Journal of Neuro-Ophthalmology, June 1994, Volume 14, Issue 2

Neuro ophthalmology and systemic disease.

Journal of Neuro- Ophthalmology 14( 2): 105- 117, 1994. © 1994 Raven Press, Ltd., New York Neuro- Ophthalmology and Systemic Disease An Annual Review ( 1993) Nancy J. Newman, M. D. Any disease process affecting the nervous sys­tem may have neuro- ophthalmologic manifesta­tions and implications. Whereas others have re­viewed the recent neuro- ophthalmologic literature anatomically, this review will highlight those ad­vances in our knowledge of systemic disease as they appear to the neuro- ophthalmologist. Many of the most important contributions of 1993 were in the areas of molecular genetics and vascular dis­ease. GENETIC DISEASE Abnormalities of the nuclear and mitochondrial genomes have been implicated in human disease, and recent advances in molecular genetics have facilitated the diagnosis and furthered our under­standing of genetic diseases that have neuro-ophthalmologic manifestations. Several reviews are of interest, and the mitochondrial genome has proved a particularly fertile ground for investiga­tion and publication ( 1- 4). The circular mitochondrial DNA ( mtDNA) con­tains only 16,500 bases as compared to the 3 x 109 bases contained within the nuclear genome. How­ever, given that there are 2- 10 mtDNAs in each mitochondrion and hundreds of mitochondria per cell, the mtDNA comprises approximately 0.3% of the cell's total DNA. Its relative small size makes the mtDNA more accessible to study, and the en- From the Departments of Ophthalmology, Neurology, and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, U. S. A. This work was supported in part by a departmental grant ( Ophthalmology) from Research to Prevent Blindness, Inc., New York, N. Y., and by NIH grant # P30 EY06360 ( Ophthal­mology). Address correspondence and reprint requests to Dr. Nancy J. Newman, Neuro- Ophthalmology Unit, Emory Eye Center, 1327 Clifton Road, N. E., Atlanta, GA 30322, U. S. A. tire gene sequence has been determined. Mito­chondrial DNA codes for all the transfer RNAs and ribosomal RNAs required for intramitochondrial protein production, as well as for 13 proteins es­sential to the oxidative- phosphorylation system. The majority of proteins crucial to normal oxida­tive- phosphorylation function are encoded on nu­clear genes, manufactured in the cytoplasm and transported into the mitochondria. Hence " mito­chondrial disease" could conceivably result from genetic defects in either the nuclear or mitochon­drial genomes. Many of the recent publications on mitochon­drial genetics have continued to advance our un­derstanding of Leber's hereditary optic neuropa­thy ( LHON). In a recent review ( 5), I summarized the clinical and genetic developments regarding LHON, a maternally inherited, bilaterally-sequential optic neuropathy that occurs in other­wise healthy young adults, primarily men. Visual acuity usually deteriorates permanently to 20/ 200 or worse, although spontaneous recovery, even years later, has been reported. Funduscopic ap­pearance during the acute phase of visual loss may be normal, or there may be optic disc hyperemia, telangiectasias, pseudoedema, or vascular tortuos­ity. Ultimately, there is optic disc pallor with sig­nificant loss of nerve fiber layer, predominantly in the papillomacular bundle. Since 1988, several point mutations in the mtDNA have been associated with LHON, and they are named for their nucleotide position along the circular mitochondrial genome. So- called " pri­mary" mutations are believed to confer a genetic risk for LHON expression by themselves, change the coding for evolutionarily conserved amino ac­ids in essential proteins, are found in multiple dif­ferent LHON pedigrees, and are absent or rare among controls. So- called " secondary" mutations are found with greater frequency among LHON 105 106 N. J. NEWMAN patients than controls, but may not in and of themselves confer a risk of blindness. They may interact synergistically with each other, the pri­mary mutations, or environmental or nuclear fac­tors to increase the risk of disease expression. Pri­mary mutations previously described include those at positions 11778 ( accounting for 40- 90% of LHON), 3460 ( accounting for 8- 25% of LHON), 14484 ( accounting for approximately 10% of LHON), and 15257 ( accounting for approximately 10% of LHON). There has been some debate whether the mutation at position 15257 should be considered primary or secondary ( 6). Secondary mutations may include those at nucleotide posi­tions 3394, 4216, 4917, 5244, 7444, 13708, and 15812. During 1993, three new mtDNA mutations were proposed as causal in LHON ( 7,8). Johns and Neufeld ( 7) reported two new mtDNA mutations at positions 9438 and 9804 within the gene encod­ing for subunit III of cytochrome oxidase, complex IV in the respiratory chain. The 9438 mutation was found in five independent LHON probands, the 9804 in three, accounting for approximately 4% of LHON probands. These mutations were not found in 400 controls. Howell and colleagues ( 8) reported a missense mutation at position 13730 in the mtDNA of one LHON proband. The mutation al­ters an evolutionarily conserved codon in the ND5 subunit of complex 1 in the respiratory chain. It would not be surprising to discover other individ­ual mtDNA point mutations associated with LHON in one or two isolated probands, poten­tially accounting for the remainder of the as yet molecularly unidentified LHON cases ( approxi­mately 10% of LHON). It is now clear that the LHON phenotype can result