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Show journal of Neuro- Ophthalmology 14( 3): 141- 154, 1994. > o 1994 Raven Press, Ltd., New York Part One Annual Review in Neuro- Ophthalmology The Anterior Visual Pathways Alfredo A. Sadun, M. D., Ph. D. and Jung Dao This review of neuro- ophthalmology of the anterior visual pathways is one of the first of a series of reviews in the ] ournal of Neuro- Ophthalmology, which is now the official journal of the North American Neuro- Ophthalmology Society. As the first review of the anterior visual pathways, we have taken the liberty of extending the period covered beyond the somewhat traditional one year. Hence, this review will cover articles from the beginning of 1992 through 1993. In addition, it will include a few of the most important articles that were published prior to 1992 and several articles published in early 1994 during the preparation of this manuscript. The visual system will be covered from the retina through the optic disc, the optic nerve, the optic chiasm, the optic tracts, through to the primary visual nuclei, which will include the lateral geniculate nucleus, the pretectum, the superior colliculus and the other minor primary visual nuclei in the mesencephalon and diencephalon. Two major topics were addressed: 1) mechanisms of axonal injury and recovery as well as the effects of corticosteroid and of surgical therapy on two common optic neuropathies; and 2) the segregation of visual information into separate channels, which constitutes parallel processing of the visual system. MODULATING THE PROCESSES OF NEURONAL INJURY AND RECOVERY Neurons, whether in the eye or the brain, are susceptible to ischemic injury as a consequence of From the Department of Ophthalmology, Doheny Eye Institute, University of Southern California School of Medicine, Los Angeles, California, U. S. A. Address correspondence and reprint requests to Dr. Alfredo A. Sadun, Estelle Doheny Eye Institute, 1450 San Pablo Street, Los Angeles, CA 90033, U. S. A. a variety of insults. If blood flow is interrupted for more than several minutes, irreversible damage occurs. There have been several recent advances in our understanding of the mechanisms of hypoxic cellular injury, and with it new strategies in stroke management. Many of these issues apply also to tissue damage due to ischemia at the level of the eye and the optic pathways. Several cytotoxic amino acids including gluta-mate, N- methyl- D- aspartic acid ( NMDA) and kainic acid, stimulate neurons to permit an influx of calcium, which can lead to damage and cell death. Increased calcium leads to activation of proteases and phosphorylases that destroy cellular membranes, and uncouple oxidative phosphorylation of the mitochondria. The cell attempts to pump out the calcium. The pumping mechanism itself leading to lactic acid or is a further intracellular injury. The affinity of neurotoxins for the NMDA receptor site can be blocked by certain antagonists. Receptor sites other than that of NMDA ( so- called non- NMDA receptor sites) can also mediate toxic reactions initiated by glutamate and other agonists. Various strategies have been employed in attempts to block the NMDA receptor site so as to protect neurons from further ischemic damage. For example, dextromethorphan and MK- 801 non-competitively bind to the site, and thus act as antagonists to the effects of glutamate and other neurotoxins. Zinc and magnesium act competitively with calcium to keep the channel open, and a variety of calcium channel blockers such as nimo-dipine have been used to restrict the flow of calcium into the cells. What follows is a discussion of investigations on modulating ischemic injury in the retina, optic disc and optic nerve. 141 142 A. A. SADUN AND J. DAO Retina The article by Schumer and Podos ( 1), which appeared at the beginning of 1994, approached the subject of glaucoma from the unusual angle of asking how cytotoxic agents and blocking mechanisms might apply at the level of the retina and optic disc in general and in glaucoma in particular. They reviewed the NMDA receptor site, its agonists and other cytotoxins, antagonists to the NMDA receptor site, calcium- induced damage of retinal cells and strategies of calcium channel blockage. Finally, they also reviewed recent studies on nitrous oxide as an intracellular messenger, and the role of free radicals and how scavengers might be used to mitigate this damage. Unfortunately, the first attempts to modulate ocular blood flow with calcium channel blockers have not proven particularly successful ( 2). Similarly, the use of calcium channel blockers to prevent damage attributable to glaucoma also has not proven useful ( 3). Nonetheless, ophthalmologists now are initiating studies based on what is known about the action of NMDA and nonNMDA associated neurotoxins and transmitters as acquired from the neurologists and neurosurgeons. Interesting papers include the review of various NMDA receptors and their agonists and that by Albers and colleagues describing the use of NMDA antagonists to minimize the effects of injury to neurons. A variety of excitatory amino acid neurotoxins may be released following neuronal injury from ischemia. These neurotoxins stimulate opening of Ca+ f ion channels, which permits a massive influx of calcium to the interior of the neurons. As mentioned previously, the rise in intracellular Ca *" + activates various lipases and prostaglandins producing irreversible membrane damage. It is interesting to note that excitoneurotoxins produce a specific pattern of cell death in the retina ( 1). It is intriguing to postulate that the pattern of cell death could be due to the differential effect of various neurotoxins on various retinal ganglion cells. Glaucoma and Alzheimer's disease are two examples of diseases due to cell specific injury in which there appears to be a predilection for the loss of one retinal ganglion cell type versus others and thus damage to one channel of information ( see later section on parallel processing). Excitatory neurotoxins such as kainic acid and NMDA will lead to the immediate death of rat retinal ganglion cells ( 6), but this can be modulated by pre- treatment with NMDA antagonists such as dextrophan or dextromethorphan. It has been suggested, therefore, that activation of NMDA receptors may mediate cellular damage in the retina in a variety of ischemic and degenerative diseases including glaucoma, Parkinson's Huntington's and Alzheimer's disease ( 1). Harrison ( 7) has demonstrated that certain drugs can be used clinically in the treatment of stroke to modulate