Journal of Neuro-Ophthalmology, June 1996, Volume 16, Issue 2

The Anterior Visual Pathways

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. Thus ends part I of this annual review; part II begins with the retrolaminar optic nerve and takes us from diseases of the optic nerve, by the optic chiasm, and into the parallel processing of the primary visual nuclei. REFERENCES 1. Dillon EC, Sergott RC, Savino PJ, Bosley TM. Diagnostic management by gatekeepers is not cost effective for neuro- ophthalmology. Ophthalmology 1994; 101: 1627- 30. 2. Keltner JL, Johnson CA. Short- wavelength automated pe­rimetry in neuro- ophthalmologic disorders. Arch Ophthal­mol 1995; 113: 475- 81. 3. Wild JM, Moss ID, Whitaker D, ONeill EC. The statistical interpretation of blue- on- yellow visual field loss. Invest Ophthalmol Vis Sci 1995; 36: 1398- 410. 4. Sample PA, Martinez GA, Weinreb RN. Short- wavelength automated perimetry without lens density testing. Am J Ophthalmol 1994; 118: 632- 41. 5. Lutze M, Bresnick GH. Lens- corrected visual field sensi­tivity and diabetes. Invest Ophthalmol Vis Sci 1994; 35: 649- 55. 6. Harwerth RS, Smith EL III, DeSantis L. Mechanisms me­diating visual detection in static perimetry. Invest Ophthal­mol Vis Sci 1993; 34: 3011- 23. 7. Schuman JS, Hee MR, Puliafito CA, et al. Quantification of nerve fiber layer thickness in normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol 1995; 113: 586- 96. 8. Weinreb RN, Shakiba S, Zangwill L. Scanning laser polar-imetry to measure the nerve fiber layer of normal and glaucomatous eyes. Am ] Ophthalmol 1995; 119: 627- 36. 9. Miglior S, Rossetti L, Brigatti L, Bujtar E, Orzalesi N. Re­producibility of retinal nerve fiber layer evaluation by dy­namics scanning laser ophthalmoscopy. Am J Ophthalmol 1994; 118: 16- 23. 10. Rohrschneider K, Becker M, Fendrich T, Volcker HE. Ki­netic fundus controlled perimetry with the scanning laser ophthalmoscope. Klin Monatsbl Augenheilkd 1995; 207: 102- 10. 11. Jonas JB, Schiro D. Localized retinal nerve fiber layer de­fects in nonglaucomatous optic nerve atrophy. Graefes Arch Clin Exp Ophthalmol 1994; 232: 759- 60. 12. Hedges TR III, Legge RH, Peli E, Yardley CJ. Retinal nerve fiber layer changes and visual field loss in idiopathic in­tracranial hypertension. Ophthalmology 1995; 102: 1242- 7. 13. Niessen AG, van den Berg TJ, Langerhorst CT, Bossuyt PM. Grading of retinal nerve fiber layer with a photo­graphic reference set. Am ] Ophthalmol 1995; 120: 577- 86. 14. Wall M, Ketoff KM. Random dot motion perimetry in pa­tients with glaucoma and in normal subjects. Am J Oph­thalmol 1995; 120: 587- 96. 15. Wall M, Montgomery EB. Using motion perimetry to de­tect visual field defects in patients with idiopathic intra­cranial hypertension: a comparison with conventional au­tomated perimetry. Neurology 1995; 45: 1169- 75. 16. Barton JJ, Rizzo M. Motion perception in optic neuropa­thy. Neurology 1994; 44: 273- 8. 17. MacMillan ES, Cummins D, Heron G, Dutton GN. The simultaneous interocular brightness sense test. A test of optic nerve function. Arch Ophthalmol 1994; 112: 1190- 7. 18. Cummins D, MacMillan ES, Heron G, Dutton GN. Simul­taneous interocular brightness sense testing in ocular hy­pertension and glaucoma. Arch Ophthalmol 1994; 112: 1198- 203. 19. Lou BG. Modified threshold Amsler grid testing. Chung Hua Yen Ko Tsa Chih 1993; 29: 94- 6. 20. Cerovski B, Car Z, Brzovic Z, Sikic J. Classic migraine and visual field defects. Acta Med Croatica 1995; 49: 127- 31. 21. Johnson LN. The relative afferent pupillary defect and a novel method of fusion recovery with the Worth 4- dot test. Arch Ophthalmol 1996; 114: 171- 5. 22. Burde RM, Landau WM. Shooting backward with Marcus Gunn: a circular exercise in paralogic. Neurology 1993; 43: 2444- 7. 23. Kawasaki A, Moore P, Kardon RH. Variability of the rel­ative afferent pupillary defect. Am J Ophthalmol 1995; 120: 622- 33. 24. Zabriskie NA, Kardon RH. The pupil photostress test. Ophthalmology 1994; 101: 1122- 30. 