PAPILLEDEMA, WITH SPECIAL REFERENCE TO PAPILLEDEMA ASSOCIATED WITH SINUS DISEASE* ALBERT D. FROST, M.D. Columbus, Ohio INTRODUCTION The problems presented by two patients in whom papill- edema was relieved temporarily by astringent packs in the nose and permanently by operations effecting aeration of the ethmoid and sphenoid sinuses stimulated a study of this subject in an effort to reach certain conclusions as to the mechanism involved in the production of the papilledema present in these and similar instances. A review of the literature has revealed many diverse opinions as to the optic nerve-sinus relationship. In 1901 attention was called to this relationship in the publications by Fuchs and by Mendel. After the work by Onodi, which emphasized the intimacy of the posterior sinuses with the course of the optic nerve, the importance of this relationship became more apparent to the average practitioner. In 1907 Birch-Hirschfeld gave a complete r6sum6 of the involvement of the optic nerve in sinus disease. Enthusiasm for the possibility of this etiologic relationship gradually grew, and soon sinus disease as a causative factor in nearly all cases of acute optic nerve disease was given first consideration. Operations on the sinuses usually were resorted to promptly, with the result that many other factors were overlooked or neglected. Improvement in eye symptoms was credited to nasal operations, but equally good results were reported in similar cases in which the sinuses were not treated surgically. More recently the pendulum has swung the other way- * Candidate's thesis for membership accepted by the Committee on Theses. 480 FROST: Papilledema Associated with Sinus Disease 481 perhaps too far-and in the opinion of Lillie, Benedict, and others there are practically no cases in which pathologic changes in the optic nerve can be attributed to diseased sinuses. In spite of his earlier opinions to the contrary, Hajek later became more skeptical in regard to the sig- nificance of the relationship between the sinuses and the optic nerve. However, the words "always" and "never" should not be used in making statements regarding this point, for most ophthalmologists agree that in rare cases the etiologic factors may lie in the sinuses. The presence of sinus disease may well be suspected by careful ophthalmic examination, and the demonstration of pus, polyps, and necrotic bone is not always essential as proof of this etiologic association. Most of the cases attributed to sinus disease are instances of so-called retrobulbar neuritis, characterized by a sudden decrease in vision with, at first, no abnormal fundus findings; later an edema of the disc may appear, a sign which may be interpreted erroneously as a true inflammation, and there- fore may be described as a papillitis or an optic neuritis, even when there is no real evidence of inflammation in the disc. De Schweinitz is of the opinion that sinusitis may also be associated with lesions manifested by true papilledema or optic neuritis, as observed in the ophthalmoscopic examina- tion. Papilledema has rarely been seen as an initial finding without evidence of an earlier loss of vision caused by con- duction interference. When the edematous disc is accom- panied immediately by loss of visual acuity without definite macular changes, it is logical to infer that there must be some depression of the fibers or retinal elements of the maculopapular bundle, or that macular changes not recog- nized by the ophthalmoscope must be present. Since in similar edema from intracranial pressure there is no early visual loss, this disturbance of vision in these cases must be explained on some other basis. Under certain circumstances papilledema appears sud- 482 FROST: Papilledema Associated with Sinus Disease denly, accompanied by a rapid diminution in vision. Clinical evidence supports the view that the loss of visual acuity is produced by a sudden pressure on the optic nerve, somewhat in the nature of a strangulation, which results in passive lymph stasis. Local treatments in the nose to produce shrinkage of the tissue may cause temporary improvement in vision and reduction in the edema, as is evidenced by the prompt decrease in the size of the enlarged blind-spot. Before these objective findings are apparent, there may be a period in which the patient complains of symptoms of eye- strain and of pain behind the eyes, which is greatly increased by extra-ocular movements and convergence, due probably to the pull of the muscles about the optic foramen. These patients may consult an ophthalmologist for refraction early in the course of their symptoms, and a careful examination may strongly suggest the presence of a nasal disorder. A rhinologic examination and the application of astringents may yield immediate relief of the eye symptoms. This points clearly to the fact that there must be some connection between the symptoms and the area thus treated. This finding does not, however, apply to all types of edematous disc that may be found in association with sinus disease, for the edema may be due to combined mechanical, inflammatory, and toxic factors. There undoubtedly are cases of true retrobulbar or axial neuritis in which an edematous disc may be produced by lymph stasis secondary to an inflammatory focus in the nerve, but in these cases one would not expect the response to astringents applied to the nose to be so rapid. When one is confronted with the sudden appearance of bilateral papilledema with loss of vision in a patient who on repeated ophthalmic examinations for asthenopia has shown normal findings, the question of the etiologic factor presents a real problem to the examiner and demands an explanation of the phenomenon. A brief review of the literature concerning the nature of FROST: Papilledema Associated with Sinus Disease 483 the several types of papilledema presents many interesting problems. Apparently the edema of the disc is the same pathologic condition in all, but may result from a variety of causes. PAPILLEDEMA General Considerations. -The term papilledema implies only that there is an edema of the papilla; this may be produced by a variety of pathologic processes. In a large number of instances the appearance of the nerve head is such as to confuse the most skilful observer in differentiating between an edema of inflammatory origin and one produced by mechanical means. The literature contains a multiplicity of terms descriptive of diseases of the optic nerve, which in itself is evidence that ophthalmologists are still at variance in their interpretation of these conditions. Originally the terms optic neuritis and choked disc were used to distinguish a slight from a marked swelling of the papillary tissues, and a swelling measuring two diopters was selected as arbitrarily marking the dividing line between the two. It is quite generally admitted that this classification should be discarded, and that one should be chosen which would describe the processes with relation to the basic causes founded upon a pathologic-anatomic con- ception. In the vast majority of cases edema is the out- standing finding, except in those rare instances of true papillitis in which the papilla is the actual focus of the disease. Ronne and Hugo Thomsen reported their findings in a large series of pathologic sections of swollen discs. They observed that the edematous condition of the papilla was the same pathologically whether the swelling resulted from brain tumor, meningitis, nephritis, true optic neuritis, or hypotony of the globe. Similar findings were reported by Paton and Holmes. It would seem to be proper, therefore, to use the term papilledema to designate the condition seen ophthalmo- scopically, and then to qualify this diagnosis by naming 484 FROST: Papilledema Associated with Sinus Disease the probable cause as elicited by other forms of investiga- tion. True papillitis is encountered so rarely that it would probably be well to abandon the term, as it merely adds to the confusion. Classification.-In the Standard Nomenclature of Disease the term papilledema is used to describe many types of optic nerve disease, and the classification conforms substantially to that of Behr, which is as follows: A. Following passive lymph stasis of the papilla I. Through compression of the optic nerve and through it the central path of lymph conduction a. Intracranial conditions 1. With increased intracranial pressure, such as tumors, abscesses, internal hydrocephalus, etc. 2. Without increased intracranial pressure; the lesions are in the region of the optic foramen; such as aneurysm of the internal carotid artery, oxycephalus, etc.* b. Intra-orbital conditions, such as tumors, inflam- mation, hematoma, hemorrhage in the optic nerve sheaths, etc.