Journal of Neuro-Ophthalmology, June 1995, Volume 15, Issue 2

Neuro Ophthalmology and Systemic Disease

Journal of Neuro- Ophthalmology 15( 2): 109- 121, 1995. © 1995 Raven Press, Ltd., New York Neuro- Ophthalmology and Systemic Disease- Part I An Annual Review ( 1994) Nancy J. Newman, M. D. Any disease process affecting the nervous sys­tem may have neuro- ophthalmologic manifesta­tions and implications. This review highlights those advances in our knowledge of systemic dis­ease of particular interest to the neuro- ophthal-mologist. Many of the most important contribu­tions of 1994 were in the areas of genetics, vascular disease, and demyelinating disease. GENETIC DISEASE Molecular genetics continues to influence our understanding of human disease, both those dis­eases strictly heritable and those of apparently sporadic onset. Abnormalities at the molecular level may be present diffusely throughout the body or may be localized to a particular organ sys­tem or tissue. The principles and techniques of molecular genetics have been applied to increase our knowledge of how mutations cause cell dys­function and disease. This information may, in turn, allow for directed interventional therapies at the molecular level, so- called gene therapy. Be­cause of the importance of molecular genetics to the understanding of all human disease, the New England Journal of Medicine published a series of articles by Nadia Rosenthal that briefly review the principles of modern molecular medicine ( 1- 4). The first article reviews the structure of DNA, the genetic code, gene expression, and protein pro­duction ( 1). The universality of DNA structure and the genetic code allows for immediate applications to modern medicine. The second article deals with Manuscript received February 17, 1995. From the Departments of Ophthalmology, Neurology, and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, U. S. A. Address correspondence to Dr. Nancy J. Newman, Neuro- Ophthalmology Unit, 1327 Clifton Rd., N. E., Atlanta, GA 30322, U. S. A. how DNA can be manipulated by recombinant DNA technology and includes a review of bacterial cloning and polymerase chain reaction amplifica­tion. These tools have provided detailed knowl­edge of gene structure, organization, and regula­tion; have allowed for fingerprinting of inherited traits within pedigrees and through populations; have allowed for the production of large quantities of clinically useful therapeutic human proteins; and have set the stage for transplantation of genes ( 2). The third article discusses how molecular biol­ogists store and retrieve information about DNA and gene structure and location, so- called DNA libraries ( 3). Rosenthal's fourth contribution re­views the language of genetics and the regulation of gene expression ( 4). Along a similar vein, an­other article reviews the use of molecular genetics in the diagnosis of cancer ( 5). Nearly all the DNA in any human cell resides in the nucleus, but approximately 0.3% of the cell's total DNA comprises the mitochondrial genome. Abnormalities of either genome can cause human disease with neuro- ophthalmologic manifesta­tions. The nuclear DNA encodes for many proteins necessary for normal mitochondrial function. Fur­thermore, there are regulatory interactions be­tween the nuclear and mitochondrial genomes. Hence, simple phenotypic classification of these diseases as being derived from either nuclear DNA mutations or mitochondrial DNA mutations is al­most impossible. Inheritance patterns may be in­formative, as primary diseases of the mitochon­drial genome will be inherited via maternal trans­mission, while diseases originating from nuclear DNA abnormalities will be inherited in mendelian fashion. However, many of these diseases occur sporadically. Abnormalities in mitochondrial DNA ( mtDNA) may remain silent, cause lethal systemic pediatric disease, result in tissue- specific neurodegenerative 109 120 N. ]. NEWMAN disorders, or allow for late- onset degenerative dis­orders by lowering the normal threshold for ex­pression of age- acquired mtDNA mutations ( 6- 8). Over 30 mtDNA point mutations and over 100 mtDNA rearrangements have been proposed as etiological factors in human disease ( 6). Expression of these diseases reflects complex genotypic-phenotypic interactions that likely involve nuclear modifying or susceptibility factors. In my annual review last year ( 9), I summarized the clinical and genetic developments regarding Leber's hereditary optic neuropathy ( LHON), a maternally inherited, bilateral optic neuropathy caused by several point mutations in mtDNA. The mtDNA mutations associated with LHON were grouped into primary mutations ( those believed to be significant risk factors for LHON expression, found specifically in LHON families, not found in controls, and associated with LHON in pedigrees with different underlying mtDNA backgrounds) and secondary mutations ( those found with greater frequency among LHON patients than controls, but not meeting the criteria noted for pri­mary mutations). Whereas the prior five years rep­resented a period of mtDNA LHON point muta­tion discovery and publication, 1994 was notable for its articles discussing classification and patho­genesis ( 10- 18). Much debate has occurred over the criteria used to decide whether a mtDNA mutation is caus-atively associated with a disease, or whether it is a pathogenetically benign, coincidental polymor­phism ( 10- 12). Particular interest was given to the 15257 point mutation, proposed initially by two separate teams of investigators to be a primary LHON mutation ( 19,20). As various groups around the world reviewed their molecularly con­firmed cases of LHON, the mtDNA point muta­tions at nucleotide positions 11778, 3460, and 14484 clearly fit the criteria for LHON primary mu­tations. However, among the definite LHON ped­igrees of several research groups, the 15257 muta­tion was found only in association with the three certain primary mutations and never alone ( 11,13, 18). Furthermore, the 15257 mutation was recently reported in two of 135 individuals ( 1.5%) who did not have LHON, indicating its occurrence among controls ( 21). Arguing for primary