appear to interrupt primarily ascending secondary vestibular fibers, these findings suggest that the vestibular nuclei participating in the control of conjugate eye movements play their most essential role in relation to horizontal eye movements. The abducens cranial nerve appears unique among the motor cranial nerves in that it is the only cranial nerve in which lesions in the nucleus and peripheral nerve produce distinctly different disturbances. While data presented here demonstrate that well-localized lesions in the abducens nucleus produce enduring paralysis of ipsilateral con-

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jugate horizontal gaze, it is evident that: ( 1 ) complete destruction of the nucleus is not required, and ( 2 ) this syndrome is not dependent upon concomitant destruction of fibers in the ipsilateral MLF. The fact that attempted horizontal eye movements away from the forced field of gaze frequently result in dissociation of eye movements, suggests that disturbances of eye movements are not always of the same degree on each side. This may indicate that multiple neural mechanisms are involved in conjugate horizontal gaze. The two separate elements which appear to constitute the syndrome of lateral gaze paralysis are: ( 1 ) paralysis of the ipsilateral lateral rectus muscle, and ( 2 ) paresis of contralateral ocular adduction on attempted gaze to the lesion side. While the reason for the paralysis of the lateral rectus muscle is obvious, available information does not provide a satisfactory explanation for the paresis of contralateral ocular adduction. Because isolated lesions of the abducens nucleus produce predominantly crossed ascending degeneration in the M L F selectively distributed to the contralateral ventral nucleus of the oculomotor complex, it was originally postulated that the paresis of contralateral ocular adducion resulted from concomitant interruption of secondary vestibular fibers passing near or through the abducens nucleus. This hypothesis is not supported by data derived from the study of ascending vestibular fibers projecting to the nuclei of the extraocular muscles. None of the vestibular nuclei appear to project fibers to the middle and rostral thirds of the contralateral ventral nucleus of the oculomotor complex. These findings suggest that the fibers involved in this part of the syndrome may originate from: ( 1 ) cells of the so-called parabducens nucleus, an entity which has eluded most anatomists, or ( 2 ) portions of the brain stem reticular formation. However, it should be recalled that both Papez ('26) and Nauta and Kuypers ( ' 5 8 ) reported that lesions of the reticular formation produce almost no ascending degeneration in the M L F that projects to the nuclei of the extraocular muscles. Data concerning vestibular projections to the nuclei of the extraocular muscles do not contribute information relative to dissociate eye movements, but they provide an anatomical explanation for the patterned eye movements occurring in response to stimulation of the nerves from individual semicircular canals (Szentagothai, '52; Fluur, '59; Cohen, Suzuki and Bender, '64). Information from this study indicates that secondary vestibular

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fibers projecting to the nuclei of the extraocular muscles ascend exclusively in the M L F . Although lesions in individual vestibular nuclei commonly are associated with variable amounts of degeneration in the reticular formation, a considerable part of this degeneration is due to interruption of efferent cerebellar fibers that traverse the vestibular nuclei. Levels of the brain stem above the abducens nucleus revealed only sparse degeneration in the reticular formation, and none of these fibers could be traced into the trochlear or oculomotor nuclei. Fibers from the superior vestibular nucleus enter the lateral process of the M L F rostral to the facial genu, are all uncrossed, and are distributed differentially to ipsilateral nuclei of the extraocular muscles. Ascending fibers from the inferior, medial and lateral vestibular nuclei are crossed and uncrossed, and enter the M L F in the vicinity of the abducens nuclei. All fibers crossing to the opposite M L F decussate near the abducens nuclei. Fibers arising from the inferior vestibular nucleus originate from the rostral third of the nucleus and appear less numerous than those from other vestibular nuclei. Vestibulo-oculomotor fibers from the lateral vestibular nulceus arise only from ventral portions of the nucleus which receive primary vestibular fibers. The inferior, medial, and lateral vestibular nuclei project fibers bilaterally, asymmetrically, and differentially upon the abducens nuclei and subdivisions of the oculomotor complex. Certain subdivisions of the oculomotor complex receive overlapping projections from more than one vestibular nucleus. Fibers entering the oculomotor complex are confined to the lateral somatic cell columns. N o vestibular fibers appear to project to the caudal central nucleus, a cell group innervating the levator palpebrae muscle. Our observations indicate that secondary vestibular fibers passing to the nuclei of the extraocular muscles from the superior vestibular nucleus differ from those of all other vestibular nuclei. These fibers appear unique in that they: ( 1 ) are entirely uncrossed, ( 2 ) project only sparsely to nuclei of the extraocular muscles receiving fibers from other vestibular nuclei, and ( 3 ) project to cell groups innervating muscles involved primarily in vertical or rotatory eye movements (i.e., the superior and inferior oblique and inferior rectus). Consideration of these findings in conjunction with recent physiological data (Cohen, Suzuki and Bender, '64) suggests that some of the fibers from the superior vestibular nucleus may be concerned with inhibitory activities, since no excitatory influences from stimu-

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lating the nerves from any of the semicircular canals were observed in the ipsilateral inferior oblique or the contralateral superior oblique muscles. Ascending secondary vestibular fibers from the lateral and medial vestibular nuclei appear to be the most widely distributed to the nuclei of the extraocular muscles. These fibers project asymmetrically and differentially in a pattern demonstrating considerable overlap. While it is possible that certain similarities in this projection pattern for the medial vestibular nucleus may, in part, be due to concomitant interruption of efferent fibers from the lateral vestibular nucleus, our findings indicated that most of the efferent fibers from Deiters' nucleus pass along the ventral border of the medial vestibular nucleus, an area not infringed upon by our lesions. Ascending secondary vestibular fibers arising from the medial and lateral vestibular nuclei appear capable of mediating all of the patterned eye movements in different planes obtained by stimulating individual semicircular canals (Szentagothai, '52) or the ampullary nerves from the semicircular canals (Cohen, Suzuki and Bender, ' 6 4 ) . In order not to overinterpret these data, only extraocular muscles whose contractions are regarded as primary will be considered. Since stimulation of the ampullary nerve from one horizontal canal produces conjugate eye movements to the opposite side, secondary vestibular fibers conveying excitatory impulses must reach the contralateral abducens nucleus of the oculomotor complex. The only secondary vestibular fibers distributed in this manner arise from the medial and lateral vestibular nuclei. Since stimulation of the ampullary nerve from the right posterior canal produces primary contractions in the right superior oblique and the left inferior rectus muscles, excitatory impulses must reach the trochlear nucleus and the dorsal nucleus of the oculomotor complex on the opposite side. Only secondary vestibular fibers arising from the medial and lateral vestibular nuclei are distributed to these nuclei contralaterally. Similarly, since stimulation of the ampullary nerve from the right anterior canal produces primary contractions in the right superior rectus and the left inferior oblique muscles, it must be assumed that excitatory impulses reach the medial nucleus and intermediate cell column on the left side. Fibers from the medial nucleus innervate the contralateral superior rectus muscle, while fibers from the inter-

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mediate cell column innervate the ipsilateral inferior oblique muscle. The ventral border of the medial vestibular nucleus, an area not infringed upon by our lesions. Ascending secondary vestibular fibers arising from the medial and lateral vestibular nuclei appear capable of mediating all of the patterned eye movements in different planes obtained by stimulating individual semicircular canals (Szentagothai, '52) or the ampullary nerves from the semicircular canals (Cohen, Suzuki and Bender, '64). In order not to overinterpret these data, only extraocular muscles whose contractions are regarded as primary will be considered. Since stimulation of the ampullary nerve from one horizontal canal produces conjugate eye movements to the opposite side, secondary vestibular fibers conveying excitatory impulses must reach the contralateral abducens nucleus and the ipsilateral ventral nucleus of the oculomotor complex. The largest number of secondary vestibular fibers distributed in this manner arise from the medial and lateral vestibular nuclei. Since stimulation of the ampullary nerve from the right posterior canal produces primary contractions in the right superior oblique and the left inferior rectus muscles, excitatory impulses must reach the trochlear nucleus and the dorsal nucleus of the oculomotor complex on the opposite side. Only secondary vestibular fibers arising from the medial and lateral vestibular nuclei are distributed to these nuclei contralaterally. Similarly, since stimulation of the ampullary nerve from the right anterior canal produces primary contractions in the right superior rectus and the left inferior oblique muscles, it must be assumed that excitatory impulses reach the medial nucleus and intermediate cell column on the left side. Fibers from the medial nucleus innervate the contralateral superior rectus muscle, while fibers from the intermediate cell column innervate the ipsilateral inferior oblique muscle. Secondary vestibular fibers that could mediate responses in these particular extraocular muscles appear to originate only from the medial and lateral vestibular nuclei. Vestibular fibers passing to the contralateral intermediate cell column arise from both the medial and lateral vestibular nuclei, while only the lateral vestibular nucleus projects fibers to the opposite medial vestibular nucleus. It seems likely that ascending fibers arising from rostral parts of the inferior vestibular nucleus also may mediate some of the primary

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responses discussed above, but the relative paucity of demonstrated fibers f r o m this source does not permit definite conclusions. Review of the findings presented indicates that secondary vestibular fibers f r o m the medial and lateral vestibular nuclei to the nuclei of the extraocular muscles and their functional distinct subdivisions are: ( 1 ) most abundant to those nuclei innervating muscles whose primary functions concern horizontal and rotatory movements of the eyes, ( 2 ) moderate to nuclei innervating muscles whose primary function is concerned with downward eye movements, and ( 3 ) relatively modest to nuclei innervating muscles concerned primarily with upward eye movements. Particularly notable is the relatively small projection f r o m the lateral vestibular nucleus to the contralateral medial nucleus, a cell group innervating the opposite superior rectus muscle. N o fibers f r o m the vestibular nuclei appear to project to the caudal central nucleus, a cell group reported to give rise to crossed and uncrossed fibers innervating the levator palpebrae muscle ( W a r wick, ' 5 3 a ) . Evidence presented here indicates ascending secondary fibers projecting to the nuclei of the extraocular muscles and their functional subdivisions: ( 1 ) ascend exclusively in the M L F , ( 2 ) are distributed asymmetrically and differentially, and ( 3 ) are organized to play a m o r e important role in conjugate horizontal eye movements than in eye movements in other planes. REFERENCES

Bender, M. B., and S. Shanzer, 1964: Oculomotor pathways defined by electric stimulation and lesions in the brain stem of monkey. In Symposium: The Oculomotor System. Ed., Μ. Β. Bender, Harper and Row, New York, Chap. IV, 81-140. Bender, M. B., and E. A. Weinstein, 1944: Effects of stimulation and lesion of the median longitudinal fasciculus in the monkey. Arch. Neurol, Psychiat., 52: 106-113. 1950: The syndrome of the median longitudinal fasciculus. Res. Pubi. Assoc. Nerv. Ment. Dis., 28: 414-420. Brodai, Α., and O. Pompeiano, 1957: The origin of ascending fibers of the medial longitudinal fasciculus from the vestibular nuclei. An experimental study in the cat. Acta Morph. Neerl.-Scand., 1: 306-328. Carpenter, M. B., 1960: Fiber projections from the descending and lateral vestibular nuclei in the cat. Am. J. Anat., 104: 1-34.

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Carpenter, M. B., and R. E. McMasters, 1963: Disturbances of conjugate horizontal eye movements in the monkey. II. Physiological effects and anatomical degeneration resulting from lesions in the medial longitudinal fasciculus. Arch. Neurol., 8: 347-368. Carpenter, M. B., R. E. McMasters and G. R. Hanna, 1963: Disturbances of conjugate horizontal eye movements in the monkey. I. Physiological effects and anatomical degeneration resulting from lesions of the abducens nucleus and nerve. Arch. Neurol., 8: 231-247. Carpenter, M. B., and N. L. Strominger, 1964a: Cerebello-oculomotor fibers in the rhesus monkey. J. Comp. Neurol., in press. 1964b: The medial longitudinal fasciculus and disturbances of conjugate horizontal eye movements in the monkey. J. Comp. Neurol., in press. Carpenter, M. B., and J. R. Whittier, 1952: Study of methods for producing experimental lesions of the central nervous system with special reference to stereotaxic techniques. J. Comp. Neurol., 97: 73-132. Case Records of the Massachusetts General Hospital, 1953: Case 39451. New Engl. J. Med., 249: 776-780. Cogan, D. G., C. S. Kubik and W. L. Smith, 1950: Unilateral internuclear ophthalmoplegia: Report of 8 clinical cases with 1 postmortem study. Arch. Ophthal., 44: 783-796. Cohen, B., J. Suzuki and M. B. Bender, 1964: Eye movements from semicircular canal stimulation in the cat. Ann. Oto., Rhinol., and Laryngol., 73: 153-169. Crosby, E. C., 1950: The application of neurosurgical data to the diagnosis of selected neurosurgical and neurological cases. J. Neurosurg., 7: 566583. 1953: Relations of brain centers to normal and abnormal eye movements in a horizontal plane. J. Comp. Neurol., 99: 437-480. Fluur, E., 1959: Influences of semicircular ducts on extraocular muscles. Acta Oto-Laryng. Suppl., 149: 1-46. van Gehuchten, Α., 1898: Recherches sur l'origine réelle des nerfs crâniens. I. Les nerfs moteur oculaires. J. Belg. Neurol., 3: 114-129. van Gehuchten, Α., 1904: Les connexions centrales du noyau de Deiters et les masses grises voisines (Faisceau vestibulospinal, faisceau longitudinal postérieur, stries medullaries). Névraxe, 6: 19-73. Holmes, G., 1921: Palsies of the conjugate ocular movements. Brit. J. Ophthal., 5: 241-250. Klossowsky, B. E., and A. M. Levikowa, 1931: Der Mechanismus des vestibulären Nystagmus. (Über die homonyme keineswegs cruciate Innervation der Musculi recti interni von dem Oculomotoriuskern beim Nystagmus.) Arch. ges. Physiol., 228: 198-212.

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ASCENDING

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SYSTEM

97

Lorente, de Nó, R., 1926: Etudes sue l'anatomie et la physiologie du labyrinthe de l'oreille et du V H P nerf. Deuxième partie. Quelques données au sujet de l'anatomie des organes sensoriels du labyrinthe. Trav. Lab. Rech. Biol. Univ. Madrid, 24: 53-153. 1931: Ausgewählte Kapitel aus der vergleichenden Physiologie des Labyrinthes. Die Augenmuskelreflexe beim Kaninchen und ihre Grundlagen. Ergebn. Physiol., 32: 73-242. 1933: Anatomy of the eighth nerve. The central projection of the nerve endings of the internal ear. Laryngoscope, 43: 1-38, 1933. McMasters, R. E., A. H. Weiss and M. B. Carpenter, 1964: Vestibular projections to the nuclei of the extraocular muscles. Degeneration resulting from discrete partial lesions of the vestibular nuclei in the monkey. A m . J. Anat., in press. Nauta, W. J. H., and P. A. Gygax, 1954: Silver impregnation of degenerated axons in the central nervous system. A modified technique. Stain Tech., 29: 91-93. Nauta, W. J. H., and H. G. J. M. Kuypers, 1958: Some ascending pathways in the brain stem reticular formation. In Symposium: Reticular F o r m a tion of the Brain. Ed., H. H. Jasper et al. Little, Brown and C o m p a n y , Boston, Chap. I, 3-30. Papez, J. W., 1926: Reticulo-spinal tracts in the cat. Marchi method. J. Comp. Neurol., 41: 365-399. Peele, T. L., 1961: The Neuroanatomical Basis for Clinical Neurology. E d . 2. McGraw-Hill Book Company, New York, Chap. IX, p. 205, 1961. Pompeiano, O., and F. Walberg, 1957: Descending connections to the vestibular nuclei: An experimental study in the cat. J. Comp. Neurol., 108: 465-503. Sahlgren, E., and E. Hofman-Bang, 1950: A case of internuclear ophthalmoplegia (Bielschowsky) with autopsy. Acta Psychiat. Neurol. Scand., 25: 429-431. Shanzer, S., I. H. Wagman and M. B. Bender, 1959: Further observations on the median longitudinal fasciculus. Trans. Amer. Neurol. Assoc., pp. 14-17, 1959. Smith, J. L., and D. G. Cogan, 1959: Internuclear ophthalmoplegia: A review of fifty-eight cases. A . M . A . Arch. Ophthal. 61: 687-694. Spiller, W. G., 1924: Ophthalmoplegia internuclearis anterior: A case with autopsy. Brain, 47: 345-357. Strong, O. S., and A. Elwyn, 1943: Human Neuroanatomy. The Williams and Wilkins Company, Baltimore, Chap. X I V , p. 212. Szentágothai, J., 1943: Die zentrale Innervation der Augenbewegungen. Arch. f. Psychiat. u. Nervenkr., 116: 721-760.

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Szentágonthai, J., 1950: The elementary vestibulo-ocular reflex arc. J. Neurophysiol., 13: 395-407. 1952: Die Rolle der einzelnen Labyrinthrezeptoren bei der Orientation von Augen und Kopf im Räume. Akademiai Kiado, Budapest, 129 pp. Warwick, R., 1953a: Representation of the extraocular muscles in the oculomotor nuclei of the monkey. J. Comp. Neurol., 98: 499-504. 1953b: Observations upon certain reputed accessory nuclei of the oculomotor complex. J. Anat., 87: 46-52.

The Vestibular Efferent Pathway Richard R. Gacek, M . D . *

INTRODUCTION

The notion that all sensory receptors have a dual innervation has been generally accepted only recently. This concept holds that in the classical afferent pathways the transmission of the neural response initiated at the receptor organ does not proceed unmodified up to cortical levels but is subject to the influence of a centrifugal or efferent system not only in the sensory endorgan but at all concerned nuclear way stations in the central nervous system. This influence has been shown to be generally inhibitory in nature. Teleologically, one may look upon these neural "feedbacks" as creating a neural economy wherein the cerebral cortex is relieved of analyzing unimportant of unwanted sensory signals so that it may more efficiently deal with significant ones, although both types of stimuli may activate the peripheral sensory receptor. Such an efferent nerve supply has been particularly well documented in the special sense organs. Of these, the auditory system has by far been the most explored morphologically and physiologically. T h e entire neuron chain of the efferent auditory system f r o m cortex to O r g a n of Corti has been clearly demonstrated anatomically. T h e efferent olivocochlear bundle ( R a s m u s s e n ) 1 9 ' 2 0 represent the final link of this chain and has been the subject of extensive neurophysiological investigation. It was logical to assume that the vestibular labyrinth should also receive an efferent nerve supply. However, such a pathway was not * Assistant in Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

99

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9 21

clearly demonstrated until recently. · It will be the purpose of this discussion to review all that is known anatomically about the efferent vestibular component and briefly discuss the small amount of electrophysiological data available thus far. Only the most peripheral efferent neuron to the neuroepithelium of the vestibular endorgans has been demonstrated so far. The higher neurons in the efferent chain from cortex have not yet been reported. Therefore, all discussions of the efferent vestibular pathway concerns this neuron.

REVIEW

OF

LITERATURE

In 1955 at the Meeting of the American Association of Anatomists in Philadelphia, Petroff reported in abstract form his evidence for an efferent vestibular system of nerve fibers.18 After section of the whole VHIth nerve in cats he found an absence of the very fine caliber nerve fibers within the neuroepithelium and below the basement membrane of the neuroepithelium of all the vestibular endorgans in his protargol impregnated sections of the cat temporal bone. He also reported identical findings bilaterally after midline section in the floor of the fourth ventricle where the olivocochlear bundle decussates. Acceptance of these findings as conclusive evidence of efferent fibers was generally withheld because of ( 1 ) the well known difficulty of reliably demonstrating small caliber nerve fibers by protargol impregnation techniques after lengthy decalcification: and ( 2 ) the evidence presented was indirect rather than direct evidence of an efferent system. The existence of such a system was not generally accepted until 1958 when Rasmussen and Gacek made a preliminary report showing Wallerian degeneration in all branches of the vestibular nerve after certain isolated lesions in the cat's medulla oblongata. A full report of the course, distribution and size of this efferent vestibular supply was presented at the symposium on the Neural Mechanisms of the Auditory and Vestibular Systems held at Bethesda, Maryland in May 1959. 3 · 9 Dohlman's 5 demonstration in 1958 of acetycholinesterase activity in the vestibular neuroepithelium of the pigeon added strength to the concept of an efferent vestibular neuron especially since Schuknecht 24 had just shown the acetylcholinesterase activity in the organ of Corti to be related to the efferent cochlear bundle.

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Later (1961) Ireland and Farkashidy by demonstrating that A C h E activity in the vestibular sensory epithelium disappeared after section of the VHIth nerve, showed that this activity was related to the efferent vestibular system. 13 Rossi and Cortesina have reported similar findings in the vestibular sense organs. 22

T H E COURSE OF

THE

VESTIBULAR

EFFERENT

PATHWAY

The course and distribution of efferent fibers to the vestibular labyrinth as revealed by experimental neuroanatomical techniques is illustrated diagrammatically in Figure 1. These efferente, together with some pars intermedia preganglionic efferents, travel intermixed with the olivocochlear bundle in the vestibular root and the vestibular nerve in the internal auditory canal. This parent efferent bundle in the vestibular nerve separates the afferent axons of the inferior division from those of the superior division. As the efferents reach the saccular portion of the vestibular (Scarpa) ganglion the cochlear efferents leave via the vestibulo-cochlear anastomosis (Oort) to enter the cochlea. Many of the efferent vestibular fibers turn sharply into the superior division of the vestibular nerve. Here they course in that portion of the nerve which is toward the labyrinth. Most of these travel in two or three fascicles which break up into scattered fibers near the beginning of the branch to the utricle. The remainder of the efferent fibers to the superior division diverge from the parent bundle as scattered fibers and course to the endorgans along with the scattered fibers from the fascicular fibers. The scattered efferents then supply all of the branches of the superior vestibular division including Voit's bundle to the saccular macula. The efferent axons to the main saccular nerve and the posterior ampullar nerve separate from the parent efferent bundle as diffusely scattered fibers and travel to their end-organs. With light microscopy these fibers can be followed up to the basement membrane of the neuroepithelium but no further. The myelin sheaths of nerve fibers end at the basement membrane thus limiting the use of myelin stains such as Sudan Black for studying the termination of these fibers. The difficulty in consistently demonstrating these terminal portions by the usual silver techniques also presents an obstacle to study of the terminal portions of the efferent fibers.

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Fig. 1. D i a g r a m illustrates the course and distribution of the efferent fibers to the vestibular sense organs. S.A. = superior canal a m p u l l a ; H.A. = h o r i z o n t a l canal a m p u l l a ; P.A. = posterior canal ampulla; P.I. = pars intermedia nerve.

The

original

demonstration

of the

vestibular

efferent

fibers

in

1 9 5 8 and 1 9 5 9 utilized Sudan black Β and protargol silver techniques on decalcified specimens of the petrous bones of cats and chinchillas. T h e estimated number of efferent vestibular fibers in the c a t was about

200.

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103

Since then I have been successful in studying this fiber system with two ( 2 ) other techniques and have found that the number of vestibular efferents is close to 400 numerically. The first of these is the Nauta silver technique 16,17 applied to the vestibular nerve and its branches. Although this selective silver technique for degenerating axons is primarily designed for use on central nervous system material, it can be used advantageously on peripheral nerve. In order to use this method on the vestibular nerve and branches it was necessary to very carefully dissect the undecalcified petrous bone away from the enclosed nerve branches. These nerves were then embedded in 5 per cent gelatin, allowed to harden, and frozen sections were cut at the desired plane. The gelatin was then dissolved away by immersing these sections in warm distilled water. The tiny sections of nerves could then be treated by the usual Nauta method, mounted on slides, and covered. Although more artifact was constantly present in these sections than in the usual Nauta section of central nervous system tissue, it was very easy to follow degenerated axons throughout the entire course of the nerve. Figure 2 shows a typical lesion transecting the vestibular root in the medulla. This type of lesion will transect all the vestibular efferent fibers as well as the olivocochlear bundle. This animal was sacrificed 6 days after the transection was performed. Both the ipsilateral and contralateral vestibular nerves and their branches were handled in the manner described above. Figure 3 shows the degenerated parent efferent bundel in the ipsilateral vestibular nerve trunk as it gives off fascicles of degenerated vestibular efferents into the superior vestibular division. Note how the fascicles break up into scattered degenerated fibers more peripherally in the superior vestibular nerve (Figures 4 & 5 ) . Scattered degenerated fibers in the ampullar and utricular nerves are shown in Figures 6 & 7. With this method it was much easier to follow degenerated fibers impregnated with silver than in the usual protargol treated specimen. It was apparent from these sections that there were more degenerated fibers than were demonstrated with Sudan black after similar lesions. The second method used to selectively demonstrate the vestibular efferent fiber pathway is a modification of the histochemical technique which localizes acetylcholinesterase ( A C h E ) activity. The method of Gomori, using acetylthiocholine iodide, was used on frozen sections of the petrous bone which had been previously decalcified with

Fig. 2. Cross-section of cat's medulla with transection of the vestibular root near the vestibular nuclei. Lesion also interrupted the olivocochlear bundle. N a u t a stain. Survival time — 6 days. L = lesion; CN = cochlear nucleus; V = descending trigeminal root; VIII = facial genu; SO = superior olive; VEST = vestibular root.

Fig. 3. Horizontal section of ipsilateral peripheral vestibular nerve from cat with lesion shown in figure 2. Heavy arrow indicates the parent efferent bundle coursing between inferior and superior divisions. Smaller arrow points to fascicles of degenerated efferente leaving parent bundle to course in the superior vestibular division. Much of the parent bundle continues on as efferent cochlear bundle ( O C ) . Nauta technique . Lab = membranous labyrinth; SVN = superior division of vestibular nerve; I V N = inferior division of vestibular nerve.

Fig. 4. Higher power photomicrograph of degenerated efferente to the superior vestibular division. Note how the bundles (lower right) gradually break u p into scattered fibers as they travel peripherally (upper l e f t ) . Nauta. SVN = superior division of vestibular nerve. Lab. = membranous labyrinth.

Fig. 5. Photomicrograph of degenerated efferents (arrows) in superior division just before it divides into ampullar and utricular nerves. Note how the scattered efferents, traveling at first in that portion of division next to membranous labyrinth ( Lab. ), gradually disperse to all portions of nerve so they may innervate all endorgans. Nauta.

Fig. 7. Several degenerated efferent fibers coursing in nerve to horizontal canal ampulla ( H A N ) and one degenerated fiber in utricular branch (Ut. Ν . ) . Nauta technique.

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a chelating agent ( E D T A = disodium salt of ethylenediamine tetraacetic acid). This modification was developed in our histochemical laboratory by Dr. K. Balogh and Dr. Y. Nomura. 1 0 The technical aspects of this method are given elsewhere. 1 The efferent pathway was first demonstrated in the normal cat petrous bone since the A C h E actively is so much greater in the efferent fibers than in the afferent ones. After the animal was sacrificed by an overdose of Nembutal, the petrous bones with the Vllth and VHIth nerves were removed and immediately placed in cold E D T A . It was necessary to keep the cat petrous bone in E D T A for about 39 or 40 days before decalcification was complete. Frozen sections were then cut at 20 miera in a cryostat and the sections mounted. These were then incubated according to the Gomori method. Figure 8 shows the parent efferent bundle in the vestibular nerve trunk. Note also the high activity in the pars intermedia nerve. The typical course and distribution of the efferent vestibular pathway was duplicated by the activity in the nerve bundles (Figure 9) and scattered fibers (Figure 10). Again it was apparent that the number of fibers was greater than originally estimated. It was also noted that the number of fibers became more numerous in each vestibular branch as the endorgan was approached. This was apparent rather than real because the efferents branch as they course in the peripheral vestibular rami. Proof that this A C h E actively is localized in the efferent vestibular fibers was obtained by unilateral sectioning of the vestibular root in several cats as described earlier. Survival times of 1 week, 3 weeks, and 5 weeks were allowed for these animals. Loss of A C h E activity was noted in all branches of the vestibular nerve to the ipsilateral ear while the contralateral ear showed normal activity in the efferent vestibular system. A typical cat medulla with such a lesion is shown in Figure 11. Examination of the ipsilateral inner ear revealed complete loss of A C h E activity in all vestibular nerve branches while the contralateral ear revealed normal activity (Figures 12 & 13).

THE

TERMINATION

OF

VESTIBULAR

EFFERENTS

Light microscopy has been unsuccessful in demonstrating

the

ì

xm

Fig. 8. Frozen section t h r o u g h normal cat petrous bone demonstrating localization of acetycholinesterate activity in efferent nerves. Note parent efferent bundle in vestibular nerve t r u n k giving off scattred efferent fibers into posterior ampullar nerve ( P A N ) . There is a high AChE activity in pars intermedia nerves also. C N = cochlear nerve; Eff = parent efferent bundle; P A N = posterior ampullar nerve and ganglion; PI = pars intermedia nerve; OC = spiral portion of olivocochlear bundle; Vest. n. = vestibular nerve. VII = facial nerve.

Fig. 9. Frozen section more distally through normal cat ear showing AChE activity in both cochlear and vestibular efferent fibers. Note fascicles and scattered efferente ( a r r o w ) in portion of superior vestibular division toward labyrinth. V C = vestibulocochlear anastomosis carrying efferent cochlear fibers. Sac. n. = saccular nerve with scattered vestibular efferent fibers. CN = cochlear nerve; SG = spiral ganglion; SVN = superior division of vestibular nerve; VG = vestibular ganglion; VII = facial nerve.

Fig. 10. Section through normal posterior ampullar nerve displaying AChE activity in efferent fibers cut in cross section.

Fig. 11. Cross-section of cat medulla with transection (L to L) of vestibular root. Histochemical method shows AChE activity in brainstem. Note absence of activity in vestibular root. Survival time 40 days. CN = cochlear nucleus; ASO = accessory superior olive; SO = superior olive; V = descending trigeminal root; VII = facial genu; Vest. = vestibular root.

Fig. 12. Sections through posterior ampullar nerve of contralateral and ipsilateral ears of cat shown in figure 11.

A. Contralateral ear. Arrows indicate enzyme activity in normal efferent fibers of nerve. B. Ipsilateral ear. Note complete absence of AChE activity in nerve fibers. V G = vestibular ganglion ( S c a r p a ) .

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precise termination of not only the efferent vestibular system but also the efferent olivocochlear bundle. The introduction of the electron microscope into otological research by Engstrom and Wersall provided the breakthrough leading to the solution of the problem of precise termination of the efferent and afferent nerve supply to the sensory epithelium of the inner ear. Engstrom 6 , 7 and Wersall 27, 28 are primarily responsible for the original description of two types of nerve endings around the hair cells of the organ of Corti and the vestibular neuroepithelium. Since the details of the ultrastructure have been covered by Dr. Spoendlin, I shall only say that the main difference between the endings morphologically is that one type contains many small vesiculated structures while the other has relatively few vesicles. In the vestibular neuroepithelium the vesiculated endings are smaller than the non-vesiculated ones. Engstrom and Wersall have classified the hair cells and the arrangement of their nerve endings into two general categories. Type I hair cell is a flask-shaped cell with a large calyx-like non-vesiculated ending making contact with the hair cell and small vesiculated endings making contact with the non-vesiculated structure or nerve fibers. These occur more at the crest of the crista ampullaris. The type II hair cell is cylindrical and has both vesiculated and non-vesiculated endings making contact with the hair cell. These occur more at the slopes of the crista ampullaris. Because of the vesicles and other ultrastructural features the vesiculated endings are said to resemble pre-synaptic nerve terminals and the non-vesiculated endings to resemble post-synaptic terminals. By inference, then, the vesiculated endings should represent the endings of the efferent nerve fibers and the non-vesiculated endings should belong to the afferent bipolar vestibular neurons. The presumption that the vesiculated endings represent the efferent terminals was supported further by Hilding and Wersall's 12 localization of acetycholinesterase activity in the areas of the crista ampullaris where the vesiculated endings are more numerous and within the vesiculated endings themselves in the basal part of the sensory epithelium. The direct experimental evidence that these endings in the vestibular endorgans are efferent has not yet been produced. However, several investigators (Spoendlin and Gacek, 26 Iurato, 14 Kimura and Wersall, 15 Smith and Rasmussen 25 ) have demonstrated conclusively in the organ

Fig. 13. Cross-sections t h r o u g h superior vestibular division near utricular branch. Same animal as figure 11.

A. Contralateral ear. Scattered vestibular efferent fibers are located by AChE activity. B. Ipsilateral ear. Complete absence of AChE activity after efferente have degenerated.

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of Corti that the vesiculated endings are efferent, and the non-vesiculated endings are afferent. There seems little doubt therefore that the same is true in the vestibular sense organs. ORIGIN OF VESTIBULAR

EFFERENTS

The precise location of the cell bodies of these efferent vestibular fibers has not been determined. However, by examining the degeneration produced by various isolated surgical lesions in the medulla of the cat, some idea of the source of this system has been obtained. Midline transection of the olivocochlear bundles in the floor of the fourth ventricle has failed to produce degenerating axons in any of the vestibular branches. This indicates that the efferent vestibular complex is uncrossed, contrary to the findings of Petroff. Repeated electrolytic lesions of the cerebellar nuclei, the superior and medial vestibular nuclei have likewise been unproductive of Wallerian degeneration in the vestibular nerve complex. Small lesions in the lateral vestibular nucleus have produced a small number of degenerating fibers in the vestibular nerve branches, indicating that at least some of these efferente are located here. Most of these successful lesions in the lateral vestibular nucleus involved the caudal and ventral parts of the nucleus. The descending vestibular nucleus has not been definitely ruled out as a source of some efferent fibers. The greatest number of degenerating fibers to the vestibular endorgans was obtained after transection of the vestibular root in the medulla as illustrated in Figure 14. It is possible that, besides the lateral and descending vestibular nuclei, the area of brain stem medial to the vestibular root and lateral to the midline, may contain some of the cell bodies of the vestibular efferent system. The reticular formation is included in this area. Numerous attempts have been made to precisely locate the vestibular efferent neurons by the retrograde cell reaction method. The modified Gudden method as described by Brodai 2 was used after unilateral labyrinthectomy in kittens 1 to 2 weeks of age. Many additional experiments have been performed since the initial attempts. 9 Although typical retrograde cell changes have been produced in other related neurons (e.g., pars intermedia) the changes in the vestibular nuclei were not clear cut. It is very difficult to interpret retrograde

114

THE VESTIBULAR SYSTEM AND ITS DISEASES

Ν GOCH.V

Fig. 14. Drawing of cross-section through cat medulla oblongata summarizing lesions in vestibular area. T h e straight line indicates transection of vestibular root. Cross hatched area represents lateral vestibular nucleus. Arrows point to other lesions mentioned in text.

changes in medium or small sized neurons as unequivocal. Therefore, no definite statement can be made about these neurons. Further attempts to settle this problem by a different method are in progress at present. Because cells undergoing the retrograde reaction take up methionine at much higher rates than normal cells, labyrinthectomized cats will be injected with S35 methionine, sacrificed, and autoradiographs made of sections through the vestibular area of the medulla. It is hoped that the injured neurons in the vestibular nuclei will be identified by their increased radioactivity on the film. Electrophysiology has shown that the efferent fibers in most of the sensory receptors are inhibitory in nature. Again the best example of this is in the efferent olivocochlear bundel (Galambos, 11 Fex, 8 Desmedt 4 ). Schmidt 23 has demonstrated what appears to be efferent spikes in the various nerve branches to the frog vestibular labyrinth.

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However, there have not yet been reported any convincing studies relevant to the function of the vestibular efferent system. T h e most attractive speculation of the role of an efferent (inhibitory) influence in the vestibular sense organ would seem to implicate it in the adaptation or habituation property of this system.

REFERENCES

1. Balogh, K. Jr., and Nomura, Y.: A technique for the demonstration of acetylcholinesterase activity in the inner ear after decalcification with EDTA. J. Histochem. & Cytochem. (In press.) 2. Brodai, Α.: Modification of Gudden method for study of cerebral localization. Arch, of Neurol. & Psychiat. 43-46, 1940. 3. Carpenter, M. B.: Experimental anatomical-physiological studies of the vestibular nerve and cerebellar connections. In Neural Mechanisms of the Auditory and Vestibular Systems. Ed. G. L. Rasmussen and W. F. Windle. Charles C. Thomas, Publisher, Springfield, Illinois, 1960. 4. Desmedt, J. E., and Monaco, P.: Mode of action of the efferent olivocochlear bundle on the inner ear. Nature 192: 1263, 1961. 5. Dohlman, G. F., Farkashidy, J. and Salonna, F.: Centrifugal nervefibers to the sensory epithelium of the vestibular labyrinth. J. Laryngology 72: 984, 1958. 6. Engström, H.: On the double innervation of the inner ear. Acta Otolaryngologica 49: 109, 1958. 7. : The innervation of the vestibular sensory cells. Acta Otolaryng. 163: 30-41, 1961. 8. Fex, J.: Auditory activity in centrifugal and centripetal; cochlear fibers in the cat. Acta. Psych. Scand. 55 Suppl. 189, 1962. 9. Gacek, R. R.: Efferent component of the vestibular nerve. In Neural Mechanisms of the Auditory and Vestibular Systems. Ed. G. L. Rasmussen and W. F. Windle, Charles C. Thomas, Publisher, Springfield, Illinois, 1960. 10. : Nomura, Y., and Balogh, K. Acetycholinesterase activity in the efferent fibers of the stato-acoustic nerve. Acta Otolaryng. (In press). 11. Galambos, R.: Suppression of the auditory nerve activity by stimulation of efferent fibers to the cochlea. J. Neurophysiology 19: 424, 1956. 12. Hilding, D. and Wersäll, J.: Cholinesterase and its relation to the nerve endings in the inner ear. Acta Otolaryng. 55: 205-217, 1962. 13. Ireland, P. E. and Farkashidy, J.: Studies on the efferent innervation of the vestibular endorgans. Trans. Amer. Otol. Soc. 49: 20-30, 1961.

