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Show Journal of Neuro- Ophthalmology 16( 2): 137- 151, 1996. © 1996 Lippincott- Raven Publishers, Philadelphia Annual ( Almost) Review The Anterior Visual Pathways Alfredo A. Sadun, M. D., Ph. D., and Richard This second annual review of the anterior visual pathways follows, by about 2 years, the first review, which covered the years 1992- 1993. This present material will cover the subsequent 2 years ( 1994- 1995), and there will be no hiatus. In general, the last 2 years have been, in the area of afferent visual system neuro- ophthalmology, a period of consolidation. The two important clinical trials, the Optic Neuritis Treatment Trial and the Ischemic Optic Neuropathy Decompression Trial, started during the first review and, having already provided interesting results, continue to yield important information. Furthermore, this is still the decade of the brain, and neuroscientists have made great leaps forward that must be appreciated by the neuro- ophthalmic clinician both for a better understanding of pathological processes necessary in the diagnosis and characterization of diseases and also for a better handle on management options. Indeed, never before have neuro- ophthal-mologists been offered such an array of treatment modalities. The present material is divided into an introductory section of testing functions of the anterior visual pathways, followed by some of the most exciting and relevant basic science. The material then delves into the most important, interesting, and relevant clinical articles recently published on the afferent visual pathways, beginning with the inner retina and proceeding, along with the retinal ganglion cell and its axon, through the optic disc, out the eye, along the nerve, and past the optic chi- Manuscript received April 9, 1996; accepted April 14, 1996. 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. M. Rubin, M. D. asm. Along the way, this axon passes a number of interesting and critical structures that, in disease states, may impact on it. First, let us start with what has been preoccupying the minds of so many neuro- ophthalmologists. Neuro- ophthalmologists, like most subspecial-ists, have been viewing with great anxiety the anticipated move from subspecialists, as diagnosticians to a gatekeeper system that uses generalists. Although such a move may be antiacademic and even dangerous for patients, many have argued that the gatekeeper physician system is inevitable because it is cost effective. The Wills Eye Hospital group, however, has shown us, through a retrospective review of about 600 records, that prerefer-ral diagnostic testing for the most common neuro-ophthalmic problems resulted in about 20% over-testing and about $ 60,000 in excessive costs ( 1). Hence, a gatekeeper system managed by primary care physicians expended more health- care dollars than if prompt referral had been made to the appropriate subspecialty. We hope further studies of this type are undertaken and come to the attention of the bean counters. TESTING THE ANTERIOR VISUAL PATHWAYS Recent advances in the assessment of optic nerve function have been made through the continued incorporation of psychophysical principles into automated perimetry. In particular, short-wavelength automated perimetry ( SWAP) involves modification of the Humphrey field analyzer to isolate the activity of blue- sensitive mechanisms. Much of this work has been on the early detection of glaucoma and the monitoring of ocular hypertensives. Additionally, SWAP has been 137 138 A. A. SADUN AND R. M. RUBIN applied to look at neuro- ophthalmic disorders such as optic neuritis and pseudotumor cerebri ( 2). In evaluating 80 eyes from 40 patients, they found SWAP to be especially sensitive for optic neuritis and in screening patients with multiple sclerosis ( 2). Specificity may be a problem, as there is considerable between- subject variability that requires stringent statistical analysis ( 3). Time- consuming lens- density measurements may be eliminated without compromising the clinical utility of the test ( 4). Similarly, correcting for changes in lens absorption did not change the observation of localized field areas of reduced sensitivity in diabetic retinopathy ( 5). In monkeys, it was shown that opponent and nonopponent systems tested equally across the visual field but did change with stimulation at different wavelengths ( 6). Also quite useful in the quantification of nerve fiber injury in both glaucoma and other neuropathies ( clearly a neuro- ophthalmic viewpoint) are techniques such as optical coherence tomography. In a study of 59 eyes from 33 subjects, this technique compared favorably with Humphrey perimetry and correlated well with stereoscopic optic disc photography and conventional ophthalmoscopy ( 7). The nerve fiber layer in normal subjects and patients with optic neuropathies ( usually glaucoma) can also be reliably measured by scanning laser ophthalmoscopy ( SLO) or, more precisely, polarimetry ( 8). For example, Miglior and colleagues used SLO to assess retinal nerve fiber layer defects in 150 eyes of 80 consecutive patients with ocular hypertension. In observing slit, wedge, and diffuse nerve- fiber layer defects compared with a normal pattern, the authors established excellent intraobserver reproducibility ( 9). Microperimetry using SLO technology is also possible, allowing scotomas to be accurately mapped in macular lesions ( 10). With less technology, red- free photographs can be used to identify wedge- shaped defects in glaucoma or other nerve fiber layer changes associated with long- standing papilledema ( 11,12); however, the interobserver reproducibility is probably much less than with SLO. Reference photographs of the retinal nerve fiber layer assisted in reducing this interobserver reproducibility ( 13). New technologies in assessing optic nerve function also include motion perimetry ( with random dot movement). Wall and Ketoff used such a system in 50 patients ( both normal subjects and patients with primary glaucoma) and were able to distinguish easily between their two groups by means of motion detection threshold. Most importantly, by means of this new test, they found nerve fiber bundle defects in 12 glaucoma patients not previously detected by conventional perimetry ( 14,15). Patients with optic neuritis would not be expected to