pathogenicity of the 15257 mutation is one German, three- gen­eration, maternal pedigree classic for LHON, in which no primary mutation other than the 15257 has been identified ( 14). Debate continues, with some suggesting that the 15257 mutation may be of " intermediate risk" between the primary and sec­ondary LHON mutations ( 10). Similar discussion has occurred regarding the pathological signifi­cance of the mtDNA mutation at position 9438, originally proposed as a primary mutation in 1993 ( 15,16,22). Brown et al. demonstrated the 9438 mu­tation in normal African and Cuban control popu­lations at frequencies ranging from 1.7% to 18% ( 15). Clearly, the assignment of pathogenicity to a particular point mutation in this disease is prob­lematic and further complicated by the other, as yet poorly clarified, risk factors for LHON, includ­ing secondary mtDNA mutations, nuclear influ­ences, and environmental factors. Classification studies of LHON confirm that the majority of cases carry the three commonly ac­cepted primary mutations, in proportions of 31- 90% with 11778, 8- 15% with 3460, and 10- 15% with 14484, depending on ethnic origin ( 10,14,17, 18,23,24). Clinical studies of the correlations be­tween mitochondrial genotype and phenotype re­veal only one clear distinction: patients with the 14484 mutation and visual loss have a significantly greater chance of spontaneous recovery ( up to 50% of cases) and a significantly better final visual acu­ity than LHON patients with the other mutations ( 14,17,18). No consistent difference in visual recov­ery, penetrance of expression, age at onset, or presence of other neurologic abnormalities has been demonstrated among the other LHON mtDNA mutations either alone or in combination with secondary mutations. In an electrocardio­graphic study, Nikoskelainen et al. ( 25) confirmed that preexcitation syndromes are more common among maternally related members of LHON ped­igrees. The highest frequency of preexcitation syn­dromes was detected in families with the 3460 mu­tation, but the 11778- positive maternal pedigrees were also affected more than the general popula­tion and more than paternal relatives. Mackey ex­tensively reviewed LHON in Australia and con­cluded that the disease accounts for about 2% of legal blindness in individuals under age 65 years in that country, with approximately 20% of male and 4% of female carriers expected to lose vision ( 23,24). He noted that there has been a dramatic decline in the risk of visual loss among pedigrees with LHON and a definite decrease in penetrance without loss of the primary mutation or change in its homoplasmy ( 26). Another point made by Mackey is the striking difference between the small proportion of LHON singleton cases in Aus­tralia and the large numbers of cases with no fam­ily history reported from the United States ( 24). This may be due to low penetrance of the disease and ascertainment difficulties in America. Cer­tainly, the diagnosis of LHON should be consid- / Ncuro- Ophthtilmol, Vol. 15, No. 2, 1995 NEURO- OPHTHALMOEOGY AND SYSTEMIC DISEASE 111 ered in any unexplained optic neuropathy, even if the clinical presentation is atypical for the disease and there is no family history of visual loss ( 27). Neurologic abnormalities other than visual loss in patients with LHON are, in general, infrequent and mild. Exceptions include the multiple sclero­sis- like illness reported predominantly in women with the 11778 mutation ( 28,29) and the pedigrees with family members with Leber's- like visual loss and other more severe neurologic manifestations ( 30). Kellar- Wood et al. ( 31) did not find the 11778 or 3460 mutations among 307 unrelated multiple sclerosis patients ascertained from population sur­veys. However, three of 20 multiple sclerosis pa­tients selected specifically because of their promi­nent early optic nerve involvement harbored pri­mary LHON mutations, two with 3460 and one with 11778. All three were women without family histories of LHON. The authors concluded that LHON mutations do not contribute to genetically determined susceptibility in typical multiple scle­rosis patients, but a subgroup of female multiple sclerosis patients with severe bilateral visual loss should have mtDNA analysis for the primary LHON mutations. The pedigrees with Leber's- like visual loss and more severe neurologic disturbances are likely to be genetically distinct from those pedigrees with optic neuropathy alone ( 30). This may be the case in the unique Australian family with optic neurop­athy, ataxia, tremor, posterior column signs, and juvenile encephalopathy, which was found to har­bor a mutation at position 4160 in addition to that at position 14484 ( 11). A new mtDNA mutation at mtDNA position 14459 was reported in a five-generation maternal pedigree with LHON and dystonia, a family negative for the other pathoge­netic LHON mutations ( 32,33). This mutation was not found in genetically matched controls, altered a moderately conserved amino acid in the subunit 6 gene of complex I, and was heteroplasmic, all suggesting that it was the disease- causing muta­tion in this pedigree. There are other pedigrees previously reported with a similar phenotype ( 34- 36); confirmation of the 14459 mutation as the causative abnormality in these pedigrees awaits molecular analysis. Heteroplasmy, the coexistence of both wild- type and mutant mtDNA, plays an unclear role in the expression of visual loss in LHON. Howell et al. ( 37) recently studied an LHON pedigree whose maternal members were heteroplasmic for the 11778 mutation in blood. The proportion of mutant mtDNA increased in successive generations, sug­gesting either positive selection for mutant alleles or purely random drift. Interestingly, the other tis­sues of the heteroplasmic proband, including optic nerve and retina, were essentially homoplasmic, suggesting that white blood cell DNA may be a " lagging indicator" of the mutational burden in other, more pathologically involved tissues ( 37). Single- cell analysis of heteroplasmy in LHON showed that most single cells within a heteroplas­mic tissue ( in this case blood) were either ho­moplasmic mutant or homoplasmic