the neurotoxic effects of excitatory amino acids. Calcium channel blockers would theoretically reduce the toxic effect of such amino acids by preventing the great influx of calcium intracellularly. However, calcium channel blockers can also have deleterious effects such that lead to vasodilation as peripheral vasodilations and other effects on blood flow. Nitric oxide also causes vasodilation, but at a capillary level it is produced as a consequence of the stimulation of NMDA receptors; nitrous oxide, a precursor, can diffuse out of the injured cell, and exert a toxic effect on surrounding neurons ( 8,9). Verma and colleagues ( 10) have suggested that carbon dioxide can act similarly to nitric oxide and induces a neurotoxic chain reaction. In demonstrating the presence of nitric oxide synthase in the bovine eye, Geyer and colleagues ( 11) have contributed evidence that these neurotoxic events do probably occur at the level of the retina. In addition, free- radical scavengers have been demonstrated to protect the retina following ischemic injury ( 12,13). Such molecules may work by binding oxygen radicals induced by the increased intracellular calcium mediated by the NMDA receptors. Nayak and colleagues ( 14) were able to protect rabbit retinas from transient ischemia as measured by the electroretinogram. Kashii and colleagues ( 15) ( using a model of NMDA receptor mediated retinal toxicity) were able to demonstrate that dopamine protects against glutamate neurotoxicity in cultures of fetal rat retina. Rat retina can be protected from ischemic injury from other means as well. For example, Unoki and La Vail ( 16) showed that a variety of growth factors and neurotrophic agents promote survival of the retina in adult rats in which the intraocular pressure was purposefully raised to induce ischemia. Moreover, it is quite likely that cells that derive from the immune system are capable also of producing survival- promoting agents, such as neurotrophic and growth factors, that block the neurotoxic cycles described above ( 16). As these complex cycles of ischemia ( or other injury), i. e., cellular damage, release of neurotoxins, stimulation of NMDA receptors, and further cellular damage become better understood, the pathogenesis of a wide variety of diseases that im- / Ncuro- Ophthalmol, Vol. 14, No. ,3, 1994 ANNUAL REVIEW: THE ANTERIOR VISUAL PATHWAYS 143 pact the retina and the optic nerve will also become better understood. It may well be that disparate diseases share some elements of pathophysiology as well as the potential to be managed with similar pharmaceutical agents, the effect of which is to break the cycle of cytotoxic damage. While the major emphasis recently has been on the cytotoxic cycle, some other topic specific enigma have also been revisited. Blindness following transurethral resection of the prostrate has been described on many occasions. Blindness is usually bilateral and pupillary reflexes have more often than not been present, leading to the speculation that the underlying problem lies in the cortex ( 17). However, more cases with nonreactive pupils and asymmetrical visual loss have been described. In these instances, blindness has been ascribed to ischemia of the optic nerves, possibly secondary to electrolytic and metabolic disturbances caused by the intravesicular irrigating fluid used during surgery. Barletta and colleagues ( 17) describe a patient who temporarily had no light perception bilaterally, with sluggish pupils, and proposed that the cause of this visual dysfunction was the neurotoxic effect of glycine on the retina. It is likely that neuroexcitatory mechanisms play a role in both cases. A case of neuroretinitis due to syphilis was seen in a patient with the human immunodeficiency virus ( HIV). Interestingly this patient had a negative serology for syphilis ( 18), but was HIV positive on ELISA and Western blot testing. A presumptive diagnosis of syphilis was made and the patient was treated with penicillin with dramatic improvement in vision and in fundus findings. On the basis of this clinical response and the fact that he was HIV positive, it was concluded that he had seronegative syphilis with syphilitic neuroretinitis ( 18). This is a classic example of how patients with AIDS can fool the unwary physician by producing negative serologies. Leber's congenital amaurosis is a disease that often fools the clinician, since there are often only minimal retinal or optic nerve head changes in the early course of the disease. Indeed, these patients may even have a normal ERG. A retrospective review over a 15- year period of 54 patients with this diagnosis showed that it was routine to have a normal initial examination, followed by the development of retinal and optic disc changes but without further visual loss ( 19). Two patients have been described who had severe periphlebitis and retinal ischemia, the underlying etiology of which was felt to multiple sclerosis ( 20). An intensive workup failed to find any other cause of uveitis; however, as we well know such negative workup is not uncommon in uveitis and multiple sclerosis is not such a rare disease. However, the report of a severe retinitis in a 6- year- old with cat scratch disease did seem to be a related ( 21). A 2- year- old child was described as having unilateral visual loss due to neuro- retinitis associated with chicken pox ( 22). There was some question as to whether this was acute retinal necrosis ( 22). Gass and colleagues ( 23) invoking the " worm" hypothesis described the use of oral thiabendazole in four patients with diffuse unilateral subacute neuro- retinitis; all four did well. While the medication probably accelerated resolution of the visual symptoms, we know that most cases of neuro- retinitis have good long- term prognosis even untreated. Toxoplasmosis was found to be a fairly common cause of neuro- retinitis in a retrospective review ( 24). While only two patients had chorioretinal scars typical for toxoplasmosis, all were proven to have had recent serological changes with toxoplasmosis ( 24). Two patients developed visual loss associated with the use of a monoclonal antibody to prevent rejection. An electroretinogram on one of these patients led to the hypothesis that the monoclonal antibody therapy had produced direct retinal toxicity, and perhaps an optic neuropathy as well ( 25), similar to that seen with cancer- associated retinopathy ( CAR). CAR may accompany certain forms of cancer, and involves antibodies against photoreceptor protein ( 28). This 23kD protein antigen was characterized and found to have an amino