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14. Iurato, S.: Efferent fibers to the sensory cells of Corti's organ. Exp. Cell Res. 27: 162, 1962. 15. Kimura, R. and Wersäll, J.: Termination of the olivo-cochlear bundle in relation to the outer hair cells of the organ of Corti in the guinea pig. Acta Otolaryng. 55: 11. 1962. 16. Nauta, W. J. H. and Gygax, P. Α.: Silver impregnation of degenerated axons in the central nervous system, a modified technique. Stain Tech. 29: 91, 1954. 17. : Silver impregnation of degenerating axons. In New Research Techniques of Neuroanatomy, W. F. Windle (Ed.) Charles C. Thomas, Publisher, Springfield, Illinois, 1957, pp. 17-26. 18. Petroff, A. E.: An experimental investigation of the origin of efferent fiber projections to the vestibular neuroepithelium (Abstract) Anat. Ree. 121: 352, 1955. 19. Rasmussen, G. L. : The olivary peduncle and other fiber projections of the superior olivary complex. J. Comp. Neurol. 84: 141, 1946. 20. : Further observations of the efferent cochlear bundle. J. Comp. Neurol. 99: 61, 1953. 21. , and Gacek, R. R.: Concerning the question of an efferent fiber component of the vestibular nerve of the cat (Abstract) Anat. Ree. 130: 361, 1958. 22. Rossi, G. and Cortisina, G.: Il "sistema efferente colinergicovestibolare." Sintesi storico-bibliografica e ricerche personali. Minerva Otorinolaring. 12: 1-63, 1962. 23. Schmidt, R. S.: Frog labyrinthine efferent impulses. Acta Otolaryng. 56: 51-64, 1963. 24. Schuknecht, H. F., Churchill, I. Α., and Doran, R. Α.: The localization of acetylcholinesterase in the cochlea. Arch. Otolaryng. 69: 549, 1959. 25. Smith, C. A. and Rasmussen, G. L.: Recent observations on the olivocochlear bundle. Ann. Otol. Rhin. Laryng. 72: 489, 1963. 26. Spoendlin, H. and Gacek, R.: Electron microscopic study of the efferent and afferent innervation of the organ of Corti in the cat. Ann. Otol. Rhin. & Laryng. 72: 660, 1963. 27. Wersäll, J.: Studies on the structure and innervation of the sensory epithelium of the cristae ampullares in the guinea pig. Acta Otolaryng. Suppl. 126, 1956. 28. Wersäll, J.: Electron micrographie studies of vestibular hair cell innervation. In Neural Mechanisms of the Auditory and Vestibular Systems, (Ed.) G. L. Rasmussen and W. F. Windle, Charles C. Thomas, Publisher, Springfield, Illinois, 1960.

Further Observations on the Mechanism of Vestibular Suppression* Brian F. McCabe, M.D.**

The object of a series of experiments to be cited here is the acquisition of information which might lead to at least a partial explanation of the mechanism of vestibular suppression. Vestibular suppression is the same as habituation, 1 but we prefer the physiologic rather than the psychologic term. It is the consequence of repeated cupula deflection, and is measured in diminution of most of the parameters of nystagmus, particularly duration. 2 It is developed to a profound degree in figure skaters, and a study of these subjects points to a central rather than an endorgan mechanism. 3 More positive evidence as to its central nature has since been adduced, 4 but the procession of neurologic events leading to its production has not been established. In attempt to shed some light on the mechanism, the following study was carried out. It is an extension of a prior report 5 with additional experimental evidence.

EXPERIMENTAL

METHOD

Vestibular suppression in cats was produced by high speed axial rotation. High speed rotation was chosen because it provides a wider From the Department of Otorhinolaryngology and the Kresge Hearing Research Institute, University of Michigan. * This study was supported in part by the National Institute of Neurological Diseases and Blindness, National Institutes of Health, and the Aerospace Medical Division, Air Force Systems Command, U. S. Air Force. ** Present address of the author is University Hospitals and Clinics, Iowa City, Iowa.

117

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THE VESTIBULAR SYSTEM AND ITS DISEASES

range of energy transfer to the cupula enabling us to reach maximal and supra-maximal levels of stimulation. It also provides a longer duration of retention of suppression than does the caloric method. An animal axial rotating device was constructed to deliver a controlled acceleration, angular velocity, and deceleration, to impose the suppression. The apparatus is described in detail in a prior publication. 6 Data were collected by conventional corneoretinal potential nystagmography, and early in the experiment, by direct observation of the eyes of the cat through a closed circuit television system with the camera mounted on the rotating module. Animals were spun until a plateau of response decline was reached, which amounted to usually a 6 0 % reduction of postrotatory nystagmus time and slow component speed. The details of stimulation are available to the reader in the last report. 6 Suitable controls demonstrated an animal would lose no more than 6 % of its suppression in three months as a function merely of time. A series of 25 suppressed cats were then subjected to bilateral electrocoagulation of the vestibular nuclei, individually and in combination, under general anesthesia. Each of the 4 major nuclei were hit singly, and in some animals the superior and lateral nuclei were hit together. Small lesions, 1-2 mm in size, were produced, using 0.5 mm stainless steel electrodes epoxy coated in all but the tip, introduced through a small parieto-occipital trephine. The nuclei were very difficult to hit precisely and almost impossible to destroy completely without damaging an adjacent nucleus to some degree. A lesion was considered a hit when the majority of that nucleus was destroyed. (Fig. 1.) Each animal was tested just preoperatively and then postoperatively for any change in nystagmus parameters. The postrotatory nystagmus time was finally used for data comparison rather than slow component speed, for the two were always equatable. For example, in the course of suppression using high speed rotation, slow component speed declines at the same rate as postrotatory nystagmus time. Cats with lesions of the cerebellum including the nuclei fastigii and lesions in areas adjacent to the vestibular nuclei such as the descending tract of V, were used as control animals. These were animals in which the target area was missed. They are suitable as controls because of their operation and passage of an electrocoagulating needle into the brain, and absence of any other variation in

MECHANISM

OF VESTIBULAR

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119

Fig. 1. Brain stem, level of seventh nerve rootlet. T h e bilateral lesions on either side of the ventricle involve most of the superior vestibular nuclei and the upper poles of the lateral vestibular nuclei. Cat. H III ( M a r c h i ) .

method from experiments on animals to which they were compared. These control animals, numbering 15, had no change in their suppressed state postoperatively, whereas all experimental animals demonstrated a marked change. All brain lesions were localized histologically by examination of serial sections. Marchi staining was used, with a gallocyanin counterstain in most animals for identification of brain stem nuclei. The vestibular nerves of 10 animals were studied for Wallerian degeneration in effort to determine the presence or absence of efferent nerve damage. A technique similar to that described by Gacek 7 was used. Animals were sacrificed on the seventh or eight day after lesioning,

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the nerves were dissected to the endorgan after perfusion, and decalcification of the temporal bone. Longitudinally cut sections of the vestibular nerve and its branches were mounted serially and stained with Sudan black. T H E QUESTION

OF

ENDORGAN

DAMAGE

Although it is fairly well accepted now that the response decline from repeated cupula deflection, whether caloric or rotationally induced, is due to a central rather than a peripheral cause, 8 objection may be lodged here concerning the very high rotational rates used. It has been stated that rotational rates exceeding 180°/sec 2 damage the human ampullary mechanism. 9 Rotational rates used for acquisition of suppression here are 720°/sec 2 or greater. It did not seem likely to us that these rotational rates would produce endorgan damage since figure skaters can subject themselves to 2520°/sec 2 without any clinically detectable loss of labyrinthine economy. Their labyrinths are suppressed, but they have no balance difficulty such as streptomycin-toxic patients elicit. However, three studies were done to determine if any of our response decline might be due to endorgan damage. A cat was subjected to 600 spins, each time decelerating at 6 rps 2 (2160°/sec 2 ), and after perfusion the temporal bones were serially sectioned, mounted, and stained with Η & E. Examination by light microscopy failed to show any difference in the ampullary neuroepithelium or cupula from control animals. It is possible however, that submicroscopic damage could be done affecting function. Functional effects were determined in two ways. In the first, a series of four cats were subjected to increasing deceleration stimuli in series fashion (1 rps 2 , 2 rps 2 , 3 rps 2 , 4 rps 2 , 5 rps 2 , and 6 rps 2 ) and their postrotatory nystagmus time and slow component speed plotted against the stimulus. Until maximal levels of stimulus were reached (5 rps 2 ) at which point a sharp bend-over occured, the postrotatory nystagmus time was linear. (Fig. 2.) The slow component speed plotted against the stimulus was also linear. An ascending series followed by a descending series resulted in nystagmus values closely similar at the same rates. In the second, a nerve block was produced by deep general anesthesia in three cats. No response decline was seen in two, and the third showed a 5 . 7 % response decline after an amount of stimulation which produced a 3 4 % response decline in control

MECHANISM OF VESTIBULAR SUPRESSION

121

animals. Unanesthetized, the animals went on to develop suppression at a normal rate. The absence of significant response decline during

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THE VESTIBULAR SYSTEM AND ITS DISEASES

nerve block is taken to indicate absence of endorgan damage occurring during the nerve block. Temporary damage which healed during the post-anesthetic recovery period might have occured, but this could hardly explain the response decline in unanesthetized animals. Response decline is retained for long periods in the latter case, and if any occured in anesthetized animals, it was gone by the time they woke up. RESULTS

In the 25 experimental animals, the superior vestibular nucleus was hit successfully 7 times, the lateral nucleus 7 times, and the two together 3 times. The descending nucleus was hit 5 times, and the medial 3 times. The result of vestibular nuclear damage was release of suppression — that is, immediate reversal of the response decline and restoration of the postrotatory nystagmus time to near-normal levels. Mapping the individual lesions (Fig. 3.) by analyzing the serial brain stem sections and correlating the location of the lesions and quantity of nuclear matter destroyed with the degree of release of suppression permitted the following summarization: ( 1 ) Of the four nuclei, lesions of the lateral and superior produced the greatest and most consistent release of suppression. Lesions of these nuclei were always followed by release. ( 2 ) Per quantity of nuclear matter destroyed, the lateral was the most sensitive. (Fig. 4.) ( 3 ) A directional specificity of release was evidenced, i.e., if lesions were greatly asymmetric so that the nucleus on one side was heavily damaged and that on the other side only lightly damaged, release would be seen in one direction of rotation only with virtually none in the other. ( 4 ) Isolated lesions of the medial nuclei produced only a slight amount of release in one animal, and a further drop in nystagmus time in the remaining two. ( 5 ) Lesions of the descending nuclei resulted in a further drop in nystagmus time with the exception of two animals. In these two, very small lesions located rostrodorsally near the lower pole of the lateral nucleus resulted in significant release. We do not understand this and have no explanation for it.

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which it is routinely possible to obtain normal speech discrimination scores when testing normal or conductively deafened ears. In all of our audiology facilities, this level never exceeds 30 dB relative to the speech reception threshold. The use of higher presentation levels will tend to eliminate any small reduction in speech discrimination ability, and so result in the loss of valuable clinical information. SPECIAL AUDIOLOGIC TEST P R O C E D U R E S

In my experience, patients with vestibular disorders primarily related to changes of the sound conduction mechanisms of the outer

AUDIOLOGIC PATTERNS IN VESTIBULAR DISORDERS

343

or middle ear rarely require more extensive audiologic analysis than that provided by conventional pure tone and speech audiometry. An exception to this rule, however, is seen in the patient with long standing suppurative otitis media who gives a position fistula test. The suprathreshold auditory functions of these ears should be investigated to determine the degree of end organ involvement which can be secondary to the inflammatory disease process in the middle ear and mastoid cell systems. On the other hand, the information provided by the many special audiologic tests now available is of prime importance to the otologist faced with a "dizzy" patient showing a sensorineural impairment of audition. In this instance, it is essential to establish the locus of the disorder in the sensorineural auditory systems. Examination procedures now available are capable of separating, with a high degree of accuracy, these lesions primarily affecting the cochlea, the auditory portion of the VIII nerve or the central auditory pathways. To this end, we have set up and proven through extensive utilization the following battery of test procedures for patients with both vestibular and auditory symptoms. Because of the multiplicity of the test techniques developed for this purpose, some degree of selectivity is needed in the usual clinical setting in order to avoid subjecting the patient to unnecessary and time consuming auditory examination procedures. In the majority of patients showing both an auditory and a vestibular disorder, four special audiologic test procedures are now available to separate cochlear from retrocochlear disorders. Experience has determined that at least two of these four tests should be administered in order to obtain a sufficiently high degree of predictability with respect to locus of lesion. Therefore, it is of interest to examine in some detail the rationale, mode of administration and expected test results of these examination procedures which include the alternate binaural loudness balance test ( A B L B ) , the short sensitivity index test (SISI), the Bekesy type tests and the distorted speech tests. First in order of historical development is the alternate binaural loudness balance test, which is the only true test for recruitment. ( 1 ) This procedure involves the alternate oresentation of a specified pure tone of 60 seconds duration and a 50 millisecond rise-fall

344

THE VESTIBULAR SYSTEM AND ITS DISEASES

time to the subject's ears at various suprathreshold levels. T o be successful, this test can be applied only in patients with one intact ear, for interpretation of the test rests upon changes in relative loudness levels between the two ears at successively higher intensity levels which are based upon normal loudness increments. The patient is asked to equate, either verbally or by means of an attenuator the loudness levels of the tones alternately reaching the intact and the poorer ear. If the lesion is in the middle ear, there will be equal loudness sensations at all intensity levels. If the defect is in the cochlea, greater intensity levels are required in the intact ear to obtain equal loudness levels. Should the lesion be mesial to the cochlea and involve primarily the VIII nerve, there again will be equal loudness levels with equal increments in tone intensity as applied alternately to the ears. If the lesion is above the level of the lower brain stem, the ear ipsilateral to the affected ear requires 20 to 40 dB less intensity than contralateral ear to obtain equal loudness levels. In spite of the fact that the alternate binaural loudness balance test is the oldest examination procedure in this group, we have found that it is the least useful of the methods. This fact is probably related to the unusual nature of the task required of the patient and the very specialized kind of equipment needed to carry out the test. Therefore, we rarely are required to use this test because of the availability of better and more easily administered procedures. Notwithstanding its more recent origin, the short increment sensitivity index (SISI) test has established itself as a most valuable means of differentiating lesions of the auditory systems. The technique represents a modification and standardization by Jerger ( 2 ) of the older tests for intensity difference limen as first developed by European workers such as Liischer. The test is based upon the fact that ears with end organ disorders are far more sensitive to very small changes in test signal intensity than are ears with conductive or retrocochlear deficits. The mode of test administration is as follows: A baseline pure tone of a specified frequency at 20 dB above threshold is presented to the ear under test. At five second intervals, a one decibel increment is superimposed upon the base intensity and the patient is asked to indicate when the one decibel increments having a 200 millisecond peak intensity period are perceived. The test is scored

AUDIOLOGIC PATTERNS IN VESTIBULAR

DISORDERS

345

in terms of the percent of 20 increments presented monaurally, and is interpreted as follows: 1.

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Thus is obtained a bimodal distribution of test scores which separates out those ears with primary or secondary cochlear deficits. Because of the simplicity of the psychoacoustical task involved in the Sisi test, and the relatively uncomplicated equipment available as a modification for many pure tone audiometers, this test has become a very important technique for the differential diagnosis of patients with sensorineural hearing disorders. Since their development in 1947 ( 3 ) , the Bekesy type auditory tests have assumed increasing importance in the audiologic assessment of the patient with the vestibular disorder. Briefly, these tests are administered using a special, continuous frequency, self-recording audiometer that permits the graphing and comparison of a patient's threshold sensitivity for an interrupted tone (2.5 ips), either of fixed frequency or having a continuously variable frequency, and a continuously applied tone of either fixed or variable frequency. The earlier work of Jerger ( 4 ) and of our own group ( 5 ) has suggested that Bekesy audiogram patterns tend to fall roughly into four basic patterns with respect to the relationships between the interrupted and fixed frequency tracings. In Fig. 5 is seen the type I Bekesy tracing which is generally characteristic of ears with normal sensorineural function with or without a superimposed conductive deficit. Note that the tracings for the interrupted and continuous tones interweave across the entire test range from 100 to 10,000 cps. In Fig. 6 is shown the type II Bekesy audiogram which indicates a superimposition of continuous and interrupted tones up to 1,000 cps. and a moderate depression of sensitivity for the continuous tone above this frequency. Note also that the amplitude of the pen excursions is reduced above 1,000 cps., suggesting a reduced difference limen for intensity at threshold. The type II tracing is most often indicative of a primary or a secondary and organ involvement such as can be found in Meniere's disease or acoustic trauma.

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SYSTEM

AND ITS

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T y p e I : T h e t r a c i n g s for the c o n t i n u o u s a n d i n t e r r u p t e d tones a r e s u p e r i m p o s e d . T h e s e tracings a r e f o u n d with either n o r m a l h e a r i n g or a c o n d u c t i o n d e a f n e s s with normal sensorineural function. T y p e I I : T r a c i n g s a r e s u p e r i m p o s e d to 1,000 cps. A b o v e this f r e q u e n c y , t r a c i n g of c o n t i n u o u s t o n e d r o p s b e l o w the i n t e r r u p t e d t o n e a n d t h e s w i n g s a r e r e d u c e d in a m p l i t u d e . T h i s is characteristic of cochlear d e a f n e s s such as is f o u n d in Meniere's disease. T y p e I I I : T r a c i n g of t h e i n t e r r u p t e d t o n e f o l l o w s c o n v e n t i o n a l a u d i o g r a m for the s a m e patient, b u t t h e c o n t i n u o u s t o n e falls a w a y s h a r p l y t o w a r d zero as frequencies increase. Characteristic of r e t r o c o c h l e a r d e a f n e s s , u s u a l l y a c e r o b e l l o p o n t i l e a n g l e tumor. T y p e I V : T h e c o n t i n u o u s t o n e c u r v e falls b e l o w the i n t e r r u p t e d t o n e at all frequencies. T h i s is indicative of a severe c o c h l e a r lesion ( o c c u r s d u r i n g a n d immediately after an acute attack of Meniere's d i s e a s e ) o r of early r e t r o c o c h l e a r deficits. Figs. 5-8. v o n Bekesy a u d i o g r a m types. ( C o p y r i g h t The Illustrations, by F r a n k H . N e t t e r , M . D . )

Ciba

Collection

of

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AUDIOLOGIC PATTERNS IN VESTIBULAR DISORDERS

347

Fig. 7 contains the type III Bekesy audiogram which is generally characteristic of retrocochlear deafness such as that caused by a cerebellopontine angle tumor. Note the extreme loss of sensitivity for the continuous tone, even at very low test frequencies. Infrequently, a patient with a long standing chronic suppurative otitis media will give a type III Bekesy tracing. This finding is suggestive of a secondary involvement of the auditory labyrinth. These patterns sometimes give a positive fistula test. Finally, in Fig. 8 can be seen the type IV Bekesy tracing in which the continuous tone tracing falls below the interrupted tone tracing across the entire test range. Our experience has demonstrated that this audiogram configuration is indicative of either a severe cochlear deficit or an early retrocochlear lesion. Whenever a type IV audiogram is obtained, other tests are needed to separate the cochlear from the retrocochlear deficits. Similar in principle to the fixed frequency Bekesy tests, but requiring only a conventional audiometer and a watch with a second hand, is the tone decay test developed by Carhart (6) and modified by Rosenberg. ( 7 ) . This test is carried out after conventional audiometry has been done and involves the determination of an ear's ability to maintain the perception of a continuously applied tone having a fixed frequency. Administration of this test is as follows: Starting at a sensation level 5 dB above threshold, an uninterrupted tone is introduced to the test ear, making certain that the opposite ear is adequately masked. As soon as the subject indicates that the tone is no longer heard, i.e., has decayed out, tonal intensity is increased by 5 dB. This process is continued for 60 seconds, and the test findings interpreted according to the following norms: 0-15 dB decay 15-30 dB decay over 30 dB decay

- Normal to slightly depressed cochlear function. - Moderately to severely depressed cochlear function, - Possible retrocochlear deficit.

Whenever Bekesy audiometry is not available, the tone decay test should be given, especially if a retrocochlear lesion is suspected.

348

THE VESTIBULAR SYSTEM AND ITS DISEASES

Because of test variability, care must be taken to secure corroborative evidence from other auditory tests and examination procedures. So far, this discussion has been concerned with distinguishing conductive from sensorineural hearing deficits, and with separating the cochlear from the VIII nerve lesions in patients with vestibular disorders. This discussion would not be complete without a brief mention of the Bocca ( 8 ) or distorted speech tests designed to detect the presence of auditory pathway lesions above the level of the lower brain stem. There are many variations of these tests, but the rationale of their administration depends upon the fact that filtered or very faint speech signals can be heard and discriminated far better at or near threshold when detected by two ears than when presented to a single ear. The test signal should be phonetically balanced and equated word lists presented either live or as recorded material. The test is administered in the following sequence: First, conventional speech discrimination scores for undistorted speech are obtained for each ear separately. Next, low pass filtered or faint phonetically balanced word lists are presented to each ear separately at a sensation level which gives about a 5 0 % score. Finally, simultaneous presentation of filtered speech to one ear and faint, undistorted speech to both ears is carried out. The test is scored in terms of the percent correct responses to each list. Unilateral involvement of auditory pathways above the level of the lower brain stem tends to give lower scores for faint or filtered speech presented to ear contralateral to involved pathways. In addition, further evidence for such lesions is suggested by poor discrimination scores for the combined and simultaneous presentation to both ears. Patients with bilaterally normal central auditory pathways function give high ( 9 0 - 1 0 0 % ) test scores on the combined and simultaneous word list presentation, while patients with unilateral lesions above the lower brain stem tend not to show an improved speech discrimination for the binaural test condition. One word of caution is required with respect to the application and administration of the distorted speech tests. These procedures have not been used as frequently or for as long a time as the other special audiologic test procedures and hence should be interpreted with considerable reservation. Also, our knowledge of central auditory function is so scanty at present that it is extremely difficult even to guess at the source or sources of the wide variation in test

AUDIOLOGIC PATTERNS IN VESTIBULAR DISORDERS

349

responses demonstrated by patients undergoing the distorted speech tests.

SUMMARY

This report has considered the audiologic assessment of the patient with a vestibular or other balance problem. It has been suggested that audiologic testing should be a part of the clinical examination of every "dizzy" patient, for the assessment of threshold and suprathreshold auditory functions can often be a valuable aid in making the differential diagnosis. A number of specific tests have been described with respect to their value in locating the site of a lesion in the auditory systems which may be related to the genesis if the vestibular symptoms. Table 1 contains a summary of diagnostic signs of lesions in the auditory systems as reflected in presently available audiologic test procedures. Experience has shown that conventional audiologic tests are sufficient in 9 0 % of patients with a vestibular disorder. In the remaining patients, on the other hand, the special audiologic testing procedures can be of extreme value in making the differential diagnosis. It therefore seems reasonable to suggest that more widespread application of conventional and specialized audiologic assessment procedures can only result in more complete and accurate diagnosis of the patient with the vestibular disorder.

REFERENCES

1. Fowler, E. P.: Measuring the Sensation of Loudness. Arch. Otolaryng. 26: 514-521, 1937. 2. Jerger, J., Hartford, E. and Shedd, J.: On the Detection of Extremely Small Changes in Sound Intensity. Arch. Otolaryng., 69: 200-211, 1959. 3. von Bekesy, G.: A New Audiometer. Acta Otolaryng. 35: 411-422, 1947. 4. Jerger, J.: Bekesy Audiometry in Analysis of Auditory Disorders. J. Speech and Hearing Research, 3: 275-287, 1960. 5. Winchester, R. A. and Weiss, B. G.: The Bekesy Test in Otologic Diagnosis. Research in progress.

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6. Carhart, R.: Clinical Determination of Abnormal Auditory Adaptation. Arch. Otolaryng. 65: 32-39, 1957. 7. Rosenberg, P. E.: A Modification of the Carhart Tone Decay Test. Personal Communication. 8. Bocca, E. and Calearo, C.: Central Auditory Processes, in Modern Developments in Audioology, J. Jerger, Editor, New York: Academic Press, 1963. SOURCE OF FIGURES

Fig. 1 — F i g . 4, Ciba Clinical Symposium* Fig. 2 — Fig. 2, Ciba Clinical Symposium Fig. 3 — Fig. I, Ciba Clinical Symposium Fig. 4 —Original Figs. 5-8 — Page 50 — Ciba Clinical Symposium Table I — Plate VI — Ciba Clinical Symposium

* Myers, D., Schlosser, W. D., and Winchester, R. Α.: Otologic Diagnosis and the Treatment of Deafness. Ciba Clinical Symposia, Vol. 14, N o . 2, 1962.

Diagnostic Significance of Vertigo Franz Altmann, M.D.*

True vertigo can be defined as a subjective sensation of movement in the individual himself or in the surrounding objects. It is accompanied by nystagmus and often but not always by accessory vegetative phenomena such as pallor, nausea, cold sweat and vomiting. The movement usually felt is the same as that following angular acceleration (spinning or whirling). There is never an impairment or loss of consciousness. The vertigo is either continuous over periods of time of varying length and independent of the position of the head in space or it occurs only in one or several positions of the head (so called positional or postural vertigo). It is important to draw a clear line of distinction between true vertigo and the much more frequent and manifold sensations which are called dizziness by the patients, for instance lightheadedness, sensation of floating in space, feeling "drunk," inability to concentrate, seeing of spots and stars in front of the eyes, etc. True vertigo is observed not only in diseases of the vestibular endorgans but also in disorders of the entire peripheral vestibular neuron. However, the vertigo in retrolabyrinthine lesions is not always as intense and well defined as in lesions of the endorgans. In central vestibular lesions (brain stem and higher vestibular pathways) severe attacks of true vertigo with nausea and vomiting might occur, but more often these lesions are accompanied only by a sense of unsteadiness or the feeling of blacking out. If spon* From the Department of Otolaryngology, College of Physicians and Surgeons, Columbia University, in the City of New York. This work was supported by Grant B13376 of the U.S. Public Health Service.

353

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THE VESTIBULAR SYSTEM AND ITS DISEASES

taneous nystagmus is present, it is often of long duration and not accompanied by vertigo; it sometimes beats in a vertical or rotatory direction. In other instances positional nystagmus is present. The fact that true vertigo is not only the result of labyrinthine disease but also of certain retrolabyrinthine disorders cannot be emphasized strongly enough. Too often automatically the diagnosis of either "labyrinthitis" or "Menière's syndrome" is made whenever a patient suffers from true vertigo. ( Altmann, 1958.) The term labyrinthitis designates, as the suffix -itis implies, an inflammation within the labyrinthine cavities from bacterial or viral infection. The frequently used term "toxic labyrinthitis" should be avoided as incorrect or at least as confusing. A review of the histological changes caused by various toxic substances reveals that many of them do not affect the endorgans at all but the eighth nerve fibers and the ganglionic cells, particularly of the spiral ganglion. (Altmann, 1955.) However, when the endorgans are primarily affected, as in poisoning with Streptomycin, Dihydrostreptomycin, Neomycin, and Kanamycin, the pathological findings are of a purely degenerative and not of an inflammatory nature. It is, therefore, in my opinion, not appropriate to call these changes "labyrinthitis." True inflammations of the labyringth have become very rare since middle ear and meningeal infections are controlled with antibiotics. In diffuse purulent labyrinthitis there is a complete and permanent loss of hearing and of the vestibular responses with severe vertigo and nystagmus to the unaffected side which persists in full intensity for several days and then gradually subsides. Somewhat less severe forms, with at least partial return of function, are called serous labyrinthitis. A mild form of the latter with far reaching or more or less complete restoration of the inner ear function is frequently seen after fenestration — or stapes surgery; it is often accompanied by positional vertigo and nystagmus. Inflammatory changes confined to the endolymphatic spaces ("endolabyrinthitis") are the characteristic features of certain virus infections recently studied by Lindsay and collaborators (Rubella, measles, mumps). The virus enters the endolymphatic spaces from the bloodstream, mainly through the stria vascularis. Although the main clinical symptom in these cases is hearing loss, there might

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also be, depending upon the location and the extent of the damage to the vestibular portion, transient ordinary or postural vertigo with subsequent partial or complete loss of vestibular responses. The claims that vertigo might be caused by cerumen, catarrhal otitis media with or without effusion, tubal obstruction or disturbances of the occlusion (overdosed bite) are in my experience unjustified. However, one occasionally sees in cases of catarrhal otitis media with effusion vertigo of short duration after air inflation. It might be due to abnormal motility of the stapes caused by imbibition of the annular ligament with fluid. The other so frequently abused term "Meniere's Syndrome" should be avoided completely because it is a "catchall" term which is used "to denote not only cases of true Menière's disease but also of other types of organic vertigo which conform only vaguely to the established symptomatology and pathology of true Menière's disease." (Dix & Hallpike.) Menière's disease, when fully developed, is characterized by a triad of symptoms, a sensorineural hearing loss, tinnitus in the diseased ear of varying intensity and attacks of true vertigo, lasting from several minutes to several hours. The auditory disturbances are usually cahracterized by wide fluctuations in the threshold of hearing, particularly in the lower and middle range. During the attacks the threshold drops sharply, but, particularly in the early stages of the disease, may go back to normal within a few days or weeks. In advanced stages, the fluctuations become less marked and the hearing fails to return to normal or to improve markedly in the intervals between the attacks. A permanent and progressive hearing loss develops which, as a rule, is more marked in the lower and middle range. It may, however, extend uniformly over the entire tonal range or exhibit a moderate or marked loss for the high tones (see Opheim & Flotorp). Tests for recruitment show it to be present in practically every case and the speech discrimination is poor. SISI tests give a high score ( 6 0 - 1 0 0 % ) at frequencies above 1000 cps; Bekesy audiograms show usually a type II audiogram (Jerger) where the tracings for continuous and interrupted tones overlap each other at low frequencies but where the continuous tracing drops somewhere between 500 and 1000 cps 10-15 db below the interrupted tracings and runs below but parallel to it all the way out to the high fre-

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quency end. Only occasionally there is complete overlapping of the two tracings. Intermittent diplacusis binauralis dysharmonica is a very frequent finding (see Ν aito). The tinnitus is non-pulsating and either high pitched, ringing or hissing, or lew pitched and roaring in character. In many instances the tinnitus increases in intensity before the onset of the attacks, or changes from a hissing to a roaring noise; after the attacks it again becomes hissing in character. Prior to the attacks the patients often complain of a feeling of fullness in the ear which is not relieved by air-inflation. The attacks of vertigo are accompanied by horizontal-rotatory nystagmus of 3°, more frequently to the opposite side or by direction-fixed or changing positional nystagmus. They usually occur when the hearing loss and tinnitus have reached their maximum intensity, but sometimes also after they have begun to recede (so called Lermoyez's syndrome). Menière's disease and Lermoyez's syndrome are most probably different manifestations of the same disorder ( Williams, Altmann, 1955, Stoecklin, Golding-Wood). The intervals between the attacks are of various lengths; during these the vestibular symptoms either disappear completely or unsteadiness and pressure in the head persists for some time. After the attacks frequently nystagmus preponderance in the direction of the quick component of the original nystagmus is observed for a while, sometimes a fixed-direction postural nystagmus (Altmann, 1955), occasionally a direction-changing postural nystagmus (Aschan & Stahle, Stahle). In rare instances attacks of a different character and of very short duration (up to 1 min.) are observed where the patient, without any premonitory symptoms and without the sensation of nausea, suddenly falls and slumps to the floor. These attacks which are followed by almost immediate recovery were called by Tumarkin, otolith catastrophe. They are according to this author due to a flexor muscle spasm elicited from the maculautriculi. GoldingWood feels that the sudden loss of vestibular tone must not nececessarily be caused by an utricular disturbance but could also originate in the cristae ampullares. The vestibular claoric responses in the affected ear are in the beginning of the disease normal, particularly in the interval stage,

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but gradually they decrease until the vestibular function is greatly reduced or completely lost. The nystagmus preponderance which, as already mentioned, often persists lor a while might combine itself with the hypofunction. Electronystagmography has been of great value in properly analyzing the status of the vestibular system in Menière's disease and other vestibular disorders (Aschan, Bergstedt, & Stahle; Aschan & Stahle, 1957; Montandon; Pfaltz & Gulick, and others). In 80% of the cases only one ear is affected; in about 20% both ears. In bilateral cases the ears are often not simultaneously involved. The interval between the affection of the two ears does not, however, with rare exceptions, exceed 2-3 years. Endolymphatic hydrops is a constant finding in all the histologically examined cases of true Menière's disease. None of the cases quoted in the literature as Menière's disease without anatomical evidence of endolymphatic hydrops shows the characteristic triad of symptoms and none of them represent, in my opinion, true Menière's disease. The cases with fluctuating hearing loss and tinnitus of varying intensity but without attacks of vertigo are cases of so-called cochlear hydrops, which may or may not develop into Menière's disease. Nobody knows what actually happens in the inner ear during an attack but all available evidence leads to the conclusion that the attacks are due to an increase in the endolymphatic pressure with distension of certain parts of the endolymphatic system. It remains to be seen whether this increase occurs suddenly, within a few minutes, or slowly within a longer period of time, and only causes symptoms after it has reached or exceeded a certain amount. Lawrence ά Me Cabe and particularly Schuknecht explain the episodic occurrence of the auditory an devstibular symptoms with recurrent ruptures of the distended endolymphatic labyrinth. As rupture occurs there is distortion of sensory structures as well as a biochemical alteration caused by the mixing of endolymph and perilmph. The symptoms as a biochemical and structural equilibrium is achieved. Healing of ruptures appears according to Schuknecht to be a common occurrence. Long periods of remission from symptoms may represent periods of time when an open fistula is serving as an escape valve to prevent further distension of the membranous labyrinth.

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Much more frequent than Menière's disease is vertigo from circulatory disturbances in the inner ear. Since the inner ear gets its blood supply as a rule from the basilar artery, conditions which interfere with the blood flow in this artery, in the inferior anterior cerebellar artery, the internal auditory artery or its branches will, depending on the site of the disturbance, cause either vertigo and hearing loss or vertigo or hearing loss alone. In arteriosclerosis of the basilar artery, there are episodes of temporarily inadequate blood flow through the basilar arterial system. These episodes are characterized by various neurological symptoms, such as cloudiness or loss of vision, hemiparesis or hemiplegia, dysarthria or dysphagia, etc. together with tinnitus, vertigo, nausea, unsteadiness and headaches. Although each of these symptoms is relatively nonspecific, its occurrence on opposite sides of the body in definite attacks, that is for instance hemiparesis on the right side in one attack and on the left in another, suggests the diagnosis of "intermittent insufficiency of the basilar artery system" (Millikan and Siekert). In another group of patients, in addition to various neurological symptoms, attacks of vertigo, sometimes of positional character, and tinnitus are brought about by compression of the vertebral artery and of the surrounding network of automatic nerve fibers (Beickert and others), particularly on rotation or hyperextension of the head or perhaps also on emotional muscular tension. In these patients either anomalies of the vertebral arteries are present which can be demonstrated in arteriograms, such as marked differences in the width of the lumina or anomalous origin from the subclavian artery (Krayenbiihl and Yasargil; Powers, Drislane and Nevins; Fields and Weibel; and others) or they show marked osteoarthitic or spondylarthritic changes in the cervical spine (Wildhagen; Platz & Richter; Cope & Ryan; Sandstrom; Rebattu & Bonnefoy and others), which may lead to temporary compression of the vertebral arteries (see Pichler). Coexisting arteriosclerotic changes will aggravate the symptoms (see also Decher & Unterharnscheidt). Complete and sudden loss of the labyrinthine function is usually caused by hemorrhage into the inner ear either after transverse fracture of the petrous pyramid or occurs in the course of lymphatic leukemia. Occasionally it is caused by complete occlusion of the trunk of the internal auditory artery. There is severe but gradually

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subsiding vertigo and nystagmus for several weeks, followed by vertigo upon sudden movements of the head for several months but there is no postural vertigo. In order to get a better understanding of the symptomatology of the changes involving the various branches of the internal auditory artery a short review of the most common type of ramification of this artery shall be given. (Fig. 1.) The first branch leaving the internal auditory artery is the anterior vestibular artery which supplies the upper parts of the saccular wall, the macula of the utricle and the cristae ampullares of the lateral and of the superior vertical canals. The second branch given off is the vestibulocochlear artery which supplies the macula and the greater part of the wall of the saccule and then divides into two branches. One supplies the body and the lower part of the utricle and the crista ampullars

A. A U D I T I V A INTERNA * COCHLEARIS

ampulla su perioral

ampulla lateralis

A VESTIBULARIS ANTERIOR

~4¿\ampu Ua j \ posterior

RAMUS V E S T I B U L O COCHLEAR^ A. C O C H L E A RI S

RAMUS VESTIBULARIS RAMUS

COCHLEARIS

Fig. 1. Diagram of the arterial supply of the membranous labyrinth.

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of the posterior vertical canal; the other one goes to the basal turn of the cochlea. The terminal branch of the internal auditory artery is the cochlear artery (a. cochlearis propria) which enters the modiolus and supplies via the spiral arteries the other cochlear turns. The symptomatology of vascular accidents affecting the branches of the internal auditory artery has been greatly clarified by Lindsay and Hemenway (1956) and Shenker. According to these authors total destruction of one peripheral vestibular system by trauma, hemorrhage or infection is followed by severe and continuous vertigo. The recovery follows a typical course as already mentioned. Postural vertigo is not a characteristic feature during the recovery period. A gradual partial destruction of one labyrinth or of one vestibular nerve, as seen for instance in early acoustic neurinoma, also does not cause a prolonged period of postural vertigo; neither does a gradual complete destruction of the labyrinth cause postural vertigo. A sudden or rapid partial destruction of one labyrinth, as in certain virus infections such as mumps, frequently causes at the onset continuous vertigo; gradually the vertigo becomes postural in character and may persist for periods of time varying from a few weeks to several years. Postural or positional nystagmus was first studied by Barany and later on, particularly, by Nylen, Fremei, who suggested the term provocationnystagmus, by Aschan and by many others. The most commonly used nomenclature is that of Nylen, modified by Aschan, Bergstedt & Stahle. One distinguishes between Type I, a direction -changing and Type II, a direction-fixed positional nystagmus. They have one thing in common: the nystagmus observed or recorded is persistent for the duration of the common time of observation, 30-60 seconds (Aschan, 1961). Nylen's Type III includes the other types of positional nystagmus. The predominant positional nystagmus in Type III is the so called "benign paroxysmal" positional nystagmus. (Dix & Hallpike; Cawthorne). In the "benign paroxysmal" type which comprises roughly 90% of the observations, there is a latent period from 2-10 seconds between taking up the critical position of the head and the onset of the nystagmus. The latter shows a horizontal rotatory direction and a large amplitude; it is fatigable and usually lasts from 5-30

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seconds. After bringing the patient in an upright position, there may be a return of the vertigo and the nystagmus for a few seconds but in the opposite direction. After the nystagmus has disappeared it can not be elicited for a period of several minutes to one half an hour. The nystagmus and vertigo are paroxysmal in nature and appear as a rule with the head in only one position. In what the authors call the "central type" (Types I & II of Nylen) the nystagmus appears as soon as the head assumes the critical position and is "non-fatigable" persisting for the duration of the common time of observation, beating at a steady rate for as long as the head is held in this position. It furthermore starts beating again everytime the position of the head is resumed. Frequently it appears in more than one position and the observation of the nystagmus may, as already mentioned, change with the position of the head. The associated vertigo is often but not invariably relatively slight. Since the vestibular pathways and centers may be the site of the lesion, a thorough neurological workup is indicated in every case. Possible findings are tumors, encapsulated abscesses, plaques of multiple sclerosis and vascular accidents in the brain stem and cerebellum. The vascular accidents start with rapid onset of severe vertigo which later may become postural. This is for instance the case in the posterior inferior cerebellar artery syndrome (Wallenberg's syndrome) where the vertigo is associated with brainstem symptoms such as dysphagia, vocal cord paralysis, etc. (see Moberg & coll. ) Before considering the etiology of the positional vertigo and nystagmus, the discussion of the symptomatology of lesions affecting the branches of the internal auditory artery shall be continued. Occlusion of the anterior vestibular artery causes degeneration of the superior division of the vestibular nerve and of the sense ogans supplied by it, of the macula utriculi and the cristae ampullares of the horizontal and superior vertical canals (histologically examined cases of Dix & Hallpike, Lindsay & Hemenway, Cawthorne & Hallpike). Clinically the "anterior vestibular artery syndrome" (Schuknecht) is characterized by acute onset of severe vertigo without or with only insignificant auditory symptoms, such as mild tinnitus or a sense of discomfort in the ear. The vertigo is constant but gradually subsiding and eventually becomes postural in character.