wild- type, with only 16% of cells containing both mutant and normal mtDNA ( 38). Technical advances in the study of LHON include new techniques in diag­nosis, such as time- resolved fluorometry and solid- phase minisequencing, which help to avoid some of the problems inherent in restriction site analysis and Southern hybridization ( 39,40). Rapid results can be combined with quantification of het­eroplasmy. The basis for visual loss in LHON is presumed to be a reduction in normal mitochon­drial energy production because of the mtDNA point mutations occurring in genes encoding pro­teins essential to the respiratory chain. Smith et al. ( 41) confirmed a reduction in oxidative phosphor­ylation complex I activity in the platelets of pa­tients with the 3460 mutation and the 11778 muta­tion, as long as the latter were obtained from and compared to nonsmokers. It has previously been shown that the mean complex I activity of other­wise healthy individuals who smoke is signifi­cantly lower than that of those who do not smoke ( 42). Among the other disorders of mitochondrial DNA, interesting developments have been re­ported regarding chronic progressive external oph­thalmoplegia ( CPEO) and the Kearns- Sayre phe­notype in particular ( 43,44). Deletions of mtDNA have been found in about half of the patients with CPEO and nearly all of the patients with Kearns- Sayre syndrome, as well as in patients with Pear­son's syndrome ( a pediatric disease characterized by sideroblastic anemia with vacuolization of mar­row precursors, neutropenia, thrombocytopenia, exocrine pancreatic dysfunction, and abnormal liver function). The tissue distribution of mtDNA deletions is generalized and particularly measur­able in blood in Pearson's syndrome, more local­ized to muscle and the central nervous system in Kearns- Sayre syndrome, and still more localized especially to muscle in CPEO patients. Poulton et al. ( 43) have shown that the molecular genetic pic­ture is even more complicated. They demonstrated more complex rearrangements of the mtDNA than had been previously appreciated, including dupli­cations of mtDNA. Duplications of mtDNA appear / Neuro- Ophthalmol, Vol. 25, No. 2, 1995 122 N. J. NEWMAN to be a hallmark of Kearns- Sayre syndrome, are detectable in blood and muscle, are highly associ­ated with the presence of deletions in muscle, and may be pathogenetically related to the develop­ment of mtDNA deletions. Most of these patients are sporadic cases. A patient with late- onset CPEO, myopathy, cer­ebellar ataxia, peripheral neuropathy, muscle ragged red fibers, and mtDNA deletions had MRI findings localized to the cerebral white matter, indistinguishable from multiple sclerosis ( 45). Mul­tiple mtDNA deletions have been reported in pa­tients with ophthalmoplegia, peripheral neuropa­thy, leukoencephalopathy, gastrointestinal symp­toms with intestinal dysmotility, and histologically abnormal mitochondria in muscle ( called MNGIE for mitochondrial neurogastrointestinal enceph-alomyopathy) ( 46,47). The multiple different mtDNA deletions within individuals with MNGIE make faulty mtDNA replication a likely mecha­nism and a nuclear DNA abnormality a possible cause of the syndrome. Hirano et al. ( 46) sug­gested autosomal recessive inheritance in the ma­jority of their cases. An important advancement in our understanding of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke- like ep­isodes ( MELAS) was the demonstration of high proportions of mutant mtDNA in the blood vessels of muscle biopsies of patients with MELAS, sug­gesting that a similar occurrence in cerebral blood vessels may play a role in the pathogenesis of the stroke- like episodes ( 48). Of the mendelian hereditary diseases recently clarified by linkage analysis, none is of more inter­est to the neuro- ophthalmologist than autosomal dominant hereditary optic atrophy, or Kjer's dis­ease ( 49). The disorder is characterized by insidi­ous onset in the first decade of life of optic neu­ropathy of highly variable severity, blue- yellow dyschromatopsia, centrocecal visual field defects, and temporal wedges of optic atrophy. In a study of three large Danish pedigrees, Eiberg et al. ( 49) localized the abnormal gene in this disorder to the telomeric part of the long arm of chromosome 3 ( the region between D3S1314 and D3S1265). Wolfram's syndrome, or DIDMOAD ( diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a presumed autosomal recessive dis­order, characterized by juvenile onset of diabetes mellitus and insidious, symmetrical, and usually severe optic neuropathies recognized between the ages of 5 and 21 years ( 50). In addition to sensori­neural deafness and diabetes insipidus, a variety of neurologic and systemic abnormalities may be associated with this syndrome, including pigmen­tary retinopathy, ataxia, seizures, hypogonadism, anosmia, short stature, basal ganglia lesions, and elevated cerebrospinal fluid protein. Many of these abnormalities are commonly associated with mito­chondrial disease, raising the issue of underlying mitochondrial dysfunction in the pathogenesis of DIDMOAD, either as a result of primary mito­chondrial DNA defects or abnormalities of nuclear DNA encoding proteins important in mitochon­drial function ( 51). Bundey et al. ( 52) reported a patient with DIDMOAD and morphological and biochemical abnormalities of mitochondria, but no mitochondrial DNA defects were detected. Rotig et al. ( 53) described a patient with DIDMOAD and a deletion of the mitochondrial genome. However, this patient was not diagnosed with diabetes until age 17 and there was no family history of similar problems. Furthermore, in addition to optic atro­phy, diabetes mellitus, and deafness, this patient developed ataxia, retinitis pigmentosa, external ophthalmoplegia, extrapyramidal symptoms, and mental retardation. Pilz et al. ( 54) described a male patient with diabetes mellitus since age 2, seizures at age 14, and LHON- type visual loss six months after seizure onset. An audiogram at age 19 re­vealed unilateral sensorineural hearing loss, a wa­ter deprivation test was normal, and mitochondrial DNA analysis revealed the LHON 11778 mutation. Other investigators have not