from different point mutations in the mtDNA encoding for different subunits and complexes of the oxidative-phosphorylation system. This suggests that bilat­eral optic neuropathy, predominantly in young adult men, may be a manifestation of a generalized reduction in oxidative- phosphorylation capacity. Mitochondrial DNA point mutation analysis can be performed on dried blood spots by using direct polymerase chain reaction amplification ( 9,10). Im­portant in all molecular genetic diagnosis via the polymerase chain reaction and the use of restric­tion endonucleases, however, is the potential for false positive results secondary to adjacent DNA polymorphisms ( 11). It is therefore desirable to confirm the presence of a missence mutation with a second restriction enzyme and to sequence the region in question. Genetic analysis has allowed for a broader view of what constitutes the clinical profile of LHON, and many articles published in 1993 addressed this issue. Johns and colleagues ( 12,13) reported the clinical manifestations of patients with the 14484 and 15257 mutations and compared them to pre­vious descriptions of patients with the 11778 and 3460 mutations. Although total numbers are small and referral bias must be considered in the inter­pretation of these data, it would appear that among the primary mutations, patients with the 14484 mutation have the greatest potential for vi­sual recovery ( 7 of 19 [ 37%]), those with the 15257 mutation have the next highest rate of recovery ( 5 of 18 [ 28%]), and those with the 11778 mutation have the worst rate ( approximately 5%). The 15257 mutation may be associated with a higher inci­dence of minor neurologic symptoms and signs, such as peripheral neuropathy ( 13), and even ret­inal disturbances, as was noted in three cases of maculopathy ( 14). It was also proposed that met­abolic disturbances such as diabetes mellitus, sub­stance abuse, and trauma may contribute to LHON disease expression ( 12,15,16). Many cases of LHON are singleton probands without a family history of visual loss, some are women, some are outside the typical age range for LHON, and some are without the classic fundu-scopic findings ( 17). Some patients previously di­agnosed as having tobacco- alcohol amblyopia have tested positive for the primary LHON mutations, raising the question of misdiagnosis versus under­lying mitochondrial susceptibility to toxins ( 16). Previous reports of disease clinically indistinguish­able from multiple sclerosis in patients with even molecularly proven LHON have been confirmed ( 18,19), suggesting the possibility of mtDNA in­volvement in immunologically mediated pathol­ogy. Attempts to explain the male predominance of expression of LHON by an X- linked visual loss susceptibility gene have not been successful, and previous data suggesting such linkage have been reanalyzed and withdrawn ( 20). Heteroplasmy ( the occurrence of both normal and mutant mito­chondrial DNA in the same individual) may re­duce the risk of clinical expression of LHON, al­though once a person becomes symptomatic, there does not appear to be any clinical difference in disease expression ( 21). There is a tendency within pedigrees to progress toward mutant homoplasmy in successive generations. Another disease of neuro- ophthalmic interest, also linked to abnormalities of mitochondrial DNA, is MELAS ( mitochondrial myopathy, en­cephalopathy, lactic acidosis and stroke- like epi­sodes) ( 22). The classic clinical phenotype in MELAS is a patient of short stature who has the / Neuro- Ophthalmol, Vol. 14, No. 2, 1994 SYSTEMIC DISEASE 107 onset, in the first or second decades of life, of re­current headaches, seizures, stroke- like episodes with focal neurologic deficits, cognitive regression with disease progression, and ragged- red fibers on muscle biopsy. The stroke- like episodes have a pre­dilection for the posterior portions of the cere­brum, and retrochiasmal visual loss is seen in at least 60% of cases. These lesions do not respect vascular borders and there is a greater chance of recovery than is seen in classic cerebral infarction ( even when compared to young stroke patients). MELAS is either sporadic or maternally inher­ited, and has been linked with two mitochondrial DNA point mutations at positions 3243 and 3271 located in the gene that codes for a transfer RNA. Heteroplasmy for these mutations may play a role in clinical expression ( 23). Increased mutant mito­chondrial DNA in cerebral blood vessels may con­tribute to the stroke- like episodes ( 24). Radio­graphic studies showed no reduction in cerebral blood flow in these regions, suggesting metabolic dysfunction rather than ischemic stroke as the un­derlying pathogenesis ( 25). Genetic analysis has broadened our view of what constitutes the clinical phenotype of MELAS ( 26- 31). Patients with the 3243 mutation may have ptosis and external ophthalmoplegia, pigmentary retinopathy, and even optic neuropathy. Certainly the recognition of any of these neuro- ophthalmic signs in a patient with an otherwise unspecified neurologic or systemic disease should raise suspi­cion of a mitochondrial disorder. Other patients harboring the MELAS mitochondrial DNA muta­tions may be asymptomatic or present without stroke- like episodes but with migraine, sensorineu­ral hearing loss, pigmentary retinopathy, or endo­crine disorders such as diabetes mellitus. MELAS has even been mistakenly diagnosed as recurrent herpes simplex encephalitis ( 31). Another mitochondrial DNA point mutation, at position 8993 in the gene encoding for the ATPase 