acid sequence similar to bovine recoverin ( 26). A case of cancer- associated retinopathy was described in a 68- year- old man with a 35- year history of smoking ( 27). He had a rapid, unilateral loss of vision and was eventually found to have serum antibodies that reacted with retina. Corticosteroids successfully halted his visual loss and normalized his antibody titers ( 27). Ten patients were described with CAR probably related to small cell carcinoma of the lungs ( 28). All ten patients had a common antibody specific for small cell carcinoma of the lung ( 28). A 68- year- old man complained of intermittent blotchy visual loss in one eye ( 29). Although his erythrocyte sedimentation rate was only 35mm/ hour, a temporal artery biopsy was positive for giant cell arteritis. Remarkably, a fluorescein angiogram demonstrated choroidal nonperfusion, which improved after corticosteroid therapy ( 29). Subsequent report has corroborated this finding. This heuristic cases raises our level of suspicion for temporal arteritis even in patients with low eryth- / Neuro- Ophthalmol. Vol. 14, No. 3, 1994 144 A. A. SADUN AND]. DAO rocyte sedimentation rates. This report points out that ischemia can occur in a number of ocular and orbital tissues, including the choroid. In another study, patients who had sustained traumatic chorioretinal rupture with and without optic atrophy were compared ( 30). There was no correlation between the size or location of the rupture and the type or severity of the trauma; however, not surprisingly the patients with optic atrophy had larger afferent pupillary defects and worse vision ( 30). Optic Disc A recent review by Burde ( 31) addressed how certain anatomic characteristics of the optic nerve head might put it at risk for metabolic, vascular and mechanical injury. He described a " disc at risk," which was characterized by the absence of a small physiological cup, elevation of the disc margins by a thick nerve fiber layer, anomalies of blood vessel branching and, in general, the appearance of a crowded and small optic nerve head ( 31). In his analysis, Burde pointed out several features singular to the optic nerve head that may predispose it to certain types of injuries. For example, the mechanical constraints of the optic disc itself are such that relative ischemia may occur under ordinary circumstances producing axoplasmic swelling within the restricted space of the small canal leading to increasing compression of small blood vessels and further ischemia that in turn causes further axoplasmic swelling. This vicious circle, if unbroken, might be the pathophysiological basis for anterior ischemic optic neuropathy ( AION). Similarly patients who develop the papil-lopathy associated with insulin- dependent juvenile diabetes mellitus have the same optic disc anatomy. Burde suggests that this papillopathy is a forme fruste of AION. He notes that often there is engorgement of the peripapillary capillary net in response to the chronic ischemia of diabetes which might be able to shunt oxygen and prevent an overt attack in the diabetic patient's " disc at risk" ( 31). Leber's hereditary optic neuropathy ( LHON) represents another metabolic disease in which the " disc at risk" is present. In this case an error in metabolism produced by mutations of mitochondrial DNA leads to a reduction in oxidative phosphorylation efficiency. It is intriguing that what should be a generalized impairment of energy production targets the optic disc ( at risk) in particular. However, the situation is probably not dissimilar from that described by Sadun and colleagues ( 32) in Cuban epidemic optic neuropathy ( 32,33). In Cuba, a combination of nutritional deficiencies, probably compounded by chronic exposure to toxins such as methanol ( found to contaminate the ubiquitous homemade rum in Cuba), might well have set the stage for an epidemic of optic neuropathy seen in association with peripheral neuropathy ( 34,35). In particular, folic acid deficiency in combination with formate accumulation ( from methanol metabolism) would severely reduce oxidative phosphorylation efficiency ( like Leber's) ( 34). Moreover, Sadun and colleagues ( 34) described fundus findings that included loss of the papillomacular bundle and swelling of the nerve fiber layer adjacent to the papillomacular bundle. In the peripapillary swollen nerve fiber layer, tiny dilated and telangiectatic blood vessels were noted, further mimicking the fundus appearance of LHON ( 34). However, patients suffering from the Cuban epidemic were otherwise clinically distinct from LHON and, of course, did not show the same DNA mutations ( 36). The question therefore remains as to why patients with Cuban epidemic optic neuropathy or Lebers' hereditary optic neuropathy should show damage at the level of the optic disc, and most particularly injury predominantly in the papillomacular bundle. Intriguingly, similar pathophysiological changes are noted also in a variety of clinical conditions and experimental models involving several toxins. For example, the optic disc appears to be an area of particular susceptibility for acute methanol neurotoxicity. Burde ( 31) suggests that this may be because this region is served by end arterioles of the posterior ciliary circulation, and hence has a limited tolerance for periods of ischemia or respiratory insufficiency. Other peculiarities of the vasculature of the optic nerve head also might predispose it to a variety of vasculidities. For example, why is benign papillophlebitis so frequently found overlying the optic nerve head ( 37)? I share with a few other neuro- ophthalmologists the feeling that one feature of the disc that may put it at risk is that the retinal ganglion cell axons are forced to make a very sharp turn as they penetrate the lamina cri-bosa at the optic nerve head. Axoplasmic transport is a very energy dependent process, and it may well be that enormous energy demands are placed on the axoplasmic transport system in order to overcome the mechanical features of this sharp turn. If there is a basic defect in Redox potential, relative energy deficiency will produce axoplasmic swelling, compressing small vessels and initiating the aforementioned self- destructive cycle. In regards to LHON, a great deal of progress in / Nfunt- Ophthalmol, Vol. 14. No. 1, 1994 ANNUAL REVIEW: THE ANTERIOR VISUAL PATHWAYS 145 the genetics of the disease has been made recently. However, this is likely to be the subject of another review in these same pages. One item of general interest regarding LHON is that now that DNA testing is available, a number