found mitochondrial DNA defects among patients with DIDMOAD ( 55). The Wolfram's phenotype is likely etiologi-cally heterogeneous. Of all the recent advances in molecular genetics, however, none are more dramatic than the clarifi­cation of the pathogenicity of trinucleotide repeat expansion within nuclear DNA in human disease ( 56- 58). Although not strictly considered diseases of neuro- ophthalmic interest, all of the inherited disorders known to be associated with expansion of trinucleotide repeats have prominent neurologic manifestations. They include X- linked spinal and bulbar muscular atrophy, two fragile X syndromes of mental retardation, myotonic dystrophy, Hun­tington's disease, spinocerebellar ataxia type 1, and dentatorubral- pallidoluysian atrophy. La Spada et al. ( 56) classify these diseases into two categories: ( 1) multisystem disorders ( fragile X and myotonic dystrophy) with large expansions of re­peats that are not translated into proteins, and ( 2) neurodegenerative disorders with smaller expan­sions of CAG repeats within the protein encoding portion of the gene. Simple analysis of DNA in blood samples allows for highly sensitive and spe­cific identification of patients at risk ( 58). This has further allowed for the reliable diagnosis of Hun- / Neuw- Ophthalmol, Vol. 15, No. 2, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 113 tington's disease in the absence of a family history ( 59). All the expanded trinucleotide repeats are un­stable, and the phenomenon of anticipation ( wors­ening of the clinical appearance of the disease over successive generations) correlates with expansion size. Recent studies of autosomal dominant cere­bellar ataxia with retinal degeneration ( ADCA type II) reported anticipation in the offspring of affected fathers, suggesting that the gene mutation, al­though as yet not chromosomally localized, will similarly consist of an unstable trinucleotide repeat expansion ( 60- 62). VASCULAR DISEASE Vascular disease can affect the neuro- ophthal-mic afferent and efferent systems anywhere from the eye to the occipital lobes, and from the brain­stem to the extraocular muscles. Mechanisms of vascular disease include thrombosis, embolism, vascular inflammation, mechanical injury, and hemorrhage; contributing factors include athero­sclerotic risk factors such as hypertension, diabe­tes, and smoking; inflammatory vasculitides; cardiac abnormalities; and abnormalities of the normal hemostatic mechanisms controlling coagu­lation and fibrinolysis. Anterior ischemic optic neuropathy ( AION), presumably due to ischemia to the prelaminar por­tion of the optic nerve, has been associated with a number of systemic diseases, including giant cell arteritis, as well as others more commonly consid­ered risk factors for atherosclerotic disease such as hypertension, diabetes, and smoking. In an exten­sive review of 406 cases of AION in patients ages 11- 91 years, Hayreh et al. ( 63) found a multitude of accompanying systemic diseases and compared their prevalence to standard age- matched popula­tion survey prevalence rates. The authors reported significantly higher prevalence rates of arterial hy­pertension, diabetes mellitus, and gastrointestinal ulcer. When stratified by age, patients 45 years or older also showed higher prevalence of ischemic heart disease and thyroid disease, and those be­tween ages 45 and 65 years showed higher rates of chronic obstructive pulmonary disease and cere­brovascular disease. After onset of AION, patients with both hypertension and diabetes had a higher incidence of subsequent cerebrovascular disease. In a retrospective study of 137 patients with AION, Chung et al. ( 64) reported 42% with hypertension and 19% with diabetes. Twenty- eight of 126 cases were smokers, and the average age of onset of AION was younger among the smokers than the nonsmokers. In contrast, Johnson et al. ( 65) re­ported no increased prevalence of smoking among their 63 patients with AION. A vascular mechanism was proposed for optic neuropathy with severe visual loss in a woman with systemic lupus erythematosus and anti-phospholipid antibodies ( 66). However, she was not examined in the acute phase of visual loss, and the presumption of ischemia was based on the re­mote appearance of attenuated retinal vasculature. Sickle cell disease was implicated as the cause of posterior ischemic optic neuropathy in a 52- year-old man with sudden unilateral loss of vision and subsequent optic atrophy ( 67). The occurrence of either posterior or anterior ischemic optic neurop­athy in the setting of prolonged hypotension or severe blood loss has been well documented. Katz et al. ( 68) reported four patients ages 41- 65 years with ischemic optic neuropathy after prolonged multilevel lumbar laminectomy with deliberate hy­potension and concurrent anemia. Two patients suffered bilateral visual loss, three had pale swell­ing of the optic discs, and three had arteriosclerotic risk factors. In a retrospective review of 16 patients with id­iopathic recurrent branch retinal arterial occlu­sions, Johnson et al. ( 69) confirmed that the long-term visual, neurologic, and systemic prognosis of this syndrome appears to remain favorable. After a mean follow- up of nine years, 9% of eyes had lost visual acuity and 28% had significant visual field loss. Eight patients had associated vestibuloaudi-tory and/ or transient sensorimotor symptoms, but there were no serious permanent neurologic defi­cits or recurrent systemic thromboembolic events. Most patients had one or more vaso- occlusive risk factors, but no particular factor was common to all, suggesting that the etiology of this syndrome is likely heterogeneous and perhaps multifactorial. The authors theorized that many of these patients have mild or partial manifestations of the microan­giopathic syndrome of encephalopathy, hearing loss, and retinal arteriolar occlusions ( Susac syn­drome). A 66- year- old man with subacute, remitting and relapsing progressive central retinal artery occlu­sion was reported by Werner et al. ( 70). Progres­sion to visible nerve fiber layer infarction despite aspirin and calcium channel blocker therapy prompted treatment