6 protein, also accounts for a variable clinical syn­drome with neurologic and ophthalmologic mani­festations ( 32- 34). Originally designated NARP ( neurogenic muscle weakness, ataxia, and retinitis pigmentosa), the clinical syndrome associated with the 8993 mutation may be that of Leigh syn­drome, olivopontocerebellar degeneration, severe dementia with pigmentary retinopathy and sen­sorineural deafness, or merely recurrent migraine headaches. The type and extent of retinal pigmen­tary changes and neurologic findings may vary substantially, even among members of the same family, and may relate some to the degree of het­eroplasmy for the 8993 mutation in various tissues. It should be recognized that Leigh syndrome, like so many other symptom complexes in neurology and ophthalmology, is not specific for a particular mitochondrial DNA mutation or even for an ab­normality of mitochondrial DNA ( 35- 37). Indeed, many patients with this syndrome have an auto­somal recessive pattern of inheritance, and an X- linked form was recently reported ( 36). This lack of genotypic- phenotypic specificity among the metabolic diseases may also be seen among pa­tients harboring mitochondrial DNA deletions, a genetic abnormality classically associated with chronic progressive ophthalmoplegia, and the Kearns- Sayre phenotype. One patient with mito­chondrial DNA deletions and otherwise classic Kearns- Sayre syndrome was found to have a chor-oideremia- like fundus appearance rather than pig­mentary retinopathy ( 38), and another patient with deletions had the myo- neuro- gastrointestinal encephalopathy syndrome ( 39). Similarly, mag­netic resonance imaging of the mitochondrial dis­orders is not specific for particular mutations or syndromes, although there appears to be a pro­pensity for involvement of the deep gray matter and, when white matter is affected, the peripheral rather than deep white matter ( 40,41). Unfortu­nately, attempts to treat the mitochondrial dis­eases with coenzyme Q10 and multiple vitamins has in general proved ineffective ( 42). Gene ther­apy for both mitochondrial and nuclear genetic diseases is in its investigative infancy, but is likely to become reality ( 43). Abnormalities of the nuclear genome may result in metabolic diseases, syndromes with both oph­thalmologic and neurologic manifestations, disor­ders of specific ocular structures, or congenital malformation syndromes ( 44). As regards the ret­ina, the most dramatic developments have been in the identification of candidate genes and muta­tions within these genes associated with retinitis pigmentosa ( 45). As with the mitochondrial DNA mutations, molecular analysis has allowed for a broadening of the phenotype of these diseases ( 46,47). Similarly, genetic analysis has helped to define and clarify the disease states traditionally known as neurofibromatosis ( 48,49). Neurofibro­matosis type 1 ( NF1) maps to chromosome 17 and neurofibromatosis type 2 ( NF2) to chromosome 22. They have overlapping features, including an in­herited propensity for neurofibromas, tumors of the central nervous system, and hamartomas. Oc­ular manifestations of NF1 commonly include Lisch nodules and optic nerve and chiasmal glio­mas, while NF2 patients are more likely to have posterior subcapsular cataracts and epiretinal / Neuro- Ophthalmol, Vol. 14, No. 2, 1994 108 N. J. NEWMAN membranes, as well as optic nerve sheath menin­giomas and optic disc gliomas ( 48- 51). Direct diag­nosis of myotonic dystrophy is now possible using a specific DNA probe on the DNA extracted from peripheral blood ( 52). Other syndromes await metabolic and molecular characterization. Familial olivopontocerebellar at­rophy may be manifest by electroretinographic ab­normalities, even in asymptomatic family mem­bers with normal funduscopic examinations ( 53). Behr syndrome, in which early- onset optic atrophy with significant visual loss is accompanied by chronic neurologic disturbances, including ataxia, extrapyramidal dysfunction, and juvenile spastic paresis, is relatively common among Iraqi Jews, and metabolic studies showed abnormally ele­vated excretion of urinary 3- methylglutaconic acid ( 54). A newly described X- linked recessive disease in a five- generation Dutch family is manifested by optic atrophy, ataxia, deafness, flaccid tetraplegia, and areflexia ( 55). No biochemical, immunologic, or genetic defects were identified, although patho­logic examination showed almost complete ab­sence of myelin in the posterior columns. Inconti­nentia pigmenti, an X- linked disease characterized by lethality in most male embryos, should be in­cluded in the differential diagnosis of female pa­tients with peripheral retinal vascular nonperfu-sion, preretinal neovascularization, infantile reti­nal detachment, foveal hypoplasia, or cerebral ischemia and hemorrhagic necrosis, especially if there is evidence of the characteristic dermatosis ( 56). Other syndromes of ocular, neurologic, and systemic malformations reviewed during 1993 in­clude the Alagille syndrome ( 57), the lacrimoauric-ulodentodigital syndrome ( 58), and a new syn­drome of myelinated nerve fibers, vitreoretinopa-thy, and skeletal malformations ( 59). VASCULAR DISEASE Vascular diseases can affect the afferent visual system anywhere from the eye to the occipital lobes, and the suprastriate visual association areas. Similarly, the efferent system can be involved su-pratentorially or in the brainstem. The pathogen­esis of these diseases include intrinsic disease of the cerebral vasculature or its parent feeding ves­sels, embolism from