of patients who are diagnosed to have other optic neuropathies have turned out to have actually had LHON. For example, a case is described in which ischemic optic neuropathy was originally diagnosed in each of the two eyes of a 63- year- old patient; upon subsequent mitochondrial DNA studies, the patient was found to have a 11778 point mutation ( 38). More often, however, LHON is mistakenly diagnosed as a metabolic or toxic optic neuropathy. It is notable that patients previously thought to have tobacco-alcohol amblyopia have often turned out to have a primary mutation for LHON. Two of 12 patients previously diagnosed to have tobacco- alcohol amblyopia were subsequently tested and found to have the 11778 and 3460 mutations, respectively ( 39). The authors point out that, given the similar clinical characteristics of the two diseases and the possibly related pathogenesis, the diagnoses might well be confused and it is appropriate to obtain molecular genetic testing on all patients thought to have tobacco- alcohol amblyopia. However, of equal interest is that LHON associated DNA mutations may render patients more susceptible to epigenetic factors such as tobacco and alcohol. Perhaps we can add Cuban rum and Cuban dietary deficiencies to these epigenetic factors. Similar evidence that epigenetic factors may trigger an optic neuropathy in which the underlying disease is LHON comes from a case report of a nine- year- old girl in whom juvenile onset diabetes had been recently diagnosed ( 40). Over a four month period she experienced a fairly rapid loss of vision in both eyes which was clearly due to an optic neuropathy. Because there was a positive family history for LHON, blood samples were tested and found to be positive for the mitochondrial DNA marker. Of further interest is the fact that once her hypoglycemia was stabilized, she had a fairly significant improvement in vision, and the authors concluded that her diabetes was the metabolic trigger for a premature decompensation of her LHON ( 40). Similarly, there is a report of five patients ( ages 9 to 45 years) with the 11778 mutation of LHON who suffered a loss of vision and then, over a period of months to years, had significant visual recovery ( 41). These five patients represent only 3.7% of the 136 patients with the LHON mutation who were being reviewed, so this is the exception for visual recovery and not the rule. Nonetheless, it does provide some hope for patients with LHON ( 41). Of course, it should be kept in mind that a patient with LHON may have homoplasmy ( all of their mitochondria carry the genetic defect) or heteroplasmy ( in which there is a mixture of mutated and non- mutated mitochondria). In the evaluation of a large series of families with the 11778 mutation, it was determined that 14% were heteroplasmic for the defect ( 42). It is interesting that heteroplasmic individuals do not differ in the clinical severity of their disease from homoplasmic patients. Apparently whether one has mitochondrial induced decompensation is an " all- or- none" phenomenon. In the same journal issue, these authors also describe identical twin brothers with the genetic makeup to develop LHON who, of course, harbored the identical homoplasmic DNA mutation. Nonetheless, one twin had visual losses down to the 1/ 200 level in both eyes while the other's vision remained 20/ 15 in both eyes ( 43). This description of two genetically identical individuals with extremely different symptomatology further emphasizes the importance of epigenetic factors and the " all- or- none" nature of LHON. Also in the same issue, two of the authors described a maculopathy seen with the 15257 DNA mutation previously associated only with LHON ( 44). The maculopathy appeared very much like Stargardt's disease. Is it surprising that other tissues are also very susceptible to mitochondrial insufficiency? Is it possible that this is a nonspecific ocular tissue response that is specific to the 15257 mutation? In spite of our insights into the genetics of LHON and the metabolic perturbations possible, more is being learned about the association, or lack thereof, with classical epigenetic factors. Rizzo and Lessell ( 45) have revisited the issue of tobacco amblyopia. They made the diagnosis in two patients in whom there was no other risk factor ( such as alcoholism or vitamin deficiency) ( 45). They concluded that if used in sufficient quantity and type ( such as 15 large cigars daily or 5 ounces of pipe tobacco per week), tobacco alone can lead to a largely reversible papillomacular bundle injury. I have also noted that a very large percentage of my patients with tobacco- alcohol amblyopia smoked cigars or pipes. It pays to remember that cigarette smoking is a rare cause of so- called tobacco amblyopia. The concept of a disc at risk applies to other congenital optic neuropathies as well. Twenty- five patients from three pedigrees with dominant optic atrophy ( Kjer's disease) were described ( 46). As opposed to Leber's, these patients did much better in that the progression of vision began slowly and / Neuro- Ophlhalnwl. Vol. 14, No. 3. 1994 U6 A. A. SADUN AND }. DAO then stabilized and that visual acuities averaged in the 20/ 60 to 20/ 80 range ( 46). Optic nerve sheath decompressions for disc edema entered a new era with the publications of Brourman and colleagues ( 47), Sergott and colleagues ( 48), and Corbett and colleagues ( 49). In the same issue of Archives of Ophthalmology all three groups described their success in treating the papilledema of pseudotumor cerebri by optic nerve sheath decompression. Also in this issue, Keltner ( 50) explored the mechanisms by which this operation works and recommended it in cases of pseudotumor cerebri for which medical therapy had failed. The mechanisms by which optic nerve sheath decompression might work for other diseases, however, were contested far more hotly after Sergott and colleagues suggested that optic nerve sheath decompression would also improve the visual course in the progressive cascade form of AION ( 51). They described visual improvement in 12 of 14 eyes with the progressive form, but did not advocate surgery for the nonprogressive form of AION. Spoor and colleagues ( 52) confirmed the success of optic nerve sheath decompression for progressive AION and at about the same time Kel-man and Elman ( 53) suggested that the operation had merit for even nonprogressive forms of AION. The prevailing theory as expounded by the advocates of this surgery is that reducing the subarachnoid fluid pressure might gently nudge the delicate balance of forces in such