with ophthalmic artery uroki­nase infusion. Visual acuity ultimately recovered to preinfusion levels and visual field may have im­proved, but transient neurologic symptoms and neuroimaging evidence of cerebral infarction com­plicated the procedure, raising the question of its overall benefit. Other reports in 1994 associated / Neuro- Ophthalmol, Vol. 25, No. 2, 1995 224 N. /. NEWMAN retinal arterial occlusions with radiation therapy for Graves' ophthalmopathy ( 71), ulcerative colitis ( 72), mechanical factors such as preretinal arterial loops ( 73) and optic neuritis/ perineuritis ( 74), ipsi-lateral carotid artery dissection ( 75), and neurofi­bromatosis type 1 ( 76). Rizzo and Lessell ( 77) re­viewed cerebrovascular disease seen in patients with neurofibromatosis type 1, a relatively under­appreciated manifestation of this disease. Re­ported cerebrovascular events include stenosis and occlusion of large and small vessels, both system-ically and intracranially, aneurysms that may oc­casionally present as arterial dissections, arteriove­nous fistulae, moyamoya disease, spontaneous vascular rupture, and arterial adventitial infiltra­tion by neurofibroma or ganglioneuroma. Anti- phospholipid antibodies have been impli­cated in ocular vascular occlusive disorders, espe­cially arterial occlusions ( 78,79). However, in a prospective study of 75 patients with retinal vacu-lar occlusions, the majority of which were venous, Glacet- Bernard et al. ( 79) found no increased prev­alence of anti- cardiolipin antibodies or lupus coag­ulant. The authors recommend screening for anti-phospholipid antibodies only in those patients without conventional risk factors for vein occlu­sion, with symptoms or signs suggestive of lupus or a systemic thromboembolic disorder, or with clotting screen abnormalities. Another article from the same laboratory in France demonstrated ab­normal hemorheologic findings as assessed by erythrocyte aggregation and rheologic tests in pa­tients with central retinal vein occlusions and no conventional risk factors ( 80). These abnormalities seemed to correlate with poorer prognosis. Cen­tral retinal vein occlusion patients were studied with color Doppler imaging by two separate groups ( 81,82). Both demonstrated accompanying reduction of blood flow in the retinal arterial cir­culation of involved eyes. In one study, color Doppler findings of reduced flow velocities within three months of onset were predictive of the risk of subsequent iris neovascularization ( 81). Treatment of patients with branch and central retinal vein oc­clusions with troxerutin, a rheologic drug that in­hibits platelet and red blood cell aggregation and increases red blood cell deformability, showed promising preliminary results regarding visual function, retinal circulation times, decreased mac­ular edema, and diminished progression of isch­emia ( 83). An additional factor to consider in the pathogenesis of vascular disease is the vascular en­dothelium ( 84). Haefliger et al. ( 84) reviewed the role of the vascular endothelium as a regulator of the ocular circulation, with special attention to the balance of endothelium- derived relaxing and con­tracting factors and their role in the development of atherosclerotic and vasospastic disease. Giant cell arteritis causes visual loss in as many as 60% of patients with the disease. Liu et al. ( 85) reviewed the visual symptoms and signs in 45 pa­tients with biopsy- proven giant cell arteritis. Vi­sual loss was unilateral in 46%, sequential in 37%, and simultaneous in 17%. Anterior ischemic optic neuropathy was the most common neuro- ophthal-mic manifestation ( noted in 88% of eyes), and vi­sual acuity was 20/ 200 or worse in 70%. Six pa­tients lost vision during corticosteroid treatment for systemic symptoms. In the 41 patients with vi­sual loss, vision worsened in 17%, improved in 34%, and was unchanged in 49%. Subsequent fel­low eye involvement was only observed in pa­tients receiving oral steroids, and a greater propor­tion of those treated with intravenous therapy re­gained vision. Of 17 patients with AION who had temporal artery biopsies, Price and Clearkin ( 86) found higher platelet counts in the 10 patients with positive biopsies. The authors suggest that the platelet count may be useful in the diagnosis of giant cell arteritis, but further studies are certainly necessary. The color Doppler characteristics of the ocular vasculature in 22 patients with giant cell ar­teritis and visual symptoms included significant reduction in central retinal and short posterior cil­iary arterial flow velocities with increased vascular resistance, ophthalmic artery aliasing ( high-velocity and turbulent flow at presumed focal vas-culitic stenoses), and reversal of flow within the ophthalmic artery ( 87). Clinically unaffected fellow eyes also demonstrated alterations in blood flow velocity and vascular resistance, confirming the systemic nature of the disease. In a consecutive cohort of 535 patients undergoing temporal artery biopsy, Achkar et al. ( 88) demonstrated that bi­opsy positivity rates were not affected by previous treatment with corticosteroids. They concluded that temporal artery biopsy may show arteritis even after more than 14 days of corticosteroid ther­apy. The obvious concern is that many more of their corticosteroid group may have shown posi­tive biopsies if performed prior to the initiation of treatment. In the patient with suspected giant cell arteritis, biopsies should be obtained as soon as possible, but treatment with steroids should not be withheld. The parent circulation of the eye is the carotid artery system and carotid disease may cause ocular ischemia or infarction. In a study of 41 consecutive patients with transient monocular visual loss or retinal artery occlusion, Smit et al. ( 89) found no / Natro- Ophthalmol, Vol. 15, No. 2, 1995 NEURO- OPHTHALMOEOGY AND SYSTEMIC DISEASE 115 source of retinal emboli on cardiac screening tests ( electrocardiography, 24- h Holter monitoring, and precordial echocardiography) or on carotid artery duplex scanning in 27 ( 66%) cases. Ipsilateral ca­rotid disease was diagnosed in 11 patients ( 27%) and a cardiac source in only