* II. Through retention of the tissue fluids of the papilla as a consequence of marked hypotony following perforating injuries, diseases of the anterior half of the globe, etc. B. Following active lymph stasis of the papilla caused by increased outflow of lymph due to functional injury or damage to the blood vessel walls I. In general diseases and blood affections, such as nephritis, chlorosis, leukemia, polycythemia, etc. II. In contusions of the globe as a result of contrecoup In this classification, Behr does not include the edema of optic neuritis which he prefers to designate as inflammatory papilla. *It is into these groups that the instances related to sinus disease probably would fall. FROST: Papilledema Associated with Sinus Disease 485 Ronne confines his discussion to the terms choked disc and neuritis of the optic nerve, which may be either intra- ocular or interstitial, and considered from a clinical stand- point this seems to be the simplest and most practical classification. The ambiguity of terms must always be kept in mind, but the question of greatest clinical importance is whether there is present a primary edema of the papilla with secondary dysfunction or a primary dysfunction with secondary edema Fundus Findings.-The term papilla was first used by Biggs in 1676. He believed that the head of the optic nerve normally is projected into the interior of the eye. It is now known that the nerve head actually lies in the same plane as the retina. However, custom has made us familiar with the name papilla, and its usage is continued. In the normal human eye, as seen with the ophthalmoscope, there is no swelling of the disc, and the vessels pass over its edge with- out loss of their light reflex. Early stages of papilledema due to increased intra- cranial pressure, termed plerocephalic edema by Traquair, are observed but rarely, since there is no primary visual dysfunction as the result of the edema. Slit-lamp studies by Schieck, Koeppe, and others have disclosed an early clouding of the papillary center due to detachment of the internal limiting membrane, although the existence of the membrane in this area is denied by some authorities. The classic ophthalmoscopic picture of papilledema is well known, but varies greatly with the stage and severity of the edema. The extent and height of the edema, the steepness of the borders, the preservation of the physiologic excavation, and the observation with red-free light are of the greatest importance in making an ophthalmoscopic differential diagnosis between passive edema and edema of supposedly inflammatory origin, but the evidence offered by these signs is not infallible. Despite the features in the fundus picture described by 486 FROST: Papilledema Associated with Sinus Disease various authorities as pathognomonic of certain diseases, the most careful and experienced observers do not depend upon this examination alone for diagnosis. In the stage of atrophy the nerve elements exhibit irreparable degenerative changes, taking on a more grayish tone, and later a pallor, with an irregular outline of the disc and an uneven distribu- tion of peripapillary pigment. This condition is referred to usually as post-papillitic atrophy. In some cases the edema may subside, leaving signs vary- ing from a slight temporal pallor to complete atrophy of the disc, without the slightest appearance of a previous swelling or of an inflammatory reaction. In other instances the edema may disappear without leaving any trace of previous abnormality in the disc. Subjective Symptoms.-The subjective symptoms in plero- cephalic edema are mild in proportion to the extent of the changes observed with the ophthalmoscope, but there may be momentary obscurations of vision, variously interpreted as due to vascular spasm, compression of the chiasm, or constriction by a dural band at the optic foramen. That there is some conduction interference, such as a mild affec- tion of the maculopapular bundle from pressure, seems to furnish a rational interpretation, but the mechanism cannot be convincingly explained. The same subjective symptoms may be experienced in the early stage of papilledema due to other causes, and are probably dependent largely on interference with the nerve impulses, in or peripheral to the optic chiasm, which becomes more pronounced and sustained after the onset of the edema. In fact, if there is originally a conduction interference from direct pressure or interstitial neuritis, the loss of vision may considerably precede the edema. Changes in the retina itself may also cause functional loss. In the early stages of papilledema associated with sinus disease, before any objective signs are apparent, the patient may complain of pain in and behind the eyes; the pain FROST: Papilledema Associated with Sinus Disease 487 increases with eye-strain, and there is also intermittent blurring of vision. Despite these symptoms, the vision is normal when tested by the ophthalmologist, and ophthal- moscopic examination reveals no changes in the disc. Later, the papilledema appears suddenly, accompanied by serious visual disturbances. Field Changes. -The field changes produced by the fundus lesions depend, of course, on many factors, and must not be confused with the defects produced by lesions posterior to the lamina cribrosa. In uncomplicated cases of plero- cephalic edema the most characteristic change is the enlarge- ment of the blind-spot, caused by the increased thickness of the nerve-fiber layer of the papilla and by the lateral dis- placement of the retina. The steepness of the border de- pends on both of these factors. The qualitative color loss covers an area proportionate to the amount of edema. The mechanical effects of the edema are restricted to the disc and its immediate neighborhood, and the blind-spot is affected only by the swelling of the disc and the spread of fluid from it. If the edema extends into the macular area, there may be a relative central and caecocentral scotoma, with relative blue blindness due to some disturbance in the outer layer of the retina. It seems to be plausible that this disturbance may be an edema or even a peripapillary de- tachment of the retina, similar to that which Reese describes as occurring in hypotony. Reese concludes further that this same peripapillary detachment of the retina can accom- pany the papilledema from increased intracranial pressure, and is doubtlessly a factor in causing enlargement of the blind-spot. However, Traquair, in a recent personal com- munication, states that "if the retina is normal in the macular area, the scotoma is not due to edema but to some conduction interference." In a histologic study of 60 eyes Paton and Holmes found a subretinal serous exudate free from cells in the folds of the retina, but admit that this 488 FROST: Papilledema Associated with Sinus Disease might be due to postmortem changes; hence they make no definite statement regarding its significance. In the modified papilledema found in sinus disease the enlarged blind-spot usually is accompanied by a bizarre caecocentral scotoma or sector defect. The interpretation of this finding presents great difficulties, and only doubtful conclusions as to the mechanism involved can be drawn. Van der Hoeve, in 1909, was the first to describe enlarge- ment of the blind-spot in a case of posterior ethmoiditis, and later reported other cases. De Kleyn believed that enlarge- ment of the blind-spot was almost a constant accompani- ment of posterior sinusitis. Bordley, in a series of 102 cases of sinus disease, found enlargement of the blind-spot in 31 per cent., peripheral contraction in 27 per cent., and central scotoma in 11 per cent. Elschnig and Best, quoted by von Hippel, failed to find an enlarged blind-spot in any of their cases. Enlargement of the blind-spot is easily interpreted in papilledema, but in the absence of edema its explanation must rest on a different basis. Some authorities regard ocular fatigue as the cause of the enlargement in certain instances, and also consider it a factor in peripheral con- traction. Fuchs demonstrated that the immediate peri- papillary fibers of the retina lie in the periphery of the optic nerve throughout its entire course, and that any interference in these bundles would cause an enlarged blind-spot, but this view is still not universally accepted. However, it offers an explanation of the enlarged blind-spot when there is no edema of the disc, which is attributed to a conduction inter- ference in these fibers by a perineuritis or to pressure as the nerve traverses the optic canal. The literature contains voluminous studies of the normal blind-spot for white stimuli by various technical