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Show Journal of Neuro- Ophthalmology 15( 4): 241- 253, 1995. © 1995 Lippincott- Raven Publishers, Philadelphia Neuro- Ophthalmology and Systemic Disease- Part II* 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. Kaufman ( 137) reviewed the recent advances in neuroimaging, especially vascular neuroimaging, and its impact on neuro- ophthalmology. Magnetic resonance angiography ( MRA) continues to become more refined, more sensitive, and more specific to particular vascular abnormalities depending on the technical methods selected. In a masked study assessing the sensitivity of time- of- flight and phase- contrast MRA in the detection of intracranial aneurysms, three- dimensional time- of- flight MR was more sensitive than three- dimensional phase-contrast or standard MR imaging ( 138). However, although aneurysms as small as 3 mm could be detected, 5 mm appeared to be the critical size, with time- of- flight MRA providing a sensitivity of 87.5%. Combinations of multiple modalities would certainly increase sensitivity. However, aneurysms less than 5 mm in size can rupture, making conventional arteriography still essential in the patient under high suspicion for aneurysm, especially multiple aneurysms ( 139,140). Certainly in the acute- care setting, where sophisticated MR im- * Part I was published in / Neuro- Ophthalmol, 15( 2): 109- 121, 1995. 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- Opthalmology Unit, 1327 Clifton Rd., N. E., Atlanta, GA 30322, U. S. A. aging may not be available, arteriography is indicated in the patient with a pupil- involving third-nerve palsy. Walter et al. ( 141) described two patients with oculomotor nerve palsies precipitated by minor head trauma with negative CT scans, who were subsequently discovered to have ipsilat-eral posterior communicating artery aneurysms. Intracranial aneurysm must be added to the list of occult mass lesions causing third- nerve palsies in the setting of minor trauma. Giant cerebral aneurysms arising from the intracranial internal carotid artery and its branches can produce progressive visual loss from compression of the anterior visual pathways ( 142). When conventional neurosurgical intervention with clipping or trapping of the aneurysm is not feasible, percutaneous intraarterial embolization with detachable balloons or electrocoils may provide an alternative therapy. Vision may stabilize or improve and the patient may be protected against subsequent hemorrhage. Although complications of endovascular techniques are significant, coils may be preferable to balloons. Neurologic complications of cerebral angiography using transfemoral catheterization were examined in 1,000 consecutive procedures on patients ranging in age from 1 month to 96 years ( average age 53 years) at a major teaching institute ( 143). The neurologic complication rate was 1% overall and 0.5% for persistent deficits. All events occurred in patients being evaluated for stroke, transient ischemic attack, or carotid bruit, and a higher age, longer procedure time, and greater volume of radiographic contrast was noted in these patients than in the study population. In his editorial commentary, Gabrielsen ( 144) warns that most of our arteriography patients now fit into this high- risk group and not all institutions will have such favorable complication rates. However, he stresses the 241 242 N. /. NEWMAN continued importance of appropriately performed cerebral angiography in the course of modern clinical management. Ocular complications may occur during performance of the Wada test ( 145), including a possible toxic reaction to sodium amobarbitol with choroidal infarctions. Complications may also arise during carotid balloon occlusion testing, including transient monocular visual loss ( 146) and transient ocular ischemic syndrome ( 147). The latter manifested as orbital pain and visual blurring and was likely related to too rapid infusion of saline distal to a double- lumen balloon into the ophthalmic artery. In a section devoted to vascular disease, mention must be made of a remarkable report in the New England Journal of Medicine in which an unexpected episode of classic migraine was captured during a series of blood- flow measurements with positron- emission tomography ( PET) ( 148). Despite no clinically reported aura aside from a brief difficulty focusing clearly, PET images demonstrated bilateral hypoperfusion beginning in the occipital lobes and spreading anteriorly into the temporal and parietal lobes. Interestingly, the cerebral blood- flow abnormalities originated bilaterally in the visual association areas, not in the primary visual cortex. The authors and the subsequent editorial concluded that the spread of flow reduction was most consistent with the spreading depression of Leao ( 148,149). DEMYELINATING DISEASE The literature in 1994 included many contributions concerning the epidemiology, genetics, imaging, and management of multiple sclerosis ( MS). Two collections of articles, both supplements to volume 36 of the Annals of Neurology, are worth singling out as valuable references ( 150,151). Supplement 1 provides a general overview of MS based on contributions to a symposium held in September 1993. Multiple contributors well known to the MS academic community reviewed the epidemiology, natural history, genetics, and factors associated with risk or exacerbation of the disease. Basic science is reviewed, especially as regards what is known about the immunology of MS. A large section is devoted to the use of clinical trials for treatment of the disease, the techniques of clinical definition, design strategies, the role of magnetic resonance imaging in such trials, and the most promising therapies at that time, i. e., inter-feron-( 3, copolymer- 1, and aminopyridines. Future prospects are discussed, including those that take advantage of recent basic science advances in our understanding of growth factors and remyelina-tion. Supplement 2 is more specialized and reflects the reviews and recommendations of a workshop on the epidemiology and genetics of MS held in June 1993. Individual articles concerning MS include a report on the very rare diagnosis of MS among native blacks in South Africa and Zimbabwe ( 152). Twelve patients are reported, six of whom became severely visually impaired from optic neuritis. The authors claim that MS in this group of patients resembles more closely the disease as reported among Asians than among white people in Africa or black individuals living in North America. In 1993, a report from the Mayo Clinic showed no association of head injury or spinal disc surgery with the onset, exacerbation, or final disability of MS ( 153). In a subsequent letter to the editor, the same group reported no association of cervical radiculopathy or its surgery with MS ( 154). Jellinek ( 155) reviewed the controversy regarding trauma and exacerbation of MS and proposed there still may be a role for direct central nervous system trauma as a trigger of aggravation of the disease. Retrospective studies have suggested that MS may be exacerbated in the postpartum period. In a prospective study of 53 women with a total of 69 pregnancies, Sadovnick et al. ( 156) found that neither pregnancy nor the six- month period after delivery was a risk factor for relapse in MS. Similarly, in a five- year prospective study of 29 women, Stenager et al. ( 157) reported no influence of pregnancy or childbirth on the long- term prognosis for MS. Because female patients with MS are at risk for osteoporosis secondary to gender, immobility, and corticosteroid use, Nieves et al. ( 158) investigated bone mineral density, vitamin D dietary intake, and vitamin D levels in women with MS. They noted significant reductions in bone mineral density, suggesting an increased fracture risk of up to threefold and a high prevalence of vitamin D deficiency; they recommended that vitamin D supplementation be instituted in female patients with MS. The possible association of MS and intracranial hypertension was discussed in an article reporting three women with both diseases, although causation remains unclear ( 159). A multiple sclerosis- like illness was noted in a patient with deafness and pigmentary retinopathy consistent with Usher's syndrome ( 160). Movement disorders in MS are unusual. Barton et al. ( 161) described a 59- year-old man with MS, limb and head chorea, torticollis, blepharospasm, and involuntary ocular deviations, the last most reminiscent of oculogyric crises but continuous while awake. / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 243 As regards the most common neuro- ophthalmic manifestation of demyelinating