a way as to improve local vascular perfusion and relieve the impaired axoplasmic transport ( 48). However, as Hayreh has pointed out, axoplasmic stasis is not per se a cause of visual loss ( 54). Moreover, the ischemic injury of AION occurs at the level of the lamina cribrosa, where the optic nerve head receives its blood supply from the peripapillary choroid, yet the surgery is performed several millimeters posterior to this, and not in any area related to the vascular supply of the peripapillary choroid ( 55). In his review of optic nerve sheath decompression for anterior ischemic optic neuropathy as well as other optic neuropathies, Sadun evaluated several possible mechanisms by which the fenestration might work and discussed the strengths and weaknesses of several of the articles that contended that the operation was useful ( 55). A letter by Drs. McHenry and Spoor ( 56) added their experience with over 400 optic nerve sheath decompressions that they performed for anterior ischemic optic neuropathy. They contended that the procedure is most likely to work in those optic nerves in which high CSF pressure produced a subarachnoid dilatation. Sadun ( 57) replied that there still was no adequate scientific rationale for how a change in the pressure dynamics 5 mm behind the lamina cribrosa could affect blood flow at the level of the lamina. In corroboration of the concept that optic nerve sheath decompression ( ONSD) could improve blood flow in AION, 25 patients were studied with color Doppler imaging before and after optic nerve sheath decompression ( 58). Using this methodology the authors were able to demonstrate significantly lower blood flow velocities in the central retinal artery before surgery, and a significant increase in blood flow velocities in both the ophthalmic and central retinal arteries after surgery ( 58). Although they suggested that their study demonstrated that optic nerve sheath decompression improved blood flow to an ischemic optic nerve, it should be kept in mind that blood flow velocity is not the same thing as blood flow ( and indeed there are circumstances in which velocity may go up as resistance increases and there is thus a decrease in blood flow). The same authors found that in the 13 eyes with AION that had improved vision after optic nerve sheath decompression, there was also a concomitant improvement in blood flow velocity in the short posterior ciliary arteries; but in those eyes in which vision did not improve, color Doppler failed to reveal increases in blood flow velocity, lending further support to color Doppler as a means of monitoring blood flow dynamics ( 58). Hayreh and Beach ( 59) discussed this paper in open forum and suggested that some of the assumptions made about color Doppler imaging may have been incorrect and some of the theoretical explanations for how optic nerve sheath decompression could improve blood flow dynamics were scientifically unfounded. Color Doppler studies were performed on 24 eyes in patients in whom there was visual loss due to pseudotumor cerebri ( 60). Improvements in blood flow parameters post decompression were documented ( 60). Several articles have questioned the use of optic nerve sheath decompression for AION for several reasons. Hayreh ( 54) feels that the pressure dynamics described by Sergott and colleagues ( 51) are in error. Others have contended that in the natural course of nonarteritic ischemic optic neuropathy, the percentage of patients who improve is not significantly different from that of patients who have undergone optic nerve sheath decompression ( 61). Others have noted that optic nerve sheath decompression may not be as complication- free as initially reported ( 62). Nonetheless, Sergott and his colleagues have ; Nt'uro- Ophthalmol. Vol. 14, N » . .3, 1994 ANNUAL REVIEW: THE ANTERIOR VISUAL PATHWAYS 147 maintained that optic nerve sheath decompression might improve blood flow dynamics in ischemic disease, that the operation does have great promise, and that the complication rate is fairly low ( 63,64). More recently, several articles have questioned the contention that optic nerve sheath decompression improves visual function in patients with AION, and have suggested that the rate of improvement attributed to the surgery is no greater than that seen spontaneously ( 65- 68). In response to articles describing spontaneous improvements in progressive and nonprogressive AION has come a plea from a surgeon who feels that patients should receive the benefit of the doubt and be offered optic nerve sheath decompression, and that the spontaneous recoveries might have had an even better outcome had the surgery been performed ( 69,70). This is unlikely, however, since patients treated with optic nerve sheath decompression may show improvements in visual acuity and in visual field ( 69,70). Vascular/ mechanical factors are at the heart of the controversy regarding the pathophysiology of nonar-teritic AION. Sadun ( 55), in reviewing the efficacy of optic nerve sheath decompression for AION, discussed the proposal that in at least some cases of AION, a rise in optic disc perineural pressure was involved in a vicious circle of impaired perfusion led to blocked axonal transport leading to increased pressure at the level of the lamina cribrosa. It was theorized that optic nerve sheath decompression might tip this delicate balance of forces and pressures in a favorable direction ( 55,63). This controversy regarding the efficacy of optic nerve sheath decompression for AION was further fueled by the publications of Sergott et al ( 64), McHenry and Spoor ( 65), Jablons et al ( 66), and Movasas et al ( 61). In an effort to resolve many of these questions, the NIH has funded a multi- center randomized clinical trial entitled the Ischemic Optic Neuropathy Decompression Trial to be conducted in 26 US clinical sites. It is hoped that this trial will at least answer the question as to whether patients who undergo optic nerve sheath decompression have a greater likelihood of visual recovery than do patients whose disease is allowed to follow its natural course ( 71). Additionally, the trial should reveal the complication rates. The trial will probably not discern differences between patients with and without the progressive form of AION. However, even if this trial demonstrates efficacy for ONSD in AION, the absence of a strong scientific rationale will leave many of us feeling disconcerted ( 72- 74). A new method of performing optic nerve sheath decompression from the lateral side, without going through bone, was presented ( 75). Surgery is performed through