cardiac or arterial sources, or abnormalities of the normal hemostatic mecha­nisms controlling coagulation and fibrinolysis. Transient or permanent monocular visual loss can result from interruption of the retinal or cho­roidal circulations. Florid ocular infarction occurs rarely because of the rich anastomotic vasculariza­tion of the orbit, but a relative ischemic syndrome may result from global perfusion insufficiency or diffuse vasculitis ( 60). Perfusion problems should be suspected even in patients with monocular vi­sual loss in whom the cause of the problem is not detected on funduscopic examination. Appropri­ately timed and oriented fluorescein angiography may reveal occult vascular disease of either the choroid or retina ( 61). Fluorescein angiography in ophthalmologically asymptomatic patients may also demonstrate prolonged arteriovenous passage time independent of hypertension or diabetes in those with brain lacunar infarctions, supporting an underlying microcirculatory abnormality ( 62). The parent circulation of the eye and orbit is the carotid artery system, and carotid disease may re­sult in ocular ischemia or infarction. A notable ex­ception may be anterior ischemic optic neuropa­thy, in which infarction of the prelaminar optic nerve may be related to more local factors such as a crowded optic nerve head or small- vessel dis­ease. A preliminary prospective study of anterior ischemic optic neuropathy showed no association with carotid artery disease when compared with age- and sex- matched asymptomatic patients ( 63). Abnormal iris transluminance and an increased prevalence of pseudoexfoliation may be markers of extracranial carotid disease ( 64). Noninvasive du­plex ultrasound examination of the extracranial ca­rotid system provides morphologic information that may be of prognostic value for stroke or retinal infarction, especially if complex heterogeneous plaques are identified ( 65,66). Color Doppler im­aging of orbital arteries may be useful in the study of the hemodynamics of carotid artery disease and of intrinsic disease of the ophthalmic vessels ( 67). Carotid or even thoracic aorta dissections may be detected with noninvasive methods, including ca­rotid Doppler imaging, transesophageal echocardi­ography and color- coded Doppler echocardiogra­phy ( 68). Distal ischemic events may occur, includ­ing, rarely, ocular motor nerve palsies ( 69). Carotid endarterectomy in the treatment of ex­tracranial carotid disease still remains controver­sial, although some information regarding specific subgroups is now available ( 70). Previous reports in 1991 from the North American Symptomatic Ca­rotid Endarterectomy Trial ( NASCET) ( 71), the Eu­ropean Carotid Surgery Trial ( ECST) ( 72), and the Veterans Administration Symptomatic Trial ( 73) showed efficacy for surgery in patients with ipsi-lateral symptomatic carotid artery stenosis of greater than 70%. Although carotid endarterecto­my in this group was beneficial among those who presented with transient monocular visual loss, it / Neuro- Ophthalmol, Vol. 14, No. 2, 1994 SYSTEMIC DISEASE 109 is important to note that the cumulative risk for stroke at 2 years was only 17% in those patients entered into the study with retinal transient isch­emic attacks, as compared to 44% in those patients with hemispheric transient ischemic attacks ( 72). Three trials in asymptomatic patients with signifi­cant carotid stenosis failed to show a statistically significant benefit for surgery in the prevention of stroke or death, but none of the studies was large enough to exclude such a benefit ( 74- 77). Most im­portantly, the majority of deaths among patients with carotid artery disease was the result of heart disease, not stroke. Cerebral embolism is a frequent mechanism causing brain infarction. Sources of emboli include the heart ( valvular, nonvalvular), or a proximal ar­tery, so- called artery- to- artery embolism. Timsit and colleagues ( 78) reported that artery- to- artery embolic infarctions were more likely to be located superficially, while an initially abnormal CT and decreased consciousness was suggestive of a car­diac source. They concluded that arterial embolism involves smaller particle size and smaller, more distal infarction than cardiogenic embolism. Car­diac emboli will lodge more frequently in the an­terior circulation, but transcranial Doppler studies have shown that embolism to the posterior intra­cranial circulation may be more common than pre­viously believed ( 79,80). Transesophageal echocar­diography can reveal possible cardiac sources of cryptogenic stroke and retinal infarction, including patent foramen ovale and atrial septal aneurysm ( 81,82). This is particularly relevant in the young patient. Caplan ( 80) nicely reviewed the topic of brain embolism and stressed that the treatment should depend on the nature of the embolic mate­rial, if discoverable or predictable, and not on whether the source was cardiac or intra- arterial. For example, red clots ( those in patients with atrial fibrillation, cardiac wall abnormalities, or areas of reduced arterial flow) are best treated with antico­agulation, while sources of platelet- fibrin emboli ( arterial or cardiac valvular lesions) are better treated with antiplatelet agents. Intracranial large vessel disease is a significant cause of stroke in the posterior circulation ( 83). Al­though basilar artery stenosis and occlusion have been associated with fatal or severe brainstem in­farction, recent studies suggest that significant basilar disease may result in more limited stroke