25. Ettl A, Fischer- Klein C,, Chemelli A, Daxer A, Felber S. Nuclear magnetic resonance spectroscopy. Principles and applications in neuroophthalmology. Int Ophthalmol 1994; 18: 171- 81. 26. George JS, Aine CJ, Mosher JC, et al. Mapping function in the human brain with magnetoencephalography, anatom­ical magnetic resonance imaging, and functional magnetic resonance imaging. J Clin Neurophysiol 1995; 12: 406- 31. 27. Moseley ME, Glover GH. Functional MR imaging. Capa­bilities and limitations. Neuroimaging Clin North Am 1995; 5: 161- 91. 28. Takanashi J, Sugita K, Fujii K, Takatsuna Y, Niimi H. Op­tic neuritis with silent cerebral lesions: availability of FLAIR sequences. Pediatr Neurol 1995; 12: 152- 4. 29. Takehara S, Tanaka T, Uemura K, et al. Optic nerve injury demonstrated by MRI with STIR sequences. Neuroradiology 1994; 36: 512^ L 30. Gass A, Barker GJ, MacManus D, et al. High resolution magnetic resonance imaging of the anterior visual path­way in patients with optic neuropathies using fast spin echo and phased array local coils. J Neurol Neurosurg Psy­chiatry 1995; 58: 562- 9. 31. Breslau J, Dalley RW, Tsuruda JS, Hayes CE, Mara villa KR. Phased- array surface coil MR of the orbits and optic nerves. Am ] Neuroradiol 1995; 16: 1247- 51. 32. Fitzgibbon T, Funke K. Retinal ganglion cell axon diameter spectrum of the cat: mean axon diameter varies according to retinal position. Vis Neurosci 1994; 11: 425- 39. 33. Colello RJ, Schwab ME. A role for oligodendrocytes in the stabilization of optic axon numbers. / Neurosci 1994; 14: 6446- 52. 34. Gutierrez R, Boison D, Heinemann U, Stoffel W. Decom­paction of CNS myelin leads to a reduction of the conduc­tion velocity of action potentials in optic nerve. Neurosci Lett 1995; 195: 93- 6. 35. Cohen- Cory S, Fraser SE. Effects of brain- derived neuro­trophic factor on optic axon branching and remodelling in vivo. Nature 1995; 378: 192- 6. 36. Torriglia A, Blanquet PR. Immonochemical evidence for a fibroblast growth factor receptor in adult retinal optic fiber and synaptic layers. Neuroscience 1994; 60: 969- 81. 37. Kostyk SK, DAmore PA, Herman IM, Wagner JA. Optic nerve injury alters basic fibroblast growth factor localiza­tion in the retina and optic tract. J Neurosci 1994; 14: 1441- 9. 38. Sadun- AA, Dao- J. Annual review of neuro- ophthalmol­ogy: the anterior visual pathways. / Neuroophthalmol 1994; 14: 234- 49. 39. Strijbos PJ, Rothwell NJ. Interleukin- 1 beta attenuates ex­citatory amino acid- induced neurodegeneration in vitro: involvement of nerve growth factor. / Neurosci 1995; 15: 3468- 74. 40. Liberski PP, Yanagihara R, Nerurkar V, Gajdusek DC. Further ultrastructural studies of lesions produced in the optic nerve by tumor necrosis factor alpha ( TNF- alpha): a comparison with experimental Creutzfeldt- Jakob disease. Acta Neurobiol Exp 1994; 54: 209- 18. 41. Madigan MC, Rao NS, Tenhula WN, Sadun AA. Prelim- / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 148 A. A. SADUN AND R. M. RUBIN inary morphometric study of tumor necrosis factor alpha-induced rabbit optic neuropathy. Neurol Res 1996 ( in press). 42. McElhaney MR, Chandler LJ, Streit WJ. Astrocytes but not microglia express NADPH- diaphorase activity after motor neuron injury in the rat. Neurosci Lett 1994; 180: 67- 70. 43. de Knegt RJ, Gramsbergen JB, Schalm SW. 45CaC12 au­toradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia. Metab Brain Dis 1994; 9: 153- 60. 44. Otori Y, Shimada S, Tanaka K, Ishimoto I, Tano Y, Toh-yama M. Marked increase in glutamate- aspartate trans­porter ( GLAST/ GluT- 1) mRNA following transient retinal ischemia. Brain Res Mol Brain Res 1994; 27: 310^ 4. 45. Bush RA, Hawks KW, Sieving PA. Preservation of inner retinal responses in the aged Royal College of Surgeons rat. Evidence against glutamate excitotoxicity in photore­ceptor degeneration. Invest Ophthalmol Vis Sci 1995; 36: 2054- 62. 46. Kikuchi M, Kashii S, Honda Y, et al. Protective action of zinc against glutamate neurotoxicity in cultured retinal neurons. Invest Ophthalmol Vis Sci 1995; 36: 2048- 53. 