disease, optic neuritis was the topic of some notable publications in 1994. The Optic Neuritis Treatment Trial ( ONTT) continues to provide important follow- up information on its cohort of patients. The visual fields were followed longitudinally and the one- year results showed that although visual fields for the majority of patients tended to return to normal ( 55.9% at one year), new and different patterns of defects developed, including subclinical involvement of the fellow eye ( 162). Furthermore, chiasmal and retrochiasmal defects occurred more commonly than previously clinically identified ( 13.2% of patients), and those exhibiting retrochiasmal defects were more likely to have had abnormal brain magnetic resonance imaging ( MRI) at baseline than other ONTT patients. The course of visual recovery after optic neuritis was noted to be rapid, regardless of treatment with oral prednisone, intravenous methylprednisolone, or oral placebo, improvement beginning within the first two weeks in most patients and within the first month in nearly all patients ( 163). Baseline visual acuity was the only valuable predictor of six- month visual acuity outcome, although visual recovery was still good in most patients, even those with no light-perception vision. Therefore, patients who do not follow such a pattern of visual recovery, or those who worsen after termination of steroids, should be considered atypical and subjected to further diagnostic investigation. In a letter to the editor, Coyle ( 164) questioned whether the ONTT results are just as valid for men as they are for women, and whether the use of an expensive test like MRI is truly justified. In his reply, Beck ( 165) pointed out that the previously reported gender predilection of more women than men with optic neuritis developing MS has not been confirmed during the two- year follow- up in the ONTT or in a recent five-year prospective study. He also noted that the difference in prognosis for MS between those first-time optic neuritis patients with MRI lesions and those without is significant enough to justify obtaining MRIs at baseline. In a prospective study of 60 patients with optic neuritis without MS, 69% had oligoclonal bands in the cerebrospinal fluid and 53% had at least three white- matter lesions on MRI, and these findings were strongly correlated ( 166). At a mean follow- up of two years, 17 patients had clinically definite MS, 16 of whom had oligoclonal bands and 12 of whom had abnormal MRIs at presentation. In a study of patients with acute optic neuritis both with and without MS, Sellebjerg et al. ( 167) demonstrated that anti-proteolipid protein antibodies in the cerebrospinal fluid were a more specific finding for demyelinating disease than anti- myelin basic protein antibodies and that the former may arise as a consequence of the demyelinating process. The role of MRI in the detection and diagnosis of MS, in the prediction of disease expression and progression, and in the monitoring of treatment was the subject of several reviews and original articles in 1994. In a review of the use of brain MRI in MS, Goodkin et al. ( 168) discuss the importance of MRI in MS diagnosis, the difficulty with specificity for the diagnosis, especially in older patients, and the pathological correlates of these white- matter lesions on MRI. They review the correlation of lesions on MRI with traditional measures of neurologic impairment, with neuropsychologic measures, and with immune function and show how MRI, unenhanced and enhanced, has been used to follow serially patients with MS. An extension of this application is the use of MRI to monitor the response to various treatments of MS, and the authors conclude that it is important to include serial brain MRI scans as secondary or possibly primary outcome measures in future clinical trials of MS. Important questions posed include: How predictive is brain MRI when the patient presents with the first neurologic event? Does the rate of new or enhancing lesion accrual predict the clinical course? What are the optimal techniques for quantifying lesion burden? What is the optimal frequency of obtaining MRIs in MS patients? Can changes in MRI lesion burden be used as a primary outcome in treatment trials? Can different MRI techniques allow us to learn more about the active pathologic processes within the MS brain? The impact of MRI, CT, cerebrospinal fluid ( CSF) analysis, and evoked potential testing on the clinical diagnosis of MS was evaluated in 62 patients with possible or probable MS ( 169). Magnetic resonance imaging was crucial for diagnosis in 44% of cases, and in these cases the results of other tests did not contribute. In the remaining 56% of cases, further laboratory testing led to a diagnosis in only an additional 13% of patients. Khoury et al. ( 170) followed 18 MS patients clinically and with unenhanced and enhanced MRIs for one year. Positive correlations were demonstrated between accumulation of new lesions and cumulative disability, and between the number of lesions, both enhanced and unenhanced, and increasing disability. The study confirmed that new lesions may appear at times of clinical stability. Filippi et al. ( 171) performed quantitative brain MRIs over five years in 84 patients presenting with / Neuro- Ophthalmol, Vol. IS, No. 4, 1995 244 N. J. NEWMAN clinically isolated syndromes suggestive of MS ( 40 with optic neuritis). Those who developed MS during follow- up ( 45%) had a higher lesion load at presentation than those who did not, and increasing initial lesion load correlated with a decreasing time to development of MS clinically. Confirmation that new and enlarging lesions, as well as enhancing lesions, appear less often in MS patients with benign disease was provided in a study of two groups of 11 MS patients, one group with early relapsing- remitting MS, the other with long-duration benign disease ( 172). Husted ( 173) reviews refinements in MRI techniques that may provide increased sensitivity and specificity in the diagnosis and understanding of MS. Gadolinium enhancement helps to distinguish acute from chronic lesions, and the number and area of enhanced lesions has been correlated with clinical worsening. Fluid- attenuated inversion recovery ( FLAIR) improves the detection of MS lesions in the spinal cord and brainstem. Magnetization transfer imaging, in combination with enhancement, further increases lesion contrast and increases the pathological specificity of MRI. Gass et al. ( 174) found that this technique could indicate the degree of demyelination and axonal loss, and proposed its use in monitoring treatment- induced changes in tissue structure. Magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging may help elucidate the underlying biochemical mechanism of demyelination in MS ( 175,176). Progressive accumulation of neuronal damage as demonstrated by these more sensitive techniques may correlate with progressive disability better than conventional MRI ( 175). Normal- appearing white matter on the MRIs of MS patients may be biochemically abnormal ( 176). The use of MRI findings to predict clinical outcome and the role of MRI in therapeutic clinical trials of MS were reviewed by McDonald et al. ( 177) in light of the conclusions of the beta-interferon- p trial. Although therapy with inter-feron- plb significantly reduced the frequency of relapse and of new pathological activity as determined by MRI, no differences were noted between treated and untreated groups in the rate of clinical deterioration. This may have been a result of the relatively crude methods we have for measuring disability, combined with the variability of the course of MS and the relatively short duration of follow- up in the trial. The use of a variety of new MRI techniques ( see above) has shown that the frequency of new disease activity, the total extent of abnormality, and the pathologic characteristics of the lesions can indeed predict subsequent disability in MS. It remains to be seen whether a correlation will ultimately be established between MRI findings and long- term disability in treatment trials. Regarding treatment, Jacobs and Johnson ( 178) review the history of the use of interferons as treatment for MS, their biological effects, and the rationale for their use in MS and possible mechanisms of action. Interferon-^ administered intrathecally or systemically significantly reduces MS exacerbations. A practice advisory from the American Academy of Neurology ( 179) recommended that subcutaneous human interferon- p can be used in relapsing- remitting ambulatory MS patients between the ages of 18 and 50 years who have had at least two acute relapses in the prior two years, who have no other serious