syndromes, presumably on the basis of local occlu­sion of the origin of paramedian perforating arter­ies. Vertebral artery disease is the most common cause of Wallenberg's lateral medullary syndrome ( 84). The triad of Horner syndrome, ipsilateral ataxia, and contralateral hypalgesia will clinically identify a lateral medullary infarction. Ipsilateral facial weakness is common, as are ocular motility abnormalities, including nystagmus, ocular latero-pulsion, and skew deviation. Cerebellar infarc­tions are surprisingly rare. Transient ischemic attacks ( TIAs) represent an important warning sign of stroke. By means of multivariate analysis of data from the Dutch TIA study, independent risk factors for stroke, myocar­dial infarction, or vascular death were identified: age greater than 65 years, male sex, dysarthria, multiple attacks, diabetes, angina pectoris, inter­mittent claudication, CT evidence of any cerebral infarct, electrocardiographic evidence of an an-teroseptal infarct, ST depression, left ventricular hypertrophy, or left atrial conduction delay ( 85). A predictor of good outcome was transient monocu­lar attacks only. The Dutch TIA study also showed that 55% of the patients who suffered a recurrent ischemic stroke had infarctions in the same terri­tory as their qualifying ischemic events ( 86). These recurrent events from the same arterial lesion oc­curred sooner than strokes associated with other lesions. As regards therapeutic intervention for treat­ment and prevention, previous analysis of the Ticlopidine Aspirin Stroke Study revealed that ticlopidine ( at 250 mg twice daily) reduced the overall risk of stroke by 21%, compared with aspi­rin ( at 650 mg twice daily) ( 87). Further subgroup analysis suggests that the reduction of stroke seen in the entire cohort also applies to the nonwhite patients in the study ( 88), and that ticlopodine is also better than aspirin for reducing the risk of subsequent transient ischemic attacks ( 89). Ad­verse effects associated with ticlopidine included diarrhea, rash, and neutropenia, all reversible. In the European Stroke Prevention Study, patients with a recent TIA or stroke treated with aspirin plus dipyridamole, compared to patients who re­ceived placebo, had a 33% reduction in subsequent strokes or death and a 40% risk reduction of myo­cardial infarction ( 90). In patients with nonrheu-matic atrial fibrillation and a recent history of TIA or minor stroke, oral anticoagulation therapy low­ers the risk of recurrent stroke more than aspirin or placebo ( 91,92). In patients with mechanical heart valves and high- risk patients with prosthetic tissue valves, the addition of aspirin to warfarin therapy reduced mortality from vascular causes, together with major systemic embolism ( 93). Transient ischemic attacks in young patients have many clinical and etiologic differences from those in older patients, with important diagnostic ; Neuro- Ophthalmol, Vol. 14, No. 2, 1994 210 N. /. NEWMAN and therapeutic implications. In younger patients, TIAs are less likely to occur in the vertebrobasilar territory, and migraine, valvular heart disease, mi­tral valve prolapse, fibromuscular dysplasia, and oral contraceptive use are more common ( 94,95). However, even in young patients, a TIA or stroke is a strong marker for atheromatous cerebrovascu­lar disease, especially if other risk factors are present. Migrainous stroke is more common in in­dividuals with aura than those who are aura- free, but this association is of little value in attempting to distinguish patients destined for stroke from the general migraine population ( 96). Patients who do suffer migraine- associated stroke are at signifi­cantly increased risk for recurrent stroke. Vasospasm has been proposed as causal in some individuals with bouts of transient monocular vi­sual loss ( 97,98). Winterkorn and colleagues ( 97) reported nine patients with frequent attacks of pre­sumed vasospastic amaurosis fugax, many of whom had evidence of systemic coagulopathies or vasculitides. There was dramatic cessation of re­current episodes of visual loss after treatment with calcium channel blockers, specifically nifedipine. However, this cannot be used as direct evidence that the mechanism underlying these episodes of visual loss is that of vasospasm; pathophysiology cannot be assumed from the positive action of a medicine. Abnormalities of the hemostatic system proba­bly account for 15- 28% of unexplained systemic vascular thrombosis in young patients, and this may manifest as retinal arterial or venous occlu­sion ( 99,100). The presence of antiphospholipid antibodies ( 101,102) is the most frequently re­ported abnormal hematologic factor in patients with retinal vascular occlusion, followed by inher­ited deficiencies in antithrombin III, protein C, or protein S. Patients younger than 45 with a history or family history of previous thromboembolic events should be hematologically screened. Anti-cardiolipin antibodies may be an independent risk factor for first ischemic stroke, even in older pa­tients ( 102). Antiphospholipid antibodies may also predispose to cerebral venous thrombosis and a pseudotumor cerebri- like syndrome ( 103). Cerebral venous thrombosis associated with pregnancy and puerperium has a more acute onset and a better prognosis than thrombosis due to other causes ( 104). A vascular disease of utmost importance to the neuro- ophthalmologist is giant cell arteritis. Marked delay in choroidal filling on fluorescein an­giography or clinically apparent choroidal isch­emia should strongly suggest the diagnosis