be particularly sensitive to motion testing, as the former is thought to be primarily a disease of the P- cell pathway and motion a function subserved by the M- cell system; however, motion perception defects were found in eight of 15 eyes from optic neuritis patients even though most had 20/ 20 vision and no relative afferent pupillary defect ( 16). The simultaneous interocular brightness sense test was revisited with rigor in 91 normal patients ( 17). Applying this quick and simple test demonstrated that it follows the Weber- Fechner law and that brightness sense testing is not affected by ocular dominance, age, or light adaptation. In a separate study of 100 patients, the authors found that interocular brightness sense testing detected abnormalities consistent with glaucoma in seven of 12 ocular hypertensive patients and in 20 of 20 open- angle glaucoma patients. They suggested that this test be used in the routine screening of glaucoma ( 18). Cross- polarizing " brightness- sense glasses" can also be used in conjunction with the Amsler grid for more sensitive threshold Amsler grid testing. A modification of this technique involved doubling the width and height of the Amsler grid, quadrupling the area tested ( 19). Although these authors found the test much more sensitive for what they called " light" paracentral scotomas, we feel that subjective testing outside of 12 degrees from fixation is unreliable as a result of the Troxler effect. This effect relates that the visual field beyond the central 12 degrees is not fully available to our consciousness and the brain tends to fill in this peripheral area with perceived pattern. Hence, many scotomas are not appreciated subjectively. It is not always necessary to employ high technology to find new things. In a retrospective review of 116 patients with classic migraine, it was found, by conventional visual field testing, that about 30% had visual field defects, hence blurring the boundary between common/ classic and complicated migraines ( 20). The relative afferent pupillary defect ( APD) was used to assess fusion and stereopsis in 67 subjects. The APD correlated closely with the log neutral density filter required to restore fusion as measured by Worth 4- dot in patients with unilateral visual dysfunction ( 21). Burde and Landau wrote an amusing as well as enlightening review of the utility and techniques of pupillary testing ( 22). Methodologies for APD testing vary, resulting in variances in data and con- ] Neuro- Ophthalmol, Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 139 elusions regarding the sensitivity of the test ( 22). Although there are many other articles on APD testing and other psychophysical modalities of optic nerve function testing ( 23,24), they fall beyond the scope of this particular review. Routine or nuclear magnetic resonance imaging ( MRI or NMR) can no longer be considered the cutting edge of this high technology. New developments in MRI include NMR spectroscopy, which provides for the noninvasive study of metabolic processes. Using such technology in combination with conventional MRI, it is possible to gain new appreciation of the neuro- ophthalmic causes of visual loss. For example, elevated lactate is often found in traumatic, ischemic, and neoplastic brain lesions ( 25), which may be due to increased anaerobic glycolysis of ischemic brain tissue as well as that associated with macrophage infiltration. More than 800 articles on functional MRI have been published in the last 2 years. A review of this subject, as it relates to the mapping of visual function in the brain, combined functional MRI with magnetoencephalography; together they can be used to make geometric models of nuclear systems and more accurately locate the source of neural activity ( 26). An excellent review of functional MRI demonstrates how this method shows promise in the detection and evaluation of neuro- ophthalmic lesions as well as the mapping of distinct visual functions ( 27). Compared with the traditional method of functional localization, positron emission tomography ( PET), functional MRI as a new technology offers greater resolution and lower costs, besides being less invasive ( 27). Fluid- attenuated inversion recovery sequences during MRI reveal multiple cerebral lesions in patients with optic neuritis that are not visible by routine MRI ( 28). Similarly, short inversion time inversion recovery sequences revealed abnormal high signals in 10 of 11 eyes from nine patients in whom optic nerve injury was suspected following blunt head trauma ( 29). Fast- spin echo high-resolution MRI using fat suppression provided much better spatial resolution ( 0.39 x 0.39 mm) and visualization of optic nerve lesions in 72 patients ( 30). Phased- arrayed surface coil MRI also provided for high- resolution visualization of the orbital nerve as shown in 24 cases of optic neuropathies ( 31). BASIC SCIENCE Experimental animal studies continue to point the way for our understanding of human visual anatomy and function. For example, studies in cats have demonstrated that the nerve fiber spectra ( axon caliber) varies with eccentricity ( distance from the fovea) in the cat retina ( 32). Axon diameters are largest when coming from the superior and temporal retina, and the smallest- caliber fibers come from the far periphery ( 32). This finding does not conform to our simplistic notion of small-caliber P- cells coming from the area centralis. In the rodent optic nerve, oligodentrocytes appear to play a crucial role during development to turn off not only myelination but total axon numbers as well ( 33). It was also redemonstrated in the mouse that the conduction velocity of optic nerve axons depends on the extent of myelination ( 34). The role of neurotrophins in the survival and differentiation of growing axons has recently become a " hot topic" for visual neuroscientists. Such neurotrophic factors can influence optic nerve ax-onal sprouting and growth and hence retinofugal terminations in the optic tectum of the frog ( 35). In cows there is evidence that a fibroblast growth factor may also help regulate optic nerve axon proliferation and the modulation of synaptic terminals ( 36); interestingly, this may be related to glutamate release. Another study that ties neurotrophin regulation of growth, development, and specificity to the response to neuronal injury was