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The latter is often accompanied by a feeling of unsteadiness and persists from several weeks to several years, the caloric responses are either depressed or normal. If so, one has to assume that some function must have remained in the crista ampullaris of the horizontal canal. Occlusion of the vestibulocochlear branch is characterized by sudden onset of vertigo with tinnitus and high tone loss. The caloric excitability is frequently depressed in the affected ear; there is often a partial recovery in the hearing within the first few weeks. The severe and constant vertigo gradually subsides and is followed by postural vertigo which may persist for a long time, but as a rule, eventually disappears completely. Sudden high tone loss, often again followed by partial or even complete recovery, is caused by occlusion of the lumen of the cochlear branch of the vestibulocochlear artery either due to thrombosis or to spasm. More profound low tone hearing loss without vertigo could be due to change in the main stem of the cochlear artery or in its intracochlear branches. (Mehigian & Giacomelli) In a similar way vertigo could be caused by spasms or minute thrombi in small vestibular vessels. Many cases of true vertigo of psychogenic origin might belong to this group. The etiology of the positional nystagmus has by no means been completely clarified yet. The animal experiments of Fernandez and coll. and of Allen & Fernandez cast doubt on the assumption of Hallpike and Dix, that the "benign paroxysmal" positional nystagmus is due to lesions in the otolithic apparatus itself and seem to support the hypothesis of Lindsay and Hemenway which states that "the continuation of active impulses from part of the labyrinthine receptors with sudden loss (or impairment) of other receptors appears to be the situation which is characterized by postural vertigo and a positional nystagmus". According to Riesco, postural nystagmus may be due in many cases to a state of hyperexcitability of the vestibular nuclei. He assumes that the incoming signals arising in the vestibular receptors produce a qualitatively abnormal response in the cells of the nuclei. Riesco supports this hypothesis with the operative findings in a patient with postural nystagmus without signs of peripheral lesions, where an astrocytoma of the inferior vermis of the cerebellum was removed and where the

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nystagmus subsequently disappeared after one year. Other cases where lesions of the posterior vermis produced postural nystagmus were reported by Nylen ( 1 9 5 0 ) and by Aubry & coll. Fernandez and coll. were able to produce in the cat postural nystagmus of the benign postural type through sections of one utricular nerve alone or together with the lateral and superior ampullar nerves. This observation is regarded as proof that unilateral sudden partial loss of vestibular function may be followed by postural nystagmus. Electrical stimulation of the utricular nerve did not produce nystagmus but it provoked deviation of the eyes in several directions. From this observation the authors conculde that postural nystagmus is not likely to be of otolithic origin. Lesions of the cerebellum localized to or including parts of the flocculonodular lobe consistently produced a syndrome characterized by dysequilibrium and postural nystagmus of the benign paroxysmal type. The authors feel that the term "benign" is misleading because it implies that this type of postural nystagmus is associated with peripheral lesions or with pathology of simple nature. The authors were able to confirm the observation of Spiegel and Scala that the postural nystagmus disappeared after bilateral labyrinthectomy. They furthermore found that the postural nystagmus did not develop if bilateral labyrinthectomy preceded the cerebellar lesion. They point out that Riesco was essentially right when he stated that postural nystagmus of the paroxysmal type may be explained as a qualitatively abnormal response of the vestibular nuclei to the postural stimulus. He did not realize, however, that the qualitatively abnormal responses may be due to a release from cerebellar inhibitions." Schuknecht feels that the paroxysmal postural nystagmus is caused by a labyrinthine lesion and produced by loose statoconia from the utricle which in certain positions of the head are free to respond to gravitational forces and therefore to displace the cupula of the posterior canal which in the cases of the "anterior vestibular artery syndrome" is the only functioning crista. N o case of obstruction of the vestibulo-cochlear branch has so far been examined histologically but it would certainly be difficult to explain postural nystagmus in these cases with the same hypothesis.

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Although the persistent postural nystagmus (Nylen's type I and II) seems in the majority of cases been brought about by central lesions, eases have been reported where it had been produced by changes in the peripheral labyrinth (Jongkees and others.) One must therefore agree with Aschan, Bergstedt & Stahle and with A lien & Fernandez that "so far all evidence indicates that the type of postural nystagmus or any of its characteristics can not be of much help in localization. There are now reports of both central and peripheral disease causing each of the possible types of postural nystagmus already described in the literature." A review of the manifold underlying pathologic anatomic and physiologic conditions was recently given by Frenze I (1961. ) It should furthermore be mentioned that certain toxic agents such as alcohol, barbiturates and carbon monoxide may cause various types of positional nystagmus (see Aschan & coll.). Alcohol and barbiturates may produce, in addition to positional nystagmus, a gaze nystagmus of ocular origin. Misinterpretation of these forms of nystagmus may lead to grave errors in the otoneurologic evaluation of the cases in question. Attacks of vertigo or the feeling of unsteadiness, particularly when walking or standing, without hearing loss, sometimes follow acute and chronic infections of the sinuses, the tonsils, the teeth, the gastro-intestinal tract, the liver biliary tract and gallbladder. The condition is usually unilateral and characterized during the initial stage by spontaneous nystagmus toward the non-effected side. The spontaneous nystagmus may change in the course of the disease to direction-fixed positional nystagmus (Aschan & Stahle 1956), Marked anomalies of the vestibular responses are present in all cases and the responses are reduced in the great majority of them. The condition was called vestibular neuritis by Nylen, vestibular neuronitis by Dix and Hallpike, and interpreted as the result of an organic lesion of the vestibular nervous pathways from Scarpa's ganglion in the internal auditory meatus up to and including the vestibular nuclei in the brain stem. Previously these cases were incorrectly classified as ménièreiform syndrome, as focal toxic labyrinthitis, as labyrinthine allergy or as vegetative dystony of the labyrinth (see also Pfaltz, Kern and others). According to Riesco ( 1 9 6 4 ) Nylen's case is different from the cases of Dix and Hallpike because it showed vertiginous attacks on

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the first day of the disease only, followed by positional vertigo of several weeks duration. The symptomatology of the labyrinthine manifestations of Herpes zoster oticus is very similar to that of vestibular neuritis. Histological changes should be present in Scarpa's ganglion but may also be postulated in the vestibular nerve and its nuclei since in most cases there is an increase in the cellular and protein contents of the cerebrospinal fluid (Aschan, Bergstedt & Stahle). In another group of cases with vertigo following virus infections of the upper respiratory tract or other virus infections such as measles, the etiology is a postinfectious meningo-encephalitis or encephalopathia with lesions in the vestibular nuclear region of the brain stem or in the formatio reticularis. The cerebrospinal fluid shows pleocytosis and increased protein content. Other neurological signs and symptoms are usually absent and the hearing is normal (see Herberts). Most of the cases of "epidemic vertigo" (Pedersen, Furey & Kraus, and others) might belong to this group. Riesco in reviewing the vestibular findings in lesions of the posterior cranial fossa distinguishes between 3 types of syndromes, the cerebellopontine angle, the IV th ventricle — and the cerebellarsyndrome. While in many conditions associated with vertigo the establishment of the correct diagnosis is mainly of academic interest, early recognition is of the greatest practical importance in acoustic neurinoma or other types of cerebellopontine angle tumors or cysts. Tinnitus and progressive sensorineural hearing loss, as a rule without fluctuations and in most instances without recruitment, with adaptation signs and characteristic responses to certain speech tests are often the earniest clear-cut symptoms of these tumors (for details see Strauss & Fowler). Reduced corneal reflexes come later. These symptoms are followed either by the feeling of unsteadiness, by lateral gaze nystagmus or by occasional attacks of true vertigo with spontaneous nystagmus or by a combination of the two. The caloric responses are in the great majority of the cases either markedly reduced or completely absent even in acoustic neurinomas of relatively short clinical duration. In view of the potentially grave consequences of overlooking such tumors it is advisable to regard every case of hearing loss, tinnitus and vertigo or unsteadiness as a possible acoustic neurinoma

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which carefully should be ruled out before another diagnosis is made. Whereas in the cerebellopontine angle syndrome the involvement of the eighth nerve is the fundamental symptom, the nerve remains uninvolved in the two other syndromes. In the IVth ventricle-or midline-syndrome the fundamental symptom is the involvement of the vestibulo-oculo motor tract (upper portion of the medial longitudinal fasciculus). This manifests itself in spontaneous nystagmus, conjugate deviation of the eyes, positional nystagmus and abnormalities of the caloric nystagmus such as typerexcitability, inexcitability, directional preponderance and perversion. Associated symptoms are disturbances of the equilibrium, postural vomiting, papilledema and bilateral cerebellar symptoms. In the cerebellar syndrome the fundamental symptom is cerebellar dysfunction on the affected side (hypotonia, ataxia, inco-ordination, dysmetria, adiadochokinesis, etc.). Associated symptoms are papilledema and disorders of the vestibulo-oculo motor tract. The vestibular signs and symptoms which sometimes occur in lesins of the anterior and middle fossa are of little diagnostic value. Occasionally expanding supratentorial lesions may compress the brainstem and in this way produce the characteristic signs and symptoms of posterior fossa involvement. (Velasco). After severe head trauma with concussion of the brain but without fracture of the petrous pyramid, the peripheral as well as the central type of vestibular disturbances might be observed. The peripheral type results from a hemorrhage into or direct injury to the endorgans (labyrinthine concussion) and is characterized by persisting high tone loss and positional nystagmus of the "benign paroxysmal" type. The central type of vestibular disturbances is most probably due to alterations in the vestibular nuclei and pathways. There is non fatigable positional nystagmus, the sensation of vertigo is much milder and there is no hearing loss unless the central cochlear pathways are also involved. Peripheral vestibular disturbances subside, usually within a few weeks, whereas central disturbances may persist for a long time. Late symptoms include unsteadiness in walking, bending, and lying of postural character. If spontaneous nystagmus is present, which is the case more often in the weeks following the accident than later,

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it differs somewhat f r o m the nystagmus occurring in peripheral vestibular disorders. O n e finds, f o r example, marked nystagmus with pastpointing and falling but with normal hearing or marked nystagmus without pastpointing and falling, or nystagmus in an abnormal direction. Without discussing in greater detail the abnormal vestibular reactions which may follow brain concussion it shall only be mentioned that positional vertigo and nystagmus may remain as the only symptoms of damage to the vestibular system. Of particular diagnostic significance is positional nystagmus which either changes its direction in different positions of the head, beats in a vertical direction, or shows no regularity at all. The presence of normal hearing will, in m a n y instances, facilitate the diagnosis of central vestibular disorders, particularly if the neurological examination reveals certain localizing signs. T h e diagnostic difficulties are often still f u r t h e r increased by combinations of peripheral and central vestibular disorders, such as fracture of the base of the skull with severe brain concussion. Disturbances of the vestibular function m a y be combined with peripheral and central auditory disturbances, or a combination of both, factors which will make proper evaluation of these cases still more difficult. Thorough and repeated tests of hearing and of vestibular function are essential in all cases of t r a u m a to the head. T h e vestibular tests are particularly important because pathological vestibular symptoms, especially the anomalies of nystagmus and responses to stimulation can not be influenced voluntarily by the patient. T h e possibility of malingering, therefore can be eliminated in these instances. Lack of time does not permit the discussion of more unusual causes f o r vertigo. REFERENCES

Allen, G., & Fernandez, C.: Experimental observations on postural nystagmus. Acta Otolar: 51: 2, 1960. Altmann, F.: Morbus Ménière Fortsch. Hals-Nas-Ohrenheilk. 2: 1-79. S. Karger, Basel, New York, 1955. Altmann, F. : Entzündliche und degenerative Erkrankungen des peripheren Cochlear-und Vestibular Neurons. Fortschr. Hals-Nas-Ohrenheilk. 2: 80-145, S. Karger, Basel, New York, 1955.

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Altmann, F.: Die diagnostische Bedeutung des Schwindels — Wiener Klin. Wochenschrift. 70: 675, 1958. Aschan, G.: Different types of alcohol nystagmus. Acta Otolar. Supplement 140: 69, 1958. Aschan, G.: The pathogenesis of positional nystagmus, Acta Otolar. Supplement 159, 90, 1961. Aschan, G., Bergstedt, M., & Stahle, J.: Nystagmography. Acta Otolar. Supplement 129, 1956. Aschan, G., Bergstedt, M., & Goldberg, L.: Positional nystagmus in man during and after alcohol intoxication. Quart. Journal of Studies on Alcohol 17: 381, 1956. Aschan, G., & Stahle, J.: Vestibular neuritis. A nystagmographical Study Journal of Laryngol. & Otol. 70: 497, 1956 . Aschan, G., & Stahle, J.: Nystagmus in Ménière's disease during attacks. A nystagmographical study. Acta Otolar. 47: 189, 1957. Aubry, M., Pialoux, P., & Bouchet, J.: Le nystagmus de position en otoneurologie Ann. d' otarlyngol. 71: 531, 1954. Barany, R.: Diagnose von Krankheitserscheinungen in Bereiche des Otolithenapparates. Acta Otolar. 2: 434, 1921. Beickert, P.: Diskussion zur Ätiologie und Pathogenese des Morbus Ménière. Zeitschr. f. Laryngo-Rhinol-Otol. 41: 828, 1962. Cawthorne, T.: Postural nystagmus. Ann. Otol-Rhinol-Laryngol. 63: 480, 1954. Cawthorne, S., & Hallpike, C. S.: A study of the clinical and histological changes within the temporal bones, brain stem, and cerebellum of an early case of positional nystagmus of the so-called benign paroxysmal type. Acta Otolar. 48: 89, 1957. Cope, S., & Ryan, G. M. S.: Cervical and otolith vertigo. Journal Laryng. 73: 113, 1959. Decher, H., & Unterharnscheidt, F.: Cochleo-vestibuläre Reizsymptome beim synkopalen zervikalen Vertebralissyndrom. Zeitschr f. LaryngoRhinol-Otol. 38: 231,1959. Dix, M. R., & Hallpike, C. S.: Pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Ann. Otol-RhinolLaryngo. 61: 987, 1952. Fernandez, C., Alzate, R., & Lindsay, J.: Experimental observations on postural nystagmus in the cat. Ann. Otol.-Rhinol-Laryngol. 68: 816, 1959. Fields, W. S., & Weibel, J.: Effects on vascular disorders on the vestibular system in: Neurological aspects of auditory and vestibular disorders. W. S. Fields and B. R. Alford, editors, Springfield, 111. Charles C. Thomas, 1964.

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Frenzel, S.: Neure Bestrebungen zur Verbesserung der vestibulären Erregbarkeits-prufungen und zur Frage einer gezielten vestibularis—Untersuchung in der Praxis. HNO Wegweiser 4: 193, 1954. Frenzel, H.: Neure Bestrebungen zur Verbesserung der vestibulären ErregGrundlagen des Lagenystagmus. Acta oto-laryng. Supplement 159, 73, 1961. Furey, J. Α., & Kraus, R. N.: A clinical classification of vertigo. Laryngoscope 72: 1313,1962. Golding-Wood, P. H.: Ménière's disease and its pathological mechanism. Journal Laryng. 74: 803, 1960. Herberts, G.: Postinfectious meningoencephalitis as an etiologic factor in certain cases of vertigo. Acta Otolar. Supplement 118-109, 1954. Jerger, J.: Hearing tests in otologic diagnosis. Journal am. Speech and Hearing Ass. 4: 139, 1962. Jongkees, L. B.: Positional nystagmus of peripheral origin. Journal Physiol. 110: 447, 1949. Kern, G.: Zur Frage der Neuronitis vestibularis, Pract. Oto-Rhino-Laryngol. 20: 233, 1958. Krayenbuhl, H., & Yasargill, M. G.: Die vaskulären Erkrankungen in Gebiete der A. vertebralis u. A basilaris. G. Thieme Verlag, Stuttgart, 1957. Lawrence, M., & McCabe, B.: Inner- ear mechanics and deafness. J.A.M.Α. 171:1927, 1959. Lindsay, J. R., Carruthers, D. G., Hemenway, W. G., & Harrison, M. S.: Inner ear pathology following maternal rubella. Ann. Otol-RhinolLaryngol. 62: 918, 1953. Lindsay, J. R., Davey, P. R., & Ward, H. P.: Inner ear pathology in deafness due to mumps. Ann. Otol-Rhinol-Laryngol. 69: 918, 1960. Lindsay, J. R., & Hemenway, G.: Postural vertigo due to unilateral sudden partial loss of vestibular function. Ann Otol-Rhinol-Laryngol. 65: 692, 1956. Mehigian, D., & Giacomelli, F.: Zum Problem der Innerohr-Vascularisation Klinische Betrachtungen. Arch. Ohr-Nas-Kehlkopf, Heilk, 181: 65, 1962. Millikan, C. Η., & Siekert, R. G.: Studies in cerebrovascular disease I. The syndrome of intermittent insufficiency of the basilar artery system. Proc Staff. Meet. Mayo Clinic 30: 61, 1955. Moberg, Α., Preber, L., Silfverskiold, B. P., & Vallbo, S.: Imbalance nystagmus and diplopia in Wallenberg's syndrome: Clinical analysis of case and postmortem examination. Acta Otolar. 55: 269, 1962. Montandon, Α.: Etude Electronystagmographique du syndrome de Ménière. Acta Otolar. 53: 287, 1961.

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Naito, T.: Etude clinique et anatomo-pathologique de maladie de Ménière. 7th Int. Cong. Otolaryng. Paris 1961, Excerpta Medica. Int. Congress Series 35: 100, 1961. Naito, T.: Clinical Studies on Ménière's disease Rev. de Laryngol. Bordeaux 83: 361, 1962. Nylen, C. O.: Soce ocular nystagmus due to certain positions of the head. Acta Otolar. 6: 106, 1924. Nylen, C. O.: Positional nystagmus. A review and a future prospects. Journal Otolar. & Laryngo. 64: 295, 1950. Opheim, O., & Flotorp, G.: Ménière's disease. Some audiological and clinical observations. Acta Otolar. 47: 202, 1957. Pedersen, E.: Epidemic vertigo; Clinical picture. Epidemiology and relation to encephalitis. Brain: 82: 566, 1959. Pfaltz, C. R.: Diagnose und Therapie der vestibulären Neuronitis. Pract. Oto-Rhino. Laryng. 17: 454, 1955. Pfaltz, C. R., & Gulick, R.: Die pathologische calorische Labyrinthrealition. Arch-ONK, 179: 525: 1962. Pfaltz, C. R., & Richter, H. R.: Die cochleo-vestibuläre Symptomatologie des Cervicalsyndroms. Arch. Ohr-Nas-Kehlkopf-Heilk. 75: 519, 1958. Pichler, E.: Über Durchblutungsstörungen in Vertebralis-und Basilarisbereich Monatschr. f. Ohren Heilk. 97: 319, 1963. Powers, S. R., Drislane, T. M., & Nevins, S.: Intermittent vertebral artery compression: a new syndrome. Surgery 49: 257, 1961. Rebattu, J. P., Bonnefoy, J.: Le vertige et le nystagmus de position dans les arthroses cervicales. Revue d'oto-neuro ophthamol. 35: 129, 1963. Riecker, O.: Der experimentelle Lagenystagmus nach Luminalgaben. Ζ. f. Laryngol. Rhinol. Otol. 28: 138, 1948. Riesco Mac Clure, J. S.: Síndromes vestibulares en las lesiones de la fosa cerebral posterior. Rev. de Otorrinolaringología. 15: 1, 1955. Riesca Mac Clure, J. S.: Nistagmus: Su valor en el diagnostic otoneurologico. Rev. de otorrinolaringol. 15: 18, 1955. Riesco Mac Clure, J. S.: Es el vertigo aural de origin exclusiveamente periferico? Rev. Otorrinolaring. 17: 42, 1957. Riesco Mac Clure, J. S.: Caloric tests, methods and interpretation. Trans. Amer. Otol. Soc. 97th Meeting, San Francisco, April 5-6, 1964. Sandström, J.: Cervical Syndrome with vestibular symptoms. Acta Otolar. 54: 207, 1962. Schuknecht, H.: Positional vertigo. Clinical an experimental observations. Trans. Amer. Acad. Ophthal. & Otolar. 66: 319, 1962. Schuknecht, H.: Ménière's disease: correlation of symptomatology and pathology. Laryngoscope, 73: 651, 1963.

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Schuknecht, H., Benitez, J., Beekhuis, J.: Further observations on the pathology of Ménière's disease. Ann. Oto-Rhino-Laryng. 71: 1039, 1962. Shenker, D.: Clinical features and pathogenesis of acute circulatory disturbances in the region supplied by the internal auditory artery. (Russian) Vestn. Oto-Rhino-Laryng. 6: 31, 1962. Spiegel, Ε. Α., & Scala, Ν. P.: Positional nystagmus in cerebellar lesions. Journal Neurophysiol. 5: 247, 1942. Stahle, J.: Electronystagmography in the caloric and rotatory tests. Acta Otolar. Supplement 137, 1958. Stoecklin, W.: Ein Fall von wechselseitigen Ménière-Lermoyez Syndrom. Pract. Oto-Rhino-Laryng. 19: 497, 1957. Strauss, R.B., & Fowler, E. P. Jr.: Audiometry and recruitment in acoustic neurinomas. New York State Journal of Med. 63: 820, 1963. Tumarkin, Α.: The otolith catastrophe, a new syndrome. Brit. Med. Jour. July 28, 1963, p. 175. Velasco, R.: Mesa Redonda sobre algunos problems experimentales y clínicos de sistema vestibular. Rev. de Otorrinolaringol. 21: 36, 1961. Velasco, R.: Sindrome vestibular de linea media de fosa posteriore en lesiones expansivas supratentoriales. Rev. de otorrinolaringol. 23: 100, 1963. Wildhagen, F.: Ménière-Syndrom bei Affektionen der oberen Halswirbelsäule. Arch Ohr-Nas-Kehlkopf-Heilk, 1951. Williams, H. L.: Ménière's disease. Charles C. Thomas, Springfield, 111., 1962.

Discussion D R . F R E D H A R B E R T [Philadelphia, Pa.]: I should like to mention some experiences I have had with the entity known as postural vertigo and positional nystagmus. We have heard from previous essayists about the basic fundamental connections between the eye muscles and certain canals, and I think there is evidence that the Schuknecht hypothesis of the posterior canal being involved and hooked up with certain muscles can be substantiated by observations in this benign type. The nystagmus is quite wild at times but at one time it settles down to the fundamental or primary type, and in that form if the eyes are directed in one direction of gaze — in other words, if they are directed ipsilaterally to the down ear — there will be a rotary kind of nystagmus, and if turned in the opposite direction, contralateral to the ear, it will become vertical. This is an observation, I think, that is unique for the benign type of position nystagmus. D R . W A L T E R H . JOHNSON [University of Toronto, Toronto, Can.]: Mr. Chairman, I have a question I would like to ask Professor Jongkees. I was very interested in his graph in which he showed the normal variations in nystagmus response to standard caloric stimulation in any one sample of population. Have you, Professor Jongkees, noticed anything in regard to diurnal variation in any one individual within the sample? I hear there is such a thing. I would like to know if you think this is significant and, if so, how should we allow for it? PROFESSOR JONGKEES: I think there are various kinds of variations when we measure the caloric, the general vestibular reactions. First of all, there are declining responses generally in older people, especially with the rotary test and also the caloric test.

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There is another thing and that is the variation in different parts of the population. I think it will perhaps be the same in the United States and in America in general as in Holland. We are in Holland also a melting pot of people from everywhere and there are various parts of the population which react more strongly or less strongly to stimuli. For instance, in Holland we have the more dark type and the more blond type. The blond type gives not as strong reactions as the dark type, and we have people who react hardly at all; the farmers from the north in our country have very, very poor reactions and the active merchant from Amsterdam has strong reactions. So I think whenever you make up a Gaussian curve, you have to take into account all those variations and you must try to find out for your own population, for the divisions by age, etc., how you interpret this. I hope I answered your question — that that is what you meant. D R . R I C H A R D E. M A R C U S [Skokie, 111.]: Dr. Lindsay, I would like to direct some comments and questions to Dr. Winchester, and to whatever extent these may apply also to Professor Altmann. In the first instance, it seems to me that we have not yet begun to explore all the relationships between vestibular disorders and audiologic findings. For instance, I think it is quite apparent that we are dealing with peripheral disorders in a number of instances and we are dealing with nerve disorders in other instances, and we are dealing with central disorders in still other instances. We don't have an opportunity, perhaps, to see in the peripheral disorders some of the patients who are having an acute attack. We don't have the opportunity to get full audiologic responses. We would like to be able to do more but, obviously, there are clinical limitations. It would seem to me that in those instances, however, where the otoneurologist can find the opportunity to do so, he should avail himself of the full audiologic battery, and in our own limited experience in this regard we have found changes not only in pitch discrimination, for instance, on one side as compared with the other (and we would like to know more about that); we have found tinnitus bands and we have tried to indicate where those are located and the intensity of those bands; and we have found in

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many instances positive SISI at frequencies below that which we would expect. This would be in the peripheral disorder, the one that would be most likely associated with Meniére's disease as described by Dr. Altmann. In other words, we find highly positive SISI responses at 250 and 500 cycles/second. I would like to know if Dr. Winchester has any experience along that line. Of course, I think it is perfectly obvious to all of you that the various fatigue tests done for auditory nerve function can certainly give an indication as to the possibility of tumors; various kinds of tests of the vestibular function can be tied in to those. I think more of this should be done. Particularly, we should be able to know which are the first symptoms that appear and which are the first signs that are available to us, either audiologically or on the basis of vestibular function tests. I would ask this further question: In children, we have seen a number of children who give no response to rotation or to caloric tests, whose hearing is normal, and I have wondered over some period of time what the possible relationship could be and if perhaps there might be an answer forthcoming. DR. WINCHESTER: I certainly agree with Dr. Marcus that we haven't done enough in correlating audiologic findings with tests of vestibular function. We are looking toward this in the future, but at the present time, as I stated in my formal presentation, I have not been able to determine or to find any recurrent pattern of a pure tone audiogram, for example, that would correlate well with varying types of vestibular disorders. There just doesn't seem to be much of a correlation there. This, I think, points to the fact that we must go toward subtler investigations of auditory function, such as perhaps pitch perception or the difference limen in intensity, things of this nature. In response to the question about positive SISI's at low levels, I have never run across this, because usually we don't find the patient giving any kind of response to the SISI test unless he has a sensory neural hearing loss, a cochlear hearing loss of at least 20 - 25 dB below normal. If it is any less than that, then he just gives a very sporadic kind of response. It may be that the type of reading has something to do with this, I don't know, but I have not found it in the cases that I have seen.

Meniere's Disease: Pathology and Manifestations* John R. Lindsay, M.D., and P. A. Sciarra, M.D.

The symptom complex described by Menière over 100 years ago and which bears his name has been shown to have as its pathological anatomical basis a dilatatio or "hydrops" of the endolymphatic spaces in the labyrinth. While "hydrops" of the labyrinth had previously been observed in several laboratories it was Hallpike and Cairns 1 in 1938 who established the relation between the idiopathic type of hydrops and Menière's disease. Since that time the histopathologic studies of this condition have been slowly increasing. The University of Chicago laboratory now contains eight specimens of the idiopathic type of hydrops from six cases. In addition, there are several examples of hydrops in human material and from experimental animals which were due to other causes. These are of some value for comparison. A case of bilateral hydrops will form the basis of this report. It is well suited for this purpose since one ear illustrates a combined cochlear and vestibular hydrops and the other a hydrops limited to the cochlea. CASE REPORT

History The available history afforded the following information. In 1951 a 56-year-old male railroad worker was examined at the * This investigation was supported in part by funds from grants by the Central Bureau of Research of the American Otological Society and The Deafness Research Foundation.

375

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THE VESTIBULAR SYSTEM AND ITS DISEASES

Wisconsin General Hospital because of episodes of vertigo. The reported findings included chronic otitis media, right, with discharge through a large perforation in the ear drum and a hearing loss of 40 percent. The left ear had a scarred ear drum with 20 percent hearing loss. Conservative treatment was recommended for the vertigo. In 1952 he was investigated again in Milwaukee for the same problem. The right ear was then reported dry. In 1957 he was examined by Dr. P. A. Sciarra in Sheboygen, Wisconsin, regarding his severe hearing loss. Pure tone thresholds by air conduction were reported as follows:

Left Right

500

1000

2000

4000

50 85

35 80

30 75

65 65

On May 15, 1962, he was again seen and the pure tone threshold level without masking was as follows:

Left Right

250

500

1000

2000

4000

45 80

55 85

65 90

70 95

65 100

In July. 1962, he was again seen by Dr. Sciarra because of a discharge from the right ear. On examination he was found to have a solid, slightly mobile object imbedded in the ear. This was removed under general anesthesia by doing a radical mastoidectomy. It proved to be foreign material of stony hardness which did not soften on attempted preparation in the laboratory. Nine days after release from hospital he became acutely ill and was readmitted. An abdominal laparotomy was done because of ileus and suspected obstruction of the large bowel. He expired a few days later. The autopsy report concluded with the following statement: The immediate cause of death on the basis of the complete autopsy examination was found to be myocardial infarction on the basis of extreme arteriosclerotic heart disease with ischemia.

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The temporal bones were removed and sent to the University of Chicago laboratory by Dr. Sciarra for processing.

HISTOPATHOLOGY

Right Ear The ear drum, malleus and incus were missing from the specimen. There was a marked degree of inflammatory thickening of the middle ear mucosa. Inner Ear. The tissues were well preserved with relatively little postmortem degeneration. Cochlea. The perilymphatic spaces were free from evidence of inflammatory reaction. The cochlear duct was extremely dilated and Reissner's membrane was intact. (Fig. 1.) In some areas the scala vestibuli was almost obliterated by the dilated cochlear duct which also bulged through the helicotrema into the scala tympani. The stria vascularis was less extensive than normal in some regions, suggestive of atrophy, but in other areas appeared normal. Corti's organ and the tectorial membrane were distinctly abnormal in the middle and basal coils. The tectorial membrane was completely severed from its normal attachment at the limbus and was adherent to the surface of Corti's organ in the basal and middle coils. It appeared to bulge down into the spaces occupied by the inner and outer hair cells with a membrane originating from Hensen's cells extending partly over its upper surface. (Fig. 2.) The hair cells and Deiter's cells were distorted to the extent that identification was difficult, but hair cell nuclei could be distinguished. The basilar membrane was in normal position. The spiral ganglion showed moderate reduction in the number of cells as well as the number of nerve fibres. The meninges in the internal meatus showed no abnormality. Vestibular Labyrinth. The stapes was intact. The saccular macula showed moderate postmortem degenerative changes but otherwise appeared normal. The saccule was extremely dilated, the walls lying in contact with the stapes footplate and bulging into the perilymphatic space in the common crus and in the small end of the horizontal canal. (Fig. 3.)

Fig. 1. Photomicrograph of midmodiolar section of the right cochlea showing extreme dilation of the cochlear duct with prolongation through the helicotrema ( arrow ). T h e stria vascularis seems to be partially atrophic in some areas.

Fig. 2. Photomicrograph showing organ of Corti in the middle coil of the right ear. T h e detached tectorial membrane (arrow) is adherent to the organ of Corti bulging into the Nuel's space and covered by a cellular membrane continuous from Hensen's cells.

Fig. 3- Photomicrograph of the vestibule of the right ear at the level of the stapes footplate. T h e membranous wall of the sacculus is dilated to fill the perilymphatic cistern and extends into the perilymphatic space in the small end of the horizontal canal ( arrow ).

Fig. 4. Photomicrograph through the junction of the utricle and ampulla of the horizontal canal. A bulge or herniation of the medial wall of the utricle is shown ( a r r o w ) at this point. T h e wall although thin appears to be intact.

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THE VESTIBULAR SYSTEM AND ITS DISEASES

The membranous semicircular canals were not distorted or dilated. At the junction of the horizontal canal with the utricle a definite bulge, or herniation, was present. The membranous wall of this dilated area appeared to be intact, although thin, and supported by the medial bony wall of the vestibule. (Fig. 4.) The utricular macula and the cristas appeared to be in good condition. Summary. The histopathologic findings included: (1) an extreme degree of dilatation of the cochlear duct, (2) separation of the tectorial membrane from its attachment at the limbus with adherence to the upper surface of Corti's organ and partial envelopment by an extension of a cellular layer mainly from the cells of Hensen in the lower and middle coils, (3) moderate atrophy of the stria vascularis in some areas, (4) moderate degeneration of the spiral ganglion cells and the peripheral cochlear neurons, ( 5 ) extreme dilatation of the saccule, and (6) one area of localized bulging or herniation outward of the wall of the utricle at its junction with the horizontal canal ampulla. Comment. The condition of the tectorial membrane and Corti's organ in this ear did not correspond to that found in other cases of "idiopathic" hydrops. The condition bore some resemblance to those found in cases where an inflammatory or irritative reaction had previously taken place, i.e., virus infections such as rubella, 2 measles3 or mumps.4 It is therefore doubtful if this condition had any etiologic relationship with the hydrops since it may have occurred during the recent middle ear inflammation due to the foreign body. The advanced degree of deafness which had been present previous to the introduction of the foreign substance had apparently become profound and possibly total afterwards. The extensive changes in the contour of the vestibular labyrinth corresponds to those found in four other cases of this type of hydrops reported by the author, as well as in some cases reported by others. 1 , 5 These changes suggest that the vestibular symptoms and findings in Meniére's disease may be related and have their explanation on a physical, or mechanical disturbance of the ampullary mechanism rather than to a chemical effect on the receptors. Either a slight movement of fluid in an ampulla or a disturbance of contour of an ampullary wall of any one of the canals could cause an imbalance and vertigo of the episodic type.

M E N I E R E ' S DISEASE —

MANIFESTATIONS

381

Left Ear The ear drum, malleus and incus were absent. The stapes was dislodged and the footplate lying mostly in the vestibule. The middle ear mucosa was not abnormal. The inner ear structures were well preserved. Inner ear fluid spaces showed no signs of inflammatory reaction. Cochlea. The cochlear duct (scala media) was dilated throughout its length. In part of the middle coil it filled the scala vestibuli, but in most regions the dilation was much less than that in the right ear. (Figure 5.) The stria vascularis showed some reduction in size in a few areas. The tectorial membrane was normal although lifted off the organ of Corti. The hair cells were preserved sufficiently to permit an estimate of their number but detailed counts of these and the spiral ganglion cells have not yet been made. (Figure 6.) Vestibular Labyrinth. The only notable abnormality of the vestibular labyrinth was a rupture of the wall of the saccule. (Fig. 7.) This had obviously occurred previous to fixation of the tissue because of wrinkling of the membrane at the borders of the rupture. The subluxation of the stapes footplate into the vestibule which had obviously occurred during removal of the bone suggests that the rupture of the saccule was due to the same postmortem trauma. The normal contour of the utricle and canals appeared well preserved. (Fig. 8.) Summary. The histopathologic findings included mainly the dilatation of the cochlear duct throughout with good preservation of the normal contour of the vestibular labyrinth, except for the ruptured saccule. The dislodged stapes footplate lying in the vestibule indicated postmortem trauma as the likely explanation of the defect in the wall of the saccule although an ante-mortem rupture might be expected to give a similar appearance. Comment. The histopathology found in this ear was essentially a "hydrops" limited to the cochlea. The history does not afford definite information as to whether the left ear had caused vertigo in life. The histopathology found was clearly compatible with the degree of hearing on the left.

Fig. 5. Photomicrograph of the midmodiolar section of the left cochlea showing the cochlear duct to be dilated throughout to a lesser degree than that of the right ear.

Fig. 6. Photomicrograph of the organ of Corti of the upper basal coil of the left ear. T h e hair cells are present although distorted by postmortem changes.

MENIERE'S DISEASE

MANIFESTATIONS

383

Fig. 7. Photomicrograph through the vestibule of the left ear. This shows a rupture of the wall of the sacculus (arrow) and the footplate of the stapes projected into the vestibule. These are undoubtedly postmortem artifacts.

PATHOGENESIS OF HYDROPS OF THE LABYRINTH

On the basis of the findings in this and previous cases of "idiopathic" hydrops as well as other types of hydrops seen in our laboratory and our clinical experiences, some comments seem to be warranted on the question of pathogenesis. 1. Hydrops or dilatation of the cochlear duct is well known in cases following an inflammatory reaction in the perilymphatic spaces. Examples are: serious labyrinthitis with hyperplastic changes in the perilymphatic spaces secondary to middle ear infection; leukemic exudation into the labyrinth; in experimental animals in which an inflammatory reaction has occurred in the perilymphatic spaces as a complication of certain experiments; following

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THE VESTIBULAR SYSTEM AND ITS DISEASES

Fig. 8. Photomcrograph through the vestbule of the left ear. The normal contour of the utricle and ampulla of the horizontal canal is demonstrated.

meningogenic spread to the labyrinth of a bacterial meningitis or of a viral meningo-encephalitis, etc. In such cases if recovery has

MENIERE'S

DISEASE —

MANIFESTATIONS

385

taken place hyperplastic changes are usually found in the perilymphatic spaces and if the endolymphatic system of spaces has not been destroyed it has usually been found to be dilated. There has usually been an advanced degree of degeneration of the nerve elements in this type of case. 2. Clinically, typical Menière's disease has been observed to follow surgery involving opening of the perilymphatic spaces as in fenestration surgery. Also, in rare cases it has been observed to follow acute non-suppurative otitis media. 3. The majority of cases of Menière's disease seem to be unfavorably influenced by stress, without relation to any known irritative or inflammatory process. Neural degenerative changes are usually absent or a late development in this so-called "idiopathic" type, although degeneration of ganglion cells and nerve fibres to the apex of the cochlea has been observed in one of our cases, a case of cochlear hydrops." On the basis of the above considerations it appears that in a few instances of Menière's disease a local, peripheral, irritative process may have disturbed the normal process of maintenance of the inner ear fluids. A disturbance of the chemical constitution of the endolymph seems to offer the best explanation for the development and maintenance of the hydrops or dilatation of the endolymphatic spaces. The hydrops is in itself, however, not necessarily the reason for the auditory disturbances. In the majority of cases of Menière's disease there is a clinical indication that stress aggravates the symptoms. This supports the hypothesis that an alteration of secretion due to an autonomic imbalance may be traced to the hypothalamus.