47. Hartmann J, Ransmayr G, Riederer P. The glycine binding site of the NMDA receptor: involvement in neurodegen-eration and new approach for neuroprotection. J Neural Transm Suppl 1994; 43: 53- 7. 48. Kunig G, Niedermeyer B, Krause F, et al. Interactions of neurotoxins with non- NMDA glutamate receptors: an au­toradiographic study. / Neural Transm Suppl 1994; 43: 59- 62. 49. Garthwaite G, Garthwaite J. Nitric oxide does not mediate acute glutamate neurotoxicity, nor is it neuroprotective, in rat brain slices. Neuropharmacology 1994; 33: 1431- 8. 50. Marin P, Maus M, Desagher S, Glowinski J, Premont J. Nicotine protects cultured striatal neurones against N- methyl- D- aspartate receptor- mediated neurotoxicity. Neuroreport 1994; 5: 1977- 80. 51. Cohen ED, Miller RF. The role of NMDA and non- NMDA excitatory amino acid receptors in the functional organiza­tion of primate retinal ganglion cells. Vis Neurosci 1994; 11: 317- 32. 52. Zeevalk GD, Nicklas WJ. Nitric oxide in retina: relation to excitatory amino acids and excitotoxicity. Exp Eye Res 1994; 58: 343- 50. 53. Youdim MB, Lavie L. Selective MAO- A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's disease. Life Sci 1994; 55: 2077- 82. 54. Buys YM, Trope GE, Tatton WG. (-)- Deprenyl increases the survival of rat retinal ganglion cells after optic nerve crush. Curr Eye Res 1995; 14: 119- 26. 55. Sugaya K, McKinney M. Nitric oxide synthase gene ex­pression in cholinergic neurons in the rat brain examined by combined immunocytochemistry and in situ hybridiza­tion histochemistry. Brain Res Mol Brain Res 1994; 23: 111- 25. 56. Morgan IG, Miethke P, Li ZK. Is nitric oxide a transmitter of the centrifugal projection to the avian retina? Neurosci Lett 1994; 168: 5- 7. 57. Fern R, Ransom BR, Waxman SG. Voltage- gated calcium channels in CNS white matter: role in anoxic injury. / Neu-rophysiol 1995; 74: 369- 77. 58. Gaspar AZ, Flammer J, Hendrickson P. Influence of nifed­ipine on the visual fields of patients with optic- nerve- head diseases. Eur ] Ophthalmol 1994; 4: 24- 8. 59. Papastathopoulos KI, Jonas JB. Focal narrowing of retinal arterioles in optic nerve atrophy. Ophthalmology 1995; 102: 1706- 11. 60. Rader J, Feuer WJ, Anderson DR. Peripapillary vasocon­striction in the glaucomas and the anterior ischemic optic neuropathies. Am ] Ophthalmol 1994; 117: 72- 80. 61. Wang AG, Liu JH, Lin CL, Yen MY. Macular star in optic neuropathy. Ann Ophthalmol 1995; 27: 107- 12. 62. Hamard P, Hamard H, Ngohou S. Leber's idiopathic stel­late neuroretinitis. Apropos of 9 cases. / Fr Ophthalmol 1994; 17: 116- 23. 63. Cohen SM, Davis JL, Gass DM. Branch retinal arterial oc­clusions in multifocal retinitis with optic nerve edema. Arch Ophthalmol 1995; 113: 1271- 6. 64. Wong MT, Dolan MJ, Lattuada CP Jr, et al. Neuroretinitis, aseptic meningitis, and lymphadenitis associated with Bartonella ( Rochalimaea) henselae infection in immuno­competent patients and patients infected with human im­munodeficiency virus type 1. Clin Infect Dis 1995; 21: 352- 60. 65. Purvin VA, Chioran G. Recurrent neuroretinitis. Arch Opthalmol 1994; 112: 365- 71. 66. Golnik KC, Marotto ME, Fanous MM, et al. Ophthalmic manifestations of Rochalimaea species. Am } Ophthalmol 1994; 118: 145- 51. 67. Goldberg MA, Kazacos KR, Boyce WM, Ai E, Katz B. Dif­fuse unilateral subacute neuroretinitis. Morphometric, se­rologic, and epidemiologic support for Baylisascaris as a causative agent. Ophthalmology 1993; 100: 1695- 701. 68. Kinnear FB, Hay J, Dutton GN, Smith HV. Presumed oc­ular larva migrans presenting with features of diffuse uni­lateral subacute neuroretinitis [ Letter]. Br J Ophthalmol 1995; 79: 1140- 1. 69. Fish RH, Hoskins JC, Kline LB. Toxoplasmosis neuro­retinitis. Opthalmology 1993; 100: 1177- 82. 70. Garcia- Arumi J, Salvador F, Corcostegui B, Mateo C. Neu­roretinitis associated with melanocytoma of the optic disk. Retina 1994; 14: 173- 6. 71. Tsai L, Jampol LM, Pollock SC, Oik J. Chronic recurrent multiple evanescent white dot syndrome. Retina 1994; 14: 160- 3. 72. Konigsreuther KA, Jonas JB. Optic disc morphology in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 1995; 233: 200- 4. 