performed on rodent retina. Basic fibroblast growth factor ( bFGF), released by crushed optic nerve, can in turn protect retinal photoreceptors against photo-damage ( 37). The tie- in is likely the excitatory amino- acid- induced neurodegeneration mediated by N- methyl- D- aspartate ( NMDA) receptors ( 38). Cytokines can also exert neurotrophic actions; recently, interleukin- 1 beta was shown to mitigate the neurodegeneration induced by glutamate, NMD A, or kainate ( 39). Conversely, another cytokine, tumor necrosis factor- alpha ( TNF- a) can, after intravitreous injection in rodents, produce optic nerve lesions that simulate Creutzfeldt- Jakob or acquired immunodeficiency syndrome ( AIDS), respectively ( 40,41), and TNF and other cytokines may produce injury by upregulating nitric oxide ( 42). Since the last such annual review, several other important articles on glutamate neurotoxicity have been published. For example, high brain glutamate levels have been shown in acute liver failure ( hyperammonemia) in rabbits ( 43). Following transient retinal ischemia in the adult rat retina, a significant increase in glutamate- aspartate transporter mRNA was found ( 44). In rats, however, glutamate excitotoxicity was shown not to play a role in the photoreceptor degeneration of a retinitis pigmentosa rat model ( 45). Zinc was found to be protective against glutamate neurotoxicity induced 7 Neuro- Ophthaltnol, Vol. 16, No. 2, 1996 240 A. A. SADUN AND R. M. RUBIN by kainate in retinal neurons cultured from fetal rats ( 46). New approaches for neuroprotection against glutamate or NMDA neurotoxicity have been tried with a variety of models and with various results ( 47- 50). Perhaps the most intriguing has been that nicotine may protect CNS neurons in cell cultures from NMDA receptor- mediated neu-rodegeneration ( 50). Closest to home is an article on retinal ganglion cells in the primate for which it was shown that excitatory amino acid receptors that were non- NMDA predominantly mediated the bipolar to ganglion cell transmission ( 51). Exposure of chick retina to glutamate, NMDA, or kainate increased cyclic GMP, which is thought to mediate retinal neurotoxicity through nitric oxide because nitric oxide synthase inhibitor blocks the damage ( 52). Indeed, some authors have postulated that in certain neurodegenerative diseases, such as Parkinson's, the basic mechanism is the overproduction of nitric oxide, which, in addition to its direct neurotoxic effects, prompts macrophages to produce oxygen- free radicals generating selective oxidative stress and low- grade inflammatory processes in such regions as the substantia nigra ( 53). From where do these neurotoxic agents derive? It was shown in rats that astrocytes, but not macrophages, contain the appropriate enzymes to produce nitric oxide during neurodegeneration ( 42). Other agents that can help protect against the cascade of reactions that lead to apoptosis ( programmed cell death) include the neurotrophin (-)- deprenyl, which has been shown to increase retinal ganglion cell survival after optic nerve crush injury in rats ( 54). On the other hand, nitric oxide is likely to have been put in the brain for other, more sustaining reasons. Gene research ( measuring the mRNA of nitric- oxide- producing enzymes) in rat brains implicates complex roles for nitric oxide as varied as being a mediator of neurodegeneration to being a neurotransmitter, particularly in cholinergic systems ( 55). In the chicken, there is staining for the nitric- oxide- producing enzyme in the isthmo- otic nucleus and tract which, once ablated, leads to degeneration of retinal ganglion cells ( 56). Ultimately, the final common pathway of most, if not all, of these neurotoxic cascades is the opening of calcium channels in the degenerating neuron, which was measured directly by means of voltage gates in the rat optic nerve. The application of calcium channel blockers, such as verapamil or nifedipine, protected the cells from anoxic injury ( 57). To date, however, clinical application of this principle has yielded less than dramatic results. For example, nifedipine used on 59 patients ( 38 with optic atrophy and visual field defects and 21 normal subjects) produced only minimal improvements ( about 1 dB); improvement was primarily in the youngest controls and not at all in patients with ischemic optic neuropathy ( 58). THE NEURORETINA It has been well established that with optic atrophy often comes constriction of retinal arterioles. This fact was recently quantified by means of color stereo fundus photographs of patients with a variety of glaucomas and other optic neuropathies ( 59). The authors found that focal retinal arteriole narrowing correlated with age and the degree of optic nerve damage, regardless of etiology. In contradistinction, Rader and colleagues found proximal constriction of retinal arterioles to be highest in nonarteritic ischemic optic neuropathy ( N-AION) ( 68%), lower in glaucoma ( 42%), and lowest in normal subjects or eyes with arteritic anterior ischemic optic neuropathy ( 5 and 11%, respectively). These authors found that only generalized narrowing ( not proximal constriction) correlated with the severity of optic nerve damage, although the former did not seem specific to disease entity ( 60). Macular stars with optic neuropathy was revisited by Wang and colleagues, who found them in about 25% of nearly 100 consecutive cases of optic neuropathy, perhaps reflecting the fact that neu-roretinitis may be more prevalent in Taiwan ( 61). Nine cases of typical Leber's idiopathic stellate neuroretinitis, characterized by optic disc edema and exudates in Henle's nerve fiber layer, were studied; all these cases were thought to have a viral etiology, and visual recovery was the rule ( 62). Seven patients with a history of cat scratches or exposure to cat fleas presented with multifocal retinitis and optic nerve edema, of whom three had cat- scratch disease titers ( 63). It was concluded that branch retinal arterial occlusions are a not uncommon complication of cat- scratch neuroretinitis ( 63). Cat- scratch neuroretinitis associated with AIDS apparently is not uncommon, having occurred in 23 patients ( 64). On follow- up, seven patients with recurrent episodes of neuroretinitis were found to have a worse than usual prognosis in terms of visual acuities, visual field, and optic disc