a large lateral canthotomy incision and the optic nerve is approached on the lateral side ( 75). Additionally, several modifications of optic nerve sheath decompression have been suggested, including the use of adjunctive mitomycin and even implantation of a Molteno tube in the subarachnoid space ( 76). For patients in whom optic nerve sheath decompression has failed to relieve the disc edema associated with pseudotumor cerebri, two orbital surgeons have suggested that a secondary optic nerve sheath decompression be performed on the other side ( 77). Since the usual first procedure is a transconjunctival medial approach these authors suggest following with a lateral approach, with or without removal of orbital bone, in those cases in which disc edema persists ( 77). Given the controversy surrounding optic nerve sheath decompression per se, it is not surprising that several letters have been exchanged regarding the use of optic nerve sheath decompression for patients with pseudotumor cerebri who show progressive visual loss even in the presence of functioning lumboperitoneal shunts. Wall advises that lumboperitoneal shunts may function on an intermittent basis, and might, with revision, prevent further visual deterioration ( 78). In pseudotumor cerebri syndrome, the cause may be obstruction of the dural sinuses. Four cases have been described in which optic nerve sheath decompression led to resolution of disc edema and improvement in vision in patients with dural sinus occlusion ( 79). Despite the prompt resolution of disc edema and visual field defects, it is very interesting to note that three of these four patients continued to have elevated cerebrospinal fluid pressure, suggesting that optic nerve sheath decompression has more of a local and less of a global effect. Optic nerve sheath decompression has also been suggested as a treatment in visual loss associated with other diseases. For example, Garrity and colleagues ( 80) suggest the use of this operation to treat the papilledema that can occur following CNS infection with cryptococcus. In addition to describing an initially favorable post operative clinical course, they published the autopsy findings on one patient who had had optic nerve sheath surgery; this showed optic nerve sheath fenestrations that were still patent ( 80). Further evidence of the patency of fenestrations following optic nerve sheath decompression was offered by Hamed and colleagues ( 81) who used neuroimaging of the optic nerve in two patients who had undergone optic ; Neuro- Ophthalmol. Vol. 14, No. 3, 1994 148 A. A. SADUN AND }. DAO nerve sheath decompression for pseudotumor cerebri. Both ultrasound and gadolinium MRI suggested that each had a cyst- like structure on the outside of the fenestration site that was contiguous with the subarachnoid space, suggestive of a glaucoma type filtering bleb ( 81). Optic nerve sheath decompression has also been suggested as a treatment for low tension glaucoma ( 82). Seven eyes of six patients with low tension glaucoma underwent optic nerve sheath decompression; two eyes showed some initial improvement but later deteriorated ( 82). This, along with the fact that the other eyes showed no improvement, raises the question as to the efficacy of the treatment for this ambiguous disease. Nonarteritic anterior ischemic optic neuropathy received attention outside of the arena of optic nerve sheath decompression as well. Katz and Spencer ( 83) revisited the notion that crowding of the optic nerve head is a precondition for AION, and found a small statistical correlation with hyperopia as a risk factor ( 83). It remains unclear whether hyperopia predisposes for the development of AION, or whether myopia is protective of the development of AION. The mechanism of ischemia in acute nonarteritic AION was explored again by fluorescein angiography ( 84). While a delay in optic disc perfusion was noted, there was no delay in peripapillary choroidal filling ( 84). Rader and colleagues noted focal constriction of retinal arteries near the optic disc in both AION and a variety of glaucomas ( 85). Control eyes had only a 57B risk of such constriction; patients with glaucoma had a 42% risk of such constriction, and patients with nonarteritic AION had a 687c likelihood of such constriction ( 85). A population- based study comparing the incidence of AION, arteritic and nonarteritic, in the state of Missouri and Los Angeles County, California was reported ( 86). While the incidence of AION appears to be slightly higher in Los Angeles County, the overall differences were not that great. For patients 50 or older, the annual incidence rate of arteritic anterior ischemic optic neuropathy was 0.35 per hundred thousand people and for nonarteritic AION it was 2.30 ( 86). Arteritic cases were three times more likely to occur in women than in men whereas nonarteritic cases had no sexual predilection. There was an increased incidence of nonarteritic AION among whites which is particularly interesting given that blacks had a higher incidence of strokes ( 86). While in the last couple of years the subject of nonarteritic AION has been approached from a " disc at risk" point of view which takes into account mechanical as well as vascular factors ( 20,24), progress has been made also using the old fashioned concept that AION is, in some cases a form of stroke of the optic nerve. Connolly and colleagues ( 87) showed that in three patients in whom hypotension had probably caused AION, an immediate and controlled rise in blood pressure brought considerable recovery of vision ( 87). This work is of considerable interest since it: 1) emphasizes the danger of iatrogenic hypotension; 2) provides a model for treating patients in whom hypotension has induced AION; and 3) reminds us that Hayreh ( 54,59) had previously proposed that nocturnal hypotension may be a frequent cause of AION. Slavin and Barondes ( 88) have pointed out that giant cell arteritic AION may first present with choroidal ischemia. In these cases, the first visual symptoms may not be accompanied by ischemic disc swelling. Fluorescein angiography demonstrated choroidal infarcts ( 88). A 47- year- old man experienced acute loss of vision due to giant cell arteritis. As before fluorescein angiography demonstrated choroidal nonperfusion ( 89), this patient had pallid swelling and blockage of a branch retinal arteriole. The patient was treated with high dose IV methylprednisolone therapy which may have been of benefit, as visual acuity went from light perception to 20/ 30 over a two month period ( 89). A retrospective five year review of