concurrent illnesses, and who are not planning pregnancy. Patients older than 50 years, with more disability, or with relapsing- progressive disease might be helped. There is no evidence to suggest the medication would be helpful in primary chronic progressive patients. Preliminary results from a trial using weekly intramuscular recombinant low- dose inter-feron- pla in the treatment of relapsing- remitting MS are also promising ( 180). In contrast to inter-feron- p, interferon-^ provokes exacerbations of MS. Although previous studies of interferon- ct in MS have shown only equivocal results ( 178), a recent randomized, double- blind, placebo- controlled pilot trial of intramuscular high- dose recombinant interferon- a2a in 20 relapsing- remitting MS patients demonstrated reduced clinical and MRI signs of disease activity with treatment ( 181). Preliminary results have been released regarding the use of copolymer- 1 in the treatment of relapsing- remitting MS ( 180). Copolymer- 1 is a synthetic polypeptide that presumably works either by producing antigen- suppressor cells specific for myelin basic protein or by interfering with T- cell activation by competing with myelin basic protein for major histocompatibility complex binding sites responsible for antigen presentation. Its daily use subcutaneously decreased the relapse rate by 24% and also decreased subsequent neurologic disability. Results of a randomized trial of 4- aminopyri-dine in the treatment of the symptoms of residual deficits in MS patients were in general positive, but there were significant toxic effects of treatment ( 182). Early studies are underway in the use of chimeric monoclonal antibodies against the CD4 antigen found on helper/ inducer T lymphocytes in the treatment of MS patients ( 183). The treatment was effective in reducing the number of CD4 lym- / Neuro- Ophthalmol, Vol. IS, No. i, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 245 phocytes, and there were no limiting side effects, but it is too early to assess clinical efficacy. The debate continues over whether intermittent intravenous cyclophosphamide therapy is beneficial in the treatment of MS, especially those patients with rapidly progressive disease ( 184,185). At the root of the controversy is the need for well- designed randomized, controlled trials. Given how commonly patients with MS are treated with glucocorticoids and ACTH, a recent report on the use of glucocorticoids in rats with experimental allergic encephalomyelitis ( EAE) is of interest ( 186). Continuous steroid treatment completely blocked EAE, but sudden withdrawal of steroids made the animals worse than control animals who had received no treatment at all. The authors conclude that abrupt discontinuation of steroids provokes inflammatory brain disease; gradual reduction of steroid therapy in inflammatory neurologic disease would appear prudent. Parainfectious encephalomyelitis may cause optic neuritis and visual loss, as well as other central nervous system signs, some of which may be related to raised intracranial pressure ( 187). Medical therapy with steroids may be helpful in treatment of the disease, although relapses, as with EAE, may occur with steroid withdrawal. Surgical shunting or decompression procedures may prove necessary if medical therapy fails and there is ongoing elevated intracranial pressure. Devic's disease, neuromyelitis optica, manifested by acute or subacute optic neuropathy with myelopathy, is considered by some to be a form of MS, by others a distinct nosological entity. Fazekas et al. ( 188) describe two women with Devic's and MRI findings restricted over several years entirely to the optic nerves, chiasm, and spinal cord, offering further support that this is a clinical entity separate from typical MS. An autosomal dominant, adult-onset leukodystrophy was described in a kindred whose symptomatic members suffered progressive, prominently cerebellar and pyramidal dysfunction similar to chronic progressive MS ( 189). Demyelination of peripheral nerves and roots is generally believed to underlie that form of Guil-lian- Barre syndrome designated Miller Fisher syndrome ( MFS) and clinically characterized by ophthalmoplegia, ataxia, and areflexia. Debate continues regarding the contribution of occasionally demonstrated central nervous system lesions to the clinical expression of this syndrome. Najim Al- Din et al. ( 190) reviewed the neuro- ophthalmic manifestations of 20 of their patients with MFS and concluded that the symmetrical nature of the ophthalmoplegia and ataxia, combined with apparent supranuclear, nuclear, and internuclear signs, favors centrally placed lesions. The same group of authors then reviewed 109 reports in the literature on MFS, representing 243 patients ( 191). They noted that most cases had symmetrical failure of upgaze followed by loss of lateral gaze and then downgaze, with recovery in the opposite pattern. Fifty- eight patients were reported with sparing of downgaze and 192 patients ( 79%) had relative sparing of the eyelids. Lid retraction, preserved Bell's phenomenon despite upgaze paralysis, and other findings suggesting supranuclear localization were also described. The authors concluded that MFS represents a brainstem syndrome rather than an unusual variant of the Guillain- Barre syndrome. A supporter of MFS as a variant of demy-elinating polyneuropathy, Ropper ( 192) proposes four syndromes of acute regional weakness, with clinical, spinal fluid, and electrophysiologic similarities to typical Guillain- Barre syndrome, as a spectrum of disease among the acute immune polyneuropathies: lumbar polyradiculopathy, facial diplegia and distal limb paresthesias, sixth-nerve paresis and distal limb paresthesias, and ophthalmoplegia with pharyngeal- cervical-brachial weakness and ataxia. A 65- year- old man with only mild ophthalmoplegia had MFS with prominent bulbar symptoms ( 193). He had high titers of GQlb- ganglioside antibodies, previously noted to be strongly associated with MFS. A 17- year- old patient with known systemic lupus erythematosus developed severe MFS ( 194). Treatment with immunoglobulins, steroids, and cyclophosphamide failed, but she had dramatic clinical improvement immediately following plasma exchange, suggesting the presence of a circulating neurotoxic factor. AIDS The number of individuals testing positive for the human immunodeficiency virus ( HIV) and the number of persons diagnosed with acquired immunodeficiency syndrome ( AIDS) continues to rise. Particularly rapid is the increase in the number of reported cases of heterosexually acquired AIDS ( 195). Persons at highest risk include adolescents and adults with multiple sex partners, those with sexually transmitted diseases, and heterosexually active persons residing in areas with a high prevalence of HIV infection among intravenous drug users. In a study of survival and disease progression according to gender of patients with HIV, HIV- infected women were at increased risk of death and bacterial pneumonia ( 196). This may re- / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 246 N. /. NEWMAN fleet differential access to health care, and standard treatments or different socioeconomic status for women compared with men with HIV. AIDS- associated neurologic conditions affect 40- 60% of AIDS patients, are the presenting symptom of AIDS in 5- 10%, and are identified pathologically in over 90%. In a multicenter AIDS cohort study of primarily highly educated homosexual and bisexual HIV- positive men over the years 1985- 1992 ( 197), the overall incidence rates of all HIV- related neurologic diseases, with the exception of HIV dementia, showed upward trends. There was a protective trend of antimicrobial prophylaxis on toxoplasmosis and cryptococcal meningitis, but use of antiretrovirus agents was not protective against HIV dementia. As more people with profound immunosuppression live longer, the overall incidence of HIV- related neurologic diseases can be expected to rise. The HIV p24 antigen, a putative marker of virus load, was detected more frequently in the cerebrospinal fluid and blood of HIV patients with significant HIV- related dementia, and the antigen concentration correlated directly with the degree of cognitive impairment, suggesting that the p24 antigen may be a useful marker for HIV dementia ( 198). Disturbances of postural control, as measured by standard static posturography and postural reflexes, were demonstrated to be one of the earliest neurological abnormalities in patients with early HIV dementia ( 199). Neuro- ophthalmologically, three cases were reported of AIDS- related non- Hodgkin's lymphoma involving the orbit: in one case a Burkitt's- type in one orbit