methods. Haycraft was the first to describe the surrounding zone for different colors, but his investigation was limited to studies made on himself. More recently Wentworth described her FROST: Papilledema Associated with Sinus Disease 489 findings in a large group of normal persons. These demon- strated an increase in area larger than the defect for form of 35 per cent. for blue; 58 per cent. for red; and 98 per cent. for green. Ferree and Rand have made studies of the blind- spot for color in many pathologic conditions, and they emphasize that in investigations of the blind-spot color stimuli are valuable in detecting small changes, and enable the observer to discover points relative to the advancement or recession of the disease. This makes the procedure of great value in prognosis: Ferree and Rand believe that there is a marked susceptibility of the color processes to pathologic conditions. In chronic glaucoma there is an enlargement of the blind-spot for blue; the enlargement is less for red, and least for green, which is the reverse of the normal sequence. These changes conform to the areas of the early Bjerrum scotoma for form. According to Traquair, a relative blue blindness suggests a functional disturbance in the outer layer of the retina, the nature of which is as yet unexplained. But since glaucoma is an intra-ocular disease, it may be assumed that the changes in the blind-spot are due to some intra-ocular phenomenon and not to nerve fiber interference. Thus there are two explanations for enlargement of the blind-spot: one, that it is due to changes in the papilla and the surrounding retina, and the other, that it results from interference with conduction. In the modified papilledema in sinus disease, either or both factors may play a part. An enlarged blind-spot alone does not affect central vision unless the spot is so large that it involves the macular region. The caecocentral scotoma, the real cause of the visual loss in this group of cases, may be large or small, of great or slight intensity, and usually has well-defined margins. Whether it is due to a true conduction interference as a result of a retrobulbar neuritis of toxic or inflammatory origin or to pressure alone has not been proved. The caecocentral scotoma is generally attributed to conduction 490 FROST: Papilledema Associated with Sinus Disease interference in the maculopapular bundle posterior to the entrance of the central vessels, in its passage through the canal or even in the chiasm. Paton -and Holmes have stated: "It is a well-ascertained fact that even moderate pressure in the nerve interferes first with the function of the macular fibers and thus gives rise to a central scotoma, which is exceedingly rare in papilledema." The maculopapular bundle courses centrally in this por- tion of the nerve, and in inflammations of the periphery is thus, theoretically at least, protected. It is generally accepted as true that these fibers constitute the portion of the nerve most vulnerable to specific toxic influences. If this is so, by the same logic they might also be more sensitive to the extension of the milder local inflammatory processes, and to pressure when the less vulnerable fibers are spared. Nevertheless, the character of the scotoma observed in the cases associated with sinus disease remains unexplained. The caecocentral scotoma in these patients bears a close resemblance to that found in tobacco amblyopia. The scotoma is limited to the temporal side of the fixation point, and, if interpreted from the standpoint of a conductive inter- ference, shows a predominant involvement of the crossed fibers of the maculopapular bundle. It does not, however, conform to the pattern of the distribution of these fibers in the retina, and there is no evidence that it is caused by changes in the retina itself; there certainly is no sign of gross inflammatory changes in the nerve. No conclusive evidence exists that these highly developed elements in the bundle are the most vulnerable to toxins. Many observers are of the opinion that the scotoma is pro- duced in the retina itself-probably in the ganglion-cell layer. As a rule, in choked disc and passive edema from other causes there are no characteristic changes in the peripheral fields until the onset of the atrophic stage, at which time FROST: Papilledema Associated with Sinus Disease 491 an irregular concentric contraction begins that progresses steadily and is a sign that the prognosis is unfavorable. Pathology. -In passive papilledema of all types the change that takes place is essentially an edema of the papilla and the optic nerve, which is usually associated with an ampullar distention of the sheath if intracranial pressure is present. At first the papillary edema is extremely slight, but never- theless produces capillary compression and local acidosis which lead to increased edema and compression of the larger vessels. The edematous fluid itself, or a coagulum of protein, accumulates between the nerve fibers and causes their separation. Later, depending on the degree of the edema, the medullated nerve fibers become swollen and may exhibit enlargement of the normal varicosities, which stain deeply with eosin and finally disintegrate into hyaline masses and cytoid bodies. In the later stage there is also a definite inflammatory response in the form of round-cell infiltration in the papilla, lamina cribrosa, nerve, and nerve sheaths, which is mild and diffuse as the result of the irrita- tion produced by the edema, and is quite different from the perivascular infiltration observed in optic neuritis. The early stages are rarely observed microscopically, but ophthalmoscopically it appears that the more laterally placed fibers become involved first, and instead of forming a regular arc, they make a double curve, taking an S-shaped course which displaces laterally the layers of the retina. Later, the centrally placed fibers show edema and cause narrowing of the physiologic cup. In interstitial neuritis anterior to the point of entrance of the central vessels, in hypotony, and often in true papillitis, the edema more frequently begins in the center of the disc. It is interesting to speculate as to why the edema is con- fined to a small area of the retina, and as to why it makes its initial appearance in a certain part of the disc. The structure of a tissue determines the amount of fluid that can be collected within it with a given capillary pressure. Al- 492 FROST: Papilledema Associated with Sinus Disease though slight edema may be present in the entire retina, the greatest amount of edema is present at the papilla. The papilla does not contain Mullerian fibers, which are believed to prevent the separation of the retina and the accumulation of fluid between the cells. The laxness of the tissue in the disc may be compared to that in the eyelids and other tissues commonly affected by edema. The edema is usually greatest where the vessels leave the disc. It is also true, however, that the nerve-fiber layer is thickest on the nasal side and thinnest temporally, where the maculopapular bundle emerges. The thickness of the nerve-fiber layer increases in the various sectors as follows: (1) maculopapu- lar bundle; (2) upper outer quadrant; (3) lower outer quadrant; (4) inner border; (5) lower and upper inner quadrant-the appearance of edema in the nerve is in inverse order. According to Fry, in cross-section the edema is greatest around the axial strand, later extending to the periphery. Behr does not agree with this view, since in degeneration of the nerve the collapse of the medullary sheaths begins in the periphery near the globe, where the quantity of glial tissue is greatest. Degeneration is followed by glial-tissue and connective-tissue infiltration, with mild inflammatory changes. It can only be assumed that a similar form of edema of the nerve is present in other types of papilledema, since, for obvious reasons, proof is lacking. Mechanism.