DISCUSSION O F F U N C T I O N A L

A uditory

DISTURBANCES

Disturbances

The condition of the peripheral sensory epithelium and neural apparatus in postmortem human material has sometimes not permitted a reliable assessment as to the premortem condition. Also, the reported findings in specimens from humans on light microscopy and electron microscopy still require comparisons with the

386

THE VESTIBULAR SYSTEM AND ITS DISEASES

normal for further verification. T h e presently available evidence, however, indicates that the degeneration of nerve elements occurs only as a late stage of the disease in the idiopathic type of hydrops. T h e characteristic gradual raising and lowering of the hearing threshold and the accompanying changes in intensity of the tinnitus seem to preclude explanation of the auditory disturbances on the basis of any sudden event such as rupture of Reissner's membrane. Although a fairly rapid improvement in hearing may follow an episode of severe vertigo with vomiting and diarrhea, this can be more logically attributed to the drastic change produced in fluid balance than to other causes. T h e wide fluctuation in hearing for low tones and the lowpitched tinnitus has suggested an explanation on the basis of an inner ear conduction impairment. However, the presence of recruitment, the frequent lowered tolerance for loud sounds, the occurrence of diplacusis in some instances and the eventual slow development of denervation of the peripheral neuron all seem to indicate a degenerative or trophic disturbance affecting the sçnsory epithelium and eventually, the peripheral neurons rather than an inner ear conductive impairment. T h e possibility that a temporary sensorineural impairment of hearing may occur due to an inflammatory or irritative reaction is well known in fenestration and stapes surgery, and also as a reversible toxic impairment due to drugs, such as salicylates and quinine, is well known. O n the basis of the evidence presently available it appears that the auditory disturbances can be best explained as an alteration in chemical constitution of the labyrinthine fluids and also that the dilatation of the cochlear duct is another expression of the same condition. Vestibular

Disturbances

T h e episodic nature of the spells or attacks of vertigo and such characteristics as the rapid and sometimes sudden onset, the extreme variation in duration, the sometimes equally sudden or rapid cessation and the unpredictability of onset in most instances suggests a different type of disturbance than that which involves the auditory receptors.

MENIERE'S

DISEASE —

MANIFESTATIONS

387

A sudden onset could be logically explained on the basis of rupture of the membrane in the region of an ampulla, or of the saccule, but the other widely variable characteristics just mentioned seem not to be adequately explained on this basis. Other observations of significance, as to the nature of the functional disturbance are: the occasional observation of a purely vertical nystagmus during an attack and the observation that acute episodes have occurred even after the horizontal and superior vertical canal have been destroyed. These suggest that one single canal may be capable of producing an attack. The occurrence of postural vertigo and positional nystagmus in some instances between attacks may also be explained on the basis of partial disruption of function. These and other characteristics suggest strongly a mechanism other than a simple pressure phenomenon acting on the sensory epithelium, or a toxic or metabolic effect such as might explain the more gradual changes in the auditory manifestations. Evidence has been demonstrated in five ears in the author's collection of herniations or irregular dilations at the point of junction of the utricle and one or more ampullae. Similar observations have been made by other observers who interpreted the findings as "ruptures." It is apparent that if ruptures had occurred in such instances, healing has subsequently taken place in such a way as to leave a bulge or sac supported by the bony wall. In most instances, however, the contour of walls can also be explained as a simple bulge at a weaker area in the membranous wall. The presence of extensive dilatation of the saccule in most specimens and its tendency to bulge into the perilymphatic spaces of the common crus and small end of the horizontal canal is evidence of the ability of the membrane to expand with gradual increase in pressure, rather than to rupture as might occur from sudden violent stimulation or instrumentation. In two of the author's specimens a ruptured saccule was found. The condition of the membrane indicated rupture before fixation of the specimen. In one there was no indication of physical trauma and rupture may have occurred during life. In the specimen presented in this report the presence of part of the stapes footplate in the vestibule, which had obviously occurred postmortem, strongly indicated trauma as the cause of the ruptured saccule.

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THE VESTIBULAR SYSTEM AND ITS DISEASES

The question of "rupture" or of a simple "bulging" of weaker portions of the walls into available space is, however, of secondary importance. Either explanation supports a mechanical rather than a chemical or metabolic effect on the vestibular receptors as the more probable explanation of the episode of vertigo. Hydrops

Limited

to the

Cochlea

One such case has previously been reported from our laboratory. A second case which appears to warrant such a diagnosis is now presented. The left ear of this case provides further evidence of the existence of a hydrops limited to the cochlea. It is an occasional clinical observation that auditory disturbances suggestive of hydrops may precede by several years the onset of episodic vertigo. Hence, although the diagnosis of cochlear hydrops can sometimes be made clinically it represents an early stage of Menière's disease. SUMMARY

A case of bilateral hydrops of the labyrinth has been presented. In one ear the process involved both the cochlear and the vestibular parts of the labyrinth. In the other ear the hydrops was limited to the cochlea. On the basis of this case as well as six other ears with hydrops of the so-called idiopathic type and of hydrops of several other types in the author's collection some discussion of pathogenesis and the cause of the functional disturbances has been offered. REFERENCES

1. Hallpike, C. S., and Cairns, H.: Observations on the Pathology of Ménière's Syndrome. J. Laryng. & Otol. 53: 625 (October), 1938. 2. Lindsay, J. R., Caruthers, Douglas G., Hemenway, W. G., and Harrison, Spencer: Inner Ear Pathology Following Maternal Rubella. Ann. Otol., Rhin, and Laryng. 62: 1201 (December), 1953. 3. Lindsay, J. R., and Hemenway, W. G.: Inner Ear Pathology Due to Measles. Ann. Otol., Rhin, and Laryng. 63: 754 (September), 1954.

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MANIFESTATIONS

389

4. Lindsay, J. R., Davey, Patricia R., and Ward, Paul H.: Inner Ear Pathology in Deafness Due to Mumps. Ann. Otol., Rhin, and Laryng. 69: 918 (September), 1960. 5. Rollin, H.: Zur Kenntnis der Labyrinthhydrops und des durch ihn bedingten Ménière. Hals-, Nasen-u. Ohrenarzt (Teil 1) 31: 73 (March), 1940. 6. Lindsay, J. R., and v. Schulthess, G.: nA Unusual Case of Labyrinthine Hydrops. Acta oto-laryng. 49: 315, 1958.

Some Observations on the Character and Mechanism of Spontaneous Nystagmus in Subjects with Tumors of the VIII Nerve C. S. Hallpike, M.D., F.R.C.P., F.R.C.S.*

Spontaneous nystagmus is a familiar finding in patients with unilateral tumors of the VIII nerve, and in this communication I propose to attempt an analysis of its neurological mechanism. As my starting point I shall take the spontaneous nystagmus and other disturbances which follow unilateral destruction of the VIII nerve. Fig. 1 is taken from Magnus' monograph and shows a rabbit shortly after destruction of the left labyrinth. The ipsilateral limbs are flexed, the contralateral limbs extended. The neck is turned to bring the affected labyrinth undermost and spontaneous nystagmus is present to the right. The condition is rapidly modified by the operation of certain processes of central compensation. The nystagmus ceases and the neck torsion diminishes. The course pursued by the abonrmalities of neck and limb posture varies in different species. Thus, while in the rabbit the neck torsion is usually severe and its correction incomplete, in man it is seldom a conspicuous feature. In all species, however, the disappearance of the spontaneous nystagmus is regularly observed. It is possible to suggest that in this course of events two mechanisms are concerned. Of these, one is dependent upon the horizontal canals and is directly concerned in inducing nystagmus. It is intrinsically nystagmogenic. The second has to do with sus* Aural Physician and Director, Otological Research Unit, Medical Research Council, The National Hospital, Queen Square, London.

390

MECHANISM OF SPONTANEOUS

NYSTAGMUS

391

tained conjugate eye deviations and is dependent upon the otolith organs. It is not directly concerned in inducing nystagmus. But it may influence nystagmus when this is induced through the canal mechanism. First let us take the canal mechanism. As we know from the work of Lowenstein and Sand ( 1 9 3 6 ) each of these organs is the source of a resting nervous discharge. From other evidence we know that this tends to produce nystagmus to its own side, the slow component being directed towards the opposite side. Normally, the action of each canal is opposed and balanced by that of its opposite, and nystagmus only occurs if the balance is upset. Now, this can be done in several ways. Thus, hot caloric stimulation of the right canal increases its resting discharge and causes nystagmus to the right. To stop it we must restore the balance. We can do this by stopping the stimulus. But we can do it as well by applying an equal hot stimulus to the left canal. The same imbalance will result if we destroy one horizontal canal or its nerve, either in isolation or as part of a labyrinth destruction or VIII nerve section. Again we shall see nystagmus to the opposite side. It need hardly be said that one of the early effects of an VIII nerve tumor is to destroy the VIII nerve, and we shall in due course consider whether the nystagmus of an VIII nerve tumor could be explained in terms of canal imbalance.

392

THE VESTIBULAR SYSTEM AND ITS DISEASES

Nystamographically, canal imbalance nystagmus has certain well known characteristics. In particular, it is checked by visual fixation and enhanced without it. In Fig. 2 are shown some records of canal imbalance nystagmus resulting from hot caloric stimulation of the right horizontal canal. The records were taken just at the end of the reaction, and no nystagmus is therefore visible while fixation is maintained, with gaze straight ahead, to the right or to the left. At the points indicated, visual fixation is eliminated by darkness and brisk nystagmus to the right appears. In accordance with Alexander's Law it is more marked with the eyes deviated to the right than to the left. We can now turn our attention to the processes of central compensation, to which it is customary to attribute the spontaneous disappearance of this canal imbalance nystagmus which follows a unilateral section of the VIII nerve.

30

Right

Τ DARKNESS

30

L e f t —>

^

I

Fig. 2. Caloric nystagmus effects of darkness and eye deviation.

Let us consider the elements of the vestibular nuclei which are associated with the horizontal canals. At rest, these nuclear elements receive the resting discharges, equal and opposite, of their associated canals. If the discharge of the one canal, let us say the

MECHANISM OF SPONTANEOUS NYSTAGMUS

393

left, is interrupted by division of the left VIII nerve, a canal imbalance nystagmus will result. Now, we come to the process which brings about its disappearance. Here, it is said that the left nuclear elements, being deprived of the resting discharge from the left canal, are in some way able to establish an activity of their own. In this way their output is brought into balance with that of the right nuclear elements and the nystagmus ceases. If, now, a lesion is made of the left nuclear elements themselves, then once more we have a state of imbalance. The nystagmus returns and is now more lasting. So far, I have confined my remarks upon the nystagmic sequelae of unilateral VIII nerve destruction to the part played by the horizontal canals and their associated nuclei. However, another mechanism which is also concerned is that of the vestibular tonus elements which exert a certain controlling eifect upon conjugate eye deviations. As I have argued in my communication on the directional preponderance of caloric nystagmus, the control is exerted by groups of elements situated caudally in the vestibular nuclear complexes on the left and right sides of the brain-stem. Peripherally, each group is thought to receive a tonic in-flow from the otolith organs of the ipsilateral labyrinth, in all probability the utriclc. Each group, at rest, tends to produce contralateral eye deviation, and in this is normally opposed and balanced by its opposite. From this it would follow that any one-sided lesion of these tonus elements would bring about an imbalance, with ipsilateral deviation of the eyes. Since the lesion in question could well be an VIII nerve tumor the matter is clearly relevant to our subject, and to it I shall later return. We can now say something of these tumors themselves, and I speak in particular of the commonest of these, the acoustic neurofibroma. As shown by Hardy & Crowe ( 1 9 3 6 ) , this seems to originate in the vestibular elements of the VIII nerve in the region of Scarpa's ganglion and for a time, often a long time, is confined to the region of the porus acusticus. In this, the first or otological stage of its development, the clinical course of the tumor is notoriously insidious. For this the reason is that the destruction of the vestibular nerve is very slow, and with it the process of central compensation is able to keep pace. Hence, a patient may

394

THE VESTIBULAR SYSTEM AND ITS DISEASES

well progress to the point of complete destruction of the vestibular nerve without at any time experiencing any symptoms of vestibular dysfunction. The tumor then enters upon its second or neurological stage. It emerges from the porus acusticus, presses upon the brain-stem, and now for the first time we see nystagmus. It is important to appreciate that when this appears it is due to involvement of the brain stem and, furthermore, of the brain-stem in which the process of central compensation for the destruction of one VIII nerve is already far advanced or complete. Having outlined some of the anatomical and physiological factors which provide the background for the spontaneous nystagmus of an VIII nerve tumor, we will now consider the clinical material which we have used for its study. It consisted of a series of 90 subjects examined at Queen Square in the last 15 years. The tumors were all neurofibromata arising from the nerve itself and we have limited our selection to those cases, by far the most common, in which the nystagmus occurred only in the horizontal plane. Furthermore, in order to simplify analysis and discussion, we have considered all tumors of the right VIII nerve as if they were tumors of the left, and have transposed accordingly the laterality of their nystagmus and other relevant signs. In effect, therefore, our material may be said to consist of 90 cases of neurofibroma of the left VIII nerve. The data are presented in Table I and establish the fact that the nystagmus is essentially bilateral occurring, that is to say, with gaze deviation either to left or to right. Furthermore, there is a marked preponderance of the nystagmus to the right. We believe, too, that in the majority of cases the character of the nystagmus tends to develop in a certain sequence — that it appears first as Type 7 developing, it may be, into Type 4, or more often into Type 5. We cannot, of course, be quite certain of this sequence, since in many of our cases the nystagmus type recorded was that seen at our first and only examination. In consequence, if we take as an example a case of Group 5 it could be claimed that the nystagmus, from the time of its first appearance, had been present unchanged in this particular form.

MECHANISM O F SPONTANEOUS

s t u j y op

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NYSTAGMUS

395

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NYSTAGMUS ABSENT

75 CASES

15 CASES

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NYSÎ WHOLLY OR PREPGNDE& JÍTLY TO PICHT. 35 CASES

T a b l e 1.

While this possibility cannot be denied, the strong directional pattern of the data presented in the Table, together with the fact that the sequence in question has been actually observed in some of our subjects, strengthens our belief that it is generally followed in the others. Let us consider next the character of the nystagmus as observed in the course of routine clinical examination. Whether this is equal to both sides or preponderant to the right, it is nearly always possible to observe that the nystagmus to the left is rather slower and a little less regular than that to the right. However, this difference may be small and it must be said, too, that both to left and right the nystagmographic wave forms usually present a striking similarity. We anism extent could

now come to our of the nystagmus. to which a canal hardly arise from

central problem: the neurological mechHere, an obvious point of inquiry is the imbalance could play a part. If so, this destruction of the VIII nerve itself, since

396

THE VESTIBULAR SYSTEM AND ITS DISEASES

with the slow rate of its destruction no imbalance at the nuclear level could develop; an inference which is validated by the very common finding of complete loss of the left caloric responses in the absence of any spontaneous nystagmus. As a further possibility we might expect a canal imbalance to result from tumor pressure affecting the canal elements of the left vestibular nuclei. For this there is some nystagmographic evidence. Thus, in some cases of our Group 7, in whom the nystagmus is of the 1st degree only to the right, we have found that it may display to a minor degree the same enhancement in darkness as that which follows section of the left VIII nerve. However, the finding is not a common one and soon seems to become obscured as the nystagmus develops into its characteristic bilateral form. We have accordingly concluded that although canal imbalance may play a part in the early stages of the spontaneous nystagmus of an VIII nerve tumor, the part is a small one. Other and more important mechanisms are concerned and on the nature of these, nystagmographic studies have provided much information. In Fig. 3 are shown the nystagmographic findings in a characteristic case. This is taken from Group V of our series, and therefore exhibits 2nd° nystagmus to the right with 1st" nystagmus to the left. The records are taken in the light with the eyes open, with visual fixation maintained upon the patient's thumb, supported before

C.W.D.

Age 58

L e f t JLooustio Neurofibroma

Spontaneous Nystagmic 2nd 0 B i g h t ,

1st0 Left.

K f f e o t on Hysta&us at Conjugate D e v i a t i o n s . V i s u a l f i x a t i o n maintained. Right 30v

Left

30 »•

S i g h t 30°

Left

Fig. 3.

30

MECHANISM OF SPONTANEOUS NYSTAGMUS

397

him upon a rest at various known angular deviations to left and right of the straight ahead line. With gaze straight ahead slight but definite nystagmus is seen to the right. With gaze to the right nystagmus is increased, well sustained and extremely regular. With gaze to the left lst° nystagmus to the left is present. It has a rather smaller amplitude than that to the right. Its frequency, too, is less and also the speed of its slow component. The records presented in Fig. 4 show the effect upon the nystagmus of abolishing fixation. First, as before, the patient in the light fixes his gaze upon his thumb deviated to right and left, and we see the nystagmus to right and to left. Between the arrows there is darkness, and the patient makes no attempt to maintain fixation upon his thumb. We can say that under these conditions fixation, both visual and proprioceptive, ceases. Both from the left and the right the eyes swing back towards the mid-line and the nystagmus ceases. The records presented in Fig. 5 show what happens to the nystagmus when we adopt a rather different test procedure. First, again the patient in the light fixes his gaze upon his thumb deviated to right and left. Initially there is lst° nystagmus to right and to left.

C.W.D.

Age 38 L e f t Aooustic Neurofibroma

E f f e c t of darkness upon Nystagmus. Fixation on Thumb. ^

30u

Fig. 4

"i r

Not maintained i n Darkness. DARKNESS

J^

398

T H E VESTIBULAR S Y S T E M AND ITS DISEASES

C.W.D.

Age 38

Left Acoustio Neurofibroma

Effect of Darkness upon Nyetagmua. fixation on Thumb.

u. or

i

Maintained in Darkness.

DARKNESS

I

DARKNESS

1 Fig. 5.

Between the arrows visual fixation is abolished, but the patient then endeavours to maintain fixation upon his thumb by means of his proprioceptors. It will be seen that both for gaze to the right and to the left the conjugate ocular deviations are quite well maintained, and with this some nystagmus persists. Its character, however, changes. It now has a larger amplitude but is irregular and a great deal slower, particularly in respect of the speed of its slow component. It is therefore clear that this kind of nystagmus differs radically from the canal imbalance nystagmus which follows section of the VIII nerve. In that, it will be recalled, the nystagmus tends to be suppressed by visual fixation, but is enhanced without it. In the nystagmus shown in Figs. 3, 4 and 5 the situation is very different. The elimination of fixation, far from enhancing the nystagmus, tends to abolish it. Expressed in reverse the nystagmus is increased by fixation, and seems to depend upon it. It is often called a 'fixation nystagmus' and Gordon Holmes and others have so described it. There is however, a considerable difficulty about this. The term fixation is best reserved for the maintenance upon the fovea of a particular object of interest. It is a purely visual mechanism. But, as will be seen from the records shown in Figs. 3, 4 and 5, what determines the nystagmus is not fixation per se but

MECHANISM

OF SPONTANEOUS NYSTAGMUS

399

rather the maintenance of a certain gaze deviation. If for its maintenance the visual fixation mechanism is used, as in Fig. 3, then the deviation is well maintained, with nystagmus which is rapid and of small amplitude. But if, in the absence of vision (Fig. 5) the deviation is maintained by means of the proprioceptive mechanisms, the nystagmus still occurs. But the deviation control is then less precise and the nystagmus is therefore less regular and of larger amplitude. Since, therefore, the nystagmus depends upon the maintenance of gaze deviation, it seems both correct and convenient to designate it a deviation maintenance (D.M.) nystagmus. Now that we have specified the characteristics of the spontaneous nystagmus in a typical case of tumor of the left VIII nerve, we can define our task more closely. We have to explain two things; firstly, why the tumor by virtue of its growing pressure upon the left side of the lower brain stem should produce in definite succession first nystagmus to right followed closely by nystagmus to the left. Secondly, why the nystagmus both to right and left should be of the D.M. type. As we shall argue, the answers to these questions are to be found in the derangement, resulting from tumor pressure, of certain brain stem mechanisms which regulate conjugate eye deviation in the horizontal plane. This phrase 'conjugate eye deviation' I propose for simplicity to abbreviate to the single word 'deviation.' The subject is one of great complexity, and has been notably illuminated by the work of Bender (1964) and his associates. They used the electrical stimulation technique in monkeys and among the matters which they considered was the contralateral deviation which, as we have known from the time of Ferner, is brought about by stimulation of one cerebral hemisphere. Although Bender confirmed the occurrence of the deviation, he found little to validate the opinion that it is dependent upon certain localized regions of the hemisphere such as area 12 of the frontal cortex which has for so long figured in text book treatments of the subject. Instead, Bender inclines to the view that the deviation depends upon a mechanism which is much more diffusely distributed throughout the hemisphere. Bender also provides valuable information upon the topography of the pathway from hemisphere to brain stem, whereby this devi-

400

THE VESTIBULAR SYSTEM AND ITS DISEASES

ation mechanism is subserved. He concludes that above the level of the oculomotor nuclei the pathway is ipsilateral in respect of the activating hemisphere. Just below this level, however, it crosses to the opposite side and continues caudally to below the level of the VI nerve nuclei. In other words, the pathways for left deviation crosses the mid-line just below the level of the oculomotor nuclei. Above this level it lies on the right; below it on the left. The conclusions of Jane Hyde ( 1 9 6 4 ) accord very closely with those of Bender. Hyde also used the Electrical Stimulation technique and was able to identify a left deviation mechanism on the right side of the brain stem near to the superior corpus quadrigeminum. This could be traced downwards across the mid-line to the left side of the lower brain stem. The topography of the pathway is shown in these brain stem diagrams presented in Fig. 6 reproduced from Hyde's paper. Her observations certainly seem to show that within voluntary deviation to the left is subserved by this ipsilateral pathway lying on the pons and medulla. In this situation it is clearly vulnerable to pressure by a left acoustic neurofibroma in the neurological stage of its development. So much for the mechanism of the voluntary eye deviations. I shall return to this but, meanwhile, I wish to consider the part played in the control of eye deviation by the tonus elements of the vestibular nuclei. In my communication on the subject of Directional Preponderance, it was argued that an important part in the regulation of deviation is played by tonic influences emanating from groups of elements situated caudally in the vestibular nuclear complex on the left and right side of the brain stem. Each group tends at rest

MECHANISM OF SPONTANEOUS

NYSTAGMUS

401

to cause a contralateral deviation, and in this is normally opposed and balanced by its opposite. From this it would follow that any onesided lesion of these tonus elements would bring about an imbalance, with ipsilateral deviation. Thus, in the case of a left acoustic neuroma involving the tonus elements on the left side of the brain-stem, there would be slight deviation to the left. In Fig. 7 the interplay of these forces has been put into diagrammatic form. It may be described as a bifocal section of the lower brain stem. Bifocal, because it shows the voluntary deviation elements (Vol.) at a level rather above the VI nerve nuclei, together with the vestibular tonus elements (Ves.) at a lower level. The eyes are represented by the pointer. On it, each voluntary mechanism exerts an ipsilateral, each vestibular mechanism a contralateral pull. With deviation to the right, the right voluntary mechanism acts with the left vestibular mechanism, their opposites being inhibited. Clearly, if both voluntary mechanisms are weakened there will be weakness of deviation in either direction. But the same or similar result will occur if both vestibular mechanisms are weakened, since in this event, with deviation in either direction, the

i

L £ FT

ACOUSTIC

Fig. 7.

y

RICH

402

THE VESTIBULAR SYSTEM AND ITS DISEASES

operative voluntary mechanism will be deprived of the normal supporting action of its associated vestibular mechanism. Let us now consider the effect upon these elements of a left acoustic neurofibroma in its neurological stage. In most cases this is first exerted upon the vestibular mechanism with resultant weakening of contralateral deviation. This explains the Deviation Maintenance type of spontaneous nystagmus to the right which is so characteristically the first to appear. At this time or a little later, the left voluntary mechanism begins to be affected. This causes weakness of ipsilateral deviation and explains the deviation maintenance type of nystagmus to the left which is so characteristic of the later stages of the tumor. To return now to our objective: to explain the characteristics and development of the spontaneous nystagmus of a left acoustic neurofibroma in the neurological stage of its development. This explanation can now be summarized. Tumor pressure first affects the left vestibular tonus elements and this causes the Deviation Maintenance type of spontaneous nystagmus to the right. At the same time, but usually a little later, the left voluntary deviation elements are affected and this is the cause of the Deviation Maintenance type of spontaneous nystagmus to the left. Both to right and to left the nystagmus is due to weakening of a deviation mechanism. Hence, in both directions the nystagmus is of the Deviation Maintenacne type. Certain differences can usually be observed. Thus, the ipsilateral nystagmus may be noticeably slower than the contralateral, and of larger amplitude. That there should be a difference is not perhaps surprising. Certainly it must be argued that in the control of deviation the two mechanisms concerned have a close functional similarity. Nevertheless, we should not expect this to be complete. In what I have said of these nystagmic mechanisms, I have confined myself to the motor aspects of eye deviation control. I need hardly add that important subsidiary mechanisms are also likely to be involved. Thus, in the normal subject a very exact control of deviation is provided through the reflex mechanism of foveal fixation, which has recently been studied with such precision by Ditchburn and his co-workers (1955 ).

MECHANISM OF SPONTANEOUS NYSTAGMUS

403

In the normal subject, too, good control of voluntary eye deviation is possible in the absence of visual fixation through the operation of the proprioceptive mechanisms of the extra ocular muscles. The importance of these subsidiary mechanisms is particularly well illustrated in the case of a typical canal imbalance nystagmus which immediately follows a unilateral VIII nerve section. Here, if active visual fixation be permitted, then a very brisk nystagmus can be suppressed. In this situation, of course, the subsidiary mechanisms are intact. By contrast, however, we should have to expect their derangement in the neurological stage of an acoustic neurofibroma, and this must accordingly be a factor of importance in the nystagmus which then occurs. As to the neurological basis of this derangement, it seems clear that for their proper working the subsidiary mechanisms in question must depend upon a measure of cerebellar control, exercised through cerebello-fugal pathways. The pathways in question must traverse the closely crowded zone of the brain-stem which has been affected by the tumor, and are thus themselves subject to functional derangement. In this sense, therefore, it would seem proper to say of the spontaneous nystagmus of an acoustic neurofibroma that in part, at least, it may be of cerebellar origin. REFERENCES

1. Bender, M. B. & Shanzer, S.: The Oculomotor System, Harper & Row, New York & London, 1964, p. 81. 2. Ditchburn, R. W. & Fender, D. H., 1955: Optica Acta, 2, 128. 3. Hardy, M. & Crowe, S. J., 1936; Arch. Surgery, Chicago, 32, 232. 4. Hyde, J. E.: The Oculomotor System, Harper & Row, New York & London, 1964, p. 141. 5. Löwenstein, O. & Sand, Α., 1936: J. Exp. Biol. 13, 416. 6. Magnus, R.: Korperstellung, Julius Springer, Berlin, 1924.

Benign Positional Vertigo M. Spencer Harrison, M.D., F.R.C.S., F.R.C.P.

The researches of Ewald (1892), Mach (1875), Breuer (1874) and Crum-Brown (1875) during the latter part of the last century followed by the animal work of Magnus and De Kleyn (1924) directed attention on the otoliths as the gravity receptor organs. Hence when Barany (1921) first became aware of the strange and dramatic vertigo which occurs in certain head positions he was led to describe the condition as otolith nystagmus. Since then many papers have been written on the subject. Nylen's (1931) clinical and animal studies are well known, particularly his monograph on positional nystagmus occurring in intracranial tumours. In a survey of the subject in 1950 he gives a bibliography of no less than 297 papers by 192 authors. The clinical significance of a positional type of nystagmus lies in the fact that its demonstration affords proof of an organic disorder of the vestibular mechanism. Furthermore, the characteristics of the nystagmus itself may be of help in localising the lesion and is often also of prognostic value. In general the transitory forms are associated with benign lesions, while in the persistent forms the prognosis is uncertain. Unfortunately, though clinical progress has been rapid, it has not been possible as yet to reach agreement on the nomenclature and classification of the forms of positional nystagmus, and the neural mechanism underlying the condition is not clear. Several of the classifications proposed are known by the authors' names, those of Nylen (1950) and Lindsay (1951) (Fig. 1) are probably best known but others have been proposed by Seiferth (1937), Aubry (1954) and Aschan (1956). Nylen and Lindsay base 404

BENIGN

LINDSAY'S Type

I

(a)

(Ì95ÌÌ

II

Direct/on

CLASSIFICATION nystagmus

(b)

limited

(c)

early

(d)

delayed appearance nystagmus

duration

of

nystagmus

appearance

of

nystagmus

Positional

(a)

nystagmus

(b)

spontaneous by pos iti on

fi

405

VERTIGO

ma i nta i ned

Direction-chanqinq

Type

POSITIONAL

of

Nystagmus

only

on

nystagmus ing

positioning increased

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Fig. 1.

their classification on the direction and duration of the nystagmus. If the direction of the nystagmus changes with the head position then it is called 'direction changing' type I. If the direction does not change it is called 'direction fixed' type II. If the nystagmus does not behave in either way regularly, but varies f r o m Type I to Type II it is termed irregular type III. T h e nystagmus type I is usually maintained as long as the position of the head is steady and is called 'tonic', or by Aschan 'persistent'. In type II it lasts only for a limited time and it is termed 'transitory'. In England valuable contributions have been m a d e by Hallpike and his co-workers. In their study of positional nystagmus published in 1952 Dix and Hallpike paid special attention to the particular variety of the disorder which was described by Barany ( 1 9 2 1 ) . (Fig. 2 ) This was of the 'direction fixed' type and stress was laid upon certain clinical features which were obviously of considerable importance. Thus the character of the nystagmus was essentially paroxysmal and the course of the disease was in the

406

THE VESTIBULAR SYSTEM AND ITS DISEASES

DIX I

II

& HALLPIKE'S

(1952)

Benign

paroxysmal ver t i go

Central

continuous nystagmus

CLASS

IFICATION

positional

positional

Fig. 2.

majority of cases essentially benign, that is to say it was seldom associated with evidence of any progressive intracranial disease and tended to recover with time and simple sedative measures. For these reasons the name benign paroxysmal positional nystagmus was given to it. Dix and Hallpike were also able by means of a clinicopathological study to show that in accordance with Barany's views there was an organic lesion due in all probability to vascular occlusion of the otolithic apparatus of one labyrinth. To their observations further references will be made. Type II is occasionally associated with a condition which is not benign. Riesco ( 1 9 5 7 ) described this type of nystagmus in a patient suffering from an astrocytoma of the cerebellar vermis. Fernandez ( 1 9 5 9 ) and his associates have shown that lesions of the nodulus in the cat may produce type II nystagmus. They have also shown that in the cat persistent always changed into transitory nystagmus with paroxysmal characteristics and they consider that cerebellar lesions in man may be accompanied by any form of positional nystagmus. Unfortunately similar lesions in man and animals in many cases produce different types of nystagmus and in animals compensation is rapid. Positional nystagmus type I is thus a clinical sign of what is frequently a central vestibular affection. In my experience it is comparatively rare. On the other hand type II, especially the benign paroxysmal type of Dix and Hallpike is both common and important and I propose to start by reviewing our experiences of this condition beginning with its clinical features. Symptoms. The story given by the patient is characteristically that the giddiness comes on when he lies down in bed or when he turns over in bed, or when such a position is taken up during the

BENIGN

POSITIONAL

VERTIGO

407

day: for instance, in lying down beneath a car or in throwing the head backward to paint a ceiling. The patient sometimes, although not always, recognises that the onset of the vertigo is associated with this critical position and will say that he does his best to avoid it. He may sometimes also say that he has noticed the phenomenon of adaptation which Barany ( 1 9 2 1 ) described so well in his patients, and can cause his vertigo to disappear by maintaining his head in the disagreeable position, or by taking up this position slowly. The vertigo is essentially transient and it is generally accompanied, but not always, by nausea and, it may be, by vomiting. Cochlear symptoms are generally absent; one other symptom of interest is of discomfort, and it may be of tenderness in the occipital region which is present in the many types of vertigo. The nystagmus is induced, as Barany (1921) said, by a critical position of the head in space. The test procedure used to elicit it is made as simple as possible, but it is easy to produce adaptation by slow head movements without detecting the nystagmus, so that the movement must be brisk enough to show this response. On the other hand a severe nystagmic response is very disturbing and if the history indicates this then the patient is first laid supine upon a couch and asked to keep his eyes focussed on the examiner's glabellar region during the whole of the test, his head is then turned over first to one side for ten seconds and then the other. Otherwise the patient is sat upright at once and his head turned 30-45 degrees to one side and backwards as though he is looking at a plane over his shoulder. The examiner then grasps the patient's head firmly between his hands and briskly pushes the patient back into the critical position. This last procedure is well explained in the drawing taken from one of Hallpike's (1953) papers. (Fig. 3.) Barber ( 1 9 6 4 ) has described a more detailed method of testing. The reaction which results calls for some detailed description. First of all there is nearly always a marked latent period. Sometimes this is as long as 5 / 6 seconds. Occasionally it is very short and indeed the reaction may seem to come on at once. This, however, is uncommon. The onset of the nystagmus is nearly always preceded by an appearance of distress. The colour may change; the patients may close their eyes, cry out in alarm and make active efforts to sit up again. At this point it is necessary to reassure the patient and maintain the position of the head. The

408

THE VESTIBULAR SYSTEM AND ITS DISEASES

PROCEDURE USED T O ELICIT P O S I T I O N A L NYSTAGMUS

Fig. 3.

nystagmus is chiefly rotatory, the direction of the rotation being towards the undermost ear. In addition to the rotatory element there is generally a horizontal component which is again directed towards the undermost ear. The nystagmus increases in rapid crescendo in a period which may be as short as 2 / 3 seconds, or as long as 10 seconds. Thereafter it rapidly declines and the patient's distress is relieved. If the patient is then allowed to sit up, a recurrence of the vertigo in a slighter form is generally noted, and if the eyes are examined at this point nystagmus can be seen, the direction of which is, on the whole, reversed. If this is allowed to disappear and the critical supine position is again assumed, the nystagmus again makes its appearance but generally in slighter form and disappears more rapidly than before. After two or three repetitions of this test it is generally found that the reaction has been eliminated altogether and cannot be elicited except, as Barany ( 1 9 2 1 ) pointed out, after a period of rest. It is important to emphasize that as a result of the paroxysmal nature of the condition it is sometimes impossible to demonstrate the vertigo. Schiller et al ( 1 9 6 0 ) describe this as a false negative. The symptoms are however so typical in most cases that testing

BENIGN

POSITIONAL

VERTIGO

409

appears hardly necessary, but unfortunately a more difficult situation arises in a case of positional nystagmus, apparently of the benign type, in which the characteristics of the nystagmus are not entirely clear cut. This is the atypical or irregular type, type III. Thus, although the vertigo may be severe and the nystagmus paroxysmal, its direction may be atypical. Here, mistakes are liable to arise and in some the diagnosis of a benign lesion has been followed by the development of a clearly central type of positional nystagmus accompanied by obvious neurological and other evidence of a neoplastic deposit within the vetibulo-cerebellar connections. It follows that in patients presenting with what appears to be a benign type of positional nystagmus, any qualitative deviation of the nystagmus from the typical pattern should put the examiner on guard against the possibility of a serious central lesion. Preber et al (1957) have found that the electro-nystagmogram with the eyes closed in type II is not so well defined as might be expected. The clinical findings in two different series in my own practice have been analysed. Firstly, a study has been made of the characteristics of positional nystagmus as seen in a series of subjects found to exhibit this phenomenon, together with a study of the associated clinical features and the possible aetiological factors concerned. Secondly, the vestibular signs and symptoms observed in a consecutive series of 108 subjects admitted because of head injury to a particular hospital have been analysed. Here again, particular attention has been directed towards the frequency of occurrence and characteristics of the phenomenon of positional nystagmus. Series /. The case notes of 289 consecutive cases of positional nystagmus were reviewed, the majority of whom were seen in hospital Out-Patient Departments. (Fig. 4) Sex and age distribution was as follows: Age 0-20 Type 1 I Type II 3 Type III

21-30 8 18

31-40 12 34

41-50 26 65 2

51-60 6 74 3

61-70 —

33 1

+70 —

3

Totals 53 230 6

It will be seen that in the great majority, 230 of the 289 cases (Fig. 6 and Fig. 7 ) , the positional nystagmus was of type II, oc-

410

THE VESTIBULAR SYSTEM AND ITS DISEASES

CLASS

IF¡CATION

POSITIONAL (289

No.of cases

Type

N/len

I

53

NYSTAGMUS CASES)

Character of : Nystagmus

Vertigo

Direction

Unusual

Cause

Unuilly

central

changing. Sustained. Obi ¡que. Case} Nyle'n II 230 Di χ and Ha I I ρ ike Benign Paroxysmal

Direction fixed. Trans I ent .