73. Barrett TG, Bundey SE, Macleod AF. Neurodegenera-tion and diabetes: UK nationwide study of Wolfram ( DIDMOAD) syndrome. Lancet 1995; 346: 1458- 63. 74. Joko S, Nakano H, Sugai H, Kagoshima M, Kitano S, Hori S. Image analysis of optic disk swelling in diabetic retinop­athy. Nippon Ganka Gakkai Zasshi 1994; 98: 1010- 3. 75. Bertram B, Reim H, Reim M. Bilateral posterior ischemic optic neuritis in an adolescent with diabetes mellitus with decompensated blood glucose homeostasis. Klin Monatsbl Augenheilkd 1995; 206: 39- 45. 76. Honrubia FM, Ferrer E, Torron C, Gonzalez I. Study of the retinal fiber layer in patients with acquired immunodefi­ciency syndrome. Ger J Ophthalmol 1994; 3: 1- 4. 77. Wurdeman AE, Rao NS, Tenhula WN, Foote T, Sadun AA. Optic nerve morphometry following axonal degener­ation from SAIDS in rhesus monkeys. Curr Eye Res 1994; 13: 619- 23. 78. Sadun AA, Pepose JS, Madigan MC, Laycock KA, Ten­hula WN, Freeman WR. AIDS- related optic neuropathy: a histological, virological and ultrastructural study. Graefes Arch Clin Exp Ophthalmol 1995; 233: 387- 98. 79. Wills- EJ, Ghadially- FN. Comments by the panel. " Rasp­berry" particles in optic nerves from an AIDS patient. Ul-trastrud Pathol 1995; 19: 135- 6. 80. Madigan- MC, Sadun- AA. Case for the panel. " Rasp­berry" particles in optic nerves from an AIDS patient. Ul-trastruct Pathol 1995; 19: 133- 5. 81. Madigan MC, Sadun AA, Rao NS, Dugel PU, Tenhula WN, Gil PS. Tumor necrosis factor- alpha- induced optic neuropathy in rabbits. Neurol Res 1996; 18: 176- 84. 82. Sadun AA, Petrovich MS, Madigan MC. Pentoxifylline: clinical application in human immunodeficiency virus-associated optic neuropathy [ Letter]. Ann Neurol 1995; 38: 483. 83. Sweeney BJ, Manji H, Gilson RJ, Harrison MJ. Optic neu­ritis and HIV- 1 infection. / Neurol Neurosurg Psychiatry 1993; 56: 705- 7. 84. Malessa R, Agelink MW, Diener HC. Dysfunction of vi­sual pathways in HIV- 1 infection. / Neurol Sci 1995; 130: 82- 7. / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 THE ANTERIOR VISUAL PATHWAYS 149 85. Bylsma SS, Achim CL, Wiley CA, et al. The predictive value of cytomegalovirus retinitis for cytomegalovirus en­cephalitis in acquired immunodeficiency syndrome. Arch Ophthalmol 1995; 113: 89- 95. 86. Mansor AM, Li HK. Cytomegalovirus optic neuritis: char­acteristics, therapy and survival. Ophthalmologica 1995; 209: 260- 6. 87. Qavi HB, Green MT, Pearson G, Ablashi D. Possible role of HHV- 6 in the development of AIDS retinitis. In Vivo 1994; 8: 527- 32. 88. Smit RL, Baarsma GS, Koudstaal PJ. The source of embo­lism in amaurosis fugax and retinal artery occlusion, lnt Ophthalmol 1994; 18: 83- 6. 89. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am } Ophthalmol 1994; 117: 429^ 11. 90. Katz B, Hoyt WF. Intrapapillary and peripapillary hemor­rhage in young patients with incomplete posterior vitre­ous detachment. Signs of vitreopapillary traction. Ophthal­mology 1995; 102: 349- 54. 91. Budenz DL, Farber MG, Mirchandani HG, Park H, Rorke LB. Ocular and optic nerve hemorrhages in abused infants with intracranial injuries. Ophthalmology 1994; 101: 559- 65. 92. Onda E, Cioffi GA, Bacon DR, van Buskirk EM. Microvas-culature of the human optic nerve. Am ] Ophthalmol 1995; 120: 92- 102. 93. Olver JM, Spalton DJ, McCartney AC. Quantitative mor­phology of human retrolaminar optic nerve vasculature. Invest Ophthalmol Vis Sci 1994; 35: 3858- 66. 94. Cioffi GA, van Buskirk EM. Microvasculature of the ante­rior optic nerve. Surv Ophthalmol 1994; 38( Supp): S107- 17. 95. Orgul S, Mansberger S, Bacon DR, van Buskirk EM, Cioffi GA. Optic nerve vasomotor effects of topical beta-adrenergic antagonists in rabbits. Am ] Ophthalmol 1995; 120: 441- 7. 96. Lovasik JV, Gagnon M, Kergoat H. A novel noninvasive videographic method for quantifying changes in the chro-maticity of the optic nerve head with changes in the in­traocular pressure, pulsatile choroidal blood flow and vi­sual neural function in humans. Surv Ophthalmol 1994; 38 ( Suppl): S35- 51. 97. Ahmed J, Linsenmeier RA, Dunn R Jr. The oxygen distri­bution in the prelaminar optic nerve head of the cat. Exp Eye Res 1994; 59: 457- 65. 