one patient. Perez- Burkhardt et al. ( 90) prospectively studied 81 pa­tients with amaurosis fugax with carotid duplex scanning and found greater than 70% ipsilateral stenosis in 55 patients. There was also a high prev­alence of hypertension, smoking, and previous ce­rebrovascular events. Forty- two of the 55 patients endarterectomized had ulcerated carotid plaques. As part of the North American Symptomatic Ca­rotid Endarterectomy Trial ( NASCET), Sauve et al. ( 91) determined that cervical bruits alone were not sufficiently predictive of high- grade symptomatic carotid stenosis to be useful in selecting patients for angiography, as bruits were absent in over one third of patients with high- grade stenosis. Carotid disease may also contribute to the risk of cerebrovascular infarctions outside of the conven­tional territory supplied by the anterior circulation. This frequently depends on the underlying con­genital vascular anatomy and the development of collateral circulations. Gasecki et al. ( 92) reported on a 76- year- old man with bilateral occipital infarc­tions related to an ulcerated left carotid stenosis, presumably via embolization through a persistent trigeminal artery. In patients with carotid artery occlusion, the risk of watershed infarction was de­creased in the presence of posterior communicat­ing arteries measuring at least 1 mm in diameter ( 93). The role of carotid endarterectomy in the treat­ment of extracranial carotid disease, symptomatic and asymptomatic, continues to be of great inter­est and debate as more information from random­ized trials becomes available. In a review of the information on this topic available by the end of 1993, Easton and Wilterdink ( 94) reported the re­sults of NASCET, the European Carotid Surgery Trial, and the Veterans Administration Symptom­atic Trial as showing efficacy for surgery in pa­tients with symptomatic carotid artery stenosis of greater than 70%. Although carotid endarterecto­my in this group was also beneficial among those who presented with transient monocular visual loss, the cumulative risk for stroke at two 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. An additional benefit of endarterectomy at an average follow- up of 18 months was the reduction of functional im­pairment, including vision, in those patients with recent symptomatic cerebral ischemia and ipsilat­eral high- grade stenosis ( 95). Three trials in asymptomatic carotid stenosis patients failed to show a statistically significant benefit for surgery in the prevention of death or stroke, but none of these studies were large enough to exclude such a benefit ( 94). Therefore, it was with great interest that the Clinical Advisory from the National Insti­tutes of Health regarding the interim results of the Asymptomatic Carotid Atherosclerosis Study ( ACAS) ( 96) was received. The interim results are based on 1662 patients with greater than 60% ca­rotid stenosis randomized to either endarterecto­my or observation, although all patients received aspirin and advice on risk factors. After 4465 cu­mulative patient years of observation, an aggre­gate risk of any stroke or death was 4.8% among patients assigned to surgery and 10.6% among those in the nonsurgical arm. Carotid endarterec­tomy was reported as beneficial with a statistically significant absolute reduction of 5.8% in the risk of stroke within five years and a relative risk reduc­tion of 55%. The success of the operation was de­pendent on a perioperative morbidity and mortal­ity of less than 3%. Interestingly, following endar­terectomy, men had a 69% relative risk reduction of stroke within five years, whereas women had only a 16% relative risk reduction. There was no stratification by degree of stenosis provided, and patients were highly selected to avoid excessive surgical risk. The statistics were based on " intent to treat," meaning that randomization depended on carotid Doppler diagnosis, and patients subse­quently discovered to have insignificant stenosis on arteriography ( 7.4% of cases) were not endart­erectomized but analyzed as surgically treated pa­tients. The results are somewhat at odds with the findings in a British study of 3000 patients with asymptomatic carotid stenosis ( 97), which found a risk of stroke or death at three years of only 3.9% in 970 patients with stenoses ranging from 30 to 79%. This is equivalent to an approximately 6.5% risk of stroke or death at five years, somewhat less than the 10.6% reported in the nonsurgical arm of ACAS. Caution must be used in the referral of asymptomatic patients with carotid stenosis of less than 79%. However, it is most important to re­member that cerebrovascular symptoms, both transient and permanent, are markers not only for subsequent stroke, but also for myocardial in­farction and cardiac death. In an ancillary study from the Dutch TIA Trial Study Group, Pop et al. ( 98) reported independent predictors for cardiac events in patients with cerebral ischemia, includ- / Ncuro- Ophthalmol, Vol. 15, No. 2, 1995 116 N. ]. NEWMAN ing age older than 65 years, male sex, angina pec­toris, diabetes, and electrocardiographic abnormal­ities such as signs of anterior infarction, left ven­tricular hypertrophy, and inverted T waves. Risk factors for stroke other than ipsilateral ca­rotid artery disease have been clarified in several new studies ( 99- 102). Once again, hypertension was confirmed as the most common and severe isolated risk factor for future stroke. Atrial fibrilla­tion and hyperglycemia also elevated the risk for stroke. Combination of more than one risk factor increases the chance of stroke. In one study, a sub­group of patients with carotid plaques and silent cerebral infarctions, as demonstrated by magnetic resonance imaging, had a short- term stroke risk of almost 50% by age 60 ( 101). In addition to older age, hypertension, obesity, smoking, and diabe­tes, elevated levels of naturally occurring tissue plasminogen activator ( TPA) were demonstrated to be an independent risk factor for stroke in the Harvard Physician's Health Study ( 102). The ele­vated TPA levels are likely a marker for systemic atherosclerotic vascular disease. Cerebral embolism is a