changes, suggesting a less benign form of idiopathic neuroretinitis exists ( 65). Treatment of cat-scratch neuroretinitis ( of Rochalimaea species) is usually successful with ciprofloxacin or doxycy-cline ( 66). / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 141 Nonviral etiologies may also be associated with neuroretinitis. Morphologic, serologic, and epidemiological evidence for Baylisascaris procyonis, one of the nematodes responsible for diffuse unilateral subacute neuroretinitis, suggests that the raccoon may be a vector for this disease ( 67). Ocular larva migrans as a cause of subacute neuroretinitis was described in a 49- year- old patient ( 68). Toxoplasma gondii infection can also produce a likeness more typical for Leber's idiopathic stellate retinopathy than the usual vitritis/ retinitis picture ( 69). A case of classic neuroretinitis associated with optic disc melanocytoma was described in which all serological tests were negative ( 70), although this case should not be taken as demonstration of this new association. Lengthy follow- up on several patients provided an update on chronic recurrent multiple evanescent white- dot syndrome, which is known sometimes to produce optic disc changes with peripapillary choroiditis and a large blind spot; the authors suggest that it has a chronic recurrent form ( 71). What is the effect of diabetic retinopathy on the appearance of the optic disc? In a study of about 100 patients with diabetic retinopathy, no changes were seen in optic disc morphology, and only a minor tendency for thinning of the retinal nerve fiber and mild temporal pallor was noted ( 72). Wolfram syndrome, however, is described as the association of diabetes mellitus and optic atrophy ( often with diabetes insipidus and deafness as well). A study of 45 patients with Wolfram syndrome helped to establish its prevalence ( one in 770,000), inheritance pattern ( autosomal recessive with a carrier frequency of one in 354), and probable association with a mitochondrial ( 3243) mutation ( 73). Other systems involved in Wolfram ( DIDMOAD) syndrome include cerebellar ( 62%) and renal ( 58%) abnormalities and, less commonly, gastrointestinal dysmotility and gonadal atrophy ( 73). More specific optic nerve complications include juvenile diabetic papillopathy ( 74). Recently, a case of bilateral posterior ischemic optic neuritis was described in a 14- year- old patient whose diabetes was poorly controlled ( 75). Several studies have contributed to our understanding of human immunodeficiency virus ( HIV)- related optic nerve and retinal nerve fiber damage. An investigation of the nerve fiber layer in AIDS reminds us that repeated nerve fiber layer infarcts ( cotton- wool spots) can accumulatively lead to nerve fiber layer thinning and even optic atrophy. Red- free fundus photography was used to evaluate the retinas of patients with AIDS or asymptomatic HIV infections, and a variety of nerve fiber layer defects were described ( 76). Additionally, by means of careful follow- up and visual field testing, the authors confirmed the histopathological studies of Sadun and colleagues that not all fiber losses in AIDS are secondary to cotton- wool spots. These histopathological studies were extended in demonstrating axonal degeneration from monkeys with SAIDS ( a rhesus monkey analog of AIDS) in the absence of retinal lesions ( 77). Sadun and colleagues studied optic nerves from patients with AIDS who had careful follow- up and were shown never to demonstrate any infectious retinitis. Viro-logical and ultrastructural investigations, including polymerase chain reaction ( PCR) amplification techniques on 12 nerves, suggested that axonal degeneration was mediated by HIV- infected macrophages and is due neither to retinal lesions nor to direct viral infection of neurons ( 78- 80). How do HIV- infected macrophages induce axonal damage? As mentioned, macrophages can produce cytokines, including TNF- a. Intravitreous injections of TNF- a in rabbits can induce similar axonal degeneration ( 41,81). Perhaps most excitingly, this axonal degeneration can be blocked by giving pentoxifylline, a TNF- a inhibitor ( 82). A primary AIDS- induced lesion in the optic nerve may therefore be an additional cause of optic neuropathy ( 83). Further evidence of what may be a subtle, subclinical but common manifestation of the AIDS- associated optic neuropathy was provided by Malessa and colleagues, who demonstrated electrophysiological evidence of optic nerve dysfunction in 100 HIV- positive men ( not symptomatic AIDS) compared with 40 age-matched controls ( 84). This is not to say that the most severe or common cause of visual loss in AIDS is from a noninfectious optic neuropathy. For example, cytomegalovirus ( CMV) infection involves 40% of AIDS retinas that come to autopsy and 2% of AIDS optic nerves ( 85). CMV optic neuritis is described in 35 eyes of 30 consecutive subjects with AIDS and found to carry a similar prognosis for survival to CMV retinitis ( 86). Interestingly, HHV- 6, in association with HIV- 1, may predispose the retina to CMV infection ( 87). Also, as Freeman and colleagues showed in 1992 ( 38), visual dysfunction as well as optic neuropathy, in the absence of infectious retinitis, can occur as an accumulation of nerve fiber layer infarcts in the retina. Axonal degeneration from a primary AIDS- associated optic neuropathy may be supplemental to this condition ( 38). In addition to microvascular insults, the optic nerve and retina are vulnerable to large- vessel dis- 1 Neuro- Ophthalmol, Vol. 16, No. 2, 1996 242 A. A. SADUN AND R. M. RUBIN ease. Extensive cardiac and carotid artery evaluations in 41 consecutive patients with amaurosis fugax or central retinal artery occlusion revealed a source of emboli in only 34% of patients ( 88). The most common abnormality was carotid artery stenosis, which could be found by carotid duplex scanning. In a massive review of more than 1,000 patients with various types of retinal vein occlusions, Hayreh and colleagues found six subcategories of the disease ( 89). Ischemic forms of vein occlusions occurred in about 20% and carried a much worse prognosis. Nonischemic central retinal vein occlusions converted to the ischemic form in about 15% of cases within one year. THE OPTIC NERVE HEAD Hemorrhages can occur around the optic disc in patients, especially younger patients, with