98. Chou PI, Sadun AA, Lee H. Vasculature and morphome­try of the optic canal and intracanalicular optic nerve. / Neuro- ophthalmol 1995; 15: 186- 90. 99. Jimenez- Castellanos J, Carmona A, Castellanos L, Cata-lina- Herrera CJ. Microsurgical anatomy of the human oph­thalmic artery: a mesoscopic study of its origin, course and collateral branches. Surg Radiol Anat 1995; 17: 139- 43. 100. Spencer AF, Vernon SA. Optic disc measurement with the Zeiss four mirror contact lens. Br / Ophthalmol 1994; 78: 775- 80. 101. Ruben S. Estimation of optic disc size using indirect bio­microscopy. Br I Ophthalmol 1994; 78: 363- 4. 102. Jonas JB, Papastathopoulos KI. Ophthalmoscopic mea­surement of the optic disc. Ophthalmology 1995; 102: 1102- 6. 103. Jonas JB, Konigsreuther KA. Macrodiscs in eyes with flat and large corneas. Ger J Ophthalmol 1994; 3: 179- 81. 104. Papastathopoulos KI, Jonas JB, Panda- Jonas S. Large optic discs in large eyes, small optic discs in small eyes. Exp Eye Res 1995; 60: 459- 61. 105. Papastathopoulos KI, Jonas JB, Panda- Jonas S. Large optic discs in large eyes, small optic discs in small eyes. Exp Eye Res 1995; 60: 459- 61. 106. Rohrschneider K, Burk RO, Kruse FE, Volcker HE. Repro­ducibility of the optic nerve head topography with a new laser tomographic scanning device. Ophthalmology 1994; 101: 1044- 9. 107. Janknecht P, Funk J. Optic nerve head analyser and Heidelberg retina tomograph: accuracy and reproducibili­ty of topographic measurements in a model eye and in volunteers. Br J Ophthalmol 1994; 78: 760- 8. 108. Stromland K, Hellstrom A, Gustavsson T. Morphometry of the optic nerve and retinal vessels in children by com­puter- assisted image analysis of fundus photographs. Graefes Arch Clin Exp Ophthalmol 1995; 233: 150- 3. 109. Burgoyne CF, Quigley HA, Varma R. Comparison of cli­nician judgment with digitized image analysis in the de­tection of induced optic disk change in monkey eyes. Am ] Ophthalmol 1995; 120: 176- 83. 110. Varma R, Tielsch JM, Quigley HA, et al. Race-, age-, gen­der-, and refractive error- related differences in the normal optic disc. Arch Ophthalmol 1994; 112: 1068- 76. 111. Miglior S, Brigatti L, Velati P, et al. Relationship between morphometric optic disc parameters, sex and axial length. Gun Eye Res 1994; 13: 119- 24. 112. Tomita G, Honbe K, Kitazawa Y. Reproducibility of mea­surements by laser scanning tomography in eyes before and after pilocarpine treatment. Graefes Arch Clin Exp Oph­thalmol 1994; 232: 406- 8. 113. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thi-bault DJ, Zack DJ, Retinal ganglion cell death in experi­mental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995; 36: 774- 86. 114. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994; 117: 603- 24. 115. Strominger MB, Liu GT, Schatz NJ. Optic disk swelling and abducens palsies associated with OKT3. Am J Ophthal­mol 1995; 119: 664- 5. 116. Khawly JA, Rubin P, Petros W, Peters WP, Jaffe GJ. Ret­inopathy and optic neuropathy in bone marrow transplan­tation for breast cancer. Ophthalmology 1996; 103: 87- 95. 117. Lawton AW. Optic neuropathy associated with clomi-phene citrate therapy. Fertil Steril 1994; 61: 390- 1. 118. Manesis EK, Petrou C, Brouzas D, Hadziyannis S. Optic tract neuropathy complicating low- dose interferon treat­ment. / Hepatol 1994; 21: 474- 7. 119. Dupuy O, Flocard F, Vial C, et al. Disulfiram ( Esperal) toxicity. Apropos to 3 original cases. Rev Med Interne 1995; 16: 67- 72. 120. Tabandeh H, Crowston JG, Thompson GM. Ophthalmo­logic features of thallium poisoning. Am } Ophthalmol 1994; 117: 243- 5. 121. Russo PA, Chaglasian MA. Toxic optic neuropathy asso­ciated with ethambutol: implications for current therapy. / Am Optom Assoc 1994; 65: 332- 8. 122. Kohler K, Zrenner E, Weiler R. Ethambutol alters spinule-type synaptic connections and induces morphologic alter­ations in the cone pedicles of the fish retina. Invest Oph­thalmol Vis Sci 1995; 36: 1046- 55. 