with concurrent widespread abdominal involvement ( 200), in the second case presenting simultaneously in both orbits ( 201), and in the third case presenting simultaneously in the ipsilat-eral eye and orbit ( 202). In another report, a 44- year- old HIV- positive man presented with bilateral uveitis and myelitis, for which no opportunistic infectious cause other than the HIV itself could be found ( 203). Symptoms and signs improved with only oral zidovudine and topical ocular steroids, suggesting primary HIV infection of the spinal cord and eye. Balint's syndrome was produced by bilateral parieto- occipital lesions, confirmed histo-pathologically to be caused by progressive multifocal leukoencephalopathy ( PML) ( 204). AIDS- related PML was the cause of a bizarre movement disorder, beginning with motor awkwardness, progressing through generalized motor slowness to dystonic movements and ultimately generalized myoclonus ( 205). Although PML was demonstrated pathologically, especially involving the subcortical U fibers, MRI performed two months after symptom onset and five months prior to death was normal. Cytomegalovirus was determined to be the cause of a severe multifocal neuropathy in 15 patients in the late stages of HIV infection ( 206). Detection of cytomegalovirus DNA by PCR in the cerebrospinal fluid was useful. Fourteen of 15 patients improved after treatment with ganciclovir or foscarnet. The incidence of tuberculosis has increased in recent years, at least in part as a result of AIDS, and outbreaks of multidrug-resistant organisms has heightened concern ( 207). In an excellent review of the recent developments regarding tuberculosis, especially in the AIDS patient, Haas and Des Prez ( 207), discussed how the manifestations of tuberculosis in AIDS patients are influenced by the degree of immunosuppression. The authors stressed that patients with AIDS and pulmonary tuberculosis are highly contagious but that appropriate infection control and complete courses of multiple drug therapy are effective. Horowitz et al. ( 208) described the case of a 29- year- old HIV- positive man with cerebral syphilitic gumma diagnostically confirmed by silver- impregnation staining, immunofluorescence, and the polymerase chain reaction on autopsy tissue. It has been suggested that patients with HIV infection are at greater risk of acquiring neurosyphilis, that neurosyphilis in HIV- coinfected patients follows a more aggressive or atypical course, that serologic tests for syphilis may be falsely negative in the presence of HIV coinfection, and that syphilis in the HIV patient may respond differently to antibiotic treatment. Gordon et al. ( 209) showed that in HIV patients with early syphilis, therapy with intravenous penicillin G for 10 days may fail, and neurosyphilis may develop. In a most remarkable editorial, Simon ( 210) read-dressed the issues of neurosyphilis in the HIV patient and concluded that there is no hard evidence to support the contention that syphilis is an opportunistic infection in HIV- coinfected patients or that it is more aggressive, clinically atypical, or more refractory to treatment. Serum antibodies to Roch-alimaea henselae, the pathogen associated with cat-scratch disease, were found more frequently among HIV- positive patients with neurologic disease than those without, suggesting the possibility that some AIDS- related encephalopathies may be due to central nervous system invasion by this organism ( 211). Further corroborative studies are necessary. Primary central nervous system lymphoma ( PCNSL) arises in 1.5- 5% of AIDS patients and conventional therapy with steroids and cranial radiation provides a median survival of only two to J Neuro- Ophthalmol, Vol. 15, No. i, 1995 NEURO- OPHTHALMOEOGY AND SYSTEMIC DISEASE 247 five months ( 212). Compared to PCNSL in immunocompetent patients, PCNSL in AIDS patients is more likely to be multifocal, to involve the meninges, to be ring- enhancing, and to hemorrhage. Forsyth et al. ( 212) treated 10 AIDS patients with PCNSL with chemotherapy in addition to radiation therapy; although there was a response to chemotherapy, only two patients survived for one year or longer. To determine whether sociodemographic characteristics of HIV patients influence the use of prophylactic drug therapy, Moore et al. ( 213) studied 838 patients and found that blacks were significantly less likely than whites to have received an-tiretroviral therapy or Pneumocystis prophylaxis when first referred to an HIV clinic. This disparity suggests a need for interventions to ensure uniform access to treatment and uniform standards of care. In a comparison of the long- term prognosis of patients with AIDS treated and not treated with zidovudine, the death rate within the first year since starting treatment was markedly lower among the treated patients, but after two years the beneficial effect had disappeared ( 214). Furthermore, for asymptomatic patients treated with 500 mg of daily zidovudine, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with delay in the progression of HIV disease ( 215). Although reverse transcriptase inhibitors such as zidovidine are effective in the treatment of acute infection of target cells, they have no effect on chronically infected cells ( 216). Furthermore, resistance of HIV to zidovidine has been documented to occur. For patients with HIV infection who cannot tolerate or have not responded to zidovudine, zalcitabine and didanos-ine are equally efficacious in delaying disease progression and death ( 217). However, patients with advanced disease appear to have a clinical course that may not be markedly altered by any of the currently available nucleoside analogs used as monotherapy. New therapies are needed and investigations continue regarding combination therapy with nucleoside and nonnucleoside reverse- transcription inhibitors ( 218), protease inhibitors ( 218), vaccines ( 219,220) and gene therapy ( 221). INFECTIOUS DISEASE Advances in diagnostic molecular microbiology have revolutionized the identification of infectious agents, including bacteria, mycobacteria, fungi, and viruses that either are fastidious and grow slowly or cannot be cultured ( 222). These techniques have shortened the time necessary to identify fastidious microorganisms, expanded the number of identifiable human pathogens, and improved the accuracy of subtyping of pathogens. The two principal molecular techniques are nucleic acid hybridization with a specific DNA or RNA probe and DNA amplification by the polymerase chain reaction ( PCR) ( 222). These techniques have provided further insight into Rochalimaea henselae infection, a presumed zoonosis, with the domestic cat, via its fleas, as the major persistent reservoir ( 223- 225). The microorganisms are small gram-negative rods, classically assigned to the Rickettsi-aceae, although recent evidence favors reclassification among the Bartonellaceae ( 225). The most common manifestation in humans is cat- scratch disease, a persistent necrotizing inflammation of the lymph nodes, which is estimated to affect 22,000 people in the United States annually ( 223). In the immunocompromised patient, such as those with AIDS, these gram- negative bacteria may cause bacillary angiomatosis, a potentially lethal vascular proliferative response to the organism in skin, bone, or other organs. Lee et al. ( 226) reported on a 70- year- old immunocompetent man with bacillary angiomatosis of the conjunctiva, and Le et al. ( 227) used a conjunctival swab and PCR to identify Rochalimaea henselae as the causative organism of a conjunctival nodule in an HIV- positive man who had recently acquired a kitten. Golnik et al. ( 228) described four patients with intraocular inflammation, visual loss, white retinal lesions, macular exudate, and optic nerve head swelling, all with elevated serum antibody titers to Rochalimaea henselae and Rochalimaea quintana. Improvement occurred after treatment with oral ciprofloxacin hydrochloride and prednisone or doxycycline hyclate, but the natural history of ophthalmic manifestations of this disease remains unknown. The authors concluded that lack of a history of previous cat scratches or lymphadenopathy does not preclude the presence of Rochalimaea infection; that patients with viteitis, retinitis, neuroretinitis, or optic perineuritis of unknown etiology should be investigated for Rochalimaea; and that antibiotics afford the best chance for maximal visual recovery. It remains unclear whether efforts at the public health level should be instituted, including treatment or vaccination of cats and flea control ( 225, 229). Lyme disease, the result of infection with the spirochete Borrelia burgdorferi, may cause long- term