-The actual mechanism of the production of papilledema is still a much disputed question and is de- pendent on many factors. The theory that choked disc is due to inflammation has few supporters, since pathologically there is no evidence of inflammatory change. Furthermore, simple trephining causes disappearance of the edema, even when the intracranial tumor is not removed. The theory that the cause is congestive has many adherents, but few investigators agree with von Graefe that edema of the disc is due primarily to blood stasis in the cavernous sinus, since FROST: Papilledema Associated with Sinus Disease 493 Seseman demonstrated that there is an anastomosis of the central retinal vein with the facial vessels, and that choked disc is not a clinical symptom of cavernous sinus thrombosis. Lauber, on the contrary, maintains that papilledema is present in this condition, and also in thrombosis of the central vein, but that it is not recognized as such because of the associated intense edema of the retina. Swift ascribes increased intracranial pressure, and hence choked disc, to venous congestion in the cranial venous sinuses. Most adherents to this theory believe that venous compression occurs at the point where the central vein passes through the intervaginal spaces. According to Fry, this compression causes a transudation of lymph into the tissues of the optic nerve. Schieck was of the opinion that the compression was caused by the entrance of cerebrospinal fluid into the perivascular lymph spaces. Wolfe and Davis, in their reports of experiments on dogs recently published, have failed to show that there is any such continuity of the perivascular and subarachnoid spaces, but these investigations do not disprove their existence in man. Kornder's experiments on dogs show that both the in- crease of intracranial pressure and the increase of venous pressure are necessary to produce choked disc. The rise in venous pressure is systemic, and is due to slowing of the heart through vagus stimulation, but does not take place in atrophinized animals. Kornder, by similar experiments, also proved that venous stasis alone cannot produce choked disc, and this finding has been corroborated by Cushing. Although these investigations shed some light on the problem generally, experiments on animals do not permit convincing deductions as to the pathogenesis of papilledema to be drawn, since the cranial structures in the animals used in the laboratory differ so greatly from those in man. It is necessary, therefore, to formulate opinions largely on clinical observations. 494 FROST: Papilledema Associated with Sinus Disease Lauber's studies in intra-ocular arterial and venous blood- pressure lend support to the theory of congestion. He maintains that between venous and arterial pressure there is a normal ratio of about 1 to 2.6, and that if there is a rela- tive rise in the intra-ocular venous pressure, papilledema will appear. Consequently, choked disc is not common in patients with hypertension, and appears more frequently in those with low blood-pressure, who display the same degree of intracranial pressure. This may explain to some extent the observations of neuro-surgeons that choked disc is not present in all cases of increased intracranial pressure. Ulrich, Parinaud, and Kampherstein believe that the edema is transmitted directly from the brain to the optic nerve, but without involving the vaginal spaces, and that this edema causes interference with circulation, which results in choked disc. Behr is of the opinion that there is a normal current of lymph from the eye through the nerve to the brain, the blocking of which current causes choked disc. Many au- thorities, including Saenger, are in agreement with this con- cept, but they do not accept Behr's view that the blockage is produced by the pressure of a dural band at the cranial end of the optic canal. The recent experimental work of Berens tends to corroborate the theory that there is a backward flow of lymph from the eye. He has shown that granules of Prussian blue were found in the perivascular spaces in the axial strand within twenty-four minutes after the injection of Weed-Wegefarth solution into the vitreous. Numerous variations of the transport theory have been advanced since Schwalbe demonstrated the continuity of the subarachnoid space with the intervaginal space of the optic nerve. Schmidt-Rimpler assumed that there was an infiltra- tion of fluid through channels into the lamina cribrosa. Schieck believed that the fluid was forced into the perivas- cular strand by direct connection with the intervaginal space, but Levinson was of the opinion that the normal perivascular FROST: Papilledema Associated with Sinus Disease 495 outflow was thus blocked. Manz believed that pressure in the ampulla strangulated the nerve at its forward end. The experiments of Parker are of the greatest significance, and establish the fact that there is a definite ratio of intra- ocular pressure to intracranial pressure. Disturbance of this ratio by a relative hypotony or by an increase in intracranial pressure will produce papilledema. Lymph flow from the eye by the posterior route is maintained by the intra-ocular tension; hence papilledema is rarely seen in glaucoma and is common in hypotony. The statement that papilledema is not present in myopia has not been substantiated. Cushing, in 1909, reported that he had never observed a case of myopia with increased intracranial pressure in which choked disc was absent. There has been, it seems, a tendency to attribute all types of edema of the disc to a single cause. In true plerocephalic edema the congestive theory of compression of the vein in the intervaginal space is most generally accepted, but this can- not be the cause in those conditions in which the central retinal vessels are not likely to be compressed. Although these theories have been cited here but briefly, it is obvious that few can be applied to the mechanism of the papilledema associatedwith sinusdisease. Theviews set forth by Behr and by Saenger seem to have some application, in that they consider that the interference of the posterior lym- phatic drainage of the globe and the optic nerve may be a factor in producing the edema. If a lymph current exists, and if the obstructive pressure on the nerve or vessels is greater than the lymph pressure exerted in the stretching of the retinal tissues, the edema will be maintained. Since no true lymphatics have been demonstrated, it is more nearly correct to speak of these channels as tissue spaces containing tissue fluid. Behr has demonstrated by injection of the optic nerve a subpial system of hollow spaces which are continuous about the nerve bundles but which show no connection with the perivascular or intervaginal spaces. These spaces are 496 FROST: Papilledema Associated with Sinus Disease supported by glial tissue, and Behr regards them as organs of nutrition of the optic nerve. In papilledema this periph- eral glial mantle and the axial strand show the greatest amount of edema, and initial atrophy of the nerve fibers takes place in the same areas. It is entirely possible that there may be two distinct systems of these tissue spaces, both play- ing a part in the mechanism. The perivascular spaces prob- ably continue with the vessels across the intervaginal spaces and pass out of the orbit through the jugular lymph trunks, since their continuity with the subarachnoid space has not been demonstrated. Intra-orbital affections, such as tumors, inflammation, and hematoma, as well as hemorrhage, primary tumor, or metas- tases in the sheath of the optic nerve, may all produce an edema of the disc by compression of the central vessels. In such instances the theory that the mechanism is congestive may be applicable. Papilledema has also been observed in cases of constriction of the optic nerve in the canal, in orbital tumors behind the entrance of the vessels, and in meningiomas of the sphenoid ridge. It appears that pressure exerted on the optic nerve at the apex of the orbit, without the presence of inflammation, can produce a passive edema of the disc, as may be seen from the following case report: The patient, a school boy, was struck over the upper outer rim of the left orbit by a swing. A small laceration of the skin was closed by a suture and the wound healed by first intention. Within ten days there was a gradually increasing exophthalmos of 11 mm. over that of the right eye. The globe was pushed forward, down- ward, and outward, and was immobile. It was not painful, or tender on palpation. The eyelids and conjunctiva were not edema- tous or congested, and there was no evidence of venous obstruction in any of the orbital veins. The vision was 20/70, and there was a papilledema of four diopters without hemorrhages or exudates. The blind-spot was enlarged. An incision through the upper eyelid exposed a large subperiosteal hematoma which had dissected the periorbita of the roof and nasal wall from its anterior margins to the Fig. 1.