123. Boulanouar A, Abdallah E, el Bakkali M, Benchrifa F, Ber-raho- Hamani A. Severe toxic optic neuropathies caused by isoniazid. Apropos of 3 cases. / Fr Ophtalmol 1995; 18: 183- 7. 124. Thomas RJ. Neurotoxicity of antibacterial therapy. South Med } 1994; 87: 869- 74. 125. Rizzo JF III, Lessell S. Tobacco amblyopia. Am J Ophthalmol 1993; 116: 84- 7. 126. Golnik KC, Schaible ER. Folate- responsive optic neurop­athy. / Neuroophthalmol 1994; 14: 163- 9. 127. Borruat FX, Hirt L, Regli F. Optic neuropathy caused by alcoholism and smoking: a diagnostic pitfall of Leber's op­tic neuropathy. Rev Neurol 1994; 150: 799- 801. 128. Swartz N, Savino PJ. Is all nondefinable optic atrophy Le­ber's hereditary optic neuropathy? Surv Ophthalmol 1994; 39: 146- 50. 129. Kerrison JB, Howell N, Miller NR, Hirst L, Green WR. Leber hereditary optic neuropathy: electron microscopy and molecular genetic analysis of a case. Ophthalmology 1995; 102: 1509- 16. 130. Sadun AA, Kashima Y, Wurdeman AE. Morphological / Neuro- Ophthalmol, Vol. 16, No. 2, 19% 150 A. A. SADUN AND R. M. RUBIN findings in the visual system in a case of Leber's heredi­tary optic neuropathy. Clin Neurosci 1994; 2: 165- 72. 131. Sadun AA, Sadun F. Leber hereditary optic neuropathy [ Letter]. Ophthalmology 1996; 103: 201- 2. 132. Kerrison JB, Miller NR, Green WR, Hirst L, Howell N. Leber hereditary optic neuropathy [ Author's Reply]. Oph­thalmology 1996; 103: 202. 133. Olsen NK, Hansen AW, Norby S, Edal AL, Jorgensen JR, Rosenberg T. Leber's hereditary optic neuropathy associ­ated with a disorder indistinguishable from multiple scle­rosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 1995; 91: 326- 9. 134. Hanefeld FA, Ernst BP, Wilichowski E, Christen HJ. Le­ber's hereditary optic neuropathy mitochondrial DNA mutations in childhood multiple sclerosis [ Letter]. Neuro-pediatrics 1994; 25: 331. 135. Kellar- Wood H, Robertson N, Govan GG, Compston DA, Harding AE. Leber's hereditary optic neuropathy mito­chondrial DNA mutations in multiple sclerosis. Ann Neu­rol 1994; 36: 109- 12. 136. Harding AE, Riordan- Eva P, Govan GG. Mitochondrial DNA diseases: genotype and phenotype in Leber's hered­itary optic neuropathy. Muscle Nerve 1995; Suppl 3: S82- 4. 137. Shoffner JM, Brown MD, Stugard C, et al. Leber's hered­itary optic neuropathy plus dystonia is caused by a mito­chondrial DNA point mutation. Ann Neurol 1995; 38: 163- 9. 138. Nikoskelainen EK, Marttila RJ, Huoponen K, et al. Leber's " plus"; neurological abnormalities in patients with Leber's hereditary optic neuropathy. / Neurol Neurosurg Psychiatry 1995; 59: 160- 4. 139. Amemiya T, Honda A. A family with optic atrophy and congenital hearing loss. Ophthalmic Genet 1994; 15: 87- 93. 140. Sadun AA, Martone JF, Muci- Mendoza R, et al. Epidemic optic neuropathy in Cuba. Eye findings. Arch Ophthalmol 1994; 112: 691- 9. 141. Sadun AA, Martone JF. Cuba: response to medical science to a crisis of optic and peripheral neuropathy. Int Ophthal­mol 1995; 18: 373- 8. 142. Hirano M, Cleary JM, Stewart AM, et al. Mitochondrial DNA mutations in an outbreak of optic neuropathy in Cuba. Neurology 1994; 44: 843- 5. 143. Johns DR, Neufeld MJ, Hedges TR III. Mitochondrial DNA mutations in Cuban optic and peripheral neuropa­thy. / Neuro- ophthalmol 1994; 14: 135- 40. 144. Johns DR, Sadun AA. Cuban epidemic optic neuropathy. Mitochondrial DNA analysis. / Neuro- ophthalmol 1994; 14: 130- 4. 145. Newman NJ, Torroni A, Brown MD, Lott MT, Fernandez MM, Wallace DC. Epidemic neuropathy in Cuba not as­sociated with mitochondrial DNA mutations found in Le­ber's hereditary optic neuropathy patients. Cuba Neurop­athy Field Investigation Team. Am } Ophthalmol 1994; 118: 158- 68. 146. Roman GC. An epidemic in Cuba of optic neuropathy, sensorineural deafness, peripheral sensory neuropathy and dorsolateral myeloneuropathy. / Neurol Sci 1994; 127: 11- 28. 147. The Cuba Neuropathy Field Investigation Team. Epidemic optic neuropathy in Cuba: clinical characterization and risk factors. N Engl} Med 1995; 333: 1176- 82. 148. Borrajero I, Perez JL, Dominguez C, et al. Epidemic neu­ropathy in Cuba: morphological characterization of pe­ripheral nerve lesions in sural nerve biopsies. / Neurol Sci 1994; 127: 68- 76. 