incomplete posterior vitreous detachments ( 90). The vit-reopapillary traction of an incomplete detachment may traumatize the peripapillary vessels; fortunately, the prognosis remains good, as none of these patients went on to develop N- AION ( 90). Unfortunately, the peripapillary hemorrhages seen in infants may have a more severe cause and worse prognosis. Peripapillary hemorrhages were found histopathologically at necropsy in 11 of 13 infants who died of acute intracranial injuries, suggesting that such observations may serve to distinguish traumatic from nontraumatic causes of death in infants ( 91). The microvasculature of the human optic nerve head was beautifully disclosed by Onda and colleagues, who showed a stunning series of micrographs of methacrylate casts made on 18 normal eyes ( 92). They confirmed the usual ( 11 of 13 eyes) configuration of a circle of Zinn- Haller fed by the short posterior ciliary arteries contributing the major blood supply to the laminar optic disc through radial branches. The peripapillary choroidal contribution is minimal ( 92). Similar techniques were used by Olver and colleagues in making morpho-metric measures of the retrolaminar optic nerve vasculature. They found a complete circle of Zinn- Haller, which they called the perioptic nerve arteriolar anastomosis, in 75% of the 18 casts examined ( 93). In more than 80% of their specimens, the anastomotic circle was fed by both the lateral and medial short posterior ciliary arteries. Autoregula-tion of the optic nerve head vasculature in rabbits was studied by inducing vasoconstriction with En-dothelin- 1, thereby establishing sites of vasomotor control in the prelaminar optic nerve ( 94). In contradistinction, chronic administration of apracloni-dine hydrochloride, an adrenergic agonist ( alpha- 2) in rabbits, did not produce any observable changes to the optic nerve head vasculature as observed by postmortem corrosion casting ( 95). Perfusion of the anterior optic nerve head can be measured clinically by means of videographic assessment of the chromatic reflection. Reductions of ocular perfusion pressure, produced in normal human subjects by transient elevation of the intraocular pressure ( IOP), resulted in alterations in the hue, saturation, and brightness of the optic disc viewed funduscopically ( 96). More precise measurements of oxygen were made in the prelaminar region of the cat optic nerve head by means of microelectrodes; transiently raising the IOP did not lower oxygen tensions from normal values ( 97). Methacrylate casting methodology was also applied on 25 specimens from 13 cadavers by Chou and colleagues to investigate the vasculature of the intracanalicular optic nerve. They found that the ophthalmic artery gives off three branches that pierce the dura and feed the very delicate pial circulation ( 98). Conventional microdissection techniques demonstrated that the ophthalmic artery, as a branch of the internal carotid artery, has considerable variation intracranially; however, its dorsal course along the optic nerve in the orbit was invariable ( 99). There is considerable variability in the size and shape of optic nerve heads; however, such measurements must account for magnification factors intrinsic to the Galilean optic system of the eye. For example, optic disc diameters may be measured with a Zeiss four- mirror lens in conjunction with a slit lamp, using knowledge of the slit beam length and the magnification factors involved ( 100). A 90- diopter fundus lens or Goldmann contact lens can be used in the same way ( 101,102). Larger optic discs, measured by conventional color fundus photographs, correlated with larger and flatter corneas; however, this correlation might be explicable on optical principles ( 103). Yet correcting for this, investigators showed that " large optic discs [ are found] in large eyes [ and] small optic discs [ are found] in small eyes" ( 104). Larger optic discs also appear to be present in eyes with a higher number of photoreceptors ( 105). Scanning laser tomography can reliably provide optic disc measures ( 106). An instrument called the Heidl-berg retina tomograph stacks focal planes that are scanned to gain three- dimensional information about the optic nerve head, correcting for optical complexities ( 107). Using a digitized image of fundus photographs, computer manipulations can / Neuro- Ophthalmol Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 143 also provide reliable information about optic disc size and shape ( 108). Topcon Imagenet System digital image analysis permits assessment of optic disc changes within the same monkey optic discs before and after posterior deformation ( 109). These investigators also compared the Topcon system with the ability of clinicians to detect differences on fundus photographs. With the machine's statistical image analysis, the computer came out on top ( 104). Using this instrument and technique to measure optic discs on human eyes, Varma and colleagues found significant racial differences; however, no gender-, refractive-, or age- related differences were noted ( 110). Using SLO to establish reliable morphometry of the optic disc, Miglior and colleagues showed that optic disc size correlated with both axial length and gender ( larger in males) ( 111), although this finding is curiously in contradiction to the findings of Varma, Quigley, and colleagues ( 110). The SLO measurements of the optic discs were repeated several times in 10 normal eyes before and after pilocarpine treatment, and considerable differences were noted, presumably due to variations in the eye's optics ( 112). In addition to being a rich source of information on optic disc morphometry, the glaucoma literature also provides models of retinal ganglion cell death. For example, Quigley and colleagues showed that in experimental glaucoma in monkeys, as well as optic nerve transsection in monkeys and rabbits, produced in retinal ganglion cells morphologic features of apoptosis, such as chromatin condensation and apoptotic bodies ( 113). Nonarteritic anterior ischemic optic neuropathy and other ocular ischemic disorders have remained subjects of great interest. Hayreh and colleagues showed, through 24- hour blood pressure monitoring, that there is a significant drop in both systolic and diastolic measures at night and that this effect is particularly great in normal- tension