of gi­ant cell arteritis ( 105,106). Postel and Pollock ( 107) reported a 47- year- old man with fulminant giant cell arteritis, severe visual loss, profoundly de­layed choroidal filling with choroidal infarction, and ocular and orbital ischemia. Aggressive treat­ment with intravenous corticosteroids resulted in dramatic improvement. A retrospective study of the visual prognosis in giant cell arteritis con­cluded that the development or progression of vi­sual loss was rare after the initiation of steroids ( 108). However, the number of cases was too small to assess the optimal initial dosage, route of administration, or maintenance dosage of gluco­corticoids in the treatment of giant cell arteritis. Other vasculitides with ophthalmic and neuro-ophthalmic manifestations include polyarteritis nodosa ( 109), Churg- Strauss vasculitis ( 110), pulseless ( Takayasu) disease ( 111), idiopathic granulomatous angiitis of the central nervous sys­tem ( 112), and Wegener's granulomatosis ( 113- 116). Wegener's granulomatosis may also present with prominent meningeal or intracranial involve­ment, in the absence of nasal or renal disease. An-tineutrophil cytoplasmic autoantibodies are very helpful in making the diagnosis of Wegener's granulomatosis and cyclophosphamide is often successful in treatment. Other possible causes of cerebral ischemia, ocu­lar ischemia, or infarction include cocaine use ( 117), hyperhomocysteinemia ( 118), meningeal carcinomatosis ( 119), primary thrombocythemia ( 120), dural arteriovenous fistula ( 121), postradia-tion vasculopathy of the moyamoya type ( 122), and spondolytic compression of the vertebral ar­tery ( 123,124). Other vascular lesions of neuro-ophthalmic interest include carotid cavernous fis­tulas of the direct and dural type, arteriovenous malformations, aneurysms, and dolichoectatic ves­sels. They may cause symptoms and signs by a variety of mechanisms in addition to vascular oc­clusion and hemorrhage, including mass effect or local meningeal irritation or inflammation. The clinical spectrum of unruptured intracranial aneu­rysms was recently reviewed ( 125). Magnetic res­onance angiography may ultimately obviate con­ventional angiography in the workup of patients with many of these vascular disorders ( 126). AIDS The neuro- ophthalmic manifestations of the ac­quired immunodeficiency syndrome ( AIDS) are protean, frequently involving the optic nerve, and commonly caused by opportunistic infections. Re­cent reports have emphasized the importance of I Neuro- Ophthalmol, Vol. 14, No. 2, 1994 SYSTEMIC DISEASE 111 cryptococcosis as a cause of significant visual loss in AIDS patients ( 127- 129). Most of these patients have an underlying cryptococcal meningitis. Pro­posed mechanisms of visual loss include optic nerve infiltration, constrictive arachnoiditis of the anterior visual pathways, and acute or chronically elevated intracranial pressure with papilledema. Amphoteracin B, the " mainline" treatment for fungal disease, may be toxic to the optic nerve, especially in patients with cryptococcal disease. Vi­sual loss in AIDS patients with cryptococcosis may be gradually progressive or may occur suddenly, bilaterally, and profoundly. Treatment should at­tempt to prevent proliferation of fungal organisms at the earliest stage possible. One group advocates optic nerve sheath fenestration as a treatment al­ternative in those AIDS patients with cryptococcal meningitis, papilledema, and progressive visual loss who have failed maximum medical manage­ment ( 129). Visual function may improve, but the risk- benefit ratio may not be sufficient to justify such invasive management in these patients. Herpes zoster may be the first manifestation of AIDS and the presence of a zoster infection in a person younger than 45 should raise suspicion of an underlying immunodeficiency ( 130). The risk of AIDS appears to be greatest among those zoster patients with facial or neck involvement. Acute retinal necrosis may occur more frequently in these patients. One group suggests initial high- dose in­travenous and long- term oral prophylactic acyclo­vir, as well as careful retinal monitoring, in those AIDS patients with herpes zoster ophthalmicus ( 130). Toxoplasmic encephalitis is the most common cause of focal central nervous system dysfunction in patients with AIDS ( 131). Oral clindamycin and pyrimethamine are an effective treatment for tox­oplasmic encephalitis, and this regimen may be used empirically. However, in those patients who have early neurologic deterioration despite treat­ment or who do not improve neurologically after 10 to 14 days of therapy, brain biopsy should be considered, particularly with attention to the pos­sibility of lymphoma. It is important to remember to administer concurrent leucovorin therapy with this treatment regimen. Other opportunistic pro­cesses such as cytomegalovirus, Candida, and ce­rebral lymphoma may result in vasculopathy and subsequent stroke in AIDS patients ( 132). As regards the general treatment of AIDS, zidovudine was of benefit in the treatment of symptomatic and asymptomatic patients infected with the human immunodeficiency virus ( HIV) whose CD4+ cell counts were less than 500 per cubic millimeter ( 133). The European- Australian Collaborative Group recently reported that treat­ment with zidovidine benefits early asymptomatic HIV- infected persons with CD4+ cell counts above 400 per cubic millimeter ( 133,134). However, preliminary results from the Concorde Trial indi­cate that immediate treatment with zidovidine pro­vided no survival advantage as