Marked

Infec t/on : Local ear Genera I Head in jury Τ ox i c Centra I

ParoxysmaI. RotationaI,

Nylex

III

6

Atypical. Nystagmus clear cut

Idiopathic

Inconstant

Uncertain

not

Fig. 4.

curring nearly always in the age group 40-60 in which the incidence of vascular insufficiency is important. It should be borne in mind that if the other causes of Type II are eliminated the age incidence of benign idiopathic nystagmus is raised (Fig. 7 ) . This gives some support to the view that small vascular occlusions affecting the otolith apparatus is the commonest aetiological factor. In 206 ( 9 0 % ) of the 230 patients with type II nystagmus the chief complaint was of rotational vertigo and in 6 9 % of these the symptoms had been noticed in bed, particularly when turning over (Fig. 8 ) . In none of the cases was there present any abnormal neurological sign or symptom apart from the eighth nerve system. In 152 cases some evidence of local ear disease was found and in 31 an obvious infective process was present, tonsillitis, dental sepsis, sinusitis, syphilis or tuberculosis. It is interesting that Schiller and Hedberg (1960) considered that in 26 per cent of their series the

140

I3 31 46

BENIGN POSITIONAL

POSITIONAL

411

VERTIGO

NYSTAGMUS

(289

cases)

Male

Ferna I e

Total

Type

I

33

20

53

Type

I I

Ì 16

/ 14

230

3

3

Type

I II

6

Fig. 5.

positional nystagmus was associated with anxiety neurosis and that the cause in these cases was emotional. A small number ( 6 ) of patients in the present series have stated that worry or overwork were present at the onset of the condition. A nystagmus similar to type II also occurs in patients after general anaesthesia or after prolonged illness, and it may be associated with basilar insufficiency. The role of ear disease in the causation of positional nystagmus type / / . The otological abnormalities in the 152 subjects with evidence of ear disease are tabulated as follows:

Otitis media in ear placed beneath in test position Caloric abnormalty only in under ear Caloric abnormalty with deafness in under ear Deafness with no other evidence of an aural lesion

No. of Cases Type II Type I 11 2 91 26 17 33

In 14 other subjects the only aural abnormality was an abnormal caloric response in the uppermost ear, while in 30 other cases the caloric responses, though abnormal, were symmetrical. It will be seen that, of the 152 subjects with evidence of aural disease, the disease appeared to be unilateral in 133. In 119 of these the affected ear was that placed undermost in the test position. These findings appear to be in very good accord with those of Dix and Hallpike ( 1 9 5 2 ) who found that of 24 cases with substantial evidence of unilateral ear disease, the positional nystag-

412

ACE

THE VESTIBULAR SYSTEM AND ITS DISEASES

INCIDENCE

Type

0-20

OF

21-30

289

CASES

31-40

OF

41-50

POSITIONAL

51-60

1

I

8

12

26

6

1 1

3

18

34

65

74

2

3

11 1

NYSTAGMUS

61-70

33 1

Fig. 6.

mus was directed towards the affected ear, when placed beneath, in n o less than 21. (Fig. 9.) Pathology. A serious obstacle to a better understanding of the pathology of disorders of the labyrinth has always been the benign course they follow, so that the opportunity for detailed histological examination of the labyrinth rarely arises and this has applied particularly to positional nystagmus. The temporal bones of only three patients have so far been examined to my knowledge (Dix and Hallpike 1952, Lindsay and Hemmenway 1956, Cawthorne and Hallpike 1957) and some doubt has been expressed concerning the site of the lesion in these cases. The patients developed type II positional nystagmus some time before death. There are minor differences in the histology of these ears, but it seems likely that all are manifestations of the same disorder. Hallpike (Cawthorne and Hallpike 1957) considered the most important structural abnormality revealed by histological examination of the temporal bones was the early degeneration found in the antero-medial part of the utricular macula with reduction in the number of related sensory nerve fibres and suggested it was the result of a circumscribed occlusive lesion of the vascular supply from the anterior vestibular artery. Degenerative changes were also present in the sensory epithelium of the cupula of the horizontal semi-circular canal. (Figs. 10-19.) Schuknecht ( 1 9 6 2 ) agrees on the occurrence of degeneration in the superior division of the vestibular nerve and its as-

BENIGN POSITIONAL

POSITIONAL

2Ì-30

0-20

31-40

AGE DISTRIBUTION

NYSTAGMUS

41-50

IN

413

VERTIGO

CASES

51-60

WITH

61-70

HEAD

*

INJURY

Fig. 7.

sociated sense organs, and thinks McCabe's ( 1 9 6 4 ) view that a nystagmic reaction may be produced by stimulation of the otolithic organ is an interesting one. The neural mechanism concerned in the production of positional nystagmus is incompletely understood. Spiegel and Scala (1941) and later Fernandez and his colleagues (1959) have helped show that release of cerebellar inhibition of the vestibular centres may be accompanied by positional nystagmus. They have shown a functional localization of the vestibular system in the nodulus, which has a triple function as an inhibitor of the vestibuloocular reflex arc, a facilitator of vestibulo-vegetative reflexes, and

70

414

THE VESTIBULAR SYSTEM AND ITS DISEASES

POSITIONAL

NYSTAGMUS

Complaint

of Vert

Type

I

Type

II

In

Type

In

Type

(289

cases)

Rotational i go

28

(53%)

206

(90%)

"

only 16 complaint

patients of

had vertigo

no

only 10 complaint

patients of

had vertigo

no

I

II

noted

in

bed

"

41% "

69%

Fig. 8.

to maintain equilibrium independently of the peripheral vestibular, ocular and other proprioceptive systems (Fernandez and Lindsay 1 9 5 9 ) . Thus the vestibulo-ocular and vestibulo-spinal pathways POSITIONAL (289 Evidence

Un i

of

aural

cases) disease

lateral les i on in under-most

8i I at era I Fig. 9.

NYSTAGMUS

152

133

ear

119

19

BENIGN POSITIONAL VERTIGO

415

Fig. 10. Normal healthy human utricular macula. T h e layer of sensory cells evenly arranged with superimposed otolith membrane.

Fig. 11. Magnified view of above.

416

THE VESTIBULAR SYSTEM AND ITS DISEASES

Fig. 12. Macula of utricle in Dix and Hallpike's (1952) first case. The otolith membrane is absent and the sensory epithelium is disorganized and the connective tissue meshwork beneath it is affected.

Fig. 13· Magnified view of above shows irregular cellular infiltration and degenrative changes.

Fig. 15. Right defective utrcular macula and reduced number of nerve fibres in internal auditory meatus.

418

THE VESTIBULAR SYSTEM AND ITS DISEASES

Fig. 17. Higher magnification. Loss of differentiation of cells and reduced thickness.

BENIGN

POSITIONAL

VERTIGO

419

Fig. 18. In this case the lateral canal cupula was also affected. Left horizontal semicircular canal. Normal.

Fig. 19. Right horizontal semicircular canal cupula with reduction in thickness of the epithelium and loss of cell differentiation.

420

THE VESTIBULAR SYSTEM AND ITS DISEASES

are not necessarily involved in posterior fossa lesions associated with positional nystagmus. Signals from the peripheral end organs are required before positional nystagmus can be produced and positional nystagmus associated with cerebellar lesions ceases after destruction of both labyrinths. Clinical evidence of the site of the lesion in benign paroxysmal positional vertigo, is considered in detail by Hallpike and his associates (Dix and Hallpike 1952, Cawthorne and Hallpike 1957). Its causation by intra-medullary vascular lesions is unlikely in the absence, in most cases, of neurological involvement of the fifth nerve or other structures closely related within the brain stem and cerebellum to the vestibular elements. The possibility of some organic affection limited to the vestibular neurones in the brain stem or vestibular nerve is unlikely as caloric and other vestibular tests may be normal. It appeared thus by exclusion that the site of the lesion was in the labyrinth itself. In a high proportion of Dix and Hallpike's cases unilateral ear disease was present in the undermost ear. Further evidence in favour of this view was the abolition of the positional nystagmus by destruction of the labyrinth or division of the eighth nerve (Citron and Hallpike 1956 and 1962). Citron and Hallpike (1962) have also expressed the view that the nystagmus is essentially dependent upon a lesion of a complex neuronal circuit of which the undermost labyrinth is a part. The lesion may be situated in the labyrinth itself. Nevertheless they do not exclude the possibility that a lesion affecting the central parts of the same neuronal circuit might have the same effect. This would include a lesion of the nodule as indicated by the animal experiments of Fernandez and his co-workers. Recent work in Toronto has shown that positional alcohol nystgamus, probably central in type, ceases if the canals only are destroyed (Nito et al 1964.) Caloric test results. In most of the subjects with positional nystagmus the caloric responses have been normal. In some cases the character of the abnormality was indicative of a lesion of the labyrinth placed underneath in the test position. In others, however, the upper labyrinth has been implicated. The significance of this is difficult to explain. According to the findings of Dix and Hallpike (1952) the otolithic lesion responsible for the positional nystagmus is located in the under labyrinth and this might be taken

BENIGN

POSITIONAL

VERTIGO

421

to warrant the expectation that the same labyrinth would also be implicated by an abnormality of the caloric responses when this was present. It must, however, be borne in mind that, as Dix and Hallpike ( 1 9 5 2 ) have themselves shown, caloric abnormalities are by no means constantly present in cases of positional nystagmus: furthermore, that the vestibular injuries which result from head trauma are likely from its nature to be widespread and may involve both labyrinths. In this way positional nystagmus resulting from a lesion of the otolith apparatus of the under labyrinth without alteration of its caloric responses might well occur in conjunction with a lesion of the canal organs of the upper labyrinth with alteration of its caloric responses. Diagnosis. It is clear that while positional nystagmus may sometimes be a sign of a serious disorder, this is seldom the case. It is usually simple to differentiate the two main types of nystagmus one from the other, since in their typical forms they exhibit clear-cut differences and it is not then difficult to tell them apart. In type I a central lesion is to be anticipated, the direction of the nystagmus varies, it may be vertically upward or downward or horizontally towards the uppermost ear. Vertigo may be slight or absent with little or no latent period of adaptation. Nylen ( 1 9 5 0 ) and Hallpike ( 1 9 5 2 ) have both shown that type I nystagmus may be associated with involvement of the vestibulo-cerebellar connection by vascular lesions, neoplasms, primary or secondary, or disseminated sclerosis. X-ray of the chest is important, for a secondary deposit in the vermis from the bronchus should be kept in mind. In type II the history and ear, nose and throat examination may help decide in which group the condition lies, but though this type of positional nystagmus is usually benign, an examination of the central nervous system is always advisable before this conclusion is reached. Cervical vertigo (see Kleyn 1927, Nylen 1950, Ryan and Cope 1955, Brain 1963 and others) is associated with bending of the neck, but not positioning the head in space. Cervical traction, injury or spondylitis may produce this form of vertigo. Neither the nystagmus nor the vertigo are as definite and regular as in type II positional nystagmus and it is not likely that the two will be confused by a clinician with experience of the two types of vertigo.

422

THE VESTIBULAR SYSTEM AND ITS DISEASES

Prognosis. In type I when the cause is an intracranial neoplasm the outlook is serious. In type II a large majority are benign, the prognosis in the others in this group depends to some extent on the cause. Further reference will be made to the prognosis of positional nystagmus associated with head injury. Treatment. As much as in most forms of vertigo, patients with the positional type are anxious and afraid and the first and vital step in management is to make an accurate diagnosis. Then if, as in by far the greatest number, it is benign, reassurance of the patient is very important. It should be emphasised that the diagnosis must be accurate. If the nystagmus is atypical there is need for caution. As the symptoms of type II positional nystagmus usually disappear spontaneously the effect of treatment is often difficult to assess. It is, of course, essential that the cause which has been found should be dealt with. Exercises to produce a habituation to movements producing vertigo are beneficial in many cases. The treatment will be well tolerated in most cases provided it is carried out carefully. This should be combined with drug threapy. If the hearing is very defective and the positional nystagmus long drawn out and troublesome, the affected labyrinth may be destroyed. Spector ( 1 9 6 1 ) has used ultrasonic treatment for positional nystagmus associated with chronic ear infection as it does not destroy the hearing. The role of head injury in the causation of type II positional nystagmus. In 46 ( 1 6 % ) of the 289 cases, already analysed in series I, a clear history of head injury was given. This class of case is of great clinical and medico-legal importance and therefore a separate investigation of positional vertigo as found in these 46 cases and also in a series of 108 subjects admitted to hospital with head injuries has been undertaken. As with epilepsy of late onset the possible causal significance of antecedent head injury is often difficult to evaluate and in these 46 cases the circumstances connecting the injury with the subsequent vertigo have, therefore, been considered with some care. 26 of the patients were admitted to hospital with head injury, 19 were unconscious, but in 7 it was not possible to say if unconsciousness had occurred. 30 patients volunteered head injury as the cause of the vertigo and 3 patients associated head injury with the onset of

BENIGN

the vertigo.

POSITIONAL

423

VERTIGO

Symptoms were present almost immediately after the

injury in 26 patients, in two after a week, in 3 after seven weeks and the rest after varying lengths of time up to 13 years.

16 patients

developed the vertigo whilst still in-patients after the head injury, 14 attended

the out-patient

department

within

three months

of

the onset of the vertigo, 5 others within six months and the rest up to 30 years after the onset of the vertigo.

15 patients were shown

by X-rays to have fractures of the skull, 7 of the occipital bone, 6 of the base of the skull involving the temporal bone, and 2 of the base and vault of the skull.

In 12 cases no evidence of fracture

was found radiologically and in the remaining 19 cases X-rays were considered unnecessary. ( F i g . 2 0 . )

POSITIONAL Head

In jury

46

cases

15

VERTIGO

as c a u s e in series (289

present cases )

c1 ear h i story in jury showed fracture on X-Ray

oF

head of

7

occipital

6

basal

fracture

2

fracture vault

of

skull

fracture

base

and

Fig. 2 0.

A f t e r careful study of these 46 cases it seemed justifiable to accept head injury as a significant factor in the causation of the positional nystagmus. In a large percentage the onset of the vertigo followed the head injury sufficiently closely for the association to be obvious.

In the remaining cases the head injury appeared the

important aetiological factor in the history and no other cause for the nystagmus was found in the history or detailed examination. The

clinical

features

of

these

post-traumatic

cases

were,

in

424

THE VESTIBULAR SYSTEM AND ITS DISEASES

every other respect, indistinguishable from those of the other members of the group. Series II. The occurrence of positional nystagmus in a series of cases of head injury. Systematic observations for positional nystagmus were carried out upon 108 consecutive cases of head injury admitted to one general hospital. In nearly all some complaint was made of dizziness. Much doubt and confusion exists concerning the pathological basis of this symptom and in the present investigation the chief endeavour has been to ascertain the extent to which it could be attributed to organic disorder, as shown by the occurrence of positional nystagmus. Results are stated briefly as follows: Age distribution of all fracture cases: Age

0-20 38

21-30 17

31-40 22

41-50 14

51-60 7

61-70 5

+70 5

Occurrence of positional nystagmus. 17 of the 108 subjects ( 1 5 % ) exhibited characteristic positional nystagmus of type II to one side or the other when first seen within fourteen days of the head injury. The age distribution of cases with head injury and positional nystagmus was as follows: (Fig. 21) Age 0-20 4 5 9

21-30 6 10 16

31-40 3 11 14

41-50 — 8 8

51-60 1 8 9

61-70 2 4 6

+70 1 Series II — Series 1 1 Total

In this series it will be noted how much earlier the peak incidence occurs. Occurrence and character of dizziness apart from positional nystagmus. Although, as stated, some complaint of dizziness was made by nearly all of the 108 subjects, a rotational element was a feature of this dizziness in only 3 of the 91 cases without positional nystagmus, while it was present and marked in 15 of the 17 cases with it. Occurrence and significance of skull fractures. In a number of the cases skull fractures were present, but in none was the labyrinth involved. In the present series, therefore, neither the occurrence of this kind of fracture nor the length of the period of amnesia appear to be related to the occurrence of positional nystagmus.

BENIGN POSITIONAL VERTIGO

POSITIONAL

AGE

0-20

tal

DISTRIBUTION

21-30

IN

31-40

425

NYSTAGMUS

CASES

41-50

WITH

HEAD

51-60 -

INJURY

61-70

4

6

3

1

2

5

10

11

8

8

4

9

16

14

8

9

6

+70 1

1

Fig. 2 1

Prognosis. In head injury cases the period of recovery f r o m dizziness appears to be dependent to an important extent upon the occurrence or otherwise of positional nystagmus. When this was absent, the recovery period averaged two and a half months. 5 of the 17 patients with positional nystagmus, however, continued to exhibit this symptom, though with diminished severity, for more than twelve months. These findings, taken in conjunction with the observations of the duration of the positional nystagmus following head injury in 46 subjects in our first group indicate that the symptom, if still present twelve months after a head injury, is likely to persist for a considerable time. O u r findings therefore indicate that serious persistent dizziness following head injuries, not necessarily associated with skull fracture, is very frequently, particularly when it is of a rotational character, due to positional nystagmus. The diagnosis is dependent upon the demonstration of a particular type of positional nystagmus by means of a simple clinical test. Though the lesion is essentially a benign one, the severe nature of the symptoms to which it gives rise is often a cause of severe distress, in particular when its cause is left unexplained. T h e medico-legal implications of these findings would appear to be considerable. Positional nystagmus as stressed by Gordon ( 1 9 5 4 ) may be a serious cause of in-

426

THE VESTIBULAR SYSTEM AND ITS DISEASES

capacity for work following a head injury. If it passes unrecognized, the organic basis of the patient's symptoms will be overlooked and proper recognition of a claim to compensation might unjustly be refused. Such a course of events may bring about severe neurotic sequelae. Thus the importance of early and accurate diagnosis, nearly always quite an easy one, cannot be exaggerated. Summary. The classification, pathology and other features of positional nystagmus are discussed. 289 cases of this condition are analysed in series I. In series II the relation of head injury to positional nystagmus is considered with emphasis on its medico-legal aspects. ACKNOWLEDGMENTS

Diagrams 10, 11, 12 and 13 reproduced from the article of Carmichael, Dix & Hallpike, Β. Medical Bulletin 12, 2, 1956. Diagrams 14, 15, 16, 17, 18, and 19 reproduced from the article of Cawthorne & Hallpike, Acta Oto-laryng. 48, 1-2, 1957. I am most grateful to Miss M. I. Burgess for secretarial help and Mr. A. France for photographs and diagrams. REFERENCES

Aschan, G., Bergstedt, M. & Stahle, J., 1956: Acta Otolaryng. Suppl. 129. Aubry, M., Pialoux, P. & Bouchet, J., 1954: Ann. Otol. & Laryng. 71, 531. Bairati, Α., Iurato, S., Pernis, B., 1957: Evp. Cell Research Suppl. 13, 207. Bárány, R., 1921: Acta Otolaryng. 2, 434. Barber, H. O., 1964: Laryngoscope, 74, 7, 891. Bruer, J., 1874: Wien. med. Jahrbuch 4, 72. Brain, 1963: B.M.J. I, p. 771. Cawthorne, Τ. E., Dix, M. R., Hallpike, C. S. & Hood, J. D., 1956: Brit. M. Bull. 12, 2, 131. Cawthorne, T. E. & Hallpike, C. S., 1957: Acta Otolaryng. 48, 1. Citron, L. & Hallpike, C. S., 1956: J. Laryng. & Otol. 70, 253. Citron, L. & Hallpike, C. S., 1962: J. Laryng. & Otol. 76, 28. Crum-Brown, Α., 1875: J. Anat. & Physiol. 8, 327. deKleyn, A. & Nieuwenhuyse, P., 1927: Acta Otolaryng. (Stockh.) 11, 115. Dix, M. R. & Hallpike, C. S., 1952: Proc. R. Soc. Med. 45, 341. Ewald, J., 1892: Physiol. Wiesbaden, Bergmann. Fernandez, C., Alzate, R. & Lindsay, J. R. 1959: Ann. Otol. Rhin. & Laryng. 68, 816.

BENIGN

POSITIONAL

VERTIGO

427

Gordon, N., 1954: Lancet, 1, 1216. Hallpike, C. S., 1955: Postgraduate M. J. 31, 330. Harrison, M. S., 1956: Brain 79, 3, 474. Lindsay, J. R., 1951: Ann. Otol. Rhin. & Laryng. (St. Louis) 60, 1134. Lindsay, J. R. & Hemenway, W. G., 1956: Ann. Otol. Rhin. & Laryng. 65, 692. Magnus & de Kleyn, 1924: Handbuchder Normalen & Pathologischen Physiologie (Berlin) 11, 568. Mach, E., 1875: Leipzig, Engelmann. Grundlinien der Lehre von den Bewegungsempfindungen. McCabe, B. F., 1964: Laryng. 74, 3, 372. Nito, Y., Johnson, W. H., Money, Κ. E., Ireland, P. E., 1964: Acta Otolaryng. 58, 1, p. 65. Nylen, C. O., 1931: Acta Oto-laryng. (Stockh.) Suppl. 15. Nylen, C. O., 1950: J. Laryng. & Otol. 64, 295. Preber, L. & Silverskiöld, Β. P., 1957: Acta Otolaryng. (Stockh.) 48, 3, 255. Riesco, Mac-Clure, J. S., 1957: Rev Oto Rhino-laryng. 17, 42. Ryan, G. M. S. & Cope, S., 1955: Lancet 31, 1355. Schiller, F. & Hedbergh, W. C., 1960: A. M. A. Arch. Neurol. 2, 309. Schucknecht, H. F., 1962: Trans American Acad, of Ophthal. & Otolaryng. May, 319. Seiferth, L. B., 1937: Arch. f. Ohren. Nasen-u Kehlk opfh. 143, 52. Spector, M., 1961: J. Intern. College Surgeons 36, 3, 359. Spiegel, E. A. & Scala, Ν. P., 1941: Arch. Ophth. 26, 661. Spiegel, E. A. & Scala, Ν. P., 1942: J. Neurophysiol. 5, 247.

The Pathophysiology of Angle Tumors* Harold F. Schuknecht, M. D.**

INTRODUCTION

The two most common types of tumors which arise within or near the internal auditory meatus and destroy its contents are acoustic neurinomas and meningiomas. Acoustic neurinomas may occur bilaterally as a manifestation of Von Recklinghausen's disease. Both types grow slowly and produce symptoms by compression of adjacent structures. 1.

Symptoms

Tumors arising within the internal auditory meatus produce unilateral auditory and vestibular disorders which the patient often ignores for several months or years until the symptoms of a spaceoccupying lesion of the posterior fossa become apparent. The success of surgical removal is related directly to the size and location of the tumor so that early diagnosis assumes great importance. The symptoms may be listed as follows: a) Eighth cranial nerve. 1,2 The auditory symptoms consist of hearing loss and tinnitus and the vestibular symptoms of unsteadiness and occasionally of true vertiginous episodes. The onset of eighth nerve symptoms usually is gradual but can be sudden. * Supported in part by a grant from The Deafness Research Foundation and in part by a grant from the Public Health Service, National Institute for Neurological Diseases and Blindness, Research Grant No. N B 3524-03. ** Chief, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston; Professor of Otology and Laryngology, Harvard Medical School, Boston.

428

PATHOPHYSIOLOGY OF TUMORS

429

b) Headache. Head pain often is located in the occipital or frontal regions and is aggravated by stooping, straining, or sneezing. c) Cerebellar symptoms. Encroachments upon the cerebellum creates incoordination of movement affecting the lower limbs more than the upper. d) Involvement of adjacent cranial nerves. The enlarging tumor compresses the trigeminal (Vth) nerve and often causes first paroxysmal pain and later parasthesias and numbness of the face. Loss of corneal reflex is an early sign. The facial nerve is peculiarly resistant to injury but varying degrees of facial palsy may occur when the tumor becomes large. Involvement of the glossopharyngeal (IX) and vagus ( X ) nerves occurs in the terminal stages and is manifested by pharyngeal and laryngeal paralysis with dysphasia and dysphonia. e) Increased intracranial pressure. As the tumor enlarges in the posterior fossa there is interference with the normal outflow of cerebrospinal fluid resulting in internal hydrocephalus. Symptoms of headache, diplopia, loss of vision, and vomiting become increasingly severe until death occurs from cerebellar crisis or pulmonary complications. 2. Involvement

of the Cochlear and Vestibular

Nerves

The first sign of involvement of the cochlear nerve is a loss in speech discrimination in the involved ear. Thus, a patient may report "I can hear but cannot understand what is being said in that ear". This usually is detected first when using the telephone. During this early stage when nerve fibers are rendered nonfunctional by compression or destruction, there is progressive loss of speech discrimination with minimal or moderate threshold loss for pure tones. The earliest threshold losses often occur for the low frequencies (Fig. 1). Other auditory manifestations characteristic of a partial loss of nerve fibers are absence of loudness recruitment, absence of decreased intensity difference limen, and auditory fatigue. 3 A loss of cochlear nerve fibers may occur without injury to the organ of Corti so long as the blood supply to the cochlea is preserved (Fig. 2 ) . Furthermore, animal experiments have shown that as much as 7 5 % of the nerve fibers may be destroyed to a

430

THE VESTIBULAR SYSTEM AND ITS DISEASES

Fig. 1. Audiogram of patient with early acoustic neurinoma showing low tone hearing loss and severe loss of speech discrimination. T h e r e is absence of loudness recruitment.

region of the cochlea without creating pure tone threshold losses provided the organ of Corti is not injured (Fig. 3 ) . The functional implication is that only a few nerve fibers are needed to transmit pure tone stimuli of threshold magnitude whereas many fibers are necessary to carry the complex neural patterns which code speech. 4 The auditory symptoms usually are slowly progressive until there is total loss of hearing for pure tones as well as speech. Tinnitus in varying degrees is always present and may constitute a chief complaint. The sudden onset of varying degrees of hearing loss or total deafness has been reported to occur as an initial symptom of acoustic tumor. This may be due to sudden extension of the tumor be-

PATHOPHYSIOLOGY OF TUMORS

431

Fig. 2. Six months after partial section of the cochlear nerve the organ of Corti appears n o r m a l ( c a t ) .

yond its capsular confines, hemorrhage into the tumor mass, or obstruction of a blood vessel supplying the labyrinth. Destruction of the vestibular nerves often occurs very slowly so that vestibular function in the involved ear may be completely destroyed with little or no symptoms. This attests to the remarkable ability of the system to compensate for vestibular deficits. Attacks of unsteadiness or vertigo probably are related to functional loss of groups of vestibular nerve fibers followed on each occasion by compensatory recovery. In rare cases an early symptom may be a sudden and severe vestibular upset, with compensatory recovery occurring over a period of days or weeks. 3.

Involvement

of Sense

Organs

In addition to destroying the structures within the internal audi-

432

THE VESTIBULAR SYSTEM AND ITS DISEASES

CAT

4 125 2 5 0

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Fig. 3- Audiogram and graph indicating percentage of cochlear neurones remaining after partial section of the cochlear nerve. Thus, behaviorally trained animals have near normal auditory thresholds in spite of loss of about 75% of nerve fibers to the cochlea.

tory meatus, the tumors eventually also create degenerative changes in the membranous labyrinth. There may be atrophy or complete loss of the organ of Corti. Usually the change is most severe in the basal turn. The maculi and cristi are less severely involved. Occasionally tumors in the internal auditory meaturs first create alterations of sensory function and subsequently involve the cochlear and vestibular nerves. It is probable that structural changes,

PATHOPHYSIOLOGY OF TUMORS

433

such as shrinking of the sense organs or loss of sensory or supporting cells, are secondary to obstruction of blood supply as a result of compression or invasion of vessels in the internal auditory meatus. Such structural alterations may occur in areas of the cochlea which have little or no loss of nerve fibers. In one particular specimen the correlation of the spatial distribution of pathological changes with the auditory tests reveals some interesting facts which demand careful consideration. Auditory tests were characteristic of a moderately severe sensory lesion; that is, there was moderate elevation of bone and air conduction thresholds for all frequencies along with complete loudness recruitment, and fairly good speech discrimination. Histological examination shows a loss of nerve fibers only in the 12-16 mm of the cochlea which does not account for the hearing loss (Fig. 4 ) . Structural changes in the organ of Corti are present in the basal 12 mm of the cochlea. These changes consist of absence of the organ of Corti in the basal 3 mm, partial loss of hair cells from 4-12 mm, and severe shrinking in the region from 14-21 mm. These changes in the sense organ are sufficient to explain the threshold losses for frequencies above 1000 cps, the loudness recruitment, and the relatively good discrimination score. The hearing loss for frequencies below 1000 cps, however, cannot be accounted for by changes in the organ of Corti or cochlear neurones and it seems reasonable to assume that it may be due to alterations in the inner ear fluids. Changes in staining characteristics of the perilymph are a well known phenomenon in acoustic tumors. 5 The perilymph often stains deeply with eosin or contains a finely granular precipitate possibly indicating an increased protein concentration (Fig. 5 ) . Alterations in the chemistry of inner ear fluids as a cause of "sensory type" hearing loss is not unique for acoustic tumors. The pathology of Meniére's disease is characterized by an increased volume of endolymph in the presence of a structurally normal organ of Corti and cochlear neurones.® A type of presbycusis has its pathological basis in atrophy of the stria vascularis without structural changes in the organ of Corti or cochlear neurones in which the hearing loss also may be the result of chemical alterations in the endolymph. 7 These observations support the following assumptions :

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THE VESTIBULAR SYSTEM AND ITS DISEASES

125 2 5 0

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Fig. 4. Audiogram and graphs showing cochlear pathology of ear with acoustic neurinoma. T h e degenerative changes in the organ of Corti and cochlear neurones account only partially for the hearing loss. The hearing loss for low frequencies are assumed to be the result of alterations in fluid chemistry.

1)

T h e hearing loss resulting from tumors involving the internal

auditory meatus m a y be caused, at least in part, by chemical alterations in the inner e a r 2)

fluids.

Hearing losses resulting from alterations of fluid chemistry

are characterized

by threshold losses which

are nearly equal

for

PATHOPHYSIOLOGY OF

TUMORS

435

Fig. 5. Eosinophilic precipitate in the perilymphatic spaces in an ear with acoustic neurinoma.

all frequencies (flat audiometrie curves), loudness recruitment, and relatively good speech discrimination. Presumably, in spite of decreased sensitivity at higher stimulus intensities, the organ of Corti becomes functional and performs reasonably well in the coding of neural patterns of auditory information. 4.

Deafness

in the Contra-lateral

Ear

Deafness developing in the ear on the opposite side from an angle tumor is rare, and apparently occurs only in states of extreme displacement of the brain stem against the contra-lateral skull wall. Such an ear has been carefully studied and the findings are of considerable interest. This patient with a tumor of the internal auditory meatus first developed hearing loss in the right ear (on

436

THE VESTIBULAR SYSTEM AND ITS DISEASES

the side of the tumor) and then, as the tumor increased in size, a progressive and eventually total hearing loss in the left ear. Although speech discrimination tests were not done, it was the examiner's opinion that, during the stage of partial hearing loss, the left ear was useful for speech reception, suggesting a disorder of the sense organ rather than of the neural pathways. On gross examination the brain stem and pons were displaced to the left and the 4th ventricle was compressed to a slit. There was no gross destruction of the brain tissue. The other cranial nerves were functional until the time of death. Histopathological study of this reveals a severe loss of cochlear neurones in the basal half of the cochlea but normal in the remaining area. A finding which is difficult to evaluate is the shrunken appearance of the auditory and vestibular sense organs. None of the crytological elements of the sense organs are missing but they are agglutinated. Reissner's membrane is in the normal position and the fluid spaces are clear and free of stain. The stria vascularis is normal (Fig. 6 ) . Although these alterations in structure cannot be differentiated from post mortem autolysis, it seems reasonable to believe that they are ante mortem in nature because no such shrinking change was present in the opposite ear. It is not clear whether these changes are due to vascular disturbance, alterations in inner ear fluids, increased intra-labyrinthine pressure, accumulation in the inner ear of metabolic by-products, interference with the fluid physiology, poet mortem autolysis, or yet another cause. The obvious treatment for preventing deafness in the ear on the opposite side, when there is a progressive space-occupying lesion of the psterior fossa, is partial or total removal of the mass and decompression of the posterior fossa before extreme displacement and compression of the brain stem and pons takes place.

SUMMARY

Tumors of the cerebello-pontine angle may disturb auditory and vestibular function in several ways: 1 ) The tumor may destroy the nerve trunks in the internal auditory meatus with slowly progressive loss of hearing and vestibular function. Early in the course of the disease the auditory

Fig. 6. Photomicrographs from a patient with an angle tumor on the right with total bilateral hearing loss. (Above) There is total generation of the cochlear neurones, new bone formation in Rosenthal's canal, and a near normal appearing organ of Corti on the right. (Below) There is degeneration of the cochlear neurones in the basal half of the cochlea and, in additon, severe agglutnation of the entire organ of Corti ( as well as the vestibular sense organs ) . These changes are caused by the tumor but the mechanism of injury is not clear.

438

T H E VESTIBULAR SYSTEM AND ITS DISEASES

symptoms are characterized by loss of speech discrimination out of proportion to pure tone threshold loss. 2) The tumor may obstruct blood supply to the inner ear with resulting loss of sensory function, the auditory manifestation of which is loss of pure tone thresholds with preservation of relatively good speech discrimination. 3) In combination with the above disorders the tumor may create alterations in the chemical contents of the labyrinthine fluids with resulting sensory deficits similar ot those occurring from interference with vascular supply. In far advanced states of tumor growth deafness of the opposite ear may develop, the cause probably being disturbance of inner ear fluid physiology, vascular supply, and injury to auditory neural pathways. From these observations it is obvious that the diagnosis of cerebellopontine angle tumor cannot be made by otological examination alone but must be accompanied by other evidence of a spaceoccupying lesion of the internal auditory meatus or cerebellopontine angle. REFERENCES

1. Edwards, C. H. and Paterson, J. I.: Review of symptoms and signs of acoustic neurofibromata. Brain, 74: 144-190, 1951. 2. Olsen, A. and Horrax. G.: Symptomatology of acoustic tumors with special reference to atypical features. J. Neurosurg. 1: 371-378, 1944. 3. Goodman, A. C.: Some relations between auditory function and intracranial lesions with particular reference to lesions of the cerebellopontine angle. Laryngoscope 67: 987-1010, 1957. 4. Schuknecht, H. F. and Woellner, R. C.: An experimental and clinical study of deafness from lesions of the cochlear nerve. J. Laryng. and Otol. 69: 75-97, 1955. 5. Dix, M. R. and Hallpike, C. S.: Observations on the pathological mechanism of conductive deafness in certain cases of neuroma of the VIHth nerve. J. Laryng. and Otol. 64: 658-666 (October) 1950. Proc. Royal Soc. Med. 43: 291-298, 1950. 6. Schuknecht, H. F., Benitez, J. T., and Beekhuis, J.: Further observations on the pathology of Ménière's disease. Ann. Otol. Rhin. Laryng. 71: 1039-1053, 1962. 7. Schuknecht, H. F. and Igarashi, M.: Pathology of slowly progressive sensori-neural deafness. Trans. Am. Acad. Ophth. and Otolaryng. 68: 222-242 (March-April), 1964.

Surgery of Eighth Nerve Tumors William F. House, M.D.

Eighth nerve tumors have become recognized as a most important cause of unsteadiness and hearing loss. If these tumors can be recognized while they are still small and confined to the internal auditory canal, they can be removed along with the portion of the eighth nerve from which they arise and save the remaining functions of the eighth nerve. In most cases, this means that it would be possible to remove the tumor along with the superior or inferior vestibular nerve and save the function of the cochlear nerve. This has been accomplished in two patients to date. In most cases, however, with today's diagnostic methods, the tumors extend into the cerebellopontine angle and it is, therefore, necessary to remove them through a translabyrinthine approach. Forty-five tumors have now been removed through a translabyrinthine approach. In this series to date, there have been no deaths and in approximately 90 per cent of them, it has been possible to retain normal function of the facial nerve. This new surgical approach points up the need for accurate vestibular testing in the diagnosis of eighth nerve tumors. ( A film was then presented to illustrate the surgical technique.)

439

Discussion J A C K L. P U L E C , M.D. (Rochester, Minn.): In our work with acoustic neuromas we have found posterior fossa myelography to be an extremely useful procedure, not only in diagnosis but also in differentiating these tumors from meningiomas, primary cholesteatomas, and lesions of the cerebellar pontine angle. We also depend on this test to determine the size, extent, and blood supply of the tumor as a guide for the surgical procedure. Moreover, we have found this method to be highly superior to other types of contrast studies and have demonstrated tumors in many cases in which the augiogram or pneumoencephalogram was normal. With pantopaque myelography, we are able to determine definitely whether or not a tumor is present in the cerebellar pontine angle. We are also able to determine in most cases whether or not even a small intracanalicular tumor exists, since, in the normal case, we are able to fill the internal auditory canal with pantopaque. We use this particular method whenever there is a reasonable suspicion that a patient may have a tumor in the cerebellopontine angle. The safety of this test has been shown by Dr. Robert ScanIan of Los Angeles, who has done more than 100 such tests, and by Dr. Hillier Baker of the Mayo Clinic, who has done more than 400 of these tests, with no serious complications. The only morbidity is that which accompanies the spinal tap. Approximately a fourth of these patients will have a headache similar to the type that develops after spinal tap for a day or two after the procedure. Age and general debility may contraindícate use of the procedure involving a 30 degree head-down position for several minutes. The patient is carefully questioned regarding allergy before the test and, of course, if he is sensitive to iodine, the test is not per440

DISCUSSION

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formed. Precautions also must be taken if the patient has increased intracranial pressure. If he has papilledema or other signs of increased intracranial pressure, one must be prepared to carry out surgical decompression, if necessary, at the time of the examination. Posterior fossa myelography can be carried out by any radiologist who will learn the technique; a standard fluroscopy unit and tilt table, such as those used for myelography to determine the presence of a herniated vertebral disc should be utilized. T h e patient is placed on a tilt table in the prone position with the head extended. T e n to 12 ml. of pantopaque is instilled by lumbar puncture after spinal fluid has been withdrawn for protein determination. T h e patient is then tilted head down, and a myelogram of the lumbar, thoracic and cervical areas is made in the usual manner. With the head

Fig. I. Pantopaque within cistern of the left cerebellopontine angle outlining an acoustic neuroma 1 Vi cm. in diameter. T h e point of the arrow is at the medial end of the internal auditory meatus.

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extended by means of a sponge under the chin, the p a n t o p a q u e flows by gravity up the clivus. T h e head is then rotated until the cerebellopontine cistern is filled. It is then slowly rotated back f r o m the lateral oblique projection toward the direct frontal projection until spot-film roentgenography shows the canal in profile. If a tumor is present, it is outlined by the pantopaque. T h e pantop a q u e is then collected in the cervical region and a similar maneuver is done to demonstrate the opposite internal auditory canal. A t the conclusion of the procedure, the pantopaque is withdrawn, usually completely, through the spinal puncture needle, which has remained in place in the lumbar area. A high incidence of asymptomatic herniated intervertebral disk has been found, often with elevated spinal fluid protein; these findings lessen the value of this procedure in the differential diagnosis. A brief film strip on pantopaque myelography demonstrates a t u m o r (figure) approximately 1 Vi cm. in diameter of the right internal auditory meatus. The tumor was removed by the translabyrinthine method and was an acoustic neuroma. In summary, I would like to emphasize that, at present, pantop a q u e myelography of the posterior fossa is the best method available to confirm the presence or the absence of an acoustic neuroma.