the visual outcome in patients with giant cell arteritis seen at the Mayo Clinic revealed 245 patients of which only 14 had permanent visual loss. Two patients suffered permanent visual loss following initiation of corticosteroid therapy ( 90). Also of interest was the fact that only five patients ( 27c) showed significant improvement in vision following corticosteroid therapy. In another report, four patients were described in whom giant cell arteritis produced an ocular ischemic syndrome ( 91). In addition to the usual optic disc and retinal changes, these patients had hypotony, uveitis, and corneal edema ( 91). Visual recovery following devastating ischemia of the optic disc has been described in two different settings. The first was that of giant cell arteritis, which affected two patients and brought their vision down to no light perception following central retinal artery occlusions ( CRAO) ( 92). Each received high doses of intravenous corticosteroids and, within a day each demonstrated a remarkable recovery of vision that returned essentially to baseline ( 92). Hence, " megadose IV corticosteroid therapy" may be useful in a variety of optic neuropathies ( 93,94). These two cases are also of interest as / Ncuw- Oplithalmol. Vol. 14. No. .1, 1994 ANNUAL REVIEW: THE ANTERIOR VISUAL PATHWAYS 149 a challenge to the dictum that the retina can survive only ninety minutes following a central retinal artery occlusion. Visual recovery was also attained following mi-crocatheter infusion of urokinase into the ophthalmic artery in patients with nonarteritic central retinal artery occlusion ( 95). However, as described in a series of 14 consecutive CRAO, patients did not have giant cells arteritis ( 94). Eleven of 14 patients were treated with urokinase; the other three patients received tissue plasminogen activator. Significant improvement was noted in four of these patients and modest improvements in visual acuity in another five; hence 9 of 14 were significantly better than the outcomes of a control group of forty- one patients with CRAO in whom no intervention was attempted. Central retinal artery occlusions do not usually carry a good prognosis. Such a case was presented of CRAO following varicella infection in a child ( 96). It is likely that the varicella led to a vasculitis. Ischemia of the optic disc and surrounding tissues may also be indirectly inferred by color Doppler imaging. This new technique was used to study 21 patients with high grade carotid stenosis who had ocular ischemic syndrome ( 97). Reduced central retinal artery peak systolic blood flow velocity, as well as reversal of the ophthalmic artery flow was found in 12 eyes. Reversal of flow was found to correlate with visual acuity ( 97). Two interesting anomalies of peripapillary vessels were recently described. The veins of Kraupa are an anomaly found at the optic disc in which a single venous trunk branches at the margin of the disc instead of in the middle of the optic disc ( 98). Two cases are described in which fluorescein angiograms clearly delineate these abnormal retinal veins that exit the eye at or near the optic disc margin ( 98). Another peripapillary vascular anomaly is that of " Nettleship collaterals," which is a ring of anastomotic channels that is thought to develop due to chronic prelaminar obstruction of the central retinal artery ( 99). In a study of ocular pneumotonometry, it was shown that large pulse amplitude correlated with the presence of spontaneous retinal venous pulsations ( 100). Furthermore, the presence of veins looping over the edge of the neural rim into a deep optic cup ( termed configuration A) was highly correlated with the presence of retinal venous pulsation, whereas a shallow or nonexistent cup was rarely seen in patients with spontaneous venous pulsation ( 100). It remains to be seen whether this relates to the concept of " disc at risk" ( 20). Nine young adults about 20 years of age had transient obscurations of vision in one eye that were indistinguishable from the amaurosis fugax usually associated with carotid or cardiac disease in older patients ( 101). Thorough evaluations failed to reveal any abnormalities of embolic or atheromatous etiology. The authors concluded that this condition was distinct from that seen in older patients, was probably benign and possibly due to migrainous or other vasospasm related impairments of the choroidal circulation ( 101). A case was presented of a 58- year- old man with abrupt unilateral loss of vision in whom a retractile body was seen in a retinal arteriole. This provided a launching point for discussing the results of the North American Symptomatic Carotid Endarterec-tomy Trial ( 102). Papillitis and papilledema are not the only causes of a large blindspot. Acute idiopathic blind-spot enlargement has been described in which the optic nerve head may appear entirely normal, but there is an associated multiple evanescent white dot syndrome ( MEWDS). Although cases of acute idiopathic blindspot syndrome usually resolve over a period of one to three years, a recent case was described in which enlarged blindspots persisted for over six years due to bilateral acute idiopathic blindspot enlargement ( 103). The presence of peripapillary atrophy suggested to the authors that the etiology of this rare syndrome may be related to chronic RPE damage ( 103). Seven patients with acute idiopathic blindspot enlargement syndrome were described as having multifocal choroiditis and choroidal neovascularization ( 104). We are reminded that the multiple evanescent white dot syndrome ( MEWDS) probably reflects a spectrum of multifocal choroiditis that may or may not involve the peripapillary area. Papillophlebitis is one of several causes of an enlarged blindspot, sometimes with loss of central vision that are generally benign conditions. A case of a pregnant woman in whom papillophlebitis led to an arteriolar occlusion was described ( 105). This patient did not have eclampsia; however, because of her eye findings she underwent Cesarean section and then a three- day course of high dose corticosteroid therapy that led to complete resolution of findings and a return of vision to 20/ 20 ( 105). It is hard to say whether this good outcome was a consequence of the termination of the pregnancy, the corticosteroids, or just good luck. Another patient was described in whom a slow growing presumed pigmented mass was believed to be a melanocytoma. Finally the patient had visual loss and enucleation ( 106). Histopathologic examination demonstrated the presence of a primary malignant melanoma ( 