-The specimen is the posterior pole of a globe including the optic nerve, disc, and the adjacent sclera, choroid, and retina. The elements of the nerve are separated by a marked diffuse edema which is particularly noticeable in the interstices of the nerve bundles. The edema extends into the disc, causing a definite elevation. This papilledema is due, for the most part, to the protrusion of edematous nerve bundles which have pushed anteriorly through the sclerotico- choroidal foramen, mushrooming over the surface of the choroid adjacent to the disc and pushing the retinal elements laterally. The edema continues into the fiber layer of the retina, diminishing grad- ually from the disc. Due to fragmentation of the tissue the con- tinuity of the retinal layers is broken. This may be due in part to preparation and in part to a loss of its viability. The central vessels show a dilatation of the perivascular space. The layers of the lamina cribrosa are separated by edema, and their contour is convex an- teriorly instead of concave. The optic nerve sheaths show no appre- ciable dilatation of their spaces. The external layers of the dura and the sclera exhibit polymorphonuclear and lymphocytic infiltration. FROST: Papilledema Associated with Sinus Disease 497 apex. On inserting a probe it was found that the periosteum was separated almost completely around the nerve at the foramen. The patient's postoperative course was uneventful, the vision gradually returned to normal, and the exophthalmos and papill- edema disappeared. Recently another case afforded an opportunity to observe the changes in the eye immediately after ligation of the optic nerve. The patient, a middle-aged woman, had a carcinoma of the left antrum which involved the floor of the orbit. Eradication of the neoplasm by electrocoagulation necessitated the removal of the normal eye. Avertin anesthesia was administered, and before the operation 0.2 c.c. of Weed-Wegefarth solution was injected into the vitreous. In the operative removal of the floor of the orbit the optic nerve was exposed from below, and was tied somewhat tightly about 18 or 20 mm. behind the globe. Electrocoagulation in this region undoubtedly caused trauma and disturbance of the circulation to the eye. The globe, together with the remaining orbital contents, was removed twenty-four hours after ligation of the nerve, at which time definite edema of the papilla was observed. The eye was fixed in formalin, and the posterior portion of the globe and the optic nerve were prepared by the paraffin method and stained with hematoxylin and eosin. The photomicrograph (fig. 1) and a pathologic report byDr. Algernon B. Reese are shown opposite. It is true that many patients in whom, according to the roentgenogram, there is a constriction of the optic canals display optic atrophy, but no papilledema. It is quite likely that edema may have preceded the atrophy, or that the onset of pressure was so gradual that there was compensatory drainage of the normal backward flow of lymph in the nerve. If the blockage is sudden, edema follows, and if gradual, there may be atrophy. As stated previously, in all types of true papilledema the edema of the nerve head is essentially the same pathologi- cally. Ronne believes that a similar interference with the lymph current can take place when a sufficiently large area of the nerve is affected by inflammation, and thus may pro- 498 FROST: Papilledema Associated with Sinus Disease duce the same mechanical obstruction, without involvement of the intervaginal sheaths or of the central vessels. The presence or absence of papilledema in true axial neuritis de- pends on the character, location, and extent of the inflamma- tory reaction in the nerve trunk, and the loss of vision may be present for some time before changes in the fundus take place. From this brief review of the theories of its etiology it is obvious that no single cause is responsible for all cases of papilledema. The etiologic factors that have a bearing on the papilledema associated with sinus disease may be listed as follows: (1) The influence of a toxic substance or sub- stances which might be regarded as an allergic phenomenon (probably of rare occurrence); (2) pressure on the optic nerve, producing lymphatic stasis if the posterior portion of the nerve is affected, or venous stasis if the central vessels are obstructed; and (3) lymph stasis the result of direct exten- sion of the inflammation in the sinus mucosa or through the trans-osseous vessels to the sheaths and fibers of the optic nerve. In my opinion the following cases of papilledema in asso- ciation with disease of the posterior sinuses present clinical evidence that the swelling of the disc was caused by true lymph stasis as the direct result of pressure exerted on the nerve at the apex of the orbit. The pain, the blurred vision, and the marked increase in the size of the blind-spot were all relieved by shrinkage or inhibition of the congestion of the nasal tissues. CASE HISTORIES CASE 1. -The patient, J. N., a medical student, aged twenty- four years, was first seen on April 2, 1932. He complained of eye- strain, which was believed to be due to faulty refraction. The pain in and behind the eyes was dull and aching in character, and was increased by reading and by extra-ocular movements, espe- cially on convergence and elevation. His vision was blurred at intervals, but examination by means of the Snellen chart showed that the vision was 20/20 in each eye with correction. There was FROST: Papilledema Associated with Sinus Disease 499 an exophoria of 30 for distance, and of 120 at 14 inches. The near- point of accommodation in each eye was 75 mm., with a near-point of convergence of 120 mm., which gave rise to discomfort and was difficult to maintain. The ophthalmoscopic examination showed the fundi to be normal, as were also the blind-spots and the fields for form and color. A thorough physical examination by a competent internist re- vealed no abnormalities or evidence of systemic disease. A rhino- logic examination showed a nonobstructive deviated septum, with a moderate amount of congestion of the mucous membranes. Roentgenograms of the sinuses disclosed no abnormality. The astringents used in the examination of the nasal passages yielded immediate relief of the pain in the eyes, which relief con- tinued for several hours. This treatment was repeated daily for several days. On the fifth day a faint blurring and elevation of the upper nasal borders of both discs were observed, together with engorgement and tortuosity of the retinal veins. The central vision and blind-spots, however, remained normal. The astringent packs in the nose were omitted for three days over the week-end, and thevision suddenly dropped to 10/200 in each eye. There was a marked papilledema of about four diopters in each eye; the physiologic excavation was preserved as a narrow slit; the veins were engorged and tortuous, but no hemorrhages or exudates were present in the retina. The margins of the edematous disc were well defined, but were not so steep as those that are usually observed in choked disc due to intracranial pressure. The macular vessels were generally tortuous, but no edema of the macula could be demonstrated definitely (fig. 2). Each blind-spot was markedly enlarged, and there was an ill-defined relative cen- tral scotoma. Nasal astringent packs were again administered, and an hour and a half later the size of the blind-spots was greatly reduced (fig. 3). No improvement in vision could be demonstrated by the Snellen chart, although the patient said that the vision was much less fogged. A complete neurologic examination resulted in normal findings except for the optic nerve. Laboratory studies, including urin- alysis, Wassermann tests of the blood and the spinal fluid, and tests of the spinal fluid pressure, yielded normal results. The leukocytes were increased to 16,000, but otherwise the examination of the blood showed no significant abnormality. The eosinophil count was 1. Because of these findings and due to the failure of local treat- 500 FROST: Papilledema Associated with Sinus Disease ments to effect more than transitory relief, surgical aeration of the posterior sinuses was advised and carried out by the Halle tech- nique. The ethmoids on both sides and the left sphenoid were markedly congested and there was thickening of the lining mucous membrane, but no purulent secretion or polypoid tissue. On the following day there was a noticeable improvement in vision, which continued slowly with gradual subsidence of the papilledema during the patient's stay in the hospital. After the operation, treatment in the form of foreign protein injections of skimmed milk and Coley's serum, strychnin, 1/60 grain, and sodium salicylate, 30 grains, three times a day, was ad- ministered. In addition, hot packs were applied to the body daily for twelve days. On May 6, after the patient's discharge from the hospital, the vision in the right eye was 20/30-; and in the left eye, 20/60. The disc outlines showed a faint haziness, but no measurable elevation, and the veins were still well filled but not tortuous. The fields of vision were normal, the blind-spots were almost