glaucoma ( 114). This is but one example of a plethora of articles in the glaucoma literature relating optic disc changes to blood pressure, blood circulation, and ocular pressure, especially in normal- tension glaucoma as well as to several models of glaucoma, but these subjects go beyond the scope of the present review. THE OPTIC DISC AT RISK In our last annual review, we had the opportunity to delve into the unique anatomical and physiological aspects of the optic nerve head that may make it a vulnerable site for a variety of optic neuropathies. Indeed, three years ago Burde first coined the term " disc at risk" in commenting on why a wide spectrum of diseases as disparate as N- AION and Leber's might occur at this critical and interesting region. Optic disc swelling may of course reflect pathology of the brain or more posterior optic nerve. For example, Orthoclone OKT3, an agent to suppress the cell- mediated response after organ transplantation, can cause optic disc edema in combination with abducens palsy as reflections of increased intracranial pressure ( 115). Similarly, high- dose chemotherapy for bone marrow transplantation ( which often also involves radiation therapy) can produce an optic neuropathy ( 116). Clomiphene citrate therapy for primary infertility has been reported to cause acute visual loss from an ischemic optic neuropathy ( 117). Alpha interferon- 2b, given as treatment for chronic hepatitis, was reported to produce acute optic tract ( not nerve) neuritis in three cases ( 118); however, the central scotoma described is indicative of an optic neuritis. Disulfi-ram, used to control chronic alcoholism, can produce a dose- dependent optic neuropathy as well ( 119). Thallium toxicity, in addition to producing ptosis and ophthalmoplegia, can cause a typical toxic optic neuropathy ( 120). Ethambutal is a classic cause of drug- induced optic neuropathy, and this effect has been revisited. Patients on ethambutal need routine follow-up and visual assessment ( 121). Intravitreous injections of ethambutal in fish caused an optic neuropathy characterized ultrastructurally by alterations in the synaptic connections between cone pedicles and the horizontal cells ( the retinal ganglion cells and the optic nerve were not described) ( 122). The other antituberculosis agent known to produce an optic neuropathy was also investigated. Cases of severe irreversible bilateral optic neuropathies caused by isoniazid were described ( 123). Ethambutal differs from isoniazid in that only in the former does the papillomacular bundle appear to be selectively impaired, leading typically to losses of visual acuity, color vision, and a central scotoma. It is curious that these two antibiotics as well as chloramphenicol are toxic to the optic nerve ( 124). The classic model of a nutritional/ toxic optic neuropathy affecting the papillomacular bundle is tobacco- alcohol amblyopia ( TAA). This topic was revisited by Rizzo and Lessell, who described it as now an uncommon entity. They described two patients in whom this disorder occurred in the absence of alcohol or vitamin B- 12 deficiency ( 125). The patients recovered with cessation of smoking / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 244 A. A. SADUN AND R. M. RUBIN or hydroxocobalamin therapy alone. TAA is considered by many to be due to a number of different nutritional deficiencies or to toxins that may occur in isolation or combination. Rizzo and Lessell demonstrated that smoking can produce TAA in isolation, perhaps as a result of the pathophysiology of cyanide on oxidative phosphorylation. Golnik and Schaible described six patients with a similar presentation to TAA characterized by defects in visual acuity, dyschromatopsia, and central scotomas in whom only folic acid was found to be deficient ( 126). B- 12 levels were normal, and all six patients improved dramatically through folic acid therapy ( 1 mg/ day) alone. Of course, patients with TAA or nutritional amblyopia may in fact have an underlying genetic predisposition for which these toxic or nutritional factors are epigenetic. Examples abound, including a case report classic for TAA in a 39- year- old man in whom a similar diagnosis in his brother led to testing that showed a homoplas-mic mutation at the 11778 site ( 127). Indeed, with this idea in mind, Swartz and Savino entitled their article " Is all nondefinable optic atrophy Leber's hereditary optic neuropathy." in describing a girl who carried a variety of diagnoses following unilateral optic atrophy, until the second eye became involved and in whom eventually Leber's 11778 was diagnosed ( 128). Leber's is, of course, a mitochondrial genetic disease whose primary feature is bilateral visual loss, usually in early adulthood. There are three primary mutations ( 11778, 3460, and 14484) and about a dozen secondary mutations, which are usually insufficient to produce the phenotypic expression in the absence of other genetic or epigenetic factors. Although exciting revelations have led to the recent publication of many articles in this field, their discussion is beyond the scope of the present review, as Leber's is comprehensively covered in a separate annual review in these same pages on neuro- ophthalmology and systemic diseases. Nonetheless, a quick browse is worthwhile for its insights on the relationship of Leber's to nutritional and toxic diseases of the optic nerve that may have a predilection for the optic disc. Kerrison and co- workers provided the second ultrastructural description of a case of Leber's from a pedigree that had been genetically characterized. Their patient had mutations at nucleotide positions 14484 and 4160 ( a primary and secondary mutation, respectively) and demonstrated, among other things, electron- dense, membrane- bound calcium inclusions in the retinal ganglion cells ( 129). The original ultrastructural description of the optic nerve for a 11778 case did not reveal these calcium inclusion bodies ( 130). Furthermore, Sa-dun and Sadun, on reexamination of retinal tissues from this same case with particular attention to ganglion cells, also did not notice such structures ( 131). They questioned whether these bodies could have represented acute injury observed by chance and wondered whether these calcium inclusions were specific to the combination of mutations described by Kerrison and colleagues. Kerrison and