106). ; Neuro- Ophthalmol. Vol. U, No. 3, 2994 150 A. A. SADUN AND /. DAO Anomalies of the optic disc may sometimes be the sentinel of more generalized disease. Optic nerve head medullation ( myelinated nerve fiber layer in the peripapillary region) has been described in a mother and daughter in whom there were also musculoskeletal abnormalities ( one finger per hand and lobster- claw feet), and in a pedigree of a retinitis pigmentosa- like syndrome associated with severe degeneration of the vitreous ( 107). Because only two members of this family were identified, it was impossible to establish the mode of inheritance. A variety of disc abnormalities were described in children with cerebral malaria ( 108). The most common finding was disc edema, but in addition hemorrhages and macular edema were described. Patients with disc edema had a grim prognosis either dying or developing serious neurologic consequences ( 108). Two patients are described who had optic drusen accompanied by abrupt loss of visual field ( 109). The youth of these patients ( 18 and 29) and the optic disc features at the time of visual loss made the diagnosis of AION untenable. This paper reminds us that the two dictas relating to optic disc drusen are not absolute. These dicta are: 1) that the visual field loss is very slow and progressive; and 2) that central acuity is always maintained. In the discussion following this paper, Miller ( 110) describes sudden visual field loss in a patient with optic disc drusen in whom no other clear- cut diagnosis was found. A review of 16 patients with drusen seen in 26 eyes revealed that abnormalities of the pattern visual evoked response could be demonstrated even in patients without significant visual field loss ( 111). However, given that there is no treatment for the visual dysfunction associated with optic disc drusen, the development of a sensitive early screening test is more of academic than clinical interest. Fifteen- year- old male identical twins and an older sister were noted to have a superior segmented optic disc hypoplasia with associated inferior visual field defects ( 112). It is of note that their mother has insulin- dependent diabetes mellitus, a metabolic abnormality when present during pregnancy that has been shown to be associated with segmental optic nerve hypoplasia in their offspring ( 113). This and other neuro- ophthalmic complications of diabetes mellitus were summarized very nicely in a review by Burde ( 113). Forty children with unilateral or bilateral optic nerve hypoplasia were retrospectively studied ( 114). The majority of these patients had an absent septum pellucidum. On the basis of the associated neuroradiological abnormalities, the authors construct a categorizational system for the neurological signs associated with optic nerve hypoplasia. Optic nerve aplasia probably represents a rare extreme of the spectrum of optic nerve hypoplasia. In a 3- year- old girl with microphthalmos the visual evoked response showed a much stronger signal from the ipsilateral cerebral cortex, which the authors suggest represents an anomalous connection of temporal retinal fibers from the normal eye ( 115). However, insofar as there are numerous reciprocal excitatory and inhibitory connections between the primary visual nuclei and the visual cortex, this physiological anomaly may reflect a dis-inhibition phenomenon instead. Two patients are described with morning glory syndrome and pituitary dwarfism ( 116) accompanied by a discussion of the occasional association with midline craniofacial and neurological disorders. Dailey and colleagues described an optic disc anomaly that resembled morning glory syndrome but was without disc glial tissue and had a peripapillary choroidal neovascular membrane ( 117). The diagnosis of Beauvieux's syndrome is based upon the dirty grayish appearance of the optic disc on ophthalmological examination of very young infants who have bilateral amaurosis and absent pupillary reflexes. Fifteen patients are described who presented with poor vision at birth and in whom the optic nerve heads had this grayish appearance ( 118). Fortunately, vision improves and the disks " normalize." Visual acuity improved in these cases to the 20/ 40 to the 20/ 200 range. This condition is thought to be due to delayed optic nerve myelination. In one patient, MRI scanning revealed other areas of the brain which had not myelinated well, and three patients had albinism. The growth, development and sizes of optic disks were studied at autopsy in 95 patients ranging from five months gestation to 22 years of age ( 119). It was found that 50% of the growth of the optic disc occurred by 20 weeks of gestation, 75% by birth and 95% by age one year. An important study correlated the optic area with measures of the retinal surface area and counts of retinal rods and retinal cones ( 120). There was a remarkable range in the number of receptor cells found, from 40 to 80 million rods. A linear relationship between optic disc area and the numbers of rods and cones was noted. Other investigations morphometrically analyzed the optic disc and related its area to optic nerve fiber counts ( 121). These investigators examined 72 optic nerves and, with the assistance of computerized image analysis, found a very strong correla- / Neuro- Ophthalmol, Vol. 14, No. 3, 3994 ANNUAL REVIEW: THE ANTERIOR VISUAL PATHWAYS 151 tion between nerve fiber count and optic disc area. Perhaps of equal importance is the fact that they found that in smaller disks there was a selective decrease in the number of smaller fibers ( 121). Patients with optic disc pits and serous macular detachments were treated with gas tamponade ( 122). While vitreo- retinal surgery helped preserve visual acuity, anatomically, the gas tamponade did not close the inner retinal layer separation or preclude the flow of fluid from the optic disc pit. In addition to the esoteric, were publications of the common. We were reminded that the most common form of disc anomaly is disc edema due to increased intracranial pressure ( papilledema). A case of papilledema in a 16- year- old obese girl with pseudotumor cerebri was described whose visual loss was abrupt ( 123). The authors ascribed this sudden loss to a retinal arteriole occlusion caused by compression in a crowded edematous optic disc ( 123). Disc edema due to increased intracranial pressure with normal cerebrospinal fluid constru-ents and a normal MRI is a good definition of pseudotumor cerebri syndrome, yet in some cases the definitive diagnosis may reveal itself later. 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