normal in size. A small central scotoma was still demonstrable in the right eye, and persisted until May 25, when the vision was 20/20 in each eye, with correction. The fundi were normal in appearance. Periodic examinations have been made since, and the findings have always been normal. Roentgenograms of the optic canal have been made following attempts to instill lipiodol into the pos- terior ethmoids and sphenoids, but the opaque material was not retained in these well-aerated cells. The canals showed no abnor- malities. (Studies of the blind-spots before and after operation are shown in figures 2, 3, 4, and 5.) The following case ran an almost identical course with that of the first, but an opportunity was afforded for making a more thorough ophthalmologic study. As in the first case, an attempt at conservative treatment failed. CASE 2. -The patient, A. J., a healthy Armenian, aged twenty- five years, a dealer in Oriental rugs, first consulted me on October 14, 1933. Nearly two years earlier (January 27, 1932) the patient had been examined by a competent rhinologist, who elicited the following history and findings: The patient complained chiefly of marked bilateral obstruction of nasal respiration, with attacks of sneezing, especially in the morning, and susceptibility to colds. Two years d/V ruse / L.

Fig. 2 (Case ] ).-The blind-spots for 1 mm. white are enormously enlarged on the temporal side, the nasal limits conforming nearly to the normal distance from the fixation area. The prolongations correspond to the areas of greatest edema of the disc margins; that is, in the upper and lower nasal quadrants. This would suggest that the enlarged blind-spot is due to the edema of the disc. The ill-defined relative central scotoma may be interpreted as due to involve- ment of the maculopapular fibers by conduction interference or to a macular edema not recognizable with the ophthalmoscope. Peripheral fields for form and color are normal. The prolongations on the temporal side of the blind-spot correspond to the area of greatest edema seen with the ophthalmoscope, as shown in the inserted fundus photograph of this eye, and which follows the site of the emerging vessels.

Fig. 3 (Case 1).-Blind-spots immediately after removal of astringent packs from the nose, which had been retained for about one hour. There is marked shrinkage of the temporal border of the blind-spot, with some increase in visual acuity, but according to the statements of the patient, general fogginess of vision was markedly improved. jv~4...... -./.AV'_ I::.at- /

Fig. 4 (Case I).-There is still further decrease in the size of the blind-spot, which is in proportion to the decrease in the height and extent of the papill- edema. There is an ill-defined relative central scotoma for 0.5 mm. white.

Fig. 5 (Case 1).-The blind-spots are within normal limits. No demon- strable fundus change. FROST: Papilledema Associated with Sinus Disease 501 previously he had had a submucous resection for nasal obstruction, which had remained relieved for one year, or until his nose was broken in a fall. The nasal examination showed a slight engorge- ment and edema of the right inferior turbinate bone, and edema of the irregular septum. The middle meatus was open and free. When astringents were applied the septum was found to be gen- erally deflected to the right, with the septal ridge left anteriorly. The operative scar was 1 cm. back from the anterior border, which was the anteroposterior border of the anterior cartilage segment, which curled into the upper fragment to the left, causing obstruc- tion. There was some edema of the nasal mucous membrane of the vasomotor type. Tonsillectomy had been performed some time previously, but there was considerable tonsillar tissue at the upper right fossa. Sensitization tests were made by an allergist, who gave the opinion that the patient was suffering from a definite allergic coryza. Multiple sensitizations were made, and dietary control, avoidance of tobacco, and graduated doses of stock house dust extract were recommended, but these measures were not car- ried out by the patient. When the patient consulted me in October, 1933, his chief com- plaints were of pain in both eyes, which increased on reading and with extra-ocular movements, and a sensation of blurred vision, which increased intermittently. There was some soreness in the left eye, which became more acute on backward pressure on the globe. A complete ophthalmic examination, which included a thorough study of the fields and blind-spots, showed nothing abnormal. The convergence near-point was 100 mm., but caused pain and was difficult for the patient to maintain. These symptoms and findings recalled our experience in Case 1, and similar nasal treatments were administered, with the same immediate relief of the eye symptoms. Two days later, however, these symptoms had grown much worse, and the patient com- plained of severe pain behind the eyes and marked blurring of vision. In the right eye the vision was 20/100; and in the left, 20/200. Examination of the fundi showed a papilledema of three diopters in each eye, with marked tortuosity and engorgement of the veins, but no hemorrhages or exudate. The physiologic cup was preserved. The peripheral fields were normal for form and color, but the blind-spots were enlarged, with a caecocentral scotoma present. In spite of these alarming findings, nasal treatment was con- 502 FROST: Papilledema Associated with Sinus Disease tinued for another day, but without benefit. On October 17 the vision in right eye was unchanged, whereas in the left eye it was reduced to counting fingers. The fundus picture in each eye re- mained essentially the same as on the previous day. A complete general and neurologic examination revealed no sig- nificant abnormalities, except for the evidence of disturbance in the optic nerve. Laboratory studies, including urinalysis, Wassermann and Kahn tests of the blood, blood counts, coagulation time, bleeding time, and examination of the spinal fluid, yielded normal findings. An operation to effect bilateral aeration of the posterior ethmoid and sphenoid sinuses was performed. The after-treatment was exactly the same as in the first case. The day after the operation the patient reported much improvement in vision, but on the sec- ond day, the sight decreased and nasal astrin,gent packs were resumed. The vision again improved, and on the seventh day fol- lowing the operation the patient could read magazine print with each eye. During this period the papilledema gradually receded. On October 26, when he was dismissed from the hospital, the vision in the right eye was 20/50; and in the left eye, 20/70. The peripheral fields were normal, but the blind-spots were still greatly enlarged. There was almost complete recession of the papilledema, but some blurring of the disc margins remained. The vessels were much less engorged and less tortuous. On October 27 examination showed that the vision in the right eye was 20/30-1; and in the left eye, 20/40. After this the patient was examined at frequent intervals, during which time the vision improved to 20/20 in each eye. The fundi again were normal, as were also the fields of vision and the blind-spots. During one of these examinations lipiodol was injected into the sinuses, and roentgenograms of the optic canals showed the opaque fluid in one of the sphenoid cells situated in the margin of the optic foramen. The patient has been observed frequently since the operation, and has reported no return of the ocular symptoms. (The studies made on the blind-spots before and after operation are shown in figures 6, 7, 8, 9, and 10.) From the clinical course in these two cases I am forced to believe that the nasal condition was a direct etiologic factor, since the preoperative nasal treatments had so marked a bear- ing on the immediate relief of the symptoms, and the. patients were permanently cured by operations on the sinuses. Fig. 6 (Case 2).-Right Eye: The blind-spot is enlarged for 1 mm. white, pericaecal, hut greatest toward the macula; there is also enlargement for red and still greater increase for blue, using 2 mm. stimuli, which extend to the point of fixation. The blind-spot for green was onlv slightly larger than for white. The papilledema had not vet reached a height sufficient to produce a markedly enlarged blind-spot. Left Eye: Enlargement of the blind-spot for 1 mm. white continuous with caecocentral scotoma for the same stimulus, extending to the point of fixation, but not beyond. Loss of perception for 2 mm. blue and red on the temporal side of the point of fixation within the field of the instrument. The same color stimuli were easily distinguished on the nasal side.