149. Mas- Bermejo P, del Puerto- Quintana C, Barcelo- Perez C, Molina- Esquivel E, Canas- Perez R. Case- control study of epidemic optic neuropathy in Cuba, 1993. Bol Oficina Sanit Panam 1995; 118: 115- 26. 150. Gay J, Porrata C, Hernandez M, et al. Dietary factors in epidemic neuropathy on the Isle of Youth, Cuba. Bull Pan Am Health Organ 1995; 29: 25- 36. 151. Wallace DC. Mitochondrial DNA mutations in diseases of energy metabolism. / Bioenerg Biomembr 1994; 26: 241- 50. 152. Isashiki Y, Nakagawa M, Yamada H, Miyata M. Ocular manifestations in mitochondrial DNA abnormalities. Nip­pon Ganka Gakkai Zasshi 1994; 98: 3- 12. 153. Nijtmans LG, Barth PG, Lincke CR, et al. Altered kinetics of cytochrome c oxidase in a patient with severe mitochon­drial encephalomyopathy. Biochim Biophys Acta 1995; 1270: 193- 201. 154. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy. Population-based study in the state of Missouri and Los Angeles County, California. / Neuroophthalmol 1994; 14: 38- 44. 155. Talks SJ, Chong NH, Gibson JM, Dodson PM. Fibrinogen, cholesterol and smoking as risk factors for non- arteritic anterior ischaemic optic neuropathy. Eye 1995; 9: 85- 8. 156. Chung SM, Gay CA, McCrary JA III. Nonarteritic ischemic optic neuropathy. The impact of tobacco use. Ophthalmol­ogy 1994; 101: 779- 82. 157. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemic diseases associated with nonarteritic anterior ischemic op­tic neuropathy. Am J Ophthalmol 1994; 118: 766- 80. 158. Nasemann JE, Muller M, Pamer S. Systemic perfusion times in non- arteritic anterior ischemic optic neuropathy. Ophthalmologe 1995; 92: 79- 85. 159. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am ] Ophthalmol 1994; 117: 603- 24. 160. Acheson JF, Sanders MD. Coagulation abnormalities in ischaemic optic neuropathy. Eye 1994; 8: 89- 92. 161. Arnold AC, Hepler RS. Fluorescein angiography in acute nonarteritic anterior ischemic optic neuropathy. Am } Oph­thalmol 1994; 117: 222- 30. 162. Purvin VA. Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol 1995; 113: 1041- 4. 163. Chiari M, Manzoni GC, van de Geijn EJ. Ischemic optic neuropathy after sumatriptan in a migraine with aura pa­tient [ Letter]. Headache 1994; 34: 237- 8. 164. Katz DM, Trobe JD. Cornblath WT, Kline LB. Ischemic optic neuropathy after lumbar spine surgery. Arch Oph­thalmol 1994; 112: 925- 31. 165. Lee AG. Ischemic optic neuropathy following lumbar spine surgery. Case report. / Neurosurg 1995; 83: 348- 9. 166. Perlman JI, Forman S, Gonzalez ER. Retrobulbar ischemic optic neuropathy associated with sickle cell disease. / Neu­roophthalmol 1994; 14: 45- 8. 167. Brown RH, Schauble JF, Miller NR. Anemia and hypoten­sion as contributors to perioperative loss of vision. Anes­thesiology 1994; 80: 222- 6. 168. Connolly SE, Gordon KB, Horton JC. Salvage of vision after hypotension- induced ischemic optic neuropathy. Am } Ophthalmol 1994; 117: 235- 42. 169. Lee AG. Reversible loss of vision due to posterior ischemic optic neuropathy. Can ] Ophthalmol 1995; 30: 327- 9. 170. Johnson LN, Gould TJ, Krohel GB. Effect of levodopa and carbidopa on recovery of visual function in patients with nonarteritic anterior ischemic optic neuropathy of longer than six months' duration. Am ] Ophthalmol 1996; 121: 77- 83. 171. Haas A, Uyguner I, Sochor GE, Schmut O, Vidic B, Faul-born J. Non- arteritic anterior ischemic optic neuropathy: long- term results after hemodilution therapy. Klin Monatsbl Augenheilkd 1994; 205: 143- 6. 172. Gorman RF. The treatment of presumptive optic nerve ischemia by spinal manipulation. / Manipulative Physiol Ther 1995; 18: 172- 7. 173. Yee RD, Selky AK, Purvin VA. Outcomes of optic nerve sheath decompression for nonarteritic ischemic optic neu­ropathy. / Neuro- ophthalmol 1994; 14: 70- 6. 174. Glaser JS, Teimory M, Schatz NJ. Optic nerve sheath fen­estration for progressive ischemic optic neuropathy. Re­sults in second series consisting of 21 eyes. Arch Ophthal­mol 1994; 112: 1047- 50. 