co- workers replied that they may have been " preserved mitochondrial carcasses in surviving retinal ganglion cells," a reasonable and possibly edifying concept ( 132). Leber's has also been associated with multiple sclerosis ( 133- 136) and dystonia ( 137). Whether these associations actually reflect common underlying pathophysiological mechanisms, are simply genetically segregated together, or represent happenstance remains to be seen. Additionally, about 60% of patients with Leber's, from established pedigrees, were identified and divided into groups harboring 11778, 3460, or other mutations. When this group was reanalyzed, a wide variety of other neurological abnormalities were noted, including postural tremors, peripheral neuropathy, Parkin-sononism, multiple sclerosis, and dystonia ( 138). Nikoskelainen and colleagues suggest that these neurological illnesses, frequently found in Leber's, reflect a shared pathogenetic basis. Of course, Leber's is not the only form of a genetically based optic neuropathy. A family is described in whom bilateral optic atrophy in the 20/ 50 range is associated with a later onset of low- tone hearing loss ( 139). This case seems quite distinct from either Leber's or autosomal dominant optic atrophy ( Kjer's). As pointed out in our first review on these pages, in 1993 an epidemic of optic and peripheral neuropathy took place in Cuba in which the findings in the eye were remarkably similar to Leber's hereditary optic neuropathy ( LHON). Sadun and co- workers described the fundus finding of papil-lomacular bundle dropout with swelling of the immediately adjacent nerve fiber layer ( 140). The 20 patients they examined disclosed signs and symptoms quite reminiscent of tobacco- alcohol amblyopia, nutritional and toxic optic neuropathies, and Leber's, such as a subacute loss of central vision, dyschromatopsia, central scotomas, and losses of high spatial frequencies on contrast sensitivity testing. Many believed the disease was largely nutritional ( although possibly exacerbated by chronic exposures to agents such as methanol or cyanide), and the patients as well as the general Cuban pop- / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 145 ulation were given general vitamin supplementation. On revisiting the same patients 4 months later ( after vitamin therapy), Sadun and colleagues found dramatic recoveries of visual acuity ( from 20/ 400 to 20/ 50), color vision, and visual field ( 140). Various errors had originally led the Cuban scientists to conclude that the epidemic was viral in nature; however, their medical infrastructure proved ideal for orchestrating an extraordinarily comprehensive and expeditious vitamin therapy program, which quickly stopped the epidemic ( 141). Similarities between the Cuban epidemic of optic neuropathy and LHON led various teams to check for mitochondrial DNA mutations among the Cubans affected. Hirano and co- workers reported two of 14 blood samples from patients said to have suffered from the Cuban epidemic that were positive for LHON primary mtDNA mutations 11778 and 3460 and concluded that mtDNA mutations might be contributing to the outbreak of Cuban optic neuropathy ( 142). Moreover, Johns, Neufeld, and Hedges found two mtDNA mutations at nucleotide positions 9438 and 9738 ( secondary mutations) in the nine patients whose blood samples they studied ( 143). Johns and Sadun, examined 12 samples obtained from Cuban patients that they had directly evaluated clinically ( having eliminated several patients carrying the incorrect diagnosis) and found no LHON- associated mtDNA mutations ( 144). This finding was confirmed on a much larger scale by Newman and colleagues, who, analyzing 57 Cuban blood samples of patients with the disease, found no primary mutations. The seven secondary mutations they found ( 9438, 13708, 15257) were also seen with similar frequency in the general Cuban population ( 145). The Cuban epidemic of optic neuropathy had a number of other associated neurological abnormalities, including peripheral sensory neuropathy, sensorineural deafness, and dorsolateral myelo-neuropathy ( 140,146,147). Sural nerve biopsies revealed severe axonal degeneration, regeneration, and possibly a selective loss of the largest- caliber fibers ( 148). Investigations of risk factors for the optic form of the syndrome found that, in general, the population at greatest risk would be urban male patients aged 25 to 64 years who consumed an irregular diet ( 149). In particular, tobacco use increased the risk of optic neuropathy and higher dietary intakes of methionine, vitamin B- 12, and other vitamins reduced this risk ( 147). Other investigators emphasized that the patients most at risk demonstrated a greater weight loss, had lower body mass indices, and had a higher level of alcohol consumption ( 150). What does the Cuban epidemic of optic neuropathy have in common with other nutritional and toxic optic neuropathies or with LHON, other than similar signs and symptoms? All these diseases may reflect deficiencies of energy metabolism via acquired or genetic mitochondrial compromise; however, there are other mitochondrial injuries with entirely different features. MtDNA mutations can cause not only LHON but also myoclonic epilepsy, chronic progressive external ophthalmoplegia, Leigh's syndrome, Pearshon's marrow/ pancreas syndrome, and several other disorders ( 151). These diseases may occur separately or in combination. For example, a mutation at mtDNA 8344 is described as the cause of optic atrophy with myoclonic epilepsy and ragged- red fibers ( 152). Another case of impaired cytochrome c oxidase activity manifested itself with severe cerebellar hypoplasia, general hypotonia, myoclonic seizures, and optic atrophy ( 153). Discussions of diseases of the optic nerve head often begin and end with ischemic optic neuropathy. A population- based study of two regions ( rural Missouri versus Los Angeles) revealed that the combined annual incidence rates were 0.36 per 100,000 and 2.3 per 100,000 for arteritic and non-arteritic causes of anterior ischemic optic neuropathy, respectively ( 154). Moreover, whites were at greater risk for N- AION than blacks. In a study of 41 patients with N- AION, cholesterol and smoking were found to be significant risk factors ( 155). A 10- year follow- up study of 137 patients with N- AION not only found cigarette smoking