Vestibular Problems in Relation to Space Travel* Ashton Graybiel, Captain, MC, USN**

Among the stresses with which man must contend in the exploration of space are those which have their effect via the semicircular canals and otolith organs as a result of exposure to unusual gravitoinertial force environments. These unusual force environments will have a changing pattern in the future, depending on change in launch vehicle, spacecraft, and mission, but today we are interested in the effects of high G loading, weightlessness, and "artificial gravity." In any consideration of the effects of different force environments on the vestibular organs it is essential to consider the effects on the semicircular canals and otolith organs individually and collectively. The canals are stimulated ordinarily by inertial forces resulting from angular and gyroscopic accelerations. These accelerations are generated by active or passive movements of the head (body) or by both acting simultaneously. Active bodily movements involving rotation of the head stimulate one or more of the three pairs of canals regardless of body position. The orientation or changing orientation of the canals with reference to the force environment is, however, important partly because of individual differences in response to stimulation of different pairs of canals and partly because of other factors which are changing coincidentally. * This research was conducted under the sponsorship of the Office of Life Science Programs, National Aeronautics and Space Administration (Grant R-93). ** Director of Research, U.S. Naval School of Aviation Medicine, U.S. Naval Aviation Medical Center, Pensacola, Florida. Opinions and conclusions contained in this report are those of the author and do not necessarily reflect the views or endorsement of the Navy Department.

443

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The sensory receptors in the otolith organs are stimulated by gravity or, more particularly, by changes in position of the head in a central field force. They are also stimulated by gravitoinertial forces representing the vector sum of gravity and the linear or Coriolis forces generated by active and passive movements of the body. In man it is impossible to stimulate the otolith organs without also stimulating nonotolith gravirectors. This greatly increases the difficulty of identifying the unique role of these organs. Great emphasis has been placed on the interrelationships of canals and otoliths. Although certain relationships have been demonstrated they are probably less important than those between either canals and vision or otoliths and vision. It is known from long experience and laboratory experiments that exposure to unusual force environments even well within the physiological range may cause illusions and motion sickness. It is also known that normal persons not only vary greatly in their susceptibility to symptoms under these circumstances but also that a given person may be more affected in one type of force environment than in another. Attempts ( 1 -3 ) to elucidate the factors which are responsible for inter- and intra-individual differences have not been completely successful but have pointed up the almost incredible complexity of the factors involved. The only persons who are insusceptible are those who have suffered a loss of function of the canals and otoliths. Thus the assessment of the function of these organs is a very important point of departure in dealing either with the analysis of etiological factors or the symptomatology and effectiveness of countermeasures. Assessment of otolith function is in a far less satisfactory state than that of canal function. Assessments of combined functions may also prove to have validity in terms of susceptibility to disorder in unusual force environments. The above remarks are intended to emphasize the need for background information without which one cannot predict satisfactorily the disturbing effects of exposure to unusual force environments such as will be encountered in space flight. HIGH G F O R C E S

During launch, re-entry, and on impact the astronaut is subjected to high level linear G forces. The fact that following simula-

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tion trials on a centrifuge and exposure to high G forces on other occasions, some subjects manifested vertigo and ataxia suggests that these levels of force might be injurious. At present two lines of investigation are being pursued: first, a follow-up study of persons with a history of exposure to high level G force and second, a systematic investigation involving the exposure of primates to graded levels of gravitoinertial force followed by clinical pathological correlations. Herbert Pollack, who is conducting the followup study, has not reached a point in his investigation where a report can be made. The studies on chimpanzees now being conducted at Holloman Air Force Base are likewise incomplete. Recently, Spoendlin, Schuknecht, and Graybiel ( 4 ) have reported on experiment in which eleven squirrel monkeys were exposed to forces of either 10.92 or 5.43 G units for periods of one to ten minutes. For periods of minutes to hours following exposure several animals were ataxic. Pathological studies were limited to the macula. The ultrastructure of this organ as revealed by eleceronmicroscopy failed to show any significant changes when compared with that of normal controls. This raised two questions; namely, at what level of force will the first indications of injury appear and was the ataxia manifested by the monkeys caused by injury to the canals. More studies along these lines are needed. WEIGHTLESSNESS

The individuality of the vestibular organs is beautifully revealed under conditions of weightlessness in that there is deafferentation (suppression) of the otolith organs whereas the canals are stimulated the same or very nearly the same as under terrestrial conditions by the inertial forces generated with the rotary motions of the head. Not only the otolith apparatus but all receptors directly or indirectly stimulated by gravity are also affected in weightlessness.* These two categories of receptors are affected quite differently, however, by man's activities in a weightless spacecraft. Simulation of the otoliths could occur only in consequence of bodily movements involving the head. On the other hand, touch, superficial * Weightlessness is arbitrarily defined as any subgravity level below 10

5

G units.

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AND ITS

DISEASES

and deep pressure, kinesthetic and other somesthetic gravireceptors could be stimulated by deformations or movements of parts of the body while the head is motionless. Some of these somesthetic inputs would provide cues which would accord with the visual upright whereas even if the otoliths were stimulated by head movements, the force vector would not point, with rare exception, in the direction of the visual upright. Moreover, slight negative (headward) accelerations would tend to cause the "inversion illusion." In the light of these considerations, it is worthwhile to review very briefly the observations which have been made when subjects have been exposed to weightlessness in parabolic (5-12) and orbital flight ( 1 3 - 1 8 ) . The findings in parabolic flight must be interpreted with caution inasmuch as the weightless phase not only is brief but is preceded and followed by a maneuver which exposes the subjects to moderate G loading, and, in a typical flight, these transitions occur repeatedly. On the other hand, some advantage is gained by the fact that these interpretations are based on relatively large numbers of subjects with varying susceptibility to airsickness who have been tested under restrained and "free floating" conditions. Although more than half of the subjects who have participated in parabolic flight experienced definite symptoms of motion sickness, only a few pilots without a history of airsickness were found to be susceptible. In general, subjects when secured in a seat were less likely to experience symptoms than when free floating. Subjects with bilateral loss of labyrinthine function did not experience airsickness. The conclusion was reached that if weightlessness is a factor in precipitating symptoms of motion sickness in parabolic flight, it is not a strong factor. None of the American astronauts and only Titov among the Russian cosmonauts experienced symptoms characteristic of vestibular sickness in orbital flight. If weightlessness was the significant factor causing Titov's symptoms, then vestibular sickness does pose a problem. It suggests that he was more "susceptible" than the other astronauts or cosmonauts. Other possibilities must be considered, however, such as injury to the labyrinth, labyrinthitis from other causes, or rotations of the spacecraft. If Titov was more susceptible than most test pilots, the problem might be solved with

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more attention to selection and training, but this might be offset, in part at least, by the fact that, as spacecraft become larger, the freedom of movement of the astronauts will be greater, thus lessening their contact cues with the physical environment. Moreover, selection problems will be greater when astronauts are chosen from groups other than experienced test pilots. Weightlessness not only poses problems but also, insofar as it causes physiological deafïerentation of the gravireceptors, it affords a unique and, in man, the only opportunity to carry out certain types of investigations. With the transition into weightlessness, the otolith organs are deafferented by a procedure which in an experimental laboratory would be termed elegant. This state of deafferentation will remain until movements of the head generate inertial forces above the threshold level; this need to avoid head movements which would generate an effective stimulus is a troublesome limitation. Simultaneous deafferentation of the nonotolith gravireceptors also acts as an experimental constraint. It is possible, however, to stimulate nonotolith gravireceptors to a limited degree without moving the subject's head and thus investigate the independent role of these receptors to perception of the upright and to space perception as revealed by egocentric visual localization of the "horizontal." We very much need to learn the independent roles of otolith and nonotolith factors and their complementary functions. The inability adequately to stimulate weightlessness under terrestrial conditions poses a problem in attempting to predict the susceptibility of an astronaut to functional disturbances of vestibular origin in weightlessness. One approach is based on the argument that, even in the absence of stimulation to the semicircular canals, persons will experience motion sickness as a result of unusual patterns of afferent impulses from the otolith apparatus and that the suppression of impulses in weightlessness constitutes one unusual pattern, and other patterns may be associated with movements of the head (body) in a weightless spacecraft. The observations of Wendt (19-23) and others ( 2 4 ) that motion sickness is precipitated by exposure to rectilinear accelerations which do not stimulate the canals support this argument without, however, specifically ascribing the motion sickness to the otoliths. Some observations of Graybiel and Johnson ( 2 5 ) utilizing a counterrotating room extended Wendt's observations in one regard, namely,

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THE VESTIBULAR SYSTEM AND ITS DISEASES

that persons who had lost all or nearly all of the function of the otolith apparatus failed to experience motion sickness while normal subjects manifested varying degrees of susceptibility. In other words, stimulation of nonotolith gravireceptors was an inadequate precipitating factor although the subjects with labyrinthine and hearing loss experienced very much the same postural illusions as did the normal subjects. While this experiment failed to take into account the role of past conditioning and the possible role of the "presence of the canals," it offers the opportunity to compare the findings in such an environment with the findings in weightlessness. Final validation must of course await experience and experimentation aloft. Additional experiments in weightlessness which should be carried out include: 1) the effect of deafferentation on the resting potential of the receptors in the macula and sacculus; 2) the effect of the resting discharge, if present, on such indicators as muscle tonus and occular stability; 3) the relation between subgravity level and otolith function as revealed by counterrolling ( 2 6 ) or other indicator mechanisms under static and dynamic conditions; 4) the effects of prolonged deafferentation on the sensory receptors in animals as revealed by microscopy and on the function of the otoliths in man as revealed by a specific indicator, and 5) the effects of deafferentation on the functional organization of the central nervous system as revealed either by specific neurovegetative phenomena or their secondary effects. Weightlessness also provides an opportunity to carry out investigations on the semicircular canals. We would like to know the effect of deafferentation of the otoliths on 1 ) the resting discharge of the sensory receptors in the crista, 2) the stimulus thresholds to angular and Coriolis accelerations and thermal stimulation, and 3) the susceptibility to illusory and other functional disturbances having their genesis mainly in the semicircular canals. A few such studies have been reported (9, 27-32), and it is an area under active investigation. A R T I F I C I A L GRAVITY

The question whether astronauts can tolerate exposure to weightlessness over long periods of time has not been answered and, in

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the absence of sufficient factual information, it has given rise to speculation and controversy. A weightless environment at best will prove wearisome and messy in carrying out ordinary activities of life and may, despite countermeasures, lead to unacceptable loss of fitness. Russian scientists ( 3 3 ) have stated that, in the light of their experimental findings, exposing man to weightlessness for more than one week may not be without risk and that an upper limit of two weeks would represent a reasonable increment above previous exposure periods. The incremental approach with man will provide the factual information needed to determine whether significant functional disturbances appear, and very long exposure periods for animals will provide additional information on alterations of both a functional and pathological nature. Meanwhile, in the event artificial gravity is needed, experiments are underway to determine how much artificial gravity is necessary to preserve fitness and, if this is accomplished by rotating the spacecraft, what countermeasures are needed to prevent the unwanted side effects. We will here confine our attention to the latter problem inasmuch as these side effects not only are a limiting factor in the design of rotating spacecraft but also these side effects have their genesis mainly in the semicircular canals. In a rotating environment movement of the head in any direction or about any axis not parallel to the axis of rotation will generate, respectively, Coriolis and gyroscopic accelerations. The latter produces a gyroscopic torque which, through cross-coupling, is an effective but unusual stimulus to the semicircular canals. The bizarre nature of this stimulus may cause visual illusions and postural difficulties, and if the stimulus is sufficiently strong or the person sufficiently susceptible, severe functional disturbances. How much of the disorder is due to the stimulus per se and how much to other associated factors is not easily determined, but the essentiality of the canals for nearly all of the disturbances is readily shown. For this reason the term canal sickness has been proposed as a convenient means of distinguishing this type of motion sickness. The otolith organs, and nonotolith gravireceptors as well, are stimulated by the vector sum of gravitational, centripetal, and Coriolis forces. Near the axis of rotation the last two forces are small, but at increasing radii, for the same angular velocity, they become increasingly great. The changing values with bodily move-

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ments and at different positions with reference to the force environment will have a significant influence independently of the effects on the semicircular canals (34, 3 5 ) , but this influence is relatively small. There are important differences between the force environment in a rotating spacecraft in orbital flight and a rotating room on earth, and certain effects of these differences are exaggerated as a result of man's orientation in the gravitoinertial force environment. Aloft, the artificial gravity will be generated by rotation of the spacecraft and represented by the centripetal force with the vector at right angles to the axis of rotation. The magnitude of the force will, in all likelihood, be less than 1.0 G unit, at least in the "firstgeneration" spacecraft. Thus, the astronaut will live in a subgravity force environment, and his natural position, with respect to the gravitoinertial upright, will be at right angles to the axis of rotation with head toward the center. With a short radius of rotation there would be a significant gradient in level of force between head and foot, and bodily movements along a radius not only would change the level of centripetal force but also might generate a significant Coriolis force. At relatively long radii and correspondingly slower angular velocities, changes in centripetal and Coriolis force would have rather small significance, but walking clockwise or counterclockwise might affect significantly the effective angular velocity. On rotating the head in any direction while upright, the astronaut would generate a gyroscopic acceleration causing the canals to be stimulated in an unusual manner; only if he rotated his head about the long axis of his body while lying parallel to the axis of the spacecraft would he avoid the unusual stimulus to the canals. In the laboratory the subject in a rotating room lives in a supergravity environment, and the direction of the gravitoinertial vertical is mainly determined by the direction of gravity unless undesirably large centripetal forces are generated. Near the center of rotation his natural position is nearly upright. When the subject's head is parallel to the axis of rotation and he rotates his head about the long axis of his body, gyroscopic accelerations are not generated; they will be generated of course if the head is rotated about any other axis. To stimulate more closely conditions aloft the subject should be constrained to "live and work" while supported on air bearings near the center of rotation.

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A number of studies (36-38) have been reported in which subjects have been exposed in a rotating environment under different conditions and for periods varying from minutes to days at velocities varying from 1.0 to 10.0 RPM. At a constant angular velocity, the experimental subject may not perceive that he is rotating. The room appears to be stationary and the walls upright. On moving the head normal subjects experience symptoms, the severity of which is a function of the angular velocity of the room, other factors remaining the same. One is struck with the disparity between the small magnitude of the forces and the great severity of symptoms which the subject may experience. Seated near the center of the room, he is scarcely aware of the small centripetal force and with the head fixed, he is comfortable. Very briefly I will summarize some of the results of our investigations which have been carried out by a number of investigators working in our laboratory. These fall into two categories, brief exposures in the Slow Rotation Room (SRR) to estimate susceptibility to illusions and canal sickness and prolonged exposure to study summation and adaptation effects. Brief Exposures. Systematic observations have been made on normal subjects either for the purpose of measuring susceptibility to canal sickness or for the study of more specific evoked responses. With regard to the former, a so-called dial test (39) is used to standardize the stress to which a subject is exposed. Five dials are so placed in relation to the subject that, to set the needle at a given number on each dial, he is required to move his head and trunk to five different extreme positions which maximizes the gyroscopic stimulus to the canals. A sequence consists in setting the five dials, one every six seconds, followed by a six-second rest period. The initial velocity of rotation is 7.5 RPM, and the subject continues the task until either definite symptoms appear or until 20 sequences or 100 settings have been made. Then if 7.5 RPM is too stressful, the velocity is reduced, or if too weak, the velocity may be increased stepwise up to 20 RPM. With rare exceptions, normal persons experience definite symptoms at some velocity between 5.0 and 20.0 RPM. There is, usually, a progressive increase in number and severity of symptoms in the perrotation period, but exceptionally an initial increase is followed by a decline or even a disappearance, indicating coexisting effects of temporal summation

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and adaptation. Following cessation of rotation, symptoms in the majority of subjects disappear within a short time. In a randomly selected group of subjects a large majority will experience the typical symptoms of motion sickness including the nausea syndrome, drowsiness, pallor, and cold sweating. In some, the symptoms are more characteristic of anxiety or psychoneurosis and are further characterized by a discrepancy between the subjective and objective symptomatology. Susceptibility to motion sickness as measured by the dial test is a fairly good prediction of susceptibility to symptoms in other force environments and to prolonged exposure in the SRR. The dial test is being used in the evaluation of anti-motion sickness drugs. The procedure utilizes the double blind technique, the introduction of placebos at intervals to determine shifts in baseline susceptibility as a result of habituation, and a symmetric matrix for convenience in statistical analysis. These studies are being carried out under the direction of Professor Wood, and his reports will soon be available. It would appear that the procedure has quite good reliability, but its validity in terms of application to other force environments remains to be determined. Inasmuch as susceptibility in the SRR is a fairly good predictor of susceptibility to symptoms in different force environments explored thus far, there is a reasonable expectation that we have a useful procedure for the evaluation of anti-motion sickness drugs under laboratory conditions, including good control of strength of the gyroscopic stimulus. A number of subjects have been tested with varying degrees of loss of function of the sensory organs of the inner ears. In a group of deaf subjects with bilateral decrease or loss of canal function and either partial or complete loss of otolith function, none manifested symptoms of motion sickness. Four subjects with a history of successful treatment of Menière's disease with streptomycin sulphate ten years previously did not experience symptoms of canal sickness. All had slight to moderate loss of canal function in one or both ears, but the function of the otoliths as revealed by the counterrolling test was within normal limits in one, slightly decreased in one, and moderately decreased in the other two. Even more revealing were the observations in a few subjects with normal hearing and otolith function but slight decrease in canal function

VESTIBULAR

PROBLEMS IN SPACE TRAVEL

453

who were either insusceptible to canal sickness or experienced minimal symptoms. At present we are trying to establish what level of loss of canal function affords protection in the SRR and whether this same degree of protection is observed in other force environments, especially those in which the canals are not stimulated. It is convenient at this place to mention briefly the results of experiments on squirrel monkeys selected on the basis of high susceptibility to canal sickness. Doctors Johnson and Money, collaborators from the C a n a d i a n Defence Research Laboratories, have found that, in squirrel monkeys, unilateral destruction of the labyrinth abolishes canal sickness only temporarily but that occluding two ducts bilaterally abolishes all sickness permanently. At the suggestion of Professor Schuknecht we have attempted to abolish canal sickness by administering streptomycin sulphate. Dr. McLeod has found that there is only a small range of dosage between ineffectiveness, at one extreme, and complete loss of function at the other. Within this range we have succeeded in raising the threshold to caloric stimulation temporarily during which period susceptibility to sickness was decreased or abolished. It is especially noteworthy that ataxia was absent during this period in some of the animals. Prolonged Exposure. Prolonged rotation in the SRR affords the opportunity of studying the complete symptomatology experienced by subjects both during and after rotation and the effects of these symptoms on their performance. In general, the higher the R P M , the more severe the symptoms and the slower the adaptation if individual susceptibility is taken into account. M a n y additional but mostly minor factors must be considered, however. At 1.0 R P M even highly susceptible subjects were symptom free, or nearly so. At 3.0 R P M subjects of average susceptibility were not significantly handicapped. A t 5.4 R P M subjects with low susceptibility performed well and by the second day were almost free from symptoms. The only subject who did not adapt satisfactorily complained of symptoms characteristic of psychoneurosis. At 10 R P M , however, adaptation presents a challenging but interesting problem ( 3 8 ) . Even pilots without a history of air sickness have not fully adapted in a period of twelve days. Initially, they were forced to restrict their head movements to prevent severe nausea. After a few days they no

454

THE VESTIBULAR SYSTEM AND ITS DISEASES

longer experienced nausea and, consequently, no longer restricted their head movements. They continued to complain" of drowsiness and fatigue, however, and biochemical measurements revealed an increase in the release of corticosteriods, a striking increase in glucose utilization, and an increase in the plasma level of the enzyme lactic dehydrogenase. Even highly motivated and relatively insusceptible subjects were not fully adapted after the twelve days. Following the cessation of rotation the subjects simultaneously experienced a return of former symptoms and a decline in the residual symptoms. The lifelong habituation to the stationary environment was evident both in the mildness of the recurrent symptoms and in their short duration. These few remarks on the general symptomatology associated with exposure to a rotating environment fail to do justice either to the many observations which have been made by ourselves and others or to the more specific investigations they have inspired. Suffice it here to say that much more experimentation is required. From the operational standpoint we need to fill out the tolerance profile for unprotected subjects with varying susceptibility to full adaptation at twenty different velocities. We need to investigate the effect of many countermeasures, unfavorable physiological or environmental factors, and the possibility of maintaining simultaneously adaptation to the rotatory and stationary environment. We need to simulate more closely conditions in a rotating spacecraft by keeping the subjects at right angles to the axis of rotation and learn how this compares with adaptation when the subjects are parallel to this axis. We need to explore fully the susceptibility to canal sickness as a function of rising threshold of canal function and, if possible, learn to bring about this state in a safe and reliable manner. In conclusion I should like to emphasize the impact aviation and space medicine has had in stimulating interest in the semicircular canals and otolith organs. In the course of dealing with the applied aspects of the problems, gaps in our background knowledge of the functioning of these organs are being filled, and new procedures are being devised which will be useful to the clinical otolaryngologist and to those who wish to investigate, under controlled conditions, the influences of the canals and otoliths on central nervous system mechanisms. These last may prove to be of fundamental

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importance inasmuch as they bear on general adaptation processes and homeostatic mechanisms. It is hardly an exaggeration to state that when the mechanisms underlying the influences of the canals and otoliths are fully elucidated, it will constitute a sizable and significant contribution to an understanding of man. REFERENCES

1. McNally, E. J., and Stuart, Ε. Α.: Physiology of the labyrinth reviewed in relation to sea-sickness and other forms of motion sickness. War Med., Chicago, 2: 683-771, 1942. 2. Tyler, D. B., and Bard, P.: Motion sickness. Physiol. Rev. 29: 311369, 1949. 3. de Wit, G.: Seasickness (motion sickness). A labyrinthological study. Acta otolaryng., Stockh., Suppl. 108, 1-56, 1953. 4. Spoendlin, Η. H., Schuknecht, H. F., and Graybiel, Α.: The ultrastructure of the otolith organs in squirrel monkeys after exposure to high level G force. BuMed Project MR005.13-6001 Subtask 1 and NASA Order No. R-93. Pensacola, Fla.: Naval School of Aviation Medicine, 1964. 5. Gerathewohl, S. J.: Personal experiences during short periods of weightlessness reported by sixteen subjects. Astronautica Acta, 2: 203217, 1956. 6. Hammer, L.: Aeronautical Systems Division studies in weightlessness: 1959-1960. W A D D Technical Report 60-715. Wright-Patterson Air Force Base, Ohio: Aerospace Medical Research Laboratories, 1961. 7. von Beckh, H. J.: The incidence of motion sickness during exposure to the weightless state. Astronautik, 2: 217-224, 1961. 8. Loftus, J. P.: Symposium on motion sickness with special reference to weightlessness. AMRL-TDR-63-25. Wright-Patterson Air Force Base, Ohio: Aerospace Medical Research Laboratories, 1963. 9. Roman, J. Α., Warren, Β. H., and Graybiel, Α.: The function of the semi-circular canals during weightlessness. Aerospace Med., 34: 10851089, 1963. 10. Roman, J. Α., Warren, Β. H., and Graybiel, Α.: Observation of the elevator illusion during subgravity preceded by negative accelerations. Aerospace Med., 35: 121-124, 1964. 11. Warren, Β. H., Roman, J. Α., and Graybiel, Α.: Exclusion of angular accelerations as the principal cause of visual illusions during parabolic flight maneuvers. Aerospace Med., 35: 228-232, 1964. 12. Kellogg, R. S., Kennedy, R. S., and Graybiel, Α.: Motion sickness symptomatology of labyrinthine defective and normal subjects during

456

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14.

15.

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18.

19.

20.

21.

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zero gravity maneuvers. AMRL-TDR-64-47. Wright-Patterson Air Force Base, Ohio: Aerospace Medical Research Laboratories, 1964. Minners, Η. Α., Douglas, W. K., Knoblock, E. C., Graybiel, Α., and Hawkins, W. R. : Aeromedicai preparation and results of postflight medical examinations. In Results of the First United States Manned Orbital Space Flight, February 20, 1962. National Aeronautics and Space Administration, Manned Spacecraft Center. Pp 83-92. Minners, Η. Α., White, S. C., Douglas, W. K., Knoblock, E. C., and Graybiel, Α.: Aeromedicai studies. Clinical aeromedicai observations. In Results of the Second United States Manned Orbital Space Flight, May 24, 1962. NASA SP-6. National Aeronautics and Space Administration, Manned Spacecraft Center. Pp 43-53. Berry, C. Α., Minners, Η. Α., McCutcheon, E. P., and Pollard, R. Α.: Aeromedicai analysis. In Results of the Third United States Manned Orbital Space Flight, October 3, 1962. NASA SP-12. National Aeronautics and Space Administration, Manned Spacecraft Center, Project Mercury. Pp 23-36. Catterson, A. D., McCutcheon, E. P., Minners, Η. Α., and Pollard, R. Α.: Aeromedicai observations. In Mercury Project Summary Including Results of the Fourth Manned Orbital Flight, May 15 and 16, 1963. NASA SP-45. National Aeronautics and Space Administration, Manned Spacecraft Center, Project Mercury. Pp 229-326. Yazdoxskiy, V. I., Kas'yan, I. V., and Kopanev, V. I.: Physiological reactions of cosmonauts during the action of G-loads and weightlessness. Izv. Akad. Naak SSSR, Ser. Β., 29: 12-31, 1964. JPRS 23917. OTS 64-21924. Washington, D.C.: Joint Publications Research Service, 1964. Parin, V. V., Volynkin, Yu. M., and Vassilyev, P. V.: Manned space flight. (Some scientific results.) Seventh COSPAR Meeting and Fifth International Space Science Symposium, Florence, Italy, May 8-20, 1964. Alexander, S. H., Cotzin, M., Hill, C. J., Jr., Ricciuti, Ε. Α., and Wendt, G. R.: Wesleyan University studies of motion sickness: I. The effects of variation of time intervals between accelerations upon sickness rates. J. Psychol., 19: 49-62, 1945. Alexander, S. J., Cotzin, M., Hill, C. J., Jr., Ricciuti, Ε. Α., and Wendt, G. R.: Wesleyan University studies of motion sickness: II. A second approach to the problem of the effects of variation of time intervals between accelerations upon sickness rates. J. Psychol,. 19: 6368,1945. Alexander, S. J., Cotzin, M., Hill, C. J., Jr., Ricciuti, Ε. Α., and Wendt, G. R.: Wesleyan University studies of motion sickness: III. The

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22.

23.

24. 25.

26.

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28.

29.

30.

31.

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effects of various accelerations upon sickness rates. J. Psychol., 20: 3-8, 1945. Alexander, S. J., Cotzin, M., Hill, C. J., Jr., Ricciuti, Ε. Α., and Wendt, G. R.: Wesleyan University studies of motion sickness: IV. The effects of waves containing two acceleration levels upon sickness. J. Psychol., 20: 9-18, 1945. Wendt, G. R.: Vestibular functions. In Stevens, S. S. (Ed.), Handbook of Experimental Psychology. New York: John Wiley and Sons, Inc., 1951. Manning, G. W., and Stewart, W. G., The effect of body position on the incidence of motion sickness. J. Appi. Psychol., 1: 619-628, 1949. Graybiel, Α., and Johnson, W. H.: A comparison of the symptomatology experienced by healthy persons and subjects with loss of labyrinthine function when exposed to centripetal force on a counter-rotating room. Ann. Otol., etc., St. Louis, 72: 357-373, 1963. Miller, E. F., II: Counterrolling of the human eyes produced by head tilt with respect to gravity. Acta otolaryng., Stockh., 54: 479-501, 1962. Lowenstein, O., and Sand, Α.: The activity of the horizontal semicircular canal of the dogfish, Scyllium canícula. J. Exp. Biol., 13: 416428, 1936. Lowenstein, O., and Sand, Α.: The mechanism of the semicircular canal. A study of the responses of single-fibre preparations ton angular accelerations and to rotation at constant speed. Proc. Roy. Soc., Ser. Β., 129: 256-275, 1940. Groen, J. J., Lowenstein, O., and Vendrik, J. H.: The mechanical analysis of the responses from the end-organs of the horizontal semicircular canal in the isolated elasmobranch labyrinth. J. Physiol., London, 117: 329-346, 1952. McLeod, Μ. E., and Meek, J. C.: A threshold caloric test for the horizontal semicircular canal. BuMed Project MR005.13-6001 Subtask 1, Report No. 72 and NASA Order No. R-47. Pensacola, Fla.: Naval School of Aviation Medicine, 1962. McLeod, M. E., and Correia, M. J.: Caloric test in evaluating the effects of gravity on cupula displacement. BuMed Project MR005.136001 Subtask 1, Report No. 94 and NASA Order No. R-93. Pensacola, Fla.: Naval School of Aviation Medicine, 1964. Miller, E. F., II, and Graybiel, A,, and Kellogg, R. S.: Otolith organ activity within earthstandard, one-half standard, and zero gravity environments. Presented at the Aerospace Medical Association 35th Annual Meeting, Miami Beach, Florida, May 11-14, 1964.

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33. Gazenko, O. G., and Gurjian, Α. Α.: On the biological role of gravity — Some results and prospects of space research on satellites and spaceships. Seventh COSPAR Meeting and Fifth International Space Science Symposium, Florence, Italy, May 8-20, 1964. 34. Loret, B. J.: Optimization of space vehicle design with respect to artificial gravity. Aerospace Med., 34: 430-441, 1963. 35. Lansberg, M. P., Guedry, F. E., and Graybiel, Α.: The effect of changing the resultant linear acceleration relative to the subject on nystagmus generated by angular acceleration. BuMed Project MR005.13-6001 Subtask 1, Report No. 99 and NASA Order No. R-93. Pensacola, Fla.: Naval School of Aviation Medicine, 1964. 36. Kennedy, R. S., and Graybiel, Α.: Symptomatology during prolonged exposure in a constantly rotating environment at a velocity of one revolution per minute. Aerospace Med., 33: 817-825, 1962. 37. Guedry, F. E., Kennedy, R. S., Harris, C. S., and Graybiel, Α.: Human performance during two weeks in a room rotating at three RPM. BuMed Project MR005.13-6001 Subtask 1, Report No. 74 and NASA Order No. R-47. Pensacola, Fla.: Naval School of Aviation Medicine, 1962. 38. Graybiel, Α., et. al.: The effects of exposure to a rotating environment (10 R P M ) on four aviators for a period of twelve days. Joint Report. U. S. Naval School of Aviation Medicine, Walter Reed Army Institute of Research, and National Aeronautics and Space Administration. In preparation, 1964. 39. Graybiel, Α., Clark, B., and Zarriello, J. J.: Observations on human subjects living in a "slow rotation room" for periods of two days. Arch. Neurol., 3: 55-73, 1960.

Vestibular Neuritis Jan Stahle, M.D.

Vestibular neuritis is a rather "new" disease. There are individual cases mentioned during the 20's by, among others, Nylén ( 1 9 2 4 ) , but Dix and Hallpike in their excellent papers in 19491952 were the first to define the disease as a clinical entity. They reported on 100 cases and suggested the name "vestibular neuronitis." Since then about ten papers have been published, most of them from Europe: (Pfaltz, 1955; Frenzel, 1955; Aschan & Stahle, 1956; Kattum & Mündnich, 1957; Haas & Becker, 1958; Kern, 1958, et al.). The disease is still relatively unknown in comparison with, for example, Menière's disease. It is not possible to give an exact figure as to how usual, or more properly, how unusual, this disease is. During the past decade we in Uppsala have seen about 50 cases. An estimate shows that Menière's disease is about 10 times more common than vestibular neuritis. Unquestionably, the largest case material has been described by Dix and Hallpike in London — but this must not be taken as an indication that the disease is more common in Great Britain than in any other country.

SYMPTOMS

Vestibular neuritis is characterized by one single symptom — continuous dizziness. This dizziness starts rather acutely and can increase in severity over a period of several hours, or more usually, over a period of days, to a maximum — after which it very slowly decreases. It is not unusual for the patient to wake at night and for the first time experience this dizziness. Examples of dizziness 459

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starting while the patient was driving a tractor are described (Aschan & Stahle, 1956). It can be experienced as gyratoric movements or as a feeling of "off-balance" when walking or standing. As in other forms of organic vestibular diseases the trouble is aggravated by all kinds of head movements. The dizziness is not, as a rule, as severe as in a Meniére's attack, and vomiting is unusual. The patient examined during an early stage of the disease always shows a spontaneous or positional nystagmus. The caloric reactions are reduced on one side, the affected side. The spontaneous or positional nystagmus beats away from the "paretic" labyrinth. Although the majority of writers agree in thinking that the disease affects only one side, Dix and Hallpike ( 1 9 5 2 ) have nevertheless described double-sided cases in half of their material. The hearing is not affected, which is remarkable. N o tinnitus occurs. The patient himself is unable to localize the disease through pain or sensations of numbness, as is commonly noted in patients with Meniére's disease. There are no other signs of neurological disease. CSF is always normal, as is the E E G (Aschan & Stahle, 1956).

AGE AND SEX D I S T R I B U T I O N

The disease mostly strikes persons between 20 and 50 years of age, men and women with equal frequency. 8 5 % of our patients have been under 50. A closer examination of the age distribution shows the peak to be between 30 and 40, although patients under 20 have been reported. On the whole, it seems that the disease strikes a somewhat younger age group than Meniére's disease.

DURATION

The condition runs a protracted course, usually 2 - 3 months, during which time the dizziness and "off-balance" feeling gradually subsides, as does the nystagmus. But it is possible for the patient to have a slight feeling of insecurity in balance long after this, especially when he quickly changes the position of his head. There are also cases in which the dizziness is such a serious and

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drawnout problem, that it results in the patient's inability to work for several years. The labouring person is more handicapped in this regard, since his work requires much head movement.

PROGNOSIS

The condition is essentially a benign one — which it is not fatal. The dizzy patient, on the other hand, sickness as a real plague. The caloric reaction will be permanently reduced in and totally eliminated in about 1 0 % ; only in a slight cases does it return to normal strength.

means that regards his most cases, minority of

PATHOGENESIS

The general understanding as first presented by Dix and Hallpike (1952), is that it is an organic disease of the vestibular apparatus and is localized to its peripheral nervous pathways, or in other words, the peripheral neurone — hence the name, neuronitis. This means a lesion of the neuro-epithelium in the inner ear, the ganglion of Scarpa, the vestibular nerve and the vestibular nuclei in the brain stem. We base this understanding on the very important fact that the caloric reaction is reduced in all cases. With regard to exact location within the peripheral pathways, it has been the opinion of Dix and Hallpike, that it should be in the Scarpa's ganglion or the vestibular neurone's central thereto. This is indicated in the results of the galvanic response, which in most cases showed a significant reduction. There are, however, contradictory opinions about the interpretations of the galvanic response. Works of Bos and Jongkees (1963) and Jongkees and Philipszoon (1964) seem to indicate that a galvanic nystagmus has no relation to the vestibular system. Vestibular neuritis does not primarily affect the vestibular apparatus but in all probability appears as a complication to another condition, usually an infection in some other part of the body. Diseases of the upper respiratory pathways play an important part in its pathogenesis (Dix and Hallpike, 1952; Pfaltz, 1955; Kattum & Miindnich, 1957). Intestinal infections, nephritis and parotitis

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THE VESTIBULAR SYSTEM AND ITS DISEASES

are seen in conjunction with this disease, which has even been described in connection with pregnancy (Ascham & Stahle, 1956). The precipitating factor, which attacks the vestibular system, is probably some sort of allergy or toxicity, brought on by the infection. A direct bacterial or viral infection is less likely, as the cerebrospinal fluid in all our cases has been normal (Aschan & Stahle, 1956). Since the disease most often attacks younger people, an organic vascular lesion, atherosclerosis, or cervical spondylosis are less likely causes. The disease has a striking similarity to other diseases which also attack one single cranial nerve and on one side only: 1 ) sudden deafness, 2) retro-bulbar neuritis, and 3) Bell's palsy; diseases, in all of which the etiology is similarly obscure.

THERAPY

Treatment, unfortunately, seems to be principally symptomatic. In the acute stage, the patient will prefer to lie quietly in bed. Sedatives or drugs for motion sickness can be given to combat the dizziness. Antihistamines of different kinds and vaso-dilating drugs are also recommended. Cortisone has been tried but without any noticeable effect. When the first acute stage has passeed, it is advisable to attempt to rehabilitate the patient through simple physical exercises — just as after a labyrinthectomy. The time it will take before the patient can resume his normal occupation varies greatly, depending upon how seriously the patient has been affected by the disease, but also to a large extent on the nature of the patient's occupation. A typist will, in general, be back at work sooner than a labourer.

D I F F E R E N T I A L DIAGNOSIS

Vestibular neuritis is usually not difficult to distinguish from other diseases. The fact that the hearing is normal makes the possibility of a Meniére's disease or an acoustic tumor very unlikely. Nevertheless, it must be mentioned that Meniére's disease in unusual cases can make its first appearance with only vestibular symptoms such as dizziness, nystagmus and abnormal caloric re-

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actions. In such cases, however, the further course of the disease will give the correct diagnosis. Streptomycin damage can be eliminated on the basis of the case history. One affliction should be kept in mind -—disseminated sclerosis. It has happened that the initial stages of this disease have been erroneously interpreted as vestibular neuritis and vice versa (Dix and Hallpike, 1952, et al.). Finally, there are conditions in younger people with long-lasting dizziness, nystagmus and mostly normal caloric response, where a slight momentary increase in the number of cells in the cerebrospinal fluid can be found. We call this condition "encephalitis of the brain stem", although we are unable to prove the exact location.

E L E C T R O N Y S T A G M O G R A P H Y IN V E S T I B U L A R N E U R I T I S

Electronystagmography plays an important part in the diagnosis of vestibular neuritis (Aschan, Bergstedt & Stahle, 1956). It will reveal spontaneous or positional nystagmus even in cases where this cannot be seen with the naked eye, and it facilitates the interpretation of the caloric response. Previous studies of the caloric reaction (Stahle, 1958) have shown the superiority of assessing the reaction from its intensity (eye speed in the slow nystagmus phase, culmination, maximum intensity, total amplitude, etc.) in comparison with the duration (cf. Case 3, Fig. 4 ) . Nystagmography also makes possible a correct evaluation of the caloric reaction in cases with spontaneous nystagmus in the test position, which otherwise can be very difficult with conventional methods (cf. Case 4, Fig. 5 ) . Four typical cases have been chosen and illustrated with nystagmographical recordings: Case 1. A 26-year-old man with left-sided vestibular neuritis. He developed dizziness suddenly while driving a tractor in a corn field. There was no recent history of infection of the upper respiratory pathways. The nystagmography was performed 5 days after the onset, and he was still experiencing severe dizziness. The recordings (Fig. 1)* show a right-beating spontaneous nystagmus of moderate intensity. It is clearly seen that the nystagmus always has the same direction and intensity in all of the four illustrated * Figures 1, 2, and 3 are taken f r o m Aschan & Stahle, J. Laryng., 70, 497, 1956, and Figs. 4 and 5 f r o m Stahle, Acta oto-laryng. (Stockh.), Suppl. 137, 1958.