* :1.. 1,35

Fig. 7 (Case 2).-Right Eye: Marked enlargement of the blind-spot, with entire loss of blute perception. Red was not seen on the temporal side of the fixation area. The size of the blind-spot accounted for by the remaining edema of the disc and peripapillarv retina. Left Eye: The same general characteristics as the right eye and also indefinite relative central scotoma for 0.5 mm. white. Fig. 8 (Case 2).-Further decrease in the edema of the disc and reduction in tbe size of the blind-spot for 1 mm. white. Relative central scotoma in left eve. Return of blue color perception, but large blue blind scotoma in the macular area continuous writh the blind-spot. Temporal borders of the blind-spot for colors nearly identical with those for form.

Fig. 9 (Case 2).-With disappearance of papilledema blind-spots reduced almost to normal size. In the right eye the blind-spot for red is nearly the same as for form, but there is a relatively large blind-spot for blue. In the left eye the caecocentral scotoma for red and blue shows gradual shrinkage toward the blind-spot. FROST: Papilledema Associated with Sinus Disease 503 Discussion. -These cases present many interesting fea- tures, from which it is not easy to draw definite conclusions. They cannot be classed as papilledema due to increased in- tracranial pressure, because the visual disturbances were immediate and too severe. Neither do they present the classic picture of axial neuritis as found in the group of demyelinating diseases, so well reviewed recently by Berliner, because there was no evidence of other neurologic symp- toms or signs. Such factors as syphilis, diabetes, tobacco, and alcohol were ruled out, but it was difficult to exclude the nasal con- ditions as causative agents. It must, however, be remem- bered that the sinuses may have been the focus of a specific virus that had a predilection for the optic nerve tissues, after its dissemination by the general circulation, possibly on an allergic basis. Syme ventures the statement that, when discovered, the organism of multiple sclerosis may be found to have a pre- dilection for the sinuses. If a specific virus were present in these cells, it is not likely that it could gain entrance to the nerve either by direct extension through the tissues or through the medium of local blood or lymph -channels. Toxins enter the circulation through the capillary walls into the venous or lymphatic channels, which in this region do not pass to the general circulation by way of the optic nerve or its sheaths, and so it is unreasonable to assume that toxins can be spread in this manner directly to the optic nerve. Turner believes in the possibility of direct absorption of toxic products from the sinuses into the subarachnoid space, and in this way, to the nerves. If this hypothesis is true, it would furnish an explanation for the contralateral or bi- lateral involvement of the optic nerve occasionally found in these cases associated with sinus disease. The findings in these cases cannot be explained on the basis of an interstitial neuritis, either inflammatory or purely toxic, for'such factors could not be removed so rapidly. Un- 504 FROST: Papilledema Associated with Sinus Disease doubtedly, if these conditions were allowed to remain, fur- ther conductive interference changes would arise and cause complications of a more or less permanent nature. Thus, by a process of elimination, it is my belief that in many instances the papilledema can be produced by mechan- ical means. Traquair states that "pressure on the optic nerve may not be the direct cause of the symptoms, but the vitiated nutrition due to a disturbed circulation may be a more attractive explanation." The observations made in Case 1 regarding the striking decrease in the size of the blind-spot after shrinkage of the nasal mucous membranes, and also the improvement in vision, support the view that pressure, in the nature of strangulation on the nerve, or even on its vessels, was the prime factor in the production of this papilledema. The exact location of this pressure cannot be definitely placed in the optic foramen, but it may well be from the periosteum and the soft tissues at the apex of the orbit, which are prob- ably involved to some extent in the reaction in the adjacent sinus cells. During the period of observation of these patients, prior to the loss of vision, the painful ocular symptoms were ascribed to the very definite posterior nasal congestion and obstruc- tion, which were promptly relieved by appropriate treat- ment. It is well known that shrinkage of the mucous mem- branes is only temporary, and is usually followed by a more intense secondary congestion, which may have been the factor that produced the acute symptoms a few days after the treatment was begun. Nevertheless, such a therapeutic test, if only as a diagnostic measure, seems to be a rational procedure. The fact that there was no evidence of any loss of visual acuity or of visual field changes until after the onset of the papilledema would lend weight to the theory that the fundus changes alone were the direct cause of the visual loss. It is a debatable question as to whether the central scotoma was Fig. 10 (Case 2).--The blind-spots, vision, and fundi are normal. FROST: Papilledema Associated with Sinus Disease 505 due to a macular edema not recognized by the examiner in the presence of the other striking changes, or to a partial conduction interference in the macular fibers by pressure somewhere along their course. This could also explain the early momentary fogginess of vision complained of by both patients, which was likewise relieved by the nasal treatment. Although, in my opinion, the theory that in these cases the papilledema resulted from pressure on the optic nerve seems to be most plausible, objection might be raised to this inter- pretation, because both eyes were affected. More frequently, in papilledema associated with sinus disease, the ocular changes are unilateral, and such instances are more easily interpreted as due to pressure. However, in the cases here described the sinus disease was bilateral, and hence it is con- ceivable that there was similar pressure on both sides. In the second case there was evidence that the nasal condition had an allergic basis, which might account for the generalized swelling and bilateral pressure. Furthermore, it is possible that these patients may have had a cranial anomaly that brought the posterior sinuses into more intimate connection with the optic canal than is usual. This latter hypothesis also offers a possible explanation of the comparative rarity of this ocular complication in sinus disease. In this connection, White has also emphasized the fact that pus is seldom found in the nasal passages in patients who have papilledema associated with sinus disease. He states that edema or turgescence is the prime factor in these cases. In purulent infections of the nasal cavities there is rarely any disturbance of vision. The explanation is that the purulent process is walled off from the eye, nerves, and the rest of the body.

SUMMARY AND CONCLUSIONS A careful study of two patients with papilledema which was relieved by operation on the posterior nasal sinuses stimulated a study of the literature on this association of 506 FROST: Papilledema Associated uith Sinus Disease papilledema and sinus disease, as well as on papilledema generally. The literature discloses such diversity of opinion regarding the actual mechanism responsible for the production of pap- illedema that it is difficult to arrive at any rigid or definite conclusions regarding the process actually involved in the cases associated with sinus disease. Since the findings vary considerably in these cases, no single theory regarding the cause can explain every instance of this association. However, it seems to be likely that in some cases papilledema from sinus disease may be inter- preted on a mechanical basis. There may be pressure on the optic nerve when there is no positive evidence of an optic neuritis in the strict sense of the term. There are other cases with edema of the disc in which the term neuritis implies retrobulbar involvement of an inflammatory nature. In these instances too the papilledema is due to the lymph stasis produced by extensive infiltration of the nerve itself. It is also possible that in the early stage the fundus changes alone can account for the loss of visual function and the changes in the visual fields, particularly those in the caecocentral area. The longer this stasis exists, the more is the recovery of the patient delayed, because a mild inflammation or a toxic effect may be produced by the edema itself and thus the condition may become a true axial neuritis. REFERENCES Babbitt: Tr. Am. Acad. Ophth. & Oto-Laryng., 1930, p. 31. Bedell: New York State J. Med., 1933, xxxiii, p. 361. Bedell: Penn. M. J., September, 1932. Behr: Klin. Monatsbl. f. Augenh., 1916, lvii. Abstracted in Brit. J. Ophth., vii, p. 437. Benedict: Arch. Ophth., 1933, ix, p. 893. Berens and Posner: Tr. Am. Ophth. Soc., 1932, xxx, p. 227. Berens, Smith, and Cornwall: Arch. Neurol. & Psychiat., 1928, xx, p. 1151. Berliner: Arch. Ophth., 1935, xiii, p. 83. Birch-Hirschfeld: Arch. f. Ophth., 1907, lxv, p. 440. Bordley: Arch. Ophth., 1921, 1, p. 137. Coffin: Tr. Am. Laryng., Rhin., & Otol. Soc., 1917. Cone and MacMillan: Cytology of the Nervous System, Penfield, Section XViI. Cushing: J. A. M. A., 1909, Iii, p. 353. FROST: Papilledema Associated with Sinus Disease 507

Davis: Brit. M. J., 1923, ii, p. 873. De Grosz: Tr. Am. Acad. Ophth. & Oto-Laryng., 1930, p. 21. De Kleyn: Arch. f. Ophth., 1910, lxxv, p. 513. Duke-Elder: Text Book of Ophthalmology, C. V. Mosby Co., St. Louis, 1933, i. Elsberg and Pfeiffer: Personal communication. Ferree and Rand: Arch. Ophth., 1931, v, p. 224. Fry: Am. J. Ophth., 1931, xiv, p. 874. Fuchs, E.: Text Book of Ophthalmology, J. B. Lippincott Co., Philadelphia, 1919, p. 604. Fuchs, E.: Graefe's Arch. f. Ophth., xxxi. Gifford: Tr. Am. Acad. Ophth. & Oto-Laryng., 1930, p. 48. Gradle: Am. Ophth., October, 1915, October, 1916. Hajek: Nasal Accessory Sinuses, translated by Heitgar and Hansel, C. V. Mosby Co., St. Louis, 1926, Ed. V. Haycraft: J. Physiol., 1910, xv, p. 492. Kornder: Arch. Int. Med., 1919, xxiii, p. 197. Lauber: Personal communication. Lillie: Am. J. Ophth., 1934, xvii. MacLean: Internat. Clin., September, 1933, p. 272. Mendel: Zentralbl. f. Augenh., 1901. O'Brien: J. M. Soc. New Jersey, 1934, xxxi, p. 87. Onodi: The Optic Nerve and the Accessory Sinuses of the Nose, translated by Luckhoff, London, 1910. Onodi: Ztschr. f. Augenh., 1904, xii, p. 23. Parker: J. A. M. A., 1916, lxvii, p. 1053. Parker: Tr. Am. Acad. Ophth. & Oto-Laryng., 1924. Parsons: Pathology of the Eye, ii, p. 1349. Paton and Holmes: Brain, 1911, xxxiii, p. 389. Peter: Am. J. Ophth., 1916, xxv, p. 261. Peter: Am. J. Ophth., April, 1916, p. 261. Reese, A. B.: Tr. Am. Ophth. Soc., 1930, xxviii, p. 341. Reynolds: Laryngoscope, 1922, p. 399. Ronne: Kurzes Handbuch f. Ophth., v, p. 641. Salzmann: Anatomy and Histology of Human Eyeball, translated by E. V. L. Brown, Chicago, 1912. Sattler: System of Diseases of the Eye, Norris and Oliver, J. B. Lippincott Co., Philadelphia, 1900, iii. Sluder: Laryngoscope, 1907, xvii, p. 833. Sluder: Nasal Neurology, Headaches, and Eye Disorders, 1927. Syme: J. Laryng. & Otol., 1924, xxxix, p. 384. Traquair: J. Laryng. & Otol., July, 1924, xxxix. Traquair: An Introduction to Clinical Perimetry, C. V. Mosby Co., St. Louis, 1927. Turner: J. Laryng. & Otol., 1924, xxxix, p. 371. Vandergrift: Am. Med., xl, p. 21. van der Hoeve: Arch. Ophth., 1911. von Hippel: Graefe-Saemisch Handbuch, 1922, vii, p. 299. Walker: Boston M. & S. J., 1921, clxxxv, p. 321. Weekers: Scalpel, March 18,1933. Wentworth: Am. J. Ophth., 1931, xiv, p. 1118. White: Tr. Am. Laryng., Rhin., & Otol. Soc., 1919, ii, p. 24. White: Am. J. Otol., Rhin., & Laryng., 1924, xxxiil, p. 121. Whitnall: Anatomy of the Human Orbit, Oxford Medical Publications, 1921. Wilbrand and Saenger: Die Neurologie des Auges, Wiesbaden. Wolfe and Davis: Brit. J. Ophth., November, 1931. Wolfe: The Anatomy of the Eye and Orbit, P. Blakiston's Son & Co., Phila- delphia, 1933. Wood: Lancet, September 24, 1910, p. 937.