to be an important risk factor but also found that cessation of smoking reduced this risk of N- AION ( 156). A higher prevalence of systemic hypertension, diabetes mellitus, and gastrointestinal ulcers were also noted in an analysis of 406 patients with N- AION ( 157). Others have pointed out that systemic hypotension, particularly nocturnal hypotension, may be part of the pathogenesis of N- AION ( 158,159). There are reports of coagulation abnormalities in N- AION ( 160), which might explain delays in ocular perfusion, which have been noted ( 161). Not surprisingly, N- AION has been associated with a number of antecedent events. N- AION has been described as occurring after interferon- alpha in the treatment of neoplastic disease ( 162), sumatriptan therapy for migraine ( 163), and lumbar spine surgery ( 164,165). It has also been described in association with sickle cell disease ( 166). Surgical procedures in which positioning and severe / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 146 A. A. SADUN AND R. M. RUBIN blood loss may be important risk factors may also lead to N- AION, as described in the old as well as more recent literature; for example, in one case anemia and hypotension were seen as important risk factors associated with postoperative ischemic neuropathy ( 167). Several recent reports describe recovery of hypotension- associated ischemic optic neuropathy. Connolly and co- workers were able to administer agents to reverse the systemic hypotension that had occurred in the hospital. Each patient demonstrated remarkable recovery of their N- AION visual loss ( 168). Posterior ischemic optic neuropathy can also be produced by anemia and hypotension, and a report of visual recovery following adjustment of blood pressure is described ( 169). Remarkably, Johnson and colleagues reported using levodopa and carbidopa to obtain visual recovery in patients with N- AION of more than 6 months' duration ( 170)! Hemodilution has also been described as efficacious for recovery of vision in longstanding N- AION ( 171). Of course, we must point out that spinal manipulation has been credited with curing ischemic optic neuropathy as well ( 172)! We must keep in mind, however, the initial enthusiasm with which many neuro- ophthalmolo-gists ( particularly surgeons) had for optic nerve-sheath decompression surgery for the treatment of N- AION. The outcomes following optic nerve-sheath decompression ( ONSD), as demonstrated by the Ischemic Optic Neuropathy Decompression Trial ( IONDT) and by separate studies, did not sustain the initial applause. Yee and co- workers retrospectively reanalyzed 91 patients with N- AION in whom some had undergone ONSD. They found their recovery rates to be 39% and 32% for those with and without surgery, respectively ( 173). Gla-ser and colleagues examined a second series of 21 eyes in which ONSD had been performed for N- AION and concluded that the operation had " no beneficial effect" ( 174). Perhaps most impressive were the long- awaited results of the IONDT. In this masked, randomized, and prospective trial, conducted at 25 centers, the rate of spontaneous improvement ( 43%) was higher than the rate of recovery following ONSD surgery ( 33%) ( 175)! In an editorial summarizing these and other studies, Lessell concluded that in N- AION, spontaneous improvement is more common than previously suspected and that ONSD surgery is not effective ( 176). Several other editorials have helped to sort the data from this important trial. Beck pointed out the methodological and statistical strengths of this study and called for cessation of decompression surgery for this indication ( 177). The issue of spontaneous improvement has prompted new looks at the natural history of N- AION. The risk of spontaneous improvement has been recalculated, using criteria similar to that used in the multicentered IONDT study, as being 31%, whereas significant worsening occurred in 22% of cases of N- AION ( 178). In comparing N- AION and optic neuritis, Swartz and colleagues found the rate of retrobulbar pain to be 12% in their 41 patients with N- AION as opposed to the 92% reported in the 448 patients studied with the Optic Neuritis Treatment Trial ( 179). Arteritic anterior ischemic optic neuropathy has also been the subject of further inquiry. One patient in whom giant cell arteritis caused severe optic atrophy later developed the fairly well- established feature of glaucomatous cupping ( 180). A clinical histological comparison of 85 consecutive patients with giant cell arteritis disclosed no relationship between the severity of optic nerve involvement and the histological features found on biopsy of the temporal artery ( 181). A retrospective review of 185 patients with giant cell arteritis revealed that anterior ischemic optic neuropathy occurred in 88% of the eyes and corticosteroid treatment led to marked visual improvement in 34% of cases ( 182). Color Doppler studies were conducted on 22 consecutive cases of biopsy-proven giant cell arteritis; abnormal ophthalmic artery flow characterized by turbulence was noted ( 183). Vasculidities other than giant cell can lead to optic neuropathy. Primary Sjogren's syndrome led to anticardiolipin antibodies and an ischemic optic neuropathy in a 30- year- old woman ( 184). Polyarteritis nodosa was thought to have led to a macular star and neuroretinitis picture in a 45- year- old man ( 185). In combination with cerebral signs and symptoms, optic neuropathy was found to be due to relapsing polychondritis ( 186). Bechet's, mixed connective tissue disease ( MCTD), Churg- Strauss syndrome ( allergic angiitis), and Wegner's granulomatosis were all thought to be the cause of various forms of papillitis or optic neuritis ( 187- 191). Not surprisingly, systemic lupus erythematosus was described as a cause of bilateral optic neuritis in a 11- year- old patient ( 192) and a case of neuroretinitis ( 193). Sarcoidosis as a vasculitic cause of optic neuropathy is also revisited in several case reports, including a 43- year- old woman and a 25- year- old man, both of whom presented with optic disc edema and severe visual loss ( 194- 199). / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 147 The lamina cribosa forms the line of demarcation between the 1 mm thick optic disc and the remaining 50 mm of optic nerve. 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