175. The Ischemic Optic Neuropathy Decompression Trial Re- / Neuro- Ophthalmol, Vol. 16, No. 2, 2996 THE ANTERIOR VISUAL PATHWAYS 151 search Group Optic nerve decompression surgery for non-arteritic anterior ischemic optic neuropathy ( NAION) is not effective and may be harmful. JAMA 1995; 273: 625- 32. 176. Lessell S. Surgery for ischemic optic neuropathy [ Edito­rial]. Arch Ophthalmol 1995; 113: 273^ t. 177. Beck RW. Optic nerve sheath fenestration for anterior ischemic optic neuropathy? The answer is in [ editorial]. / Neuro- ophthalmol 1995; 15: 61- 2. 178. Arnold AC, Hepler RS. Natural history of nonarteritic an­terior ischemic optic neuropathy. / Neuro- ophthalmol 1994; 14: 66- 9. 179. Swartz NG, Beck RW, Savino PJ, et al. Pain in anterior ischemic optic neuropathy. / Neuro- ophthalmol 1995; 15: 9- 10. 180. Orgul S, Gass A, Hammer J. Optic disc cupping in arteritic anterior ischemic optic neuropathy. Ophthalmologica 1994; 208: 336- 8. 181. Schmidt D, Loffler KU. Temporal arteritis. Comparison of histological and clinical findings. ACTA Ophthalmologica 1994; 72: 319- 25. 182. Liu GT, Glaser JS, Schatz NJ, Smith JL. Visual morbidity in giant cell arteritis. Clinical characteristics and prognosis for vision. Ophthalmology 1994; 101: 1779- 85. 183. Ho AC, Sergott RC, Regillo CD, et al. Color Doppler he­modynamics of giant cell arteritis. Arch Ophthalmol 1994; 112: 938- 45. 184. Rosier DH, Conway MD, Anaya JM, et al. Ischemic optic neuropathy and high- level anticardiolipin antibodies in primary Sjogren's syndrome. Lupus 1995; 4: 155- 7. 185. Matsuda A, Chin S, Ohashi T. A case of neuroretinitis associated with long- standing polyarteritis nodosa. Oph­thalmologica 1994; 208: 168- 71. 186. Massry GG, Chung SM, Selhorst JB. Optic neuropathy, headache, and diplopia with MRI suggestive of cerebral arteritis in relapsing polychondritis. / Neuroophthalmol 1995; 15: 171- 5. 187. Gallinaro C, Robinet- Combes A, Sale Y, Richard P, Saraux A, Colin J. Neuropapillitis in Behcet disease: a case. / Fr Ophtalmol 1995; 18: 147- 50. 188. Flechtner KM, Baum K. Mixed connective tissue disease: recurrent episodes of optic neuropathy and transverse myelopathy. Successful treatment with plasmapheresis. / Neurol Sci 1994; 126: 146- 8. 189. Liou HH, Yip PK, Chang YC, Liu HM. Allergic granulo­matosis and angiitis ( Churg- Strauss syndrome) presenting as prominent neurologic lesions and optic neuritis. / Rheu­matol 1994; 21: 2380- 4. 190. Kattah JC, Chrousos GA, Katz PA, McCasland B, Kolsky MP. Anterior ischemic optic neuropathy in Churg- Strauss syndrome. Neurology 1994; 44: 2200- 2. 191. Foster WP, Greene JS, Millman B. Wegener's granuloma­tosis presenting as ophthalmoplegia and optic neurology. Otolaryngol Head Neck Surg 1995; 112: 758- 62. 192. Ahmadieh H, Roodpeyma S, Azarmina M, Soheilian M, Sajjadi SH. Bilateral simultaneous optic neuritis in child­hood systemic lupus erythematosus. A case report. / Neuro- ophthalmol 1994; 14: 84- 6. 193. Borruat FX, Prado T, Strominger M, Schatz NJ, Glaser JS. Neuro- ophthalmologic complications of disseminated lu­pus erythematous. Klin Monatsbl Augenheilkd 1994; 204: 403- 6. 194. Castagna I, Salmeri G, Fama F, Trombetta CJ, Ricci R, Traclo CD. Optic nerve granuloma as first sign of systemic sarcoidosis. Ophthalmologica 1994; 208: 230- 2. 195. el Zarka A, Hille K, Ruprecht KW. Granulomatous process of the optic papilla as an initial sign of systemic sarcoid­osis. Klin Monatsbl Augenheilkd 1995; 206: 134- 5. 196. Augustin AJ, Boker T, Seewald S, Klassen PM. Solitary retinal granuloma as a presenting sign of sarcoidosis. Ger J Ophthalmol 1994; 3: 71- 2. 197. Carmody RF, Mafee MF, Goodwin JA, Small K, Haery C. Orbital and optic pathway sarcoidosis: MR findings. Am J Neuroradiol 1994; 15: 775- 83. 198. Beck AD, Newman NJ, Grossniklaus HE, Galetta SL, Kramer TR. Optic nerve enlargement and chronic visual loss. Surv Ophthalmol 1994; 38: 555- 66. 199. Westlake, Heath JD, Spalton DJ. Sarcoidosis involving the optic nerve and hypothalamus. Arch Ophthalmol 1995; 113: 669- 70. / Neuro- Ophthalmol, Vol. 16, No. 2, 1996