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positions (supine, right-lateral, left-lateral and head hanging). Three weeks later this nystagmus had completely subsided. The caloric test showed initially a moderate left-sided canal paresis, but after three weeks, there was a complete insensitivity. Case 2. This is a 27-year-old woman with a left-sided vestibular neuritis, who developed acute vertigo during the eighth month of pregnancy without any previous infection or any signs of toxemia. The recordings were made shortly after the onset and show a brisk right-beating spontaneous nystagmus (Fig. 2 ) . One month later, when the symptoms had practically disappeared, a very slight right-beating positional nystagmus could be recorded in the leftlateral position (Fig. 3 ) . After a complete examination, including a caloric test, however, a clear spontaneous nystagmus was seen, an example of the so-called provoked nystagmus. This means that the testing, which the patient had undergone, had in fact provoked a weak spontaneous nystagmus. The phenomenon is analogous to

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Case 822 a

Fig. 2. 27-year-old woman with left-sided vestibular neuritis during the initial stage. T h e patient was in the 8th month of pregnancy. In all four positons there is a brisk spontaneous nystagmus beating to the right.

the directional preponderance in the caloric test, and appears with the greatest clarity when using ENG. Case 3. This is a 72-year-old man with right-sided vestibular neuritis. Three months before examination he developed an acute attack of dizziness with a tendency to fall to the right. His symptoms were aggravated by changes in the position of his head. At the time of this investigation he was almost symptom-free. There was no spontaneous nystagmus — only recordings in the supine position are shown (Fig. 4). The caloric test revealed a distinctly diminished sensitivity of the right labyrinth for both cold and hot water. This impairment of function, which can be seen directly on the recordings, is fully documented by the four diagrams below in Fig. 4. The duration of the caloric reactions is much shorter on the right side than on the left. The dlifference between the right

466

THE VESTIBULAR SYSTEM AND ITS DISEASES

Fig. 3. The same case as Fig. 2, one month later. In the supine ( S ) and right lateral positions ( R ) there is no definite nystagmus. In the left lateral position (L) slow, low frequency nystagmus beating to the right is recorded. The lowermost curve was recorded after a full oto-ieurological examination, and shows right-beating nystagmus in the supine position — "provoked" nystagmus.

and left ear, however, is best seen in the number of beats, total amplitude and maximum intensity — all three factors are expressions of the intensity of the reaction. This is a further example of what has been stressed in my previous lecture, namely that the caloric reaction is often best evaluated on the basis of its intensity and not its duration. Case 4. A 28-year-old woman with right-sided vestibular neuritis. In the acute stage, we find a left-beating spontaneous nystagmus with an intensity of about l l ° / s e c o n d , which means that the mean value of the speed of the eyes in the slow nystagmus phase is l l ° / s e c o n d (Fig. 5 ) . The caloric test at this moment seemed to indicate a diminished sensitivity of the right labyrinth. Although she still experienced a noticeable dizziness and "off-balance" feeling five weeks later the recording showed the same left-beating nystag-

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mus, now with an intensity of about 8°/second. The recordings from the caloric test, which can be seen to the left in the figure, show that the left-beating spontaneous nystagmus does not seem to be affected by water of either 30°C or 44°C in the right ear. On the other hand, the left ear reacts according to accepted rules. Cold water changes the direction of the left-beating nystagmus to right-beating, and hot water augments the intensity (as can be seen from the lowermost tracing). From the diagram on the right,

468

THE VESTIBULAR SYSTEM AND ITS DISEASES

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where the intensity level of the spontaneous nystagmus is marked by a shaded zone, one can see that the calorization of the right ear (cross-marked line) doesn't change the intensity of the spontaneous nystagmus as does calorization of the left ear.

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grams show us that there is a complete elimination of the caloric reaction of the right labyrinth, and the same results were achieved at the follow-up one year later.

VESTIBULAR

NEURITIS

469

SUMMARY

T h e most important facts about this disease are presented in the 12 points illustrated in T a b l e A. There are exceptions, naturally, but f r o m my own experience, and f r o m what can be found in the literature written about this disease, the majority of cases seem to fall within this scheme. Table A VESTIBULAR NEURITIS (NEURONITIS) 1. 2. 3. 4. 5.

Youngerpeople Following an infection Acute onset of dizziness Protracted course Benign lesion in the peripheral pathways 6. Unilateral in most cases

7. Reduced caloric excitability 8. Spontaneous nystagmus beating away from the diseased labyrinth 9. Reduced galvanic response 10. Normal hearing No tinnitus 11. Normal CSF Normal EEG 12. Therapy symptomatic REFERENCES

Aschan, G., Bergstedt, M., and Stahle, J., 1956: Nystagmography. Recording of nystagmus in clinical neuro-otological examinations. Acta otolaryng. (Stockh.), Suppl. 129. Aschan, G. and Stahle, J., 1956: Vestibular neuritis. A nystagmographical study. J. Laryng. 70, 497. Bos, J. H. and Jongkees, L. B. W., 1963: On galvanic stimulation of the labyrinth. Pract. oto-rhino-laryng. (Basel), 25, 345. Dix, M. R. and Hallpike, C. S., 1952: The pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Ann. Otol. (St. Louis), 61, 987. Frenzel, H., 1955: Spontan- und Provokationsnystagmus als Krankheitssymptom. Springer Verlag, Berlin — Göttingen — Heidelberg. Graf, K., 1954: Über den vestibulären Schwindel, dessen Ursachen und Bedeutung. Praxis, 43, 590. Haas, E. and Becker, W., 1958: Die vestibuläre Neuronopathie (Neuronitis) und ihre Differentialdiagnose. Z. Laryng. Rhinol., 37, 174. Hallpike, C. S., 1949: The pathology and differential diagnosis of aural vertigo. Proc. 4th Int. Cong. Otolaryngol., II, 514. Brit. Med. Assn., London.

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Jongkees, L. B. W. and Philipszoon, A. J., 1964: Electronystagmography. Acta oto-laryn., Suppl. 1 89. Kattum, F. X. and Mündnich, K., 1957: Kritische Betrachtungen zur Neuronitis vestibularis (Hallpike). Ζ. Hals—, Ñas. u. Ohrenheilk., 6, 232. Kern, G., 1958: Zur Frage der Neuronitis vestibularis. Pract. oto-rhinolaryng. (Basel), 20, 233. Nylén, C. O., 1924: Some cases of ocular nystagmus due to certain positions of the head. Acta oto-laryng., (Stockh.), 6, 106. Pfaltz, C. R., 1955: Diagnose und Therapie der vestibulären Neuronitis. Pract. oto-rhino-laryng. (Basel), 17, 454. Stahle, J., 1958: Electro-nystagmography in the caloric and rotatory tests. A clinical study. Acta oto-laryng. (Stockh.), Suppl. 137.

Discussion PROFESSOR L . Β . W . JONGKEES [University of Amsterdam]: Dr. Schlosser, Ladies and Gentlemen: Dr. Stahle has made an excellent exposé but he asked me to make a little statement because I seem to have been very unclear and it is always a great mistake to be unclear so you try to repair this mistake. It seems that quite a lot of people have got the impression that I think the caloric test is not so very important. This is untrue. I think the caloric test is very important, but as many people complain about the time-consuming tests in vestibular examinations, I always tell them, "You have to do the tests you need for a diagnosis." For instance, if you have performed the examination of hearing and you have found a hearing loss with recruitment, and then you have found spontaneous nystagmus, I think it is superfluous to make a complete caloric test. It will not give you any new information. But it is perfectly untrue and I have never stated that if you find normal hearing and no spontaneous nystagmus that you should not perform a caloric test. The caloric test is of especially great importance in cases, for instance, of vestibular neuritis. Then you can find the small reaction of the diseased labyrinth. I hope I have been clear now, and forgive me.

471

Vertigo Related to Alteration in Arterial Blood Flow William S. Fields, M.D.

"Dizziness" is a frequent, yet often unexplained, complaint of persons past middle age, and it seems likely that in some cases, at least, it may be related to the presence of vascular degenerative changes which are also common in the same age group. It is my purpose in this presentation to try to identify some of the mechanisms by which intracranial circulation is altered, thereby producing ischemia in the vestibular complex. It has long been recognized that the vestibular mechanism is peculiarly sensitive to alterations in local arterial circulation, but only recently has it become apparent that it is readily affected by circulatory changes which are produced more remotely. An increasing amount of attention is being paid to extracranial as well as intracranial causes of altered blood flow which may be responsible for ischemia in cerebral and brain stem structures. The more widespread employment of arteriography as a result of improved techniques and safer contrast media has enabled investigators to visualize many of the pathologic processes which interfere with blood flow. Furthermore, the possibility of surgical correction of certain types of extracranial lesions makes it imperative to search for a vascular origin of otherwise unexplained vertiginous symptoms. Ischemia of brain stem structures as a result of inadequacy of basilar arterial circulation is commonly referred to as basilar artery insufficiency. 1 This syndrome includes equilibratory, visual, auditory, and somatic motor and sensory disturbances. Vertigo is by 472

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far the most common symptom associated with basilar insufficiency and may be the only symptom in some attacks. 2 In most patients, however, it is accompanied by other transitory manifestations of brain stem or occipital lobe dysfunction. However, it may be necessary to probe carefully for this information when taking a history since the vertigo may be the manifestation most obvious to the patient. One frequently sees patients with transitory, relatively severe vertigo associated with changes in vertical posture and position of the head and neck. Such patients rarely have auditory symptoms, but the equilibratory disturbance is often accompanied by aberration in vision or unsteadiness of gait. These patients rarely show abnormality in routine auditory or vestibular testing. Alteration in blood flow in the basilar artery system is dependent primarily upon cardiac output, which in turn is dependent upon peripheral resistance, blood volume, and alteration in posture. Blood flow continually varies in the systemic arteries, but in normal persons the flow in the cerebral and brain stem arteries is protected from systemic changes by the vasomotor reflex effect of circulating carbon dioxide. When atherosclerosis is present, the elasticity of the vascular walls is reduced and the effectiveness of the chemical vasomotor mechanism is considerably diminished. Arteriosclerosis and inefficient vasomotor control cause the remote effects of altered systemic blood pressure to be more profound. A steep gradient in blood pressure is present between the aorta and the terminal arterioles of the brain stem. Pressure and flow distal to partial arterial obstruction, irrespective of etiology, may be greatly compromised when systemic pressure drops. In the vertebral-basilar arterial system, flow in the terminal arterioles of the long pontine branches may fall to virtually zero when systemic pressure is reduced. The vestibular nuclei are particularly vulnerable to ischemia because they are situated far laterally in the pons and are supplied by long, thin vessels usually devoid of branching. This structural relationship probably plays an important role in the occurrence of intermittent vertigo as a common early manifestation of vertebralbasilar insufficiency. Three major factors, either alone or more commonly in combination, are responsible for pressure and flow changes in the basilar

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artery. There are: (1) morphologic variations; (2) mechanical compression of the vertebral artery by extravascular structures; and ( 3 ) atherosclerosis, either localized or generalized. Since anatomical variants in the vascular channels are considered to be congenital, they are not likely to play a primary role in the pathogenesis of brain stem ischemia. However, they assume considerable importance in later life when degenerative vascular and skeletal disorders interfere with compensatory mechanisms which had previously served to prevent the occurrence of symptoms.

MORPHOLOGIC VARIATIONS

The basilar artery is a midline trunk which receives its principal blood supply from a confluence of the two vertebral arteries. The latter originate from the subclavian arteries in the lower cervical region, passing cephalad through the foramina in the transverse processes of the upper sixth cervical vertebrae. These arteries then turn posteriorly and medially around the superior articulate process of the atlas before entering the cranial cavity through the foramen magnum. Under certain circumstances, blood supply into the basilar artery is also possible from the carotid system on either side through the posterior communicating arteries of the circle of Willis. 3 Arterial developmental anomalies occur with a high degree of frequency in this part of the craniocervical circulation. 4 These variants have long been known from postmortem examinations, but it has become possible to identify them in the living subject by means of arteriography. The circle of Willis, which is extremely important as a potential source of anastomotic blood flow in the arteries at the base of the brain, is frequently defective in one or more of its segments. The most common variation in the circle is the persistence of a primitive embryologie pattern in which the posterior cerebral artery on one or both sides originates from the internal carotid artery with either no communication or a tenuous communication with the basilar artery. As a consequence of these variations, the potentiality for collateral blood flow under pathologic conditions is greatly diminished. 5

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Fig. 1. Left subclavian arteriogram demonstrating vertebral-basilar circulation. Basilar artery is dilated, irregular, and tortuous. Only the left posteror cerebral artery is visualized. Right posterior cerebral originates from carotid artery.

476 The intracranial portion of the vertebral arteries, usually the vessel on the right side, may be hypoplastic or impervious. 6 It is not uncommon for the vertebral artery on one side to terminate in the posterior inferior cerebellar artery without communication with the basilar artery. In such cases, blood flow in the basilar artery is dependent principally on supply from the opposite vertebral artery and through the circle of Willis. (Fig. 2.) The cervical portions of the vertebral arteries also vary widely in size and distribution. 7 Some of the more hypoplastic arteries terminate in the neck and do not contribute to the intracranial circulation. If there is a marked difference in size between the two vertebral arteries, the left one is usually the larger. In addition, the left vertebral artery may originate directly from the aortic arch instead of its normal origin from the subclavian artery. For this reason, the vessel may be difficult to visaulize in routine angiographic procedures and a false interpretation of left vertebral artery occlusion may be made.

ATHEROSCLEROSIS

Atherosclerotic lesions may be present in the basilar artery or in the numerous arterial channels which supply it with blood. 8 (Fig. 1.) Such lesions are not infrequent in the extracranial portions of the vertebralbasilar system or in the carotid arteries which serve as sources of collateral blood flow. For this reason, proper diagnostic evaluation of patients with basilar insufficiency requires visualization of the entire arterial tree in order to ascertain whether occlusive lesions are present in the cervical arteries, the intracranial arteries, or both, and to determine the status of collateral circulation. Panarteriography is essential if reconstructive arterial surgery of accessible extracranial lesions is contemplated. At present only those lesions located in the cervical extracranial segments of the carotid arteries or the extraspinal cervical segments of the vertebral arteries are considered surgically accessible. 9 Fortunately, lesions considered to be responsible for basilar insufficiency symptoms are frequently located in these accessible segments. Sometimes when the lesions in the vertbral arterial system are inaccessible, basilar insufficiency may be relieved by removal of accessible carotid lesions,

Fig. 2. a) Right subclavian arteriogram showing marked stenosis at origin of vertebral artery. Distal cervical portion of vertebral appears normal. b) Left subclavian arteriogram showing extremely hypoplastic vertebral artery which terminates in the upper cervical region. c) Right carotid arteriogram showing stenosis at origin of internal carotid with normal appearing distal arteries. d) Left internal carotid arteriogram showing stenosis in proximal portion of the internal carotid artery.

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provided collateral circulation through the circle of Willis is present. This can often be demonstrated angiographically. (Fig. 2.) Basilar insufficiency symptoms have been reported in patients with occlusion of the proximal portion of the subclavian artery by atherosclerosis or thrombus formation. 10 Transient attacks of brain stem ischemia are occasionally precipitated in these patients by physical exercise of the upper limb on the side of the occlusion. Blood is shortcircuited away from the basilar artery by reversal of flow in the vertebral artery on the side of the subclavian occlusion. This syndrome has been aptly called the "subclavian steal." When such an obstruction is removed surgically or relieved by bypass graft between the common carotid and the second portion of the subclavian artery, the symptoms cease and can no longer be provoked by exertion.

MECHANICAL COMPRESSION

The causes of compression of the vertebral arteries, which may result in basilar insufficiency syndromes, may be placed in the following categories: Hyperextension and Extreme the Head and Neck

Rotation

of

Because of the unique anatomic relationship of the vertebral arteries to the cervical spine, compression of these vessels on one or both sides can result from maneuvers of the head and neck. We have encountered numerous patients in whom vertiginous symptoms have been associated with the position of the head and neck in certain types of occupations requiring overhead work or when backing an automobile. 11 Extension of the neck and turning of the chin to one side severely compromise blood flow through the opposite vertebral artery. When one of the vertebral arteries is hypoplastic or circulation through it defective because of atherosclerosis, certain neck movements and head positions may severely diminish flow through the opposite side into the basilar artery. 12 The vertebral artery normally becomes compressed at the atlanto-axial level as a result of turning

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of the head to the opposite side. The compression appears to be produced by asymmetric eccentric rotation of the axis on the fixed atlanto-axial joint of the opposite side. 13 This does not usually have clinical importance unless the compensatory vascular channels are compromised. Extreme rotation of the neck away from the side being injected during arteriography may result in failure to visualize the ipsilateral vertebral artery. When the head is returned to a neutral position and the injection repeated, the artery may be noted to fill in a normal manner. It was our belief that this phenomenon resulted from atlanto-axial compression and the formation of a static column of blood in the cervical portion of the vertebral artery. This hypothesis was confirmed when we employed bilateral simultaneous injection and observed reversal of flow in the distal portion of the blocked vertebral artery from the contralateral side. It has also been noted that the vertebral artery can be compressed in the lower part of the neck by the scalenus anterior muscle. This occurs when the head is rotated partially to the opposite side and the vertebral artery originates from the posterior aspect of the subclavian artery behind the thyrocervical trunk. Vertiginous symptoms, which occasionally occur in such cases, have been relieved by section of the scalenus anterior muscle. 14 When hyperextension of the head and neck is maintained for a prolonged period, vertigo may result because of mechanical compression of both vertebral arteries at the base of the skull and faulty collateral circulation through the carotid arteries or the circle of Willis. Surgical removal of accessible carotid occlusive lesions in cases with patent posterior communicating arteries may result in complete relief of symptoms. The dynamics of these mechanisms of compression can be best understood when visualized by arteriography. Indirect techniques of injection through the infraclavicular portion of the subclavian artery, the axillary artery, or the brachial artery are most suitable for visualizing these phenomena. Direct puncture of the vertebral artery does not permit one to observe these changes since the needle will not remain in place during the procedure if the head and neck position are altered, and one runs the risk of serious complications. During the past two years we have employed a technique of bilateral simultaneous injection through infraclavicular

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catheterization of both subclavian arteries which has enabled us to observe flow patterns through the vertebral and carotid arteries with the head and neck in various positions. 15 Cervical

Spondylosis

Vertebral artery compression by spondylotic lesions of the cervical spine has been demonstrated during arteriography. 16 Indentation of the artery may be noted when the head is in a neutral position, and more severe compression of the lumen can be seen when the head is rotated and the neck extended. (Fig. 3.) Episodic basilar insufficiency may occur from this cause alone, but it is far more likely to be present when there is concomitant atherosclerosis. It is reasonable, therefore, to assume that the symptomatic patient with cervical spondylosis also has atherosclerosis or a morphologic variation in the arterial channels. In such cases, surgical removal of osteoarthritic spurs which are impinging on the vertebral arteries has been known to result in relief of vertigo and other symptoms of basilar insufficiency. u ' 1 8

CONCLUSIONS

Considerable new and valuable information about recurrent unexplained vertigo has been accumulated through employment of panarteriography of the craniocervical circulation. In our experience, arteriography has not been hazardous, and we have not had a single mortality in such cases. We have had two cases of unilateral pneumothorax in 350 patients studied, and the only other complications were local hematoma or extravasation of contrast material. I would not, however, advocate subjecting a patient to such a diagnostic evaluation unless the study is considered likely to lead to some form of definitive treatment. In some cases it may be necessary to remove or bypass atherosclerotic lesions and in others to undertake removal of cervical spondylotic spurs. In any event, rational explanations may be forthcoming in many patients with previously unexplained vertigo and specific therapy directed toward the alleviation of their symptoms.

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Fig. 3- a ) R i g h t subclavian arteriogram with head rotated to the right showing carotid system and hypoplastic right vertebral artery. b ) Left subclavian arteriogram with head in neutral position showing large left vertebral artery slightly indented by osteoarthritic spurs at C5-6. c ) Left vertebral arteriogram with head rotated to the left showing increase in compression by spurs. d ) Repeat injection with head rotated to the right showing reduction o f compression and return of lumen to normal size.

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REFERENCES

1. Denny-Brown, D.: Basilar artery syndromes. Bull. New England Med. Cen., 15: 53-60, 1953. 2. Williams, D., and Wilson, T.: The diagnosis of the major and minor syndromes of basilar insufficiency. Brain, 85: 741-774, 1962. 3. Kramer, S. P.: On the function of the circle of Willis. J. Exp. Med., 15: 348-364, 1912. 4. Alpers, Β. J., Berry, R. G., and Paddison, R. M.: Anatomical studies of the circle of Willis in normal brain. Arch. Neurol., Psychiat., 81: 409-418, 1959. 5. Riggs, Η. E., and Rupp, C. : Variations in form of circle of Willis. Arch. Neurol., 8: 8-14, 1963. 6. Niemanis, G.: Ueber Kaliberschwankungen und Verlaufsanomalien des interkranielen Abschuittes der A. vertebralis. Frankfurt. Z. Path., 67: 461-484, 1956. 7. Hutchinson, E. C., and Yates, P. O.: The cervical portion of the vertebral artery; a clinico-pathological study. Brain, 79: 319-331, 1956. 8. Meyer, J. S., Sheehan, S., and Bauer, R. B.: An artériographie study of cerebrovascular disease in man. I. Stenosis and occlusion of the vertebral-basilar arterial system. Arch. Neurol., 2: 27-45, 1960. 9. DeBakey, M. E., Crawford, E. S., and Fields, W. S.: Surgical treatment of lesions producing arterial insufficiency of the internal carotid, common carotid, vertebral, innominate and subclavian arteries. Ann. Intern. Med., 51: 436-448, 1959. 10. North, R. R., Fields. W. S., DeBakey, M. E., and Crawford, E. S.: Brachial-basilar insufficiency syndrome. Neurology, 12: 810-820, 1962. 11. Fields, W. S., and Wiebel, J.: Effects on vascular disorders on the vestibular system. In Fields, W. S., and Alford, B. R., eds. Neurological Manifestations of Auditory and Vestibular Disorders. Springfield, Illinois, Charles C. Thomas, 1964. 12. DeKleyn, Α.: On vestibular nystagmus. Confin. Neurol., 2: 257-292, 1939. 13. Tissington Tatlow, W. F., and Bammer, H. G.: Syndrome of vertebral artery compression. Neurology, 7: 331-340, 1957. 14. Powers, S. R., Jr., Drislane, T. M., and Nevins, S.: Intermittent vertebral artery compression: A new syndrome. Surgery, 49: 257-264, 1961. 15. Weibel, J., and Fields, W. S.: Direct percutaneous infraclavicular catheterization of the subclavian artery. J. Neurosurg., 20: 233-237, 1963.

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16. Sheehan, S., Bauer, R. B., and Meyer, J. S.: Vertebral artery compression in cervical spondylosis: Artériographie demonstration during life of vertebral artery insufficiency due to rotation and extension of the neck. Neurology, 10: 968-986, 1960.

Discussion

DR. DANIEL M . MARTINEZ [Dallas, Texas]: I enjoyed very much Dr. Fields' presentation and his focusing on the problem of vertigo in other areas other than the ear. I would like to ask some questions and then mention a case which brings these questions to my mind. One question is whether in the cases of atherosclerosis of any part of the carotid system he has found always a spontaneous or a positional nystagmus. T h e second question is whether he has found in these cases with atherosclerosis a decreased activity or a hypoactivity of one of the labyrinths. In my patient who had vertigo, and who had carotid endarterectomy for atheroma, the vertigo in this patient persisted and when I saw the patient, by electronystagmography I was able to determine that the patient had a positional nystagmus to the opposite side of the lesion; that is, to the opposite side of where the endarterectomy had been done, so it came to my mind whether the patient can have both things: increased blood flow into one of the carotid arteries and at the same time have some form of labyrinthine vascular pathology. This patient had hypoactivity of the same labyrinth on the side where the endarterectomy had been performed. I treated this patient with ultrasound, with a complete obliteration of the positional nystagmus, and with definite improvement of his symptoms. His last letter mentioned that he has been free from the severe episodes of vertigo that he had, so the possibility of having pathology both in the carotid arteries and in the labyrinth was brought to my mind and I wonder whether these patients should be investigated both with a neurological examination and 484

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arteriography, but also without eliminating the caloric test that would point to a labyrinthine pathology as well and perhaps a combined form of treatment. This patient did not get well with endarterectomy as far as the vertigo was concerned, and probably would not have been well if we had treated his labyrinth and had not taken care of his carotid artery. D R . F I E L D : In our experience, in those cases in whom we have had the opportunity to do such studies we have not found any positional nystagmus and most of these people do not have any spontaneous nystagmus except during the acute episode. We rarely see them when they are having such symptoms. It is between times that we have the opportunity to study them, for the most part. We are anxious to do some studies which may lead to further elucidation of the problem, but I would hasten to agree with Dr. Martinez: The people who have vascular disease, particularly atherosclerosis involving the major vessels in the extracranial portion, are just as likely to have it involving the intracranial vessels of smaller caliber with which most of you are frequently concerned. We are all aware of the syndrome of the occlusion of the labyrinthine branch of the internal auditory artery with its sudden onset of acute vertigo, with one attack and then a dead labyrinth. This is a very different kind of situation and I am satisfied that some of the patients that we have here, with extracranial disorders, may also have intracranial vascular or other pathology which involves the labyrinthine complex.

Medical Treatment of Meniere's Disease Jerome A . Hilger, M . D . *

There is no really satisfactory medical treatment for Menière's disease. This is not surprising since the cause of Menière's disease is not known. Deductions of cause from assumed therapeutic response is a perilous exercise since the natural history of the disorder involves remissions and exacerbations. The pathology of Menière's disease has been anaylzed and described. But the genesis has only been hypothesized. T h e disorder has never been produced experimentally. Fundamental questions remain unanswered. In this disorder an affect of the body system on the labyrinth rather than a primary fault in the labyrinth? Are the alterations in the humors of the labyrinth, then, a secondary phenomena as are the neural changes? Are altered vascular mechanisms within the labyrinth the primary cause of the disease? Is it possible such alterations in a given patient are not confined to this minute area but are sub-threshold in less expressive tissues, thus making Menière's disease a local response to a pattern of vascular alteration dictated by factors which could well be system wide? Is it possible that end products of local tissue injury within the labyrinth (to, for example, the stria vascularis) create the conditions essential to autoimmune responsiveness — thus laying the groundwork for exacerbation. Are the cataclysmic symptoms — the neutral volleys — the result of physical distortion or the result of direct neuroepithelial insult due to ischemic hypoxia or metabolic insufficiency? Is the physical distortion within the labyrinth due to actual pressure imbalance or the result of an osmotically-dictated fluid shift? Is it * Professor of Otolaryngology, University of Minnesota, Minneapolis,

486

Minnesota.

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possible Menière's is not a single disease entity, but rather a nonspecific response of labyrinthine tissues to a variety of systemic faults. These are the questions to be resolved before treatment can be well grounded. For to be effective therapy must focus on etiology and must be applied before irreversible neural cell and physical configuration changes occur in the endolymphatic labyrinth. There is opportunity for this only if the early signs are promptly presented and properly interpreted. This is the stage of aural fullness; decrease in auditory discrimination without sharp loss of pure tone hearing; low frequency, minor tinnitus; and, sometimes, imbalance amounting only to giddiness with abrupt movement. This is the symptomatic stage too frequently attributed to simple canal occlusion or auditory tubal closure or functional complaint. This is the stage so often resolved through natural recuperative forces — the unknown influences we would emulate with therapy. A perceptive history at this early junction often suggests that the problem is arising as an otologic consequenec of "stress" in an organism unequal to the load. General evaluation at this moment may demonstrate hormonal protective insufficiency or a reasonably adequate economy unreasonably loaded — with fatigue, faulty habit, emotional burden, etc. This is the stage for general physical study and personality evaluation. Pharmacotherapy may be limited to sedation and indicated hormonal supplement whether thyroid or adrenocortical or gonadal. The former will usually be a matter of long term continuance. The latter may be needed only for the stress reparative period. Thyroid deficiency is more readily demonstrated by diagnostic tests than are gonadal or adrenocortical insufficiency. The consumption of oxygen in the process of tissue metabolism as measured by the rate at truly basal conditions is the most reliable indication of the state of action of the thyroid catalytic hormone. This is determined by the BMR test in the well sedated patient. The nature of the thus identified hypofunction is further defined by specific determinations at each of the levels in the hormonal chain — hypophyseal, thyroid gland and terminal circulating iodothyronines. Substitution and regulation of the deficient system requires experience and long term medical supervision.

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Gonadal imbalance depends for diagnosis on a perceptive history and linkage of the symptomatic sequences to the ovarian cycle — the premenstrual period, pregnancy, or the menopause. The indicated therapeutic trial and management again is a long term medical sequence. Adrenocortical deficiency is demonstrable by laboratory tests when it is severe and chronically present. When it is neither but is relative to the overdemand of a stressing situation tests may be equivocal. A history indicative of marginal adrenocortical adequacy in the respiratory system or musculoskeletal system is sufficient background for prompt therapeutic trial in the early phase of Menière's. Substitution rather than trophic hormone injection is indicated. Removal of stress and short term treatment go hand in hand. Drugs with useful neurochemical mechanisms in Menière's disease fall into three major groups — sedatives and psychotherapeutic drugs; those with atropine-like action; and peripheral blocking agents. The presumed value of any of these drugs is their eventual influence on the neural activity incited by the Menière's pathology or on the vascular mechanisms purported to produce that neural activity. Barbiturates and a bewildering galaxy of psychotherapeutic drugs may be over- or under-valued according to the therapeutic temperment of the physician and his assessment of his patient. The unquestioned value of the atropine-like drugs and certain of the antihistamines (peripheral blocking agents) are as effectively represented for oral therapy in a combination of diphenhydramine hydrochloride and hyoscine (Benoscine) as in any other form. The combination simplifies administration and is effective in dose of diminishing frequency durng the active, exacerbating phase of the disease. Parenteral use of atropine, diphenhydramine (Benadryl) or dimenhydrinate (Dramamine) is effective during the short period of acute crisis. Ganglionic blockage with cervical sympathetic block or peripheral block with intravenous procaine is effective in this early stage also. The former has the advantage of more enduring action. On the presumption that altered arteriolo-capillary function (whether or not caused by neurochemical mechanisms) are fundamental to the labyrinthine derangement, vasodilators have been

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consistently recommended in treatment. Histamine and nicotinic acid and its elaborations are evanescent and to a degree miss the intracranial mark. Whether nylidrin (Arlidin, Perdilatal) will perform more positively in the intracranial (and intralabyrinthine) circulation as claimed remains to be verified. They probably represent advance over the former traditional two in an effort to supplement the action of the neurochemical drugs. It is certain that the most effective intracranial vasodilator is an increase in the carbon dioxide tension in the intracranial circulation. This can be obtained transiently by breathing into a common Kraft paper bag. The valued results claimed for intermittent cervical sympathetic block can parallel one or a combination of the neurochemical and vasodilator actions. The proponents claim simplicity and directness of treatment. They often combine the advantages of the block with vasodilator therapy. The ardent advocacy of surgical sympathectomy has won few adherents — perhaps for uncertainty of its permanence. Efforts to control the hydropic pathology of the diseased labyrinth by direct alteration of systemic fluid balance are not encouraged by well controlled research results. The original results reported by Mygind and Dederding and subsequent disciples could be better attributed to the undoubted systemic and peripheral vascular values obtained from the physiotherapeutic measures associated with their treatment program — the tail wagging the dog in this instance. The mechanism of action of carbon dioxide anhydrase in ocular glaucoma does not carry over in parallel to the labyrinth with this class of drug. Drugs with pure diuretic action could hardly be presumed effective in Menière's other than in the occasional case relating to ovarian imbalance with fluid retention and to the resolution of the problem of the salt drunkard. The latter can account for the rare case positively managed by the older ammonium chloride or potassium chloride regime. In deference to the existence of the unknowing salt drunkard or to the rare possibility of fault in average salt transfer it is a sound routine in Menière's management to insist on moderation in salt intake. A salt-free program, however, is difficult to enforce, miserable to endure and furnishes infinitesmal returns.

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Tissue reparative supplements though not a matter of primary or preventive treatment have frequently or usually been included in the complete management program of Menière's disease. This is nutritional therapy in the strictest sense — usually directed to repair of the vascular endothelium and restoration of intercellular ground substance or to revival of sick, not-yet-defunct neural cells. In its finest form the nutritional reparative program is represented in Robert's regime and elaborated in his text.* Some of its essence can be supplied immediately and simply in large doses of ascorbic acid and of brewer's yeast to supplement a well rounded diet or in a high potency vitamin-mineral combination. The specificity in repair or primary deficiency in cause of other nutrient elements as related to Menière's disease such as the lemon bioflavinoid complex of William's have not as yet been verified to a degree that would justify widespread, costly usage. This theory is being capably investigated by the originator and others and the results of frank appraisal will be available in due course without general hit and miss detractive usage by non-contributors. On the horizon are additional unproven agents of promise for Menière's disease : 1 ) Heparin as a local histamine antagonist in less than full anticoagulant dose. 2) Low molecular detran and related agents as blood sludge liquifiers and endothelial restorers. 3) Methysergide maleate as a histamine degranulator of the basophil to prevent the local histamine induced crisis — of which Menière's disease has been felt by some to be an example. The physician does not capitalize on his early diagnosis of Menière's disease if he does not seize this opportunity to put the patient "right with his environment". This is the time to interdict smoking, work overload, excesses, and emotional stress. Here too frequently one encounters the medical impasse of the wrong individual in the wrong life situation and here is one circumstance in which two negatives do not make a positive. Menière's disease hereafter passes into an advanced phase of pathology from which there is little return and for which one can * Ear, Nose and Throat Dysfunctions due to Deficiencies and Imbalance. S. Roberts. Charles C. Thomas, Publishers, 1957.

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offer little pharmacotherapeutic relief. Once intralabyrinthine physical distortion, neural degeneration, auto-reagenic reaction or other still unrecognized cellular change is established the stage or irreversibility is reached. For some this point is reached in the initial attack. Fortunately for most, the sequence takes time. Exacerbations which had been characterized by satisfactory or partial amelioration of symptoms and recovery of hearing now remit relative to the vertiginous crisis but retain hearing disability. Toward this residual distortion and tissue injury an awesome drug list has been directed with little reward. The natural history of Menière's disease in its inexplorable sequences results in large numbers of residual otologic cripples with gross auditory disability and variable vestibular incapacity (almost uniformly less injured than the acoustic system). Not infrequently when the vertiginous crises are long past, the vestibular reflexes remain quite responsive. The auditory stalemate would seem to represent a combination of neural deterioration and cochlear conductive fault. Today's medicine acknowledges the impossibility of nerve cell regeneration. And to this time there is no satisfactory medical means of restoring anatomic integrity to the long-standing, physically-distorted labyrinth. THERAPEUTIC SUMMARY

A. The active and progressive phase of Menière's disease: 1. Establish the patient's hormonal balance: i) Metabolic — long term ii) Ovarian — cyclic or menopausal iii) Adreno-cortical — short term for the crisis-deficient 2. Put the patient right with his environment: i) Fatigue ii) Emotionalbalance iii) Climatic iv) Tobacco, alcohol, excesses 3. Establish physical tone: i) Exercise routine ii) Physiotherapy

492

THE VESTIBULAR SYSTEM AND ITS DISEASES

4. Provide a reparative and habitual balanced nutrition (See Robert's regime) : i) Vitamin and mineral supplementation ii) Interdict abnormal sodium excess. 5. Psycho-therapeutic drugs if warranted 6. Neural blocking agents: i) the acute phase: a) parenteral atropine, diphenhydramine, dimenhydrinate b) cervical sympathetic block c) intravenous procaine ii ) the subacute phase : a) oral diphenhydramine and hyoscine (Benoscine) 7. Vasodilators i) the acute phase : a) Parenteral nicotinic acid or histamine ii) the subacute phase : a) Nylidrin B. The advanced and static phase of Menière's disease: 1, 2, 3, 4 and 5 above in the interest of preserving residual otologic function.

Surgical Treatment of Meniere's Disease Raymond E. Jordan, M.D.

According to the historian of this disease, Dr. Henry L. Williams, 1 the first account of surgical treatment for Menière's disease appeared in the literature in 1904. Quoting Williams: "In August of that year by curious coincidence, the first account of two operations to relieve aural vertigo and tinnitus, ( 1 ) by opening the semicircular canals, and (2) by intracranial division of the auditory nerve, appeared in the "Journal of Laryngology and Otology." Since the two papers appeared at the same time, no priority for surgical treatment of Menière's disease can be claimed by either the otologists or the neurosurgeons. The initial effort of most surgeons was to devise a surgical procedure which would completely control the vestibular symptoms without disturbing the cochlear function. For a time, the neurosurgical approach was the procedure of choice. Review of the literature indicates that the results obtained by partial nerve section are no better than those obtained by endorgan surgery. Explanation was supplied by the work of Rasmussen who showed that it is not possible to grossly differentiate vestibular fibers from cochlear fibers in every case. A further comparison of the two techniques shows a relatively high mortality and morbidity rate for the nerve section and a low rate for labyrinthine surgery. In my opinion, these two observations rule out the neurosurgical approach for the treatment of Menière's disease. One of the early surgical procedures done in this country for the relief of symptoms of Menière's disease was the Day 2 operation, or electrocoagulation of the labyrinth. The object of this procedure was the destruction of the vestibular labyrinth without damage to cochlear function. The operation consisted of removal of sufficient 493

494

THE VESTIBULAR SYSTEM AND ITS DISEASES

mastoid bone to expose the surgical dome of the lateral semicircular canal without disturbing the short process of the incus. A small fenestra was made in the ampulated end of the canal; and a neurosurgical coagulating needle, approximating the size of a straight pin, was passed into the vestibule. Three applications of coagulating current were used. The amount of current was calibrated for each patient at the time of surgery. The coagulating machine was regulated to produce a coagulated area of 2 mm. in diameter with one-second exposure when the tip was applied to the fresh-cut edges of the incision. In 1952, Day reported the results of his first 54 cases. In 16, or approximately 30 per cent, cochlear function was retained. The first case in this series was observed for 11 years, and the last case was operated 3 years prior to the report. Two minor stitch abscesses were the only surgical complications reported. Further analysis of this group indicated that the author was less than satisfied with the results. Quoting directly from his paper: "I was successful in preserving cochlear function in 16 of the first 54 cases. This may sound like a fine achievement but actually these patients were none too happy over the results. Four cases had a recurrence of vertigo, including two in which hearing had been preserved, evidently due to incomplete destruction of the vestibular labyrinth. Revisions to complete the destruction were done successfully in these four cases. Revision was also done on two other cases because of continued roaring tinnitus and distorted hearing, although they were already completely free of vertigo. In only four cases could I demonstrate practical hearing for speech maintained for more than two years following surgery." One of these cases is shown in Figure 1. Please note the discrimination score at the time of surgery in the involved ear was 60 per cent. Day further concluded in the same article, and I quote: "It was largely as a result of the follow-up study of this series of cases that I reached a full appreciation of the significance and the severity of the cochlear symptoms of Menière's disease. Whether hearing is preserved by differential nerve section or differential electrocoagulation, the results should be the same." After joining Dr. Day in 1946, I operated on nine cases of Menière's disease using the technique described above. These cases were not previously reported because the number was small and the results essentially the same as reported by Dr. Day. N o major

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3/17/49 125

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AMERICAN STANDARDS Fig. 1.

complications occurred in our series. Two cases of facial paralysis, however, were reported by two physicians. Both were caused by improper setting of the coagulating machine, resulting in a spread of the coagulating current to the facial nerve. In 1949, the method was abandoned in favor of total labyrinthine destruction for the following reasons: 1. The procedure lacked definite predictability as to retention of hearing. 2. Further deterioration of hearing occurred in the majority of cases. 3. Retention of cochlear function also meant retention of the tinnitus, diplacusis dysharmonica, and recruitment in most cases.