compared with de­ferred treatment in symptom- free individuals, ir­respective of their initial CD4+ cell count ( 135). This has resulted in a general trend of decreased use of zidovidine. Obviously, priority must be placed on the development of an effective vaccine against HIV. Letvin ( 136) reviews the characteris­tics of HIV, its modes of transmission, and the progress that has been made toward the develop­ment of a vaccine. MULTIPLE SCLEROSIS Many publications in 1993 were concerned with the epidemiology, risk factors, diagnosis, progno­sis, and treatment of demyelinating disease. A large study of United States veterans with multiple sclerosis ( MS) revealed that differences in ancestry contribute to the geographic distribution of MS, independent of geographic latitude ( 137). Swedish and other Scandinavian ancestry was most consis­tently associated with places with increased MS risk. Other studies suggest that having the prereq­uisite genetic background for MS does not neces­sarily result in disease development without some environmental influence ( 138,139). Psychological stress did not increase the risk of exacerbations of MS in one prospective study ( 140). In a Mayo Clinic retrospective report, there was no associa­tion of head injury or spinal disk surgery with the onset, exacerbation, or final disability of MS ( 141). Pars planitis is associated with the subsequent de­velopment of MS, especially in those patients who express the HLA- DR2 antigen ( 142). A group of 308 Swedish MS patients followed prospectively since diagnosis for at least 25 years has provided useful information regarding clinical factors predictive of long- term prognosis ( 143). Of the onset characteristics, the initial type of course was the most important prognostic factor, with primary progressive patients experiencing a much more severe subsequent course. Among those pa­tients with a relapsing- remitting course, factors at onset significantly associated with a favorable long- term prognosis included low onset age, high degree of remission after the first exacerbation, / Neuro- Ophthalmol, Vol. 14, No. 2, 1994 112 N. ]. NEWMAN symptoms from only afferent fibers ( sensory symptoms and optic neuritis), and onset symp­toms from only one region of the central nervous system. Of factors known 5 years after onset, a low number of affected neurologic systems, a low neu­rologic deficit score, and a high degree of remis­sion from the last bout were the most favorable prognostic factors. Magnetic resonance imaging ( MRI) of the head remains helpful in the diagnosis of MS, with a far greater sensitivity in demonstrating lesions than computed tomography. However, a normal MRI of the head cannot conclusively exclude the diag­nosis of MS ( 144). In patients with mild relapsing-remitting MS, a significant association was ob­served between clinical exacerbations of MS and increases in the total number of MRI lesions, num­ber of new MRI lesions and the total area of gad­olinium enhancement ( 145). In patients who present with an acute clinically isolated syndrome suggestive of demyelinating disease, such as optic neuritis or transverse myelitis, an abnormal MRI is highly predictive of the progression to clinically definite multiple sclerosis ( 146,147). In a 5- year prospective study, Morrissey and colleagues ( 146) reported the development of MS in 37 of 57 ( 65%) patients who had an abnormal MRI at initial pre­sentation and in only one of 32 ( 3%) patients with a normal MRI. In the Optic Neuritis Treatment Trial ( ONTT), 5% of optic neuritis patients with essentially normal MRI and 25% of patients with abnormal MRI developed definite MS over a 2- year period ( 147). Other factors found to confer in­creased risk for the development of MS in the ONTT were a history of optic neuritis in the con­tralateral eye, ill- defined neurologic symptoms, pos­sibly white race, and possibly family history of MS. The ONTT also provided information regarding the treatment of optic neuritis and, by extension, the treatment of MS. As regards acute optic neu­ritis, intravenous methylprednisolone hastened the recovery of optic nerve function but did not affect the ultimate outcome. However, definite MS developed within the first 2 years in only 7.5% of the intravenous methylprednisolone group as compared to 14.7% of the oral prednisone group and 16.7% of the placebo group ( 147). This bene­ficial effect of intravenous steroids appeared to lessen after the first 2 years of follow- up and was most apparent in patients with abnormal MRI scans at entry. This has prompted most clinicians to adjust their treatment practices so that MRI scans are obtained on the initial presentation of optic neuritis, and intravenous steroids are offered to those with MRI scans suggestive of demyelinat­ing disease ( especially those with two or more periventricular or ovoid white matter signal abnor­malities at least 3 mm in size). A multicenter, randomized, double- blind, pla­cebo- controlled clinical trial has shown that inter-feron- beta- lb ( IFNB), administered subcutane-ously every other day, significantly reduced exac­erbation rate and severity in ambulatory patients with relapsing- remitting MS ( 148,149). Side effects were in general sporadic and clinically relatively insignificant. The role of IFNB in the treatment of chronic progressive disease is not yet established. Previous studies have shown that a course of in­travenous cyclophosphamide and ACTH can tem­porarily halt progressive MS for a period of 1 year in the majority of patients. A more recent report from