frequent cause of brain infarction. Sources include the heart, the great ves­sels, and more distal arteries. In a prospective, case- control study using transesophageal echocar­diography to assess the frequency and thickness of atherosclerotic plaques in the aortic arch, Ama-renco et al. ( 103) demonstrated a strong indepen­dent association between atherosclerotic disease of the aortic arch and the risk of ischemic stroke. Among the 250 patients with stroke, this associa­tion was particularly strong with thick plaques ( 4 mm or larger). Kistler ( 104), in his editorial accom­panying the Amarenco article, notes that this in­formation may have implications for treatment re­garding antithrombotic versus antiplatelet ther­apy. Among cardiac sources of cerebral embolism, mitral valve prolapse has often been suggested as a risk factor. In a review of Olmsted County, MN, U. S. A., patients with echocardiographic evidence of mitral valve prolapse and first cerebral infarc­tion, most patients had other risk factors for stroke, including hypertension, smoking, athero­sclerotic heart disease, and atrial fibrillation, and other identifiable mechanisms of infarction besides embolism due to mitral valve prolapse ( 105). Bes-son et al. ( 106) demonstrated a common associa­tion of mitral valve prolapse with patent foramen ovale ( PFO) in patients younger than 45 years who had suffered ischemic stroke. Although PFO is present in 18- 35% of the normal population, a higher frequency has been noted in patients with stroke of unknown etiology, especially young pa­tients in whom it may be the only identifiable risk factor ( 107,108). Patent foramen ovales are fre­quently associated with atrial septal defects, which, in turn, may also be independent sources of cerebral emboli ( 107,109). In a transesophageal echocardiography study of 74 patients with PFO, atrial septal aneurysms were most commonly as­sociated with PFO in those patients who had suf­fered cerebral infarction without another identifi­able risk factor for stroke ( 107). A higher incidence of echocardiographic right- to- left shunting was noted in patients with cerebral infarction than in those without infarction. The importance of these findings as regards risk factors for stroke, and their relevance to treatment such as antiplatelet ther­apy, anticoagulation, or cardiac surgery, await fur­ther prospective studies. Although transesoph­ageal echocardiography is considered the " gold standard" for detecting PFOs, transcranial Dopp-ler sonography after venous injection of an ultra­sonic contrast medium is also useful and is pro­posed as less costly, less invasive, and less sonog-rapher- dependent ( 108). Other factors involved in the pathogenesis of ce­rebral ischemia in the young patient include hema­tologic disturbances that predispose to thrombosis ( 110,111). In a study of 36 patients under the age of 40 with cerebral infarction of undetermined cause, nine patients ( 25%) had a deficiency of one natural anticoagulant, most frequently protein S ( six cases) ( 110). Deficiencies of protein C, antithrombin III, and plasminogen were noted in one patient each. Resistance to activated protein C, an inherited trait believed to be the most frequently found labora­tory abnormality in patients with idiopathic deep-vein thrombosis, is not usually considered a factor in cerebral ischemia ( 112). Misra et al. ( 113) found an increased prevalence of anti- cardiolipin anti­bodies among young Indian patients with Takaya-su's arteritis. However, in a prospective controlled study of 262 patients with acute stroke, Muir et al. ( 114) found no evidence to support the hypothesis that anti- cardiolipin antibodies are an independent risk factor for stroke in young patients. Interest­ingly, they did find a higher titer of IgG anti-cardiolipin antibodies among older patients with stroke correlating with the number of vascular risk factors, suggesting that anti- cardiolipin antibodies may be a nonspecific marker of vascular disease. Among women with stroke or amaurosis fugax, independent risk factors included smoking, social class, hypertension, and oral contraceptive use ( 115). The detrimental effect of oral contraceptives may persist in those former users of the pill who / Neum- Ophthalmol, Vol. 15, No. 2, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 117 continue to smoke. An ischemic stroke was re­ported in a 21- year- old man after high doses of anabolic steroids ( 116). Transient ischemic attacks and stroke in young adults are generally believed to be benign, with a low acute mortality and few recurrences, especially if the cause of the event remains unidentified ( 117). Of 13 patients ages 8- 38 years with one or more transient attacks of bi­lateral blindness, often precipitated by exercise, stress, or postural change, none had suffered a major vascular event during a mean follow- up of 10 years ( 118). However, in one long- term follow-up study of ischemic stroke patients ages 15- 45 years, only 49% of 296 patients were still alive, were not disabled, had not suffered from recurrent vascular events, or had not undergone major vas­cular surgery ( 119). Only 42% of the survivors had returned to work, and the majority of survivors reported emotional, social, or physical sequelae that lessened their quality of life. Mechanical causes of decreased cerebral perfu­sion and ischemic stroke must also be considered, especially in the young patient. Sell et al. ( 120) described the case of a 44- year- old woman with episodes of transient blindness with turning her head caused by extrinsic compression of a verte­bral artery by a tight anterior scalene muscle. Dis­sections of the vertebral artery frequently cause neuro- ophthalmic manifestations, including symptoms such as diplopia, blurred vision, tran­sient visual diming, oscillopsia, photophobia, in­verted images, and positional transient visual ob­scurations, and signs such as nystagmus, ocular misalignment from ocular motor nerve palsy or skew deviation, Horner syndrome, decreased cor­neal sensation, ptosis, visual field defects, abnor­mal pursuits and saccades, ocular bobbing, inter-nuclear ophthalmoplegia, and anisocoria ( 