complications, including persistent arthralgias, extremity numbness, fatigue, poor concentration / Neuro- Ophthalmol, Vol. 25, No. 4, 1995 248 N. J. NEWMAN and memory loss, emotional lability, and difficulty sleeping ( 230). Delayed initial treatment is the principal risk factor for continued residual symptoms. Bergloff et al. ( 231) reviewed the ophthalmic manifestations of Lyme borreliosis, including uveitis, optic neuritis, and ocular motor nerve palsies. Although this contribution offers a much- needed review of the European literature on this subject, the ocular manifestations included are protean, and may be overly inclusive. As with other spirochetal infections, antibiotic treatment of Lyme disease may cause a Jarish- Herxheimer reaction with transient exacerbation of existing lesions, in one case worsening of presumed Lyme optic neuropathy ( 232). One patient with Lyme disease developed an isolated fascicular sixth- nerve palsy after a one- month course of oral antibiotics ( 233). Symptoms persisted with intravenous antibiotics but resolved with corticosteroid therapy. In an excellent editorial, Tyler ( 234) discussed the use of PCR as a sensitive and rapid technique in the diagnosis of viral central nervous system disease. The use of PCR on cerebrospinal fluid samples has allowed for diagnosis of herpes simplex virus ( HSV) encephalitis, obviating the need for brain biopsy. The technique has also been used in the detection and diagnosis of Epstein- Barr virus, varicella- zoster virus, and cytomegalovirus infection. PCR may prove useful in quantifying HIV load and in identifying the JC virus in presumed PML. However, the identification of viral DNA in the central nervous system by PCR does not assign a viral etiology to a disease. Baringer and Pisani ( 235) analyzed brain samples from individuals dying of nonneurological disease and detected HSV genomic sequences in 26 ( 65%) of 40 trigeminal ganglia samples and in 14 ( 35%) of 40 brains, especially in the medulla, olfactory bulbs, pons, gyrus rectus, amygdala, and hippocampus. This suggests that the virus may exist in the latent state in normal central nervous system. The treatment of acute symptomatic herpes zoster infection is controversial. In a double- blind, controlled trial, treatment with acyclovir for 21 days or the addition of oral prednisolone to acyclovir therapy conferred only slight benefits over standard seven- day treatment with acyclovir, and neither additional treatment reduced the frequency of postherpetic neuralgia ( 236). An infection also of interest to neuro- ophthal-mologists is Whipple's disease, commonly manifested by fever, weight loss, diarrhea, polyarthritis, and adenopathy, but also by central nervous system abnormalities including disorders of ocular motility. Lowsky et al. ( 237) recently used PCR techniques to identify the causative organism of Whipple's disease, the small gram- positive bacillus Tropheryma whippelii, in the peripheral blood of two patients with Whipple's disease. This identified the Whipple's bacillus as a red- cell- associated organism and demonstrated that the disease can be diagnosed on peripheral blood samples without tissue biopsy. Another infection of great neuro-ophthalmic importance is rhino- orbital- cerebral mucormycosis. Yohai et al. ( 238) extensively review mucormycosis, a highly aggressive, frequently fatal, fungal infection most commonly found in diabetic and immunocompromised patients. Factors related to lower survival include delayed diagnosis and treatment, hemiparesis, bilateral sinus involvement, leukemia, renal disease, treatment with deferoximine, and possibly facial necrosis. Standard treatment consists of amphoteracin B and aggressive surgery, with possible adjunctive therapies including local amphoteracin B irrigation, hyperbaric oxygen, and optimization of immunosuppressive regimens in transplant patients. Cystericercosis causes cerebral lesions that commonly result in seizures, headaches, and frequently hydrocephalus ( 239). Neuro- ophthalmic manifestations may reflect raised intracranial pressure or mass lesions within the cerebral parenchyma. The disease should be considered in those patients with tapeworms, exposure to those with tapeworms, or exposure to endemic areas. TUMORS AND PARANEOPLASTIC SYNDROMES Pollack ( 240) reviewed brain tumors in children, the largest group of solid neoplasms in children, second only to leukemia in their overall frequency. Specific tumors given particular attention included low- and high- grade gliomas, medulloblastomas, brainstem gliomas, ependymomas, and craniopharyngiomas. Brain tumors in children range from the very benign to the highly malignant. Age-related factors in the vulnerability of the brain to the various toxic and therapeutic effects of different therapies make management difficult. Continued enrollment of children with brain tumors in multicenter trials is essential for the development of appropriate interventions. Among children with medulloblastoma, surveillance scanning is probably of little clinical value, as scanning detected a minority of recurrences and no patient who had a recurrence survived ( 241). Weiner et al. ( 242) retrospectively analyzed the pathologic and clinical characteristics of 56 patients with craniopharyngioma and concluded that squamous papillary cran- / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 249 iopharyngiomas, like adamantinomatous tumors, may recur when subtotally resected, that the most significant factor associated with recurrence is the extent of surgical resection rather than histopath-ological subtype, that brain invasion in totally resected tumors does not predict higher recurrence, and that gross total resection is associated with a significantly lower recurrence rate and can be achieved without sacrificing functional outcome. During pregnancy, pituitary adenomas may grow and vision may be at risk, especially if bromocriptine has been discontinued. Kupersmith et al. ( 243) studied 65 women with previously untreated pituitary tumors and noted visual loss during pregnancy in six of the eight patients with macroade-nomas but none of the 57 patients with microadenomas. Gliomas of the anterior visual pathways account for less than 5% of all brain tumors in children, but up to 70% of children with optic pathway tumors have neurofibromatosis type 1 ( NF1). In a study of 176 children with NF1 and neuroimaging, Listern-ick et al. ( 244) found tumors of the anterior visual pathways in 15% of asymptomatic children with NF1. Rapidly progressive tumors usually presented during the first six years of life and subsequent tumor progression was uncommon. The authors concluded that screening neuroimaging in asymptomatic children with NF1 has limited utility, but that periodic screening ophthalmic examinations are important. Ophthalmic manifestations of neurofibromatosis type 2 ( NF2) include cataracts, retinal hamartomas, and epiretinal membranes. In a study of 63 affected individuals from 32 NF2 families ( 245), ocular symptoms were the presenting features in 12.7% of cases, while symptoms from vestibular schwannomas, other central nervous system tumors, and skin tumors were the initial features in 44.4%, 22.2%, and 12.7% of patients, respectively. On examination, however, cataracts were noted in 81% of patients. In addition to different chromosomal loci for the abnormal genes in NF1 and NF2 ( chromosome 17 for NF1; chromosome 22 for NF2), the two disorders have little phenotypic overlap. The paraneoplastic syndromes reflect the remote effects of systemic cancers and frequently involve the central and peripheral nervous systems. As more clinical syndromes are defined and more antibodies associated with the syndromes are characterized, attempts are being made to organize and classify the increasingly complex array of syndromes and antigen- antibody interactions ( 246- 248). Thirkill ( 249) provided an extensive review of the most common ocular paraneoplastic syndrome, cancer associated retinopathy, or CAR syndrome. Two articles appearing in Ophthalmology address the paraneoplastic retinopathy associated with cutaneous malignant melanoma, or MAR syndrome ( 250,251). Kim et al. ( 250) reported on three men with melanoma- associated retinopathy who presented with flickering black and white spots, shimmering patches of colors, and night blindness that was acute and nonprogressive. They confirmed that the flash electroretinographic b- wave was diminished, similar to the pattern seen in congenital stationary night blindness. Weinstein et al. ( 251) confirmed the presence of high- titer immunoglobulins reactive only with a subset of retinal bipolar cells in MAR syndrome. Harris et al. ( 252) proposed