the Northeast Cooperative Multiple Sclerosis Treatment Group showed that outpatient intrave­nous cyclophosphamide booster injections every other month provided a significant benefit at 24 and 30 months, especially in those progressive MS patients 40 years of age and younger ( 150). The use of this regimen remains controversial. The large, focal, tumor- like demyelinating le­sions of the brain, recently reviewed by Kepes ( 151), represent a form of demyelinating disease with features of both multiple sclerosis and postin-fectious/ postvaccination encephalitis. Features suggesting a postinfectious etiology include an acute onset of symptoms, location outside the typ­ical areas for MS, dramatic response to steroid treatment, and the absence in most patients of pro­gression or recurrence. These lesions are fre­quently mistaken for primary or metastatic brain neoplasms on neuroimaging and even on biopsy. An unexpectedly poor clinical outcome was re­ported in several of these patients who had been treated with tumoricidal doses of radiation, sug­gesting that radiation may be especially injurious to patients with demyelinating lesions ( 152). An­other syndrome of demyelinating disease is De-vic's neuromyelitis optica, manifested by acute or subacute optic neuropathy with myelopathy. Some consider Devic's to be a form of MS, others regard it as a separate neurologic and neuropatho-logic syndrome. Mandler and colleagues ( 153) re­ported the clinical, imaging, laboratory, and pathologic features of several patients with Devic's syndrome and concluded that it is a separate entity from MS. In none of their patients was the brain, brainstem, or cerebellum affected, even after sev­eral years of disease, and various immunosuppres­sive treatments were of no benefit. Pathology re­vealed a severe necrotizing myelopathy with thick­ening of blood vessel walls and no lymphocytic / Neuw- Ophthalmol, Vol. 14, No. 2, 1994 SYSTEMIC DISEASE 113 infiltrates, denoting a necrotizing rather than a de-myelinating process. Prognosis was poor. PARANEOPLASTIC SYNDROMES The paraneoplastic syndromes reflect the remote effects of cancer and may involve the peripheral and central nervous systems, often with distinct clinical syndromes. Antineuronal antibodies are present in many cases and nervous system dam­age may reflect autoantibody cross- reactivity with the tumor and host neurons. Cancer- associated retinopathy ( CAR) classically presents with acute or subacute bilateral visual loss, nightblindness, photopsias, ring scotomas, retinal arteriolar nar­rowing, and abnormal flash electroretinograms ( 154- 156). There may be associated retinal phlebi­tis and vitritis ( 154,156). The most common under­lying neoplasm is small cell carcinoma of the lung. Patients with small cell carcinoma of the lung and CAR consistently produce high titers of antibodies against a 23- kd retinal antigen, specifically iden­tified as the photoreceptor protein recoverin. Thirkill and coworkers ( 155) recently identified a protein antigenically similar to the 23- kd retinal CAR antigen expressed by in vivo cultivated small-cell carcinoma of the lung, lending further support to immunologic cross- reactivity in the pathogene­sis of CAR. Other malignancies such as cervical, colon, prostate, and breast carcinoma are occasion­ally associated with CAR and the 23- kd retinal antigen/ antibody reaction. Autoantibodies against retinal bipolar cells, rather than against the CAR antigen, were recently identified in the paraneo­plastic retinopathy associated with cutaneous ma­lignant melanoma ( 157). Another paraneoplastic syndrome of neuro-ophthalmic interest is the opsoclonus- myoclonus syndrome, occurring with childhood neuroblas­toma or with a number of carcinomas in adults ( 158). In women with opsoclonus, ataxia, and breast carcinoma, the finding of anti- Ri antineu­ronal antibodies has supported an autoimmune pathogenesis. Dropcho and colleagues ( 158) re­ported a 45- year- old woman with steroid- re­sponsive exacerbations of opsoclonus, myoclonus, and ataxia, with high titers of anti- Ri antibodies but no neoplasm detected after more than 3 years. A new brainstem syndrome was proposed as para­neoplastic in two patients successfully treated for prostate cancer ( 159). The patients first lost volun­tary horizontal eye movements followed by se­vere, persistent muscle spasms of the face, jaw, and pharynx, and mild gait unsteadiness. One pa­tient exhibited facial and abdominal myoclonus. Serum antineuronal antibodies were not identi­fied. INFECTIOUS DISEASE Although cat- scratch disease has been recog­nized for many years, progress was only recently made in the identification of the microbes that cause this disorder ( 160,161). Cat- scratch disease is strongly associated with owning a kitten and fleas may be involved in its transmission. Strong evi­dence supports an etiologic role for Rochalimaea henselae, and the measurement of serum antibodies to this microbe may be useful diagnostically ( 162). Typically, there is malaise, low- grade fever, and lymphadenopathy, which resolves spontaneously over months, but occasionally there are more se­vere complications, such as encephalitis or neu-roretinitis. The indications and specifics of treat­ment are not yet determined. The occurrence of neuroretinitis should raise suspicion of cat- scratch disease, but other infectious agents have been im­plicated, including unspecified viruses, herpes simplex, mumps, syphilis, salmonella, Toxocara ca­ms, and Toxoplasma gondii ( 163). 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