121). Symptoms of vertebrobasilar ischemia from verte­bral artery dissections may be delayed more than a week after traumatic injury, and occult fractures of the second cervical vertebra may not be detected unless looked for specifically with polytomogra-phy or computed tomography ( CT) ( 122). Sponta­neous dissections of the cervicocephalic arteries in children less than 19 years old occur more fre­quently in the anterior than posterior circulations ( 123). Intracranial dissections are relatively more common in children than adults and have a poorer prognosis for good clinical recovery than extracra­nial dissections. Carotid dissections in 48 patients were monitored noninvasively with sequential du­plex Doppler studies for up to two years, and grad­ual recanalization was noted in 68% of dissections after an average interval of 51 days ( 124). Although dissections of the cervical extracranial arteries are commonly multiple on presentation ( 28% of pa­tients in one study), the risk of recurrence of dis­section is only about 1% per year after the first month and seems to occur only in arteries not pre­viously involved ( 125). Stroke syndromes of neuro- ophthalmic interest reviewed in 1994 included 33 patients with lateral medullary infarction ( 126) and 22 patients with pure midbrain infarction ( 127). The former had a high percentage of Horner syndrome and nystag­mus, the latter a predominance of eye movement abnormalities. Both studies beautifully correlated neuroimaging with clinical syndromes and vascu­lar anatomy. Contralateral conjugate eye deviation in acute supratentorial stroke ( wrong- way eyes) was reviewed by Tijssen ( 128), who added five more cases to the literature and concluded that the phenomenon is always associated with hemor­rhagic lesions, most commonly in the thalamus, and prognosis is poor. Another phenomenon after stroke of neuro- ophthalmic interest is denial of eye closure ( 129). Denial of eye closure occurs in a mi­nority of patients with generalized denial of ill­ness, but supports mechanisms of denial after stroke that do not count on unilateral explanations of neglect such as hemiinattention or hemiloss of sensory input. Management of patients with cerebrovascular disease, particularly the role of hospitalization, was clarified by the report from the Task Force on Hospital Utilization for Stroke of the American Academy of Neurology ( 130). In general, patients with a transient ischemic attack or stroke onset of less than 48 h previously should be hospitalized immediately. Frequent transient ischemic attacks clinical features suggesting high- grade carotid ste­nosis, or clinical features suggesting posterior cir­culation ischemia should also prompt hospital ad­mission. Aside from carotid endarterectomy, therapeutic intervention for prevention and treatment of isch­emic cerebrovascular disease consists of antiplate­let agents and anticoagulation. Patrono ( 131) re­viewed the role of aspirin as an antiplatelet agent, its molecular mechanisms, clinical pharmacologic data, and results of randomized clinical trials of its use in thrombotic prophylaxis and treatment of ce­rebrovascular and cardiovascular diseases. Prog­ress in our understanding of the clinical pharma­cology of aspirin has resulted in a general down­ward trend in the recommended daily dosage; now 75- 100 mg generally is believed to be effica­cious and safe. A collaborative overview was re­cently reported in the British Medical Journal sum- / Neuw- Ophthalmol, Vol. 15, No. 2, 1995 118 N. }. NEWMAN marizing the data from 173 randomized trials of antiplatelet therapy ( 132). Among patients at high risk for occlusive vascular disease, antiplatelet therapy was definitely protective for subsequent myocardial infarction, nonfatal stroke, and vascu­lar death, with risk reductions of one third, one third, and one sixth, respectively. The most widely tested regimen was aspirin in a daily dosage of 75- 325 mg. There was no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low- risk patients. In the Stroke Prevention Atrial Fibrillation II Study, anticoagulation with warfarin was com­pared with aspirin 325 mg daily for prevention of ischemic stroke and systemic embolism in random­ized patients with atrial fibrillation ( 133). It was concluded that warfarin may be more effective than aspirin for prevention of ischemic stroke than aspirin, but the absolute reduction in stroke rate by warfarin is small. Young patients without risk fac­tors had a low rate of stroke and older patients had a substantial risk of stroke, irregardless of which treatment was used. Similar conclusions were reached in a pooled analysis of five randomized controlled trials on the efficacy of antithrombotic therapy in atrial fibrillation ( 134). Warfarin consis­tently decreased the risk of stroke in patients with atrial fibrillation ( a 68% reduction in risk) with es­sentially no increase in the frequency of major bleeding. The efficacy of aspirin was less consis­tent, with an overall pooled risk reduction of 36%. Patients with atrial fibrillation younger than 65 years without a history of hypertension, previous stroke, transient ischemic attack, or diabetes were at very low risk of stroke, even without treatment. From a pool of 900 articles dealing with medical treatment for stroke prevention, Matchar et al. ( 135) identified 33 papers reporting the results of randomized controlled trials of anticoagulant or antiplatelet agents and combined the outcome data and follow- up. They concluded that warfarin is strongly recommended for patients with nonval-vular atrial fibrillation who are older than 60 years or who have additional risk factors for stroke, that aspirin should be used first in the treatment of patients with transient ischemic attacks or minor stroke, that ticlopidine may be used in patients who do not tolerate or respond to aspirin or who have had a major stroke, and that aspirin is rec­ommended in patients who have had myocardial infarction for the prevention of recurrent myocar­dial infarction but that it only slightly reduces the risk for stroke. Similar conclusions were reached by Barnett et al. 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