that a patient with non- Hodgkin's lymphoma suffered bilateral orbital myositis, cranial neuropathies, and a sensory polyneuropathy as a paraneoplastic syndrome. Extraocular muscle biopsy revealed granulomatous inflammation without neoplastic invasion, and the cranial neuropathies and myositis improved with immunosuppressive therapy even as the patient's underlying neoplasia progressed. Some neurologic paraneoplastic antibodies have been characterized based on antibody- antigen specificity and have been linked to particular paraneoplastic syndromes that are associated more commonly with certain systemic tumor types ( 247). The anti- Hu antibodies occur most frequently with small cell lung cancer and are associated with clinical syndromes of encephalomyelitis, sensory neuropathy, and autonomic neuropathy ( 253). The anti- Yo antibodies are seen most commonly with ovarian and breast cancer and typically are associated with cerebellar degeneration ( 247). Anti- Ri antibodies also occur most frequently in those patients with breast cancer and ocular movement disorders, particularly opsoclonus, commonly accompanied by axial ataxia ( 247). However, overlap of clinical syndromes are not uncommon, unusual tumors may underlie the syndromes, otherwise clinically classic antibody-negative cases can occur, and the antibodies may be present in patients with neoplasms but no paraneoplastic syndrome. Hersh et al. ( 254) found anti- Hu antibodies in a patient with small cell lung cancer and opsoclonus, myoclonus, ataxia, and encephalopathy. Verschuuren et al. ( 255) found anti- Hu antibodies in a patient with sensory and autonomic neuropathy and a metastatic chondrosarcoma that expressed Hu antigens. This patient's paraneoplastic syndrome improved after surgical treatment of the tumor and immunosuppressive treatment, including plasmapheresis. Five patients / Neuro- Ophthalmol, Vol. 25, No. 4, 1995 250 N, } . NEWMAN were described in whom paraneoplastic sensory neuropathy was stable or only slowly progressive over time, despite high titers of anti- Hu antibodies ( 256). Casado et al. ( 257) reported on a 57- year- old woman with opsoclonus, myoclonus, ataxia, encephalomyelitis, and positive anti- Ri antibodies, in whom no underlying malignancy could be found. A similar case of a 73- year- old woman with progressive ataxia, opsoclonus, dementia, peripheral neuropathy, and high titers of anti- Ri antibodies came to autopsy, where no tumor was found ( 258). Anti- Ri reactivity was identified in immunoblots of all regions of the brain, predominantly the pons and dorsal midbrain, supporting an autoimmune antibody- mediated mechanism for the disorder. Ahern et al. ( 259) reported on a 38- year- old patient with temporal lobe seizures and an isolated amnestic syndrome occurring three years prior to the discovery of a testicular tumor. A serum autoantibody demonstrated an affinity for the nucleolus of cerebral cortical neurons, an antigen different from previously identified paraneoplastic neurologic antigens Hu, Yo, and Ri. MISCELLANEOUS Organ transplantation has become more common, and with it numerous complications, many of which involve the nervous system ( 260). Depending on the type of organ transplanted, neurological problems are reported in 30- 60% of transplant recipients. The neurologic complications may be specifically related to transplant type, but more commonly reflect the necessary immunosuppression, i. e., neurotoxic side effects from immunosuppressive drugs, infections, and the development of malignancies. As with the vitreoretinal complications of bone marrow transplantation ( 261), the neuro- ophthalmic manifestations may reflect direct neurotoxicity of immunosuppressive agents, infections, new lymphoproliferative disorders, or complications of the transplant procedure. Of particular neuro- ophthalmic interest is the leu-koencephalopathy that occurs with cyclosporine therapy, which can cause reversible cerebral blindness. A more recently introduced immunosuppressive agent is tacrolimus ( FK 506), which appears to have equal efficacy with cyclosporine in terms of patient and graft survival, but may have more adverse side effects, including neurotoxicity ( 262). Obviously an important disease to neuro-ophthalmologists, myasthenia gravis is the subject of two comprehensive and extremely valuable reviews ( 263,264). Drachman ( 263) reviewed the diagnosis and practical management of the disease, as well as the newer developments regarding pathogenesis, immunology, and molecular biology. Weinberg et al. ( 264) extensively reviewed ocular myasthenia, with extraordinarily comprehensive referencing. Historical background, pathophysiology, immunogenetics, diagnostic testing, treatment options, and drug- induced myasthenic syndromes were discussed. Deficiency states may cause neuro- ophthal-mologic symptoms and signs. The clinical and subclinical ophthalmic findings of vitamin A ( retinol) deficiency are described among patients with recognized and unrecognized hepatic dysfunction ( 265). Although nyctalopia may suggest the underlying deficiency, the patient may present with unexplained bilateral visual loss and an otherwise unremarkable ocular examination. Patients with predisposing conditions such as hepatic dysfunction or malabsorption states should be monitored carefully and supplemented accordingly. Wernicke encephalopathy, presumably also a result of nutritional deficiency, manifests with ataxia, abnormalities of ocular motility, and acute confusion. Recently, the MRI features of the disorder were clarified ( 266- 268). On T2- weighted images acutely, symmetrical bilateral hyperintense lesions are noted periaqueductally in the midbrain, in the hypothalamic/ mammillary body region, and around the third ventricle and dorsal thalamus. Gadolinium enhancement of the mammillary bodies may be the only acute MRI finding. Late findings include substantial atrophy in these regions, especially of the mammillary bodies. Lieb et al. ( 269) described a patient with the rare association of orbital myositis and giant cell myocarditis, a usually fatal syndrome. The authors recommended a high index of suspicion for giant cell myocarditis in patients with inflammatory orbital polymyositis in the absence of Graves disease. A recent report in Science regarding the early diagnosis of Alzheimer's disease with pupillary testing ( 270) has captured the imagination of the media and caused many questions to come the neuro-ophthalmologist's way. In a study of 19 suspected Alzheimer patients and 32 age- matched non-cognitively- impaired controls, Scinto et al. ( 270) found that 18 of their suspect group had a marked hypersensitivity in their pupil dilation response to tropicamide compared to only two controls. No information was provided regarding corneal findings, blink rate, dry eye, or iris color. In a different study ( 271), supersensitive constriction to dilute pilocarpine was noted among 21 probable Alzheimer's patients compared to controls, but there was / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 151 substantial overlap. Caution is suggested and further corroborative studies are necessary before any pupillary test can be recommended as a diagnostic test for Alzheimer's disease. REFERENCES 137. Kaufman DI. Recent advances in neuro- imaging and the impact on neuro- ophthalmology. Curr Opin Ophthalmol 1994; 5: 52- 62. 138. Huston J III, Nichols DA, Luetmer PH, et al. Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: Importance of aneurysm size. Am J Neuroradiol 1994; 15: 1607- 14. 139. Litt AW. MR angiography of intracranial aneurysms: proceed, but with caution. AJNR 1994; 15: 1615- 6. 140. Winn HR. Intracranial aneurysms and MR angiography: questions and answers. AJNR 1994; 15: 1617. 141. Walter KA, Newman NJ, Lessell S. Oculomotor palsy from minor head trauma: initial sign of intracranial aneurysm. Neurology 1994; 44: 148- 50. 142. Vargas ME, Kupersmith MJ, Setton A, Nelson K, Beren-stein A. Endovascular treatment of giant aneurysms which cause visual loss. Ophthalmology 1994; 101: 1091- 8. 143. Heiserman JE, Dean BL, Hodak JA, et al. Neurologic complications of cerebral angiography. Am J Neuroradiol 1994; 15: 1401- 7. 144. Gabrielsen TO. Neurologic complications of cerebral angiography. AJNR 1994; 15: 1408- 11. 145. Grover DA, van Meel GJ, Berman EJ, Keunen JEE, Treffers WF, Smith DN. Ocular complications of the Wada test. Neuroophthalmologyl994:; U: 209- l< i. 146. Hurst RW, Goldberg HI. Transient monocular blindness in carotid occlusion testing. AJNR 1994; 15: 255- 7. 147. Russell EJ, Goldberg K, Oskin J, Darling C, Melen O. Ocular ischemic syndrome during carotid balloon occlusion testing. AJNR 1994; 15: 258- 62. 