496 4. In many cases in which hearing was preserved, some portion of the vestibular labyrinth retained some function. In many of these cases, vertigo occurred; and further surgery was required for complete control of symptoms. More recently, ultrasonic sound has been used to destroy the vestibular labyrinth. I, personally, have not used the ultrasonic apparatus; therefore, I must rely on reports in the literature for my evaluation of the method. The technical procedure has been reported elsewhere and need not be repeated in this presentation. In reviewing the literature, varied results have been obtained by surgeons using this method. The most enthusiastic results are those of Arslan 3 who reports vertigo relieved or improved in 95 per cent of cases and hearing improved in 30-40 per cent. Altmann 4 reported 121 cases in 1962, which is apparently the largest group of cases in this country. His results showed 72 per cent had improvement in vertigo, although some cases had to be irradiated more than once. 11 per cent had hearing improvement, 66 per cent remained unchanged, and 26 per cent experienced diminished hearing. Tinnitus improved in 18 per cent. Postoperative facial paralysis occurred in 6 per cent of the cases. In the summary of his report in 1961, Altmann 5 stated that radiation of the labyrinth with ultrasound seemed far superior to all other methods of surgical treatment. Since it preserved hearing, it can be considered at a much earlier date than destructive operations. Less enthusiastic is the report of Ariagno 6 concerning the results of 50 patients operated on over a period of 3 Vi years, including 6 patients operated on bilaterally. Quoting from his paper, he concluded: "The control of vertiginous attacks with the initial radiation is less than 50 per cent." He further stated: "Hearing is not improved with ultrasound, which contradicts Arslan's theory that ultrasound improves endolymphatic circulation. The variations in hearing postoperatively are compatible with the usual fluctuation observed in Menière's disease. This supports the contention that the only therapeutic effect of ultrasound is the destruction of the neurosensory epithelium of the vestibular labyrinth and not any alleviation of the basic pathophysiology responsible for the production of endolymphatic hydrops." The major complication of ultrasonic technique has been postoperative facial paralysis.

SURGICAL T R E A T M E N T

OF M E N I E R E ' S

DISEASE

497

Recently, another technique for the surgical control of Menière's disease has appeared in the literature. Fick 7 describes a method for decompressing the labyrinth by perforating the saccula through a small fenestra in the footplate. Although he states that the operation is "largely aimed at relieving vertigo and not restoring hearing," in his report of 50 cases, 16 per cent were cured of vertigo and tinnitus and hearing returned to normal. We have operated two cases using this technique with immediate cessation of vertigo and no change in hearing postoperatively. However, no conclusions could be drawn since the patients have been observed for only a few weeks. Recently, as a result of the work of Dr. William House, 8 attention is again focused on the saccus endolymphaticus as the operative site for surgical treatment of Menière's disease. In the April, 1964, issue of the "Archives of Otolaryngology," Dr. House presents very logical reasoning behind his procedure of subarachnoid shunt for drainage of endolymphatic hydrops. The technique of the surgery has been clearly presented and need not be repeated here. The results of 64 shunt operations were as follows, and I quote: "Vertigo was relieved in 75 per cent of cases, tinnitus was improved or relieved in 51 per cent of cases, and hearing was improved by 15 decibels or more in 11 per cent of the cases."

He further stated

and I quote, "These results in patients considered to be medical failures have led us to a definite conclusion that the operation is very worthwhile and therefore should be further studied and improved." In the same Journal is an excellent report by Michael Portman 9 presenting the combined experiences of Professor G. Portman and himself with decompression of the endolymphatic sac for the surgical treatment of Menière's disease. The original operation was done in 1926 by Professor George Portman and was based on his concept that Menière's disease was due to an increase of endolymphatic pressure, a concept that was subsequently confirmed by the work of Hallpike and Cairns 10 some years later. Quoting from M. Portman's conclusion, he states, "Simple opening of the endolymphatic sac according to the method described by the original G. Portman has seemed to provide a very satisfactory result. Though technical modifications proposed by certain authors seem to be a logical improvement, nevertheless our statistics demonstrate that simple opening of the endolymphatic sac remains an

498 excellent operation. In cases of dropsy of the labyrinth, drainage of the endolymphatic sac by whatever technique is the most logical procedure because it is the most physiological." He concluded, and I quote, "We only operate on patients stricken with vertigo when medical therapy has failed. A minimum percentage of cases with hydrops is therefore submitted to surgery, less than 10 per cent. When the surgery is necessary and the patient has a very profound deafness of more than 80 decibels, destruction of the labyrinth by way of the oval fenestra is generally advocated. When a surgical operation is necessary and the patient still shows useful hearing and is said to have a loss of less than 70 decibels, decompression by opening of the endolymphatic sac is preferred. The technique of decompression of the endolymphatic sac has given us, out of a series of 60 patients studied from 1926 to 1961, 93 per cent of good results for vertigo, 34.8 per cent good results for tinnitus, and 32 per cent good results for hearing." I find it difficult to evaluate the various surgical procedures designed to control vertigo and reserve cochlear function for several reasons: 1. Remissions are characteristic of Menière's disease. Evaluating the effects of treatment whether it be medical or surgical, without prolonged observation, can be misleading. Perhaps it might be appropriate to use five years as a standard of cure, similar to the arbitrary period of cure used in cancer surgery. 2. There is a lack of uniformity in reporting results. The term, "Vertigo improved" is frequently used in reporting the results of surgery. This could mean the attacks are less severe or less frequent. It would seem more accurate to state that vertigo was absent for a definite period of time. In reporting hearing improvement, it would also seem appropriate to give the discrimination score before and after surgery as well as the presence or absence of diplacusis dysharmonica. 3. All surgical procedures for the preservation of cochlear function reviewed in this presentation have been successful in a varying number of cases. The majority of surgeons quoted have stated that all patients operated have been medical failures. This would suggest that a time interval had occurred between the onset of the disease and surgical intervention. It is my experience that the longer the disease has been present, the less likely that usable

SURGICAL

TREATMENT

OF

MENIERE'S

DISEASE

499

hearing can be restored by any method. It is not practical to attempt to save hearing that no longer fluctuates and has a discrimination score of 40 per cent or less. At the moment, my preference is complete destruction of the involved labyrinth. For a number of years, following discontinuance of the electrocoagulation technique, the same surgical approach was used; but the fenestra was made larger and the membranous labyrinth removed with a dental broach. This method has been successful in stopping the vertiginous attacks in over 98 per cent of cases and reducing the low-pitched tinnitus in a majority of cases operated. Similar results have been reported by Cawthorne, Lempert, and others, using some form of physical destruction of the membranous labyrinth. The patients are usually able to return to full duty in three to five weeks with complete freedom from vertigo and undesirable cochlear symptoms. More recently, I have employed a transmeatal route, using a modified stapedectomy technique similar to that reported by Cawthorne. 1 1 This is a very simple procedure and can be done under local anesthesia. The middle ear is exposed by the usual transmeatal incision, the stapedius tendon cut, and the footplate elevated and rotated anteriorly without separation of the incudostapedial joint. The contents of the vestibule are removed by a small hook a n d / o r a suction tip. The stapes is then rotated back into the window and sealed with a small piece of moist gelfoam. We have done 12 cases by this procedure. Revision was necessary in three because of persistent vertigo. I have observed that the convalescent period with this technique seems longer than those in which the labyrinth has been removed through this horizontal canal. Not sufficient cases have been done or sufficient time elapsed to make a statistical analysis, however. In order not to leave the impression that I am discouraging those who continue to investigate surgical procedures that may control vertigo and preserve cochlear function, let me show you the follow-up of the patient whose slide was used to demonstrate retention of hearing by the Day method. As is shown in Figure 2, the second ear did become involved 11 years after the first ear was operated. It is noted that the patient still had approximately 60 per cent discrimination in the initially operated ear and was wearing a hearing aid quite sue-

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Fig. 5. The serial audiograms illustrate the late change which developed in another case following apparent successful ultrasonic labyrinthectomy. The patient was free of vertigo and maintained good hearing for over two years. The hearing then began to deteriorate and frequent attacks of vertigo again developed.

had been satisfactorily relieved of their vertigo. Cochlear function had remained at pre-operative levels in fourteen of the twenty subjects. Further analysis of the records of these same patients with a follow-up of at least two years has shown the following changes. Three patients initially classified as successful following the six month period, have since experienced a return of their vertigo and

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540

THE VESTIBULAR SYSTEM AND ITS DISEASES

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have required secondary labyrinthine surgery. T h e remaining fifteen have continued to be free of their vertigo. Changes in the hearing have also been noted. Five patients initially reported as having their hearing maintained or improved following surgery have since shown further auditory deterioration to the point where the hearing is now below the original pre-operative levels. Preservation of hearing has therefore been maintained in nine of the initial twenty patients after a two year follow-up. See Fig. 6. Although it is disappointing to find recurrence of vertigo and auditory changes in some apparently successful cases, it is equally gratifying to note that the ultrasonic technique was able to main-

541

LABYRINTHINE SURGERY FOR VERTIGO

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Fig. 7. T h e criteria for desructive l a b y r i n t h e c t o m y a r e defined.

tain freedom of vertigo in fifteen cases and achieve its ultimate goal of preservation of hearing coupled with freedom of vertigo in nine of the twenty patients after a two year follow-up. It should be stressed that these results were obtained with equipment that was distinctly inferior to the ultrasonic units being used today. T h e presentation of results on patients having a transmeatal labyrinthectomy is considerable easier. This operation was performed on eighteen cases having unilateral Menière's disease. Following surgery, a complete loss of cochlear and vestibular function has occurred in each instance. There were no surgical complications. T h e entire group had been completely free of vertigo since

542

THE VESTIBULAR SYSTEM AND ITS DISEASES

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Fig. 8. T h e criteria for ultrasonic labyrinthectomy are defined.

the time of surgery and there has been no evidence of vestibular activity when tested calorically.

CONCLUSIONS

The choice of labyrinthine procedures depends primarily upon the patient's existing auditory level. When dealing with unilateral disease in which the hearing is permanently below useful levels, the transmeatal labyrinthectomy is the procedure of choice. When there is one normally hearing ear, one may consider the pathologic ear as having no useful function when the hearing loss is greater than 50 db and the discrimination score is reduced to less than 5 0 % .

LABYRINTHINE

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F O R VERTIGO

543

The hearing loss must however be stable without a tendency to fluctuate to better hearing levels. As an added precaution it should be determined that the disease has been present for at least two years without evidence of involvement of the opposite ear. The criteria for destructive labyrinthectomy are listed in Fig. 7. When these criteria have been fulfilled, one may proceed with the destructive labyrinthectomy without fear that the elimination of the residual hearing will impose any additional auditory handicap on the patient. In the light of the increased possibility of failure and complication when using the ultrasonic technique, this form of surgery should be reserved for those patients in whom the vertigo is associated with useful cochlear function. The hearing should be at a threshold of less than 50 db associated with a discrimination score of better than 5 0 % . The hearing at these levels is still of value to the patient and hence an effort should be made to salvage this degree of auditory function. When bilateral disease is present, one should strive to preserve whatever hearing remains in either ear. The criteria for ultrasonic labyrinthectomy are listed in Fig. 8. Although ultrasound has been used on the labyrinth for over ten years, the procedure must still be considered in its infancy. There is no doubt that this new surgical modality can cause beneficial labyrinthine changes which enables patients to be free of their vertigo without sacrificing hearing. A discrepancy however, seems to exist between the demonstrated vestibular destruction in experimental animals and the frequently retained or modified vestibular responses in clinical cases. This difference is no doubt related to our inability to clinically determine when precisely enough radiation has been applied to cause the desired result. Until we are better able to determine this endpoint of radiation, early and late failures will continue to occur. Further research is required to clarify both the mechanical and biological effects of ultrasound on the inner ear. This basic research coupled with the further accumulation of clinical experience will undoubtedly help to solve many of the problems which we are presently experiencing. In this way it is hoped that further improvement and standardization of technique will occur to the point where the ultrasonic procedure will have still greater application and more favorable results in the treatment of vertigo.

544

THE VESTIBULAR SYSTEM AND ITS DISEASES REFERENCES

1. Schuknecht, H. F.: Ablation Therapy for the Relief of Meniere's Disease, Laryngoscope 66: 859 (July), 1956. 2. Cawthorne, T.: Membranous Labyrinthectomy via the Oval Window for Meniere's Disease, Jour, of Laryngol. and Otology, 71: 524 (August), 1957. 3. Arslan, M.: Treatment of Meniere's Syndrome by Direct Application of Ultrasound Waves to the Vestibular System. In Proceedings of the Fifth International Congress of Otolaryngology, Amsterdam, 1953, Assen, Netherlands, Van Gorcum and Co., N.V., 1953. 4. McLay, K., Flinn, M., and Ormerod, F. C : Histologic Changes in the Inner Ear Resulting from the Application of Ultrasonic Energy, Jour. Laryngol., 75: 345-357, 1961. 5. Arslan, M.: Ultrasonic Surgery of the Labyrinth in Patients with Meniere's Syndrome, Sdenta Medica Italia, 7: 301-326, 1958. 6. James, J. Α.: New Developments in the Ultrasonic Therapy of Meniere's Disease. Ann. Royal Coll. of Surgeons of England, 33: 226-244, 1963. 7. Sjoberg, Α., Stahle, J., Johnson, S., Sahl, R.: Treatment of Meniere's Disease by Ultrasonic Irradiation, Acta Oto-Laryngolica Suppl. 178, 1963. 8. Gordon, D.: Ultrasonic Rays in Diagnosis and Surgery, Transaction of Royal Soc. of Med., 79: 1-7, 1963. 9. McGee, Τ. M.: Effects of Quantified Ultrasound on Labyrinthine Structures in Animals. Laryngoscope, 73: 683-692, 1963. 10. Lumsden, R. B.: Discussion on the Conservative Management of Meniere's Disease. Proc. Roy. Soc. Med., 51: 617-623, 1958. 11. James, J. Α., Dalton, G. Α., Bullen, Μ. Α., Freundlich, Η. F. and Hopkins, J. C.: The Ultrasonic Treatment of Meniere's Disease. Jour. Laryngol., 74: 730-757, 1960. 12. Altmann, F. and Waltner, J. G.: Treatment of Meniere's Disease with Ultrasonic Waves. Arch. Otolaryngol., 75: 615-619, 1961. 13. Ariagno, R. P.: Four Years of Ultrasound in Meniere's Disease. Arch. Otolaryngol., 76: 18-22, 1962. 14. Wolfson, R. J.: The Treatment of Various Forms of Vertigo by Ultrasonic Radiation, Laryngoscope, 73: 673-682, 1963. 15. Arslan, M.: Treatment of Meniere's Disease with Ultrasonic Irradiation. Fifth International Congress of Otolaryngology. Paris, 1961. 16. Wolfson, R. J.: Ultrasonic Therapy for Vertigo with Chronic Suppurative Mastoiditis, Arch. Otolaryngol., 74: 387-390, 1961. 17. Lindahle, J. W. S„ and Robertson, M. S.: The Use of Ultrasound in the Treatment of Aural Vertigo, Jour. Laryngol., 75: 299-302, 1962.

Discussion

D R . DOROTHY W O L F F [New York City]: A couple of years ago Dr. Jan Carlo extracted a promise from me that I would examine histologically his animals which had been exposed to ultrasonics. Those of you who are old enough to remember will recall that in Toronto many years ago Dr. Lempert and I put on an exhibit of labyrinths that he had extracted from patients with Menière's syndrome. These labyrinths all showed vesiculation in the semicircular canals and destruction of the end organs. In 1939, I visited Mr. Hallpike's laboratory in London when he was just putting into publication his first case with hydrops, as he called it, of the labyrinth. Dr. Lempert and I went back and read his report and found that he also had found vesiculations in the membranous labyrinth but definitely stated that he ascribed no importance to them since he found these also in other postmortem specimens. We ascribed a great deal of importance to these vesiculations and Lempert once asked me, "Do these show any signs of rupture?" I said, "Plenty." And he said, "Well, this is the explanation. If these vesiculations rupture, a toxic solution is immediately poured over the five end organs, the brain is unable to solve the problem, and the patient drops down with a very cataclysmic attack." Lempert put as his title for that exhibit Herpes Neuritis (Menière's Disease). So I was a very curious person as to what the ultrasonics might do in this disease because I knew that ultrasonics had been applied for the destruction of bacteria. Could these also be helpful in these cases of intractable dizziness which could be or must be eliminated from all of the various types of treatment which Dr. Hilger has described?

545

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THE VESTIBULAR SYSTEM AND ITS DISEASES

Dr. Jan Carlo and Dr. Jui exposed the labyrinth semicircular canals of these cats for a period sufficiently long to induce nystagmus and then left it on until paralytic nystagmus occurred. I was then supposed to see whether I saw any new kind of destruction in these temporal bones. Both ears were left intact, the whole cat's skull was processed together, and it is very interesting that the first thing I observed was a difference in the vestibular ganglion situation. The vestibular ganglion is encased, as are all peripheral ganglion cells, in a global structure of satellite cells. Cahall was the first to describe these satellite cells, only he described them as a halo. He was looking, of course, at microscopic sections and he believed them to be — as they are — nutritional cells. We have been taught to think of the spiral ganglion and vestibular ganglion as bipolar. They are bipolar, but they are also much more complicated than that. Not only, I think, are there nutritional cells in this capsule but there are also cells whose function it is to receive communicating fibers from other branches of the vestibular system, and probably also from the efferent vestibular system, and conduct them into that nucleus, much like the nerve knots that have been described by Brain and others on the motor neurons. I noticed that in the animals which had been allowed to live just one week, and about one week and four days after the stimulation by ultrasonics, there was great agitation and dislocation in the satellite cells. Also, there might be changes in the nerve fibers on these cells. [Slide] This shows you a superior layer of the vestibular ganglion cells in a case that was exposed for one week. There are evidences of loss of the nuclear membrane in some of these cells, a loss of the cell wall with an exposure and a dissolution of the cytoplasm; some edema is evident, and this one happens to show a granulation in the fibers. [Slide] This is a higher level of the same ganglion and here you see a tendency for two ganglion cells to fuse, and this shows you a nerve fiber that shows what I would call lytic degeneration, although Brain, et al, described this as mucoid degeneration. How could it be mucoid degeneration in the nervous system? I would simply call it lytic degeneration. Here is an area of degeneration; here is a cell that has completely lost its nucleus. These show wide, somewhat liquefied nerve fibers.

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[Slide] Here you see again fusion of nuclei and this one shows a necrotic cell, and again these wide nerve fibers — fusion of nuclei, loss of normal structure. [Slide] Here you see one that is about seven weeks postoperative, and they are not all destroyed. The men found that there was great variation in animals as to how long it took to produce nystagmus, how long it took to produce paralytic nystagmus, but the satellite cells are pretty well missing here and where they are present, they are rather necrotic. [Slide] Here is one that is seven weeks after exposure and you see a large edematous area there, but there is a granulation, and I would think a tendency toward repair in this one. [Slide] Some cells drop out entirely. This is a saccule of a seven-week specimen and you see an area of cavitation in this specimen. [Slide] This is a crista in that case and here you see that the otoconia have been tossed over from the macula of the utricle to the cupula of the crista. It hasn't been very well stressed that in the sensory epithelium of both cristae and maculae you have a pseudostratified epithelium with a base line of nuclei. Disturbances occur very promptly in this base line and these cells become necrotic or tend to migrate upwards. The damage which Jan Carlo and Jui did here was not nearly so extensive as the damage shown by Dr. Arslan. [Slide] In the cochlea we found various changes. This one is minimal but here you see in one two and a half months after exposure just a tossing together of these two pillar cells. This outermost pillar cell is still there and you see a tossing together here. Quite often the cytoplasmic wall was ruptured and protoplasm was spilling out of the cells, and you notice that there is a cavitation of the nutritional cells. There is some change in the external sulcus area. [Slide] Here you see extensive cavitation two and a half months after exposure, but this happened in the basilar membrane. In the intrasulcus cells you also have a great deal of distortion; complete loss of these supporting cells which are higher cells is easily identified and we can even see some nerve fibers crossing over, which I didn't see in the tunnel of Dr. McGee's specimen. There is some edema underneath the spiral ligament.

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There were heat effects. We got the same kind of formation of blue mantles, much to Dr. Altmann's shock, that Dr. Belucci and I had gotten when we applied electric current directly to the otic capsule. In two animals we got agitation to the point of renewed growth of bone along the parietal bone of both the middle ear and the internal auditory meatus, but, personally, I have great hope for this method of treatment if you can keep the exposure controlled down to this point. In 1949, I examined the cochleas of white rats exposed to free field ultrasonics by Dr. and Mrs. Frye of Penn State, and there the tectorial membrane had simply whipped the organ of Corti completely off the basilar membrane. Such destruction was not found in these organs of Corti. The middle coil in these cochleas was really quite normal, so if it can be restricted to changes that are reparable in the vestibular system and without complete destruction of the end organ, I think there is great hope for this possibility. D R . F R A N Z A L T M A N N [College of Physicians and Surgeons, New York City]: Dr. McGee in his excellent presentation showed us the destructive power of ultrasound on elements, whether in the cochlea or in the organ of Corti, and from clinical experience we also know that we can destroy structures. However, I think not enough attention is paid to the fact that was expressed by Dr. Wolfson, that in so many cases we get a return of function; so I would suggest that Dr. McGee should perhaps continue his investigations and try to determine which structure is damaged if you give small doses of ultrasound and which structures are capable of regeneration, because we always find, as Dr. Wolfson also pointed out, that we have a loss of vestibular response and after a few months we get a return of vestibular response, similar to streptomycin damage which after six months, eight months or a year disappears. However, not the best service can be done with light microscopy and I think it would be worthwhile to do electron microscopic studies which can give the answer to this question. One should remark, Dr. Wolfson, that in the cases of bilateral Meniére with very reduced labyrinthine function, there are times when we are not sure which labyrinth is active; sometimes one labyrinth is active and sometimes the other. I find in a few cases, as suggested by Dr. Power about fifteen years ago with streptomycin

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injections, that if the patient is below 50 it is well tolerated. It takes the patient about six months to a year to regain his equilibrium but he is very unsteady, it is very unpleasant in the beginning, but after that the long-term results are quite satisfactory. D R . D A N I E L M . M A R T I N E Z [Dallas, Texas]: In commenting on Dr. Hilger's paper, I should like to mention some observations that were reported by us (Wiley, Herring and Martinez) on the vesiculation of the spiral ligament and stria vascularis. At the time of the publication we showed that histamine intravenously was able to produce an initial vasoconstriction of arterioles with immediate dialation, followed also by vasodilatation of the venules of the small blood vessels of the spiral ligament and stria vascularis. The blood flow was also increased at this time. However, when higher concentrations of histamine were given to these animals proportionate to the weight according to what we would use in the human, we found that there was cell aggregation, emboli, destruction of the endothelium of these capillaries with extravasation of blood flow. Consequently, the best increased flow without damage was obtained with small amounts of histamine intravenously. We also observed these vessels when exposed through fenestration in the cochlea of the guinea pig, without placing a cover glass as Hermann did later on. Consequently, these vessels had the ability to contract and dilate. Nicotinic acid did not show any effect on these small blood vessels in our experimental animals. Recently we have studied in a limited number of cases the effect of Arlidin, which Dr. Hilger mentioned. With Arlidin we also observed the vasodilatation of the arterioles and of the venules later, and the increased speed of the circulation, but it was interesting to note that with the use of Arlidin, the presence of sludge almost completely disappeared in some experiments, and in other experiments disappeared completely. This sludge was present after the observations had been carried out for a long time; or in touching the spiral ligament in order to produce the sludge, we noticed that with the use of Arlidin this sludge disappeared. Whether this will have an effect or not in Menière's disease in the human will be a different story, but we do use heparin (this has not been mentioned) in the treatment of Menière's, with the thought that sludge circulation, as pointed out by the late Dr. Fowler, is present in Menière's disease.

Summary of Vestibular Symposium Fred R. Guilford, M . D .

It is with respectful humility toward my elders and peers in experience in the field of otolaryngology that I take the podium to summarize this fine Symposium. I can assure you that I didn't volunteer for the job. In fact, I believe I was in the dark, with my eyes closed, when I accepted the invitation. In a more serious vein, I am sure we all join together in admiration of the Organizing Committee for arranging such an excellent program on this complex and difficult subject. W e are all most grateful to our foreign colleagues — Professor Arslan, Mr. Hallpike and Mr. Harrison, Professor Jongkees, Dr. Stahle and Dr. Spoendlin — who have contributed so much to the success of this Symposium. D e a n Nemir stated at the beginning of the Symposium that the objective of the meeting was to gain a perspective of the present field of otoneurology and the new advances in the field yet to come. I think we all can agree that the plan of the Organizing Committee has exceeded their original hopes in this regard. From the beautifully presented paper by Barry Anson on the Developmental and A d u l t Anatomy of the Membranous Labyrinth through the final paper by B o b Wolfson, we had the good fortune to hear a series of discussions by pioneers and experts in otoneurology which has never been exceeded in America. In summarizing the excellent material presented, I am sure it is obvious that time will not permit a discussion of each individual paper or to mention each speaker by name. Rather, it seems best to discuss the papers in groups since the program falls naturally into categories for such discussion.

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These categories appear to be anatomical studies and research; diagnostic methods, both clinical and experimental; pathophysiology; and therapy. In regard to the most excellent presentations in the first category, I am sure there are some in this fine audience who are especially oriented in a clinical way, who looked forward to the second day's work with the hope that we would then get into the midst of the problem of diagnosis of otoneurological problems. Looking back over the work of the last two and a half days, the wisdom of the Organizing Committee in arranging the superb array of current research problems is selfevident. While most of the anatomical connections of the vestibular pathways are known, such excellent research papers as we heard on the first day of the program not only reinforced and advanced our knowledge of the neuropathways but also illustrated our present perspective in regard to our limitations of a complete understanding of the vestibular mechanism, and they point the way to new advances yet to come. I am sure we all feel a debt of gratitude to this group of research men for their fine reports on their most excellent work. Regarding the second category of the diagnostic methods, experimental and clinical, the reports regarding tests of function of the otolith structures certainly point to new frontiers of study in the field. In the realm of clinical diagnostic tests, the clinical discussions of the caloric test by Mr. Hallpike and Professor Jongkees will be a continual reminder and example to us in our future diagnostic work. The discussions pro and con regarding the need for electronystagmography and other neurological diagnostic tools serve especially to emphasize the point that the diagnosis of vestibular disorders should be approached in a carefully organized and intelligent manner, with full knowledge that it is the man behind the machine or method, whatever it may be, who is going to make or miss the diagnosis. While great strides have been made in the development of tests for vestibular diagnosis, our present state of knowledge of vestibular tests probably compares with the status of audiological testing ten or fifteen years ago, and we now believe that a battery of audiological tests is necessary as an aid to diagnosis, and in the

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future it is probable that a battery of vestibular tests will be added and will be developed in the same way to give more complete information regarding deranged vestibular function. That is not to ignore the fact that many tests have been developed in the past and have been discarded because they didn't give the information required, and it may be that cupulometry is one of these methods that is of the past. Laterotorsion — a good report was given during the Symposium — may be an important step in the direction of adding more information and getting a valuable test developed. However, in my opinion, we cannot minimize the present importance of electronystagmography as a diagnostic aid in spite of the present controversy in this symposium. Among the essayists, there were some for it and some against it, and one man appeared to be on the fence. He early seemed to be against it and then he tended to be more favorable toward it. In that respect, I would like to say that I can't imagine electronystagmography being used in any other than a quantitative way, and I am sure that if it were used in a qualitative way it was early in its use. I might tell you something about our experience with electronystagmography since we have had problems with it, as everyone has, I am sure, but I think since our problems are more recent I do not consider myself an expert in the use of this equipment or the method. We have been using it for slightly less than two years and I will say in the beginning right now that our experience follows very closely that stated by Dr. Stahle and also by Professor Jongkees. We have found the advantages that they have listed and some of the disadvantages have been mainly those of our own experience. I would say that it is very important for one to approach this problem, as I have said, in a slow, careful manner and be aware of the problems with the equipment; also to select equipment that will be suitable for the work rather than one that might be available commercially. I would certainly suggest that one visit a laboratory where the equipment is in clinical use and see just how it is used before going to the expense of equipping one's own laboratory with it. Also, an indispensable aid, as we have found, is that we must have a very competent electronics man available to be sure that our

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equipment is in good condition and good working order all the time. I will repeat that we have seen the advantage of the equipment as far as our experince is concerned, and we hope to learn more about it. Regarding pathophysiology, the temporal bone sections shown and discussed by Professors Lindsay and Schuknecht were again outstanding contributions to this Symposium. I am sure we all agree such presentations are basic to our understanding of the clinical problems involved, and I might add that the sections by Professor Arslan and Dr. McGee and Dorothy Wolff certainly are in this category and contributed in the same way. Yesterday's program was climaxed by the magnificent film and discussion on the removal of the eighth nerve tumors by Dr. House. Surely we are in debt to Dr. House for his monumental efforts in successfully developing the transmastoid approach for the removal of cerebellopontine angle tumors. T o o much credit can't be given to him and his coworkers in this regard. In this morning's program, Dr. Fields has again illustrated in a most efficient and beautiful fashion the importance of the relation of alteration of blood flow to vertiginous complaints. While we are speaking of Dr. Fields, I would like to say that since we are just completing the First International Symposium on Vestibular Disorders, I would like to point out that Dr. Fields was the Chairman of the Organizing Committee for another international symposium on the same subject, and also including auditory disorders, and sponsored by the Houston Otoneurological Society eighteen months ago. However, I do hope that this First International Symposium connotes that there will be others, a second and a third. Regarding the treatment of Menière's disease, I think we should consider these factors and ask ourselves these questions, regardless of treatment. I don't want you to think that I am taking a cynical attitude toward any treatment that has been presented here today, but I d o think that we should be very m a t u r e in our approach to results and we should ask ourselves the questions that have been asked over and over again: W h a t are the causative factors, and are these factors corrected in the treatment? Does it stop the progression of the disease? Will hearing eventually be lost in the defective ear in spite of therapy?

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A n d before we become too enthusiastic regarding any form of therapy, we should remember McNally's advice with regard to remission. You remember that McNally stated that he had remissions in his series of cases of up to four years, and this seems like a long time to judge the effectiveness of therapy before stating that the patient has been improved, but it does give us a guide and something over two years it seems to me is reasonable in judging patients before we can say that they are definitely improved, or whether we can say that they are definitely cured; and I think that some of the material presented here today tends to illustrate that point. Certainly we cannot judge the efficiency of any treatment of Menière's disease without adequate passage of time. Dr. Henry Williams, who is in our midst, has written many classic articles on the medical treatment of Menière's disease, and he has stated that we can't hope to do any more with medical treatment than to throw the patient into a remission; so I think we should be extremely careful in judging our early results, and if we do we should use very cautious language in regard to it. We have had some experience with the hypometabolic treatment and regimen that has been presented by Godlowski, and you will remember Godlowski reported that in his series of cases treated, 70 to 80 percent of them showed the hypometabolic syndrome. Well, this was a selected series of cases because all of these patients had undergone long courses of medical treatment before they were referred to him, so I am sure there was some selection presented in this report. We examined a series of patients that had not been previously treated. As soon as the diagnosis was made, we examined them with methods practically duplicating those of Godlowski, and we found that only 35 percent of our patients definitely showed a hypometabolic syndrome. All of these did not improve on the prescribed therapy of Godlowski but some of them did tend either to go into remission or have at least temporary control of their symptoms. I think this is one thing we must consider in Menière's disease, and I think before we institute therapy we should know as much as possible about our patient. I think the patient should know as much as possible about us as physicians, and I think we are responsible to tell this patient, not only as Dr. Hilger said about his

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odd reaction possibly to his environment, but we should also tell him something about his disease, because if we don't, we don't really have any chance to follow our patient over a period of years. I think if the patient is not fully acquainted with his disorder, his attitude may be that the physician doesn't really know what is wrong with him (the patient) when he tends to have an exacerbation of his symptoms. In other words, if he is not told that he is going to have this, regardless of what treatment is given, as soon as he does have an exacerbation he is liable to become disillusioned with his treatment and then we can't follow him any longer. However, if he is told about his disorder and he is thoroughly aware of the fact that he will have exacerbations, then I think he is more reasonable and can understand his physician's position. In regard to the surgical therapy as quoted by Dr. Jordan, I think this brings up a point regarding the criteria for selection for a labyrinthectomy. Certainly, we should never base our hearing examination on one test because we are all aware of the fact that there is a fluctuation in hearing not only in pure tone hearing levels but also in speech discrimination, so if, as he says, we judge the 40 percent score as an ear that is stable and practically disabled, if we judge this on the basis of one test, we might be doing the patient a real injustice. I think that over a period of time several tests should be made, if possible, including discrimination, before this level is determined as to whether he is a candidate for a labyrinthectomy. Also, I think the case he illustrated shows the danger of doing a labyrinthectomy on a patient when he has a 4 0 or better score, or even a 30 score, when his patient finally ended up with a 12 percent discrimination score in the other ear. This patient could depend on a 40 percent score with a hearing aid, very possibly, and could get along much better than if he had totally lost his hearing. I don't pretend to have the answer for this but I think we must be very careful regarding those patients that we choose for labyrinthectomy, and I would say that in our experience the patients who are best suited for labyrinthectomy are those patients who have a very low discrimination score, a 20 or below score, and they have no fluctuations. Also, I would like to say that there is a type of treatment that we possibly haven't explored enough -— not a type but a combina-

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tion of treatments. I don't think we should depend necessarily on one form of treatment in Menière's disease because there may be more than one factor present as a causative agent, and I think we should try to use as many agents or as many methods in its treatment as we possibly can. Dr. Altmann brought this up just a moment ago. If we have treated a patient with ultrasonic therapy, there is no reason why that patient should not be treated medically after he has had ultrasonic; there is no reason why he can't have some other form of treatment — anything that will help the patient to maintain his equilibrium. Nothing was mentioned under surgical treatment in the Symposium with regard to Dr. House's shunt operation, and there was only a bare mention of the latest method by Von Fick. I don't believe Dr. House claims to have the final answer in regard to the shunt, but certainly he has had some good results with it. Certainly the results will compare with ultrasonic therapy; therefore, we should still consider it. I am sure that he is still considering it in one form or another and it is something that should not be discarded until it is thoroughly investigated. In regard to Von Fick's operation, I haven't had much experience with it. As a matter of fact, we have done only one case that seemed to improve, but I am not convinced that he has the explanation for the method of improvement because I don't believe, as I will mention later, that all of these cases reported have had thorough workup and that the records are thoroughly documented. As a matter of fact, he reports his cases only on the basis of improvement in pure tones and improvement of vertigo, but I would like to tell you about a misadventure I had not long ago that may shed some light on this situation. I was in the process of doing a stapedectomy for improvement of hearing in otosclerosis and I was so intent on what I was doing with this particular maneuver (I had a fine right-angle pick) that I evidently touched the saccule or the utricle and the patient jumped, and when he jumped I couldn't move with him quite quickly enough and he had an injury to his vestibule — into the contents of the vestibule. He was extremely dizzy, he had nystagmus, he went through all of the stages that one would expect with destruction of the

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labyrinthine function on this side. He had spontaneous nystagmus to the opposite side as shown by electronystagmography. It lasted for a period of a month and then after a month he had position nystagmus but no longer spontaneous nystagmus, according to electronystagmography, and he slowly got over his symptoms of vertigo. What happened to his hearing? His hearing was 50 db. when we operated. Now it is at an 8 db. average level. He has had a very satisfactory gain; he has good discrimination. I am wondering if instead of Von Fick putting a little hole in the saccule and allowing, as he says, the possibility of diffusion of the pressure out through a clear membrane, he is not actually destroying the labyrinthine function by this method, but yet solving the hearing problem. I had the opportunity to talk to Ben Canton not over a month ago and he had had a similar experience with the same course, so there may be some way that we can actually do this through the footplate and achieve at least the control of vertigo. In closing the discussion on the therapy portion of the program, I would like to make a plea to those who treat considerable numbers of patients with Menière's disease, and I make this plea in this way: To please select the cases that are to be reported for any given therapy very carefully, in conformity with the known characteristics of the disease. Be sure that after the diagnosis tests, such as vestibular studies and audiologic tests, you include discrimination tests that are performed regularly and in the pre- and postoperative periods, not just one test before or one test afterwards. There has been a tendency in the past to judge the patient in a subjective way regarding the relief of vertigo and to limit his hearing examinations to pure tone tests. We cannot hope to judge progress in the therapy of this, the enigma of all diseases, unless we have the reports of therapy based on adequate and thoroughly documented records. At the present time, I am not aware of any such report in support of a specific therapy for Menière's disease. I will have to say that I was extremely pleased to see Dr. Wolfson's report here of discrimination tests before and after therapy. I wish to thank the Organizing Committee for the invitation. I have certainly enjoyed this wonderful Symposium immensely and I do wish to apologize for not making a better effort in summarizing the Symposium.