148. Woods RP, Iacoboni M, Mazziotta JC. Brief report: Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689- 92. 149. Olesen J. Understanding the biologic basis of migraine. N Engl J Med 1994; 331: 1713^ I. 150. Silberberg DH, Kurland LT, Weinshenker BG, Ebers GC, Hillert J, Sadovnick AD. Multiple sclerosis: approaches to management. Ann Neurol 1994; 36:( suppl 1). 151. Poser CM, Rosati G, Benedikz J, et al. Multiple sclerosis: epidemiology and genetics. Ann Neurol 1994; 36:( suppl 2). 152. Dean G, Bhigjee AIG, Bill PLA, et al. Multiple sclerosis in black South Africans and Zimbabweans. / Neurol Neuro-surg Psychiatry 1994; 57: 1064- 9. 153. Siva A, Radhakrishnan K, Kurland LT, O'Brien PC, Swan-son JW, Rodriquez M. Trauma and multiple sclerosis: a population- based cohort study from Olmsted County, Minnesota. Neurology 1993; 43: 1878- 82. 154. Sunku J, Kurland LT. Multiple sclerosis and trauma. Neurology 1994; 44: 2416. 155. Jellinek EH. Trauma and multiple sclerosis [ Commentary]. Lancet 1994; 343: 1053- 4. 156. Sadovnick AD, Eisen K, Hashimoto SA, et al. Pregnancy and multiple sclerosis: a prospective study. Arch Neurol 1994; 51: 1120- 4. 157. Stenager E, Stenager EN, Jensen K. Effect of pregnancy on the prognosis for multiple sclerosis. A 5- year follow up investigation. Acta Neurol Scand 1994; 90: 305- 8. 158. Nieves J, Cosman F, Herbert J, Shen V, Lindsay R. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology 1994; 44: 1687- 92. 159. Newman NJ, Selzer KA, Bell RA. Association of multiple sclerosis and intracranial hypertension. / Neuroophthalmol 1994; 14: 189- 92. 160. Lynch SG, Digre K, Rose JW. Usher's syndrome and multiple sclerosis: review of an individual with Usher's syndrome with a multiple sclerosis- like illness. / Neuroophthalmol 1994; 14: 34- 7. 161. Barton JJS, Cox TA, Calne DA. Involuntary ocular deviations and generalized dystonia in multiple sclerosis. / Neuro- Ophthalmol 1994; 14: 160- 2. 162. Keltner JL, Johnson CA, Spurr JO, et al. Visual field profile of optic neuritis: one- year follow- up in the optic neuritis treatment trial. Arch Ophthalmol 1994; 112: 946- 53. 163. Beck RW, Cleary PA, Backlund JC, et al. The course of visual recovery after optic neuritis: experience of the optic neuritis treatment trial. Ophthalmology 1994; 101: 1771- 8. 164. Coyle JT. Optic neuritis treatment trial study [ Correspondence]. Arch Ophthalmol 1994; 112: 1274. 165. Beck RW. Response to Coyle JT. Optic neuritis treatment trial study [ correspondence]. Arch Ophthalmol 1994; 112: 1274- 5. 166. Soderstrom M, Lindqvist M, Hillert J, Kail T- B, Link H. Optic neuritis: findings on MRI, CSF examination and HLA class II typing in 60 patients and results of a short-term follow- up. / Neurol 1994; 241: 391- 7. 167. Sellebjerg FT, Frederiksen JL, Olsson T. Anti- myelin basic protein and anti- proteolipid protein antibody- secreting cells in the cerebrospinal fluid of patients with acute optic neuritis. Arch Neurol 1994; 51: 1032- 6. 168. Goodkin DE, Rudick RA, Ross JS. The use of brain magnetic resonance imaging in multiple sclerosis. Arch Neurol 1994; 51: 505- 16. 169. Giang DW, Grow VM, Mooney C, et al. Clinical diagnosis of multiple sclerosis: the impact of magnetic resonance imaging and ancillary testing. Arch Neurol 1994; 51: 61- 6. 170. Khoury SJ, Guttman CRG, Orav EJ, et al. Longitudinal MRI in multiple sclerosis: correlation between disability and lesion burden. Neurology 1994; 44: 2120- 4. 171. Filippi M, Horsfield MA, Morrissey SP, et al. Quantitative brain MRI lesion load predicts the course of clnically isolated syndromes suggestive of multiple sclerosis. Neurology 1994; 44: 635- 41. 172. Kidd D, Thompson AJ, Kendall BE, Miller DH, McDonald WI. Benign form of multiple sclerosis: MRI evidence for less frequent and less inflammatory disease activity. / Neurol Neurosurg Psychiatry 1994; 57: 1070- 2. 173. Husted C. Contributions of neuroimaging to diagnosis and monitoring of multiple sclorosis. Curr Opin Neurol 1994; 7: 234- 41. 174. Gass A, Barker GJ, Kidd D, et al. Correlation of magnetization transfer ratio with clinical disability in multiple sclerosis. Ann Neurol 1994; 36: 62- 7. 175. Arnold DL, Riess GT, Matthews PM, et al. Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis. Ann Neurol 1994; 36: 76- 82. 176. Husted CA, Goodin DS, Hugg JW, et al. Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and aH spectroscopic imaging. Ann Neurol 1994; 36: 157- 65. 177. McDonald WI, Miller DH, Thompson AJ. Are magnetic resonance findings predictive of clinical outcome in therapeutic trials in multiple sclerosis? The dilemma of inter-feron- p. Ann Neurol 1994; 36: 14- 8. 178. Jacobs L, Johnson KP. A brief history of the use of interferons as treatment of multiple sclerosis. Arch Neurol 1994; 51: 1245- 52. 179. Practice advisory on selection of patients with multiple sclerosis for treatment with Betaseron. Neurology 1994; 44: 1537- 40. 180. Cotton P. Options for multiple sclerosis therapy. JAMA 1994; 272: 1393. 181. Durelli L, Bongioanni MR, Cavallo R, et al. Chronic systemic high- dose recominant interferon alfa- 2a reduces exacerbation rate, MRI signs of disease activity, and lympho- / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 252 N. J. NEWMAN cyte interferon gamma production in relapsing- remitting multiple sclerosis. Neurology 1994; 44: 406- 13. 182. Bever Jr CT, Young D, Anderson PA, et al. The effects of 4- aminopyridine in multiple sclerosis patients: results of a randomized, placebo- controlled, double- blind, concentration- controlled, crossover trial. Neurology 1994; 44: 1054- 9. 183. Lindsey JW, Hodgkinson S, Mehta R, Mitchell D, Enz-mann D, Steinman L. Repeated treatment with chimeric anti- CD4 antibody in multiple sclerosis. Ann Neurol 1994; 36: 183- 9. 184. Noseworthy JH, Ebers GC, Roberts R. Cyclophosphamide and MS [ Letter]. Neurology 1994; 44: 579. 185. Weiner HL, Orav EJ, Hafler DA, Dawson DM. Cyclophosphamide and MS [ Reply]. Neurology 1994; 44: 580- 1. 186. Reder AT, Thapar M, Jensen MA. A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: implications for treatment of inflammatory brain disease. Neurology 1994; 44: 2289- 94. 187. Ellis BD, Kosmorsky GS, Cohen BH. Medical and surgical management of acute disseminated encephalomyelitis. / Neuroophthalmol 1994; 14: 210- 3. 188. Fazekas F, Offenbacher H, Schmidt R, Strasser- Fuchs S. MRI of neuromyelitis optica: evidence for a distinct entity. / Neurol Neurosurg Psychiatry 1994; 57: 1140- 1. 189. Schwankhaus JD, Katz DA, Eldridge R, Schlesinger S, Mc- Farland H. Clinical and pathological features of an autosomal dominant, adult- onset leukodystrophy simulating chronic progressive multiple sclerosis. Arch Neurol 1994; 51: 757- 66. 190. Najim Al- Din AS, Anderson M, Eeg- Olofsson O, Trontelj JV. Neuro- ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia: observations on 20 patients. Acta Neurol Scand 1994; 89: 87- 94. 191. Najim Al- Din, Anderson M, Eeg- Olofsson O, Trontelj JV. Neuro- ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia: a review. Acta Neurol Scand 1994; 89: 157- 63. 192. Ropper AH. Bifacial weakness or sixth nerve paresis with paresthesias, lumbar polyradiculopathy, and ataxia with pharyngea- cervical- brachial weakness. Arch Neurol 1994; 51: 671- 5. 193. Hammers A, Hardie RJ. Miller- Fisher syndrome with rapid recovery. Lancet 1994; 343: 1290. 194. Bingisser R, Speich R, Fontana A, Gmur J, Vogel B, Landis T. Lupus erythematosus and Miller- Fisher syndrome. Arch Neurol 1994; 51: 828- 30. 195. CDC. Heterosexually acquired AIDS- United States, 1993. MMWR 1994; 43: 155- 60. 196. Melnick SL, Sherer R, Louis TA, et al. Survival and disease progression according to gender of patients with HIV infection: the Terry Beirn community programs for clinical research on AIDS. JAMA 1994; 272: 1915- 21. 197. Bacellar H, Mufioz A, Miller EN, et al. Temporal trends in the incidence of HIV- 1- related neurologic diseases: multi-center AIDS cohort study, 1985- 1992. Neurology 1994; 44: 1892- 1900. 198. Royal W III, Seines OA, Concha M, Nance- Sproson TE, McArthur JC. Cerebrospinal fluid human immunodeficiency virus type 1 ( HIV- 1) p24 antigen levels in HIV- 1- related dementia. Ann Neurol 1994; 36: 32- 9. 199. Arendt G, Maecker H- P, Homberg V. Control of posture in patients with neurologically asymptomatic HIV infection and patients with beginning HIV- 1- related encephalography. Arch Neurol 1994; 51: 1232- 5. 200. Reifler DM, Warzynski MJ, Blount WR, Graham DM, Mills KA. Orbital lymphoma associated with acquired immune deficiency syndrome ( AIDS). Surv Ophthalmol 1994; 38: 371- 80. 201. Logani S, Logani SC, Ali BH, Goldberg RA. Bilateral, in-traconal non- Hodgkin's lymphoma in a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 1994; 118: 401- 2. 202. Batzkin DC, Slamovits TL, Rosenbaum PS. Simultaneous intraocular and orbital non- Hodgkin lymphoma in the acquired immune deficiency syndrome. Ophthalmology 1994; 101: 850- 5. 203. Hall AJH, Stawell RJ. Human immunodeficiency virus-related uveomyelitis. Arch Ophthalmol 1994; 112: 1144- 5. 204. Ayuso- Peralta L, Jimenez- Jimenez FJ, Tejeiro J, et al. Progressive multifocal leukoencephalopathy in HIV infection presenting as Balint's syndrome. Neurology 1994; 44: 1339- 40. 205. de Toffol B, Vidailhet M, Gray F, et al. Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI. Neurology 1994; 44: 2352- 5. 206. Roullet E, Assuerus V, Gozlan J, et al. Cytomegalovirus multifocal neuropathy in AIDS: analysis of 15 consecutive cases. Neurology 1994; 44: 2174- 82. 207. Haas DW, Des Prez RM. Tuberculosis and acquired immunodeficiency syndrome: a historical perspective on recent developments. Am J Med 1994; 96: 439- 50. 208. Horowitz HW, Valsamis MP, Wicher V, et al. Brief report: cerebral syphilitic gumma confirmed by the polymerase chain reaction in a man with human immunodeficiency virus infection. N Engl J Med 1994; 331: 1488- 91. 209. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high- dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med 1994; 331: 1469- 73. 210. Simon RP. Neurosyphilis. Neurology 1994; 44: 2228- 30. 211. Schwartzman WA, Patnaik M, Barka NE, Peter JB. Rochalimaea antibodies in HIV- associated neurologic disease. Neurology 1994; 44: 1312- 6. 212. Forsyth PA, Yahalom J, DeAngelis LM. Combined-modality therapy in the treatment of primary central nervous system lymphoma in AIDS. Neurology 1994; 44: 1473- 9. 213. Moore RD, Stanton D, Gopalan R, Chaisson RE. Racial differences in the use of drug therapy for HIV disease in an urban community. N Engl J Med 1994; 330: 763- 8. 214. Lundgren JS, Phillips AN, Pedersen C, et al. Comparison of long- term prognosis of patients with AIDS treated and not treated with zidovudine. JAMA 1994; 271: 1088- 92. 215. Lenderking WR, Gelber RD, Cotton DJ, et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N Engl J Med 1994; 330: 73& 43. 216. Phair JP. Effectiveness of zidovudine in treatment of advanced HIV infection [ Editorial]. JAMA 1994; 271: 1121- 2. 217. Abrams DI, Goldman Al, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994; 330: 657- 62. 218. Saag MS. What to do when zidovudine fails. N Engl J Med 1994; 330: 706- 7. 219. Rowe PM. AIDS vaccines not ready for phase III trials. Lancet 1994; 343: 1626. 220. Blower SM, McLean AR. Prophylactic vaccines, risk behavior change, and the probability of eradicating HIV in San Francisco. Science 1994; 265: 1451- 4. 221. Cotton P. High- tech assault on HIV: gene therapy. JAMA 1994; 272: 1235- 6. 222. Naber SP. Molecular medicine: molecular pathology- diagnosis of infectious disease. N Engl J Med 1994; 331: 1212- 5. 223. Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection: a new zoonosis with the domestic cat as reservoir. JAMA 1994; 271: 531- 5. 224. Tompkins LS. Rochalimaea infections: are they zoonoses? JAMA 1994; 271: 553- 4. 225. Adal KA, Cockerell CJ, Petri WA Jr. Cat scratch disease, bacillary angiomatosis, and other infections due to rochalimaea. N Engl J Med 1994; 330: 1509- 15. 226. Lee WR, Chawla JC, Reid R. Bacillary angiomatosis of the conjunctiva. Am J Ophthalmol 1994; 118: 152- 7. / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEURO- OPHTHALMOLOGY AND SYSTEMIC DISEASE 253 227. Le HH, Palay DA, Anderson B, Steinberg JP. Conjunctival swab to diagnose ocular cat scratch disease. Am J Ophthalmol 1994; 118: 249- 50. 228. Golnik KC, Marotto ME, Fanous MM, et al. Ophthalmic manifestations of Rochalimaea species. Am / Ophthalmol 1994; 118: 145- 51. 229. Grossniklaus HE. The cat scratch disease- bacillary angiomatosis puzzle. Am J Ophthalmol 1994; 118: 246- 8. 230. Shadick NA, Phillips CB, Logigian EL, et al. The long- term clinical outcomes of Lyme disease. Ann Intern Med 1994; 121: 560- 7. 231. Bergloff J, Gasser R, Feigl B. Ophthalmic manifestations in Lyme borreliosis. / Neuroophthalmol 1994; 14: 15- 20. 232. Strominger MB, Slamovits TL, Herskovits S, Lipton RB. Transient worsening of optic neuropathy as a sequela of the Jarisch- Herxheimer reaction in the treatment of Lyme disease. / Neuroophthalmol 1994; 14( 2): 77- 80. 233. Mastrianni JA, Galetta SL, Raps EC, Liu GT, Volpe NJ. Isolated fascicular abducens nerve palsy and lyme disease. / Neuro- Ophthalmol 1994; 14: 2- 5. 234. Tyler KL. Polymerase chain reaction and the diagnosis of viral central nervous system diseases. Ann Neurol 1994; 36: 809- 11. 235. Baringer JR, Pisani P. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol 1994; 36: 823- 9. 236. Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl } Med 1994; 330: 896- 900. 237. Lowsky R, Archer GL, Fyles G, et al. Brief report: diagnosis of Whipple's disease by molecular analysis of peripheral blood. N Engl} Med 1994; 331: 1343- 6. 238. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino- orbital- cerebral mucormycosis. Surv Ophthalmol 1994; 39: 3- 22. 239. Katz B. Central American mesencephalopathy. Comments by Winterkorn J, Newman SA. Surv Ophthalmol 1994; 39: 253- 9. 240. Pollack IF. Brain tumors in children. N Engl } Med 1994; 331: 1500- 7. 241. Torres CF, Rebsaman S, Silber JH, et al. Surveillance scanning of children with medulloblastoma. N Engl J Med 1994; 330: 892- 5. 242. Weiner HL, Wisoff JH, Rosenberg ME, et al. Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery 1994; 35: 1001- 11. 243. Kupersmith MJ, Rosenberg C, Weinberg D. Visual loss in pregnant women with pituitary adenomas. Ann Intern Med 1994; 121: 473- 7. 244. Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. / Pediatr 1994; 125: 63- 6. 245. Parry DM, Eldridge R, Kaiser- Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 ( NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 1994; 52: 450- 61. 246. Lennon VA, Paraneoplastic autoantibodies: the case for a descriptive generic nomenclature. Neurology 1994; 44: 2236- 40. 247. Dalmau J, Posner JB. Neurologic paraneoplastic antibodies ( anti- Yo; anti- Hu; anti- Ri): the case for a nomenclature based on antibody and antigen specificity. Neurology 1994; 44: 2241- 6. 248. Lennon VA. The case for a descriptive generic nomenclature: clarification of immunostaining criteria for PCA- 1, ANNA- 1, and ANNA- 2 autoantibodies. Neurology 1994; 44: 2412-^ 5. 249. Thirkill CE. Cancer associated retinopathy: the CAR syndrome. Neuroophthalmology 1994; 14: 297- 324. 250. Kim RY, Retsas S, Fitzke FW, Arden GB, Bird AC. Cutaneous melanoma- associated retinopathy. Ophthalmology 1994; 101: 1837- 43. 251. Weinstein JM, Kelman SE, Bresnick GH, Kornguth SE. Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology 1994; 101: 1236- 43. 252. Harris GJ, Murphy ML, Schmidt EW, Hanson GA, Dotson RM. Orbital myositis as a paraneoplastic syndrome. Arch Ophthalmol 1994; 112: 380- 6. 253. Dropcho EJ, King PH. Autoantibodies against the Hel- Nl RNA- binding protein among patients with lung carcinoma: an association with type 1 antineuronal nuclear antibodies. Ann Neurol 1994; 36: 200- 5. 254. Hersh B, Dalmau J, Dangond F, Gultekin S, Geller E, Wen PY. Paraneoplastic opsoclonus- myoclonus associated with anti- Hu antibody. Neurology 1994; 44: 1754- 5. 255. Verschuuren J, Twijnstra A, De Baets M, Thunnissen F, Dalmau J, van Breda Vriesman P. Hu antigens and anti- Hu antibodies in a patient with myxoid chondrosarcoma. Neurology 1994; 44: 1551- 2. 256. Graus F, Bonaventura I, Uchuya M, et al. Indolent anti- Hu- associated paraneoplastic sensory neuropathy. Neurology 1994; 44: 2258- 61. 257. Casado JL, Gil- Peralta A, Graus F, Arenas C, Lopez JM, Alberca R. Anti- Ri antibodies associated with opsoclonus and progressive encephalomyelitis with rigidity. Neurology 1994; 44: 1521- 2. 258. Hormigo A, Dalmau J, Rosenblum MK, River ME, Posner JB. Immunological and pathological study of anti- Ri-associated encephalopathy. Ann Neurol 1994; 36: 896- 902. 259. Ahern GL, O'Connor M, Dalmau J, et al. Paraneoplastic temporal lobe epilepsy with testicular neoplasm and atypical amnesia. Neurology 1994; 44: 1270- 4. 260. Patchell RA. Neurological complications of organ transplantation. Ann Neurol 1994; 36: 688- 703. 261. Coskuncan NM, Jabs DA, Dunn JP, et al. The eye in bone marrow transplantation: VI. retinal complications. Arch Ophthalmol 1994; 112: 372- 9. 262. U. S. Multicenter FK 506 Liver Study Group. A comparison of tacrolimus ( FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl ] Med 1994; 331: 1110- 5. 263. Drachman DB. Myasthenia gravis. N Engl ] Med 1994; 330: 1797- 1810. 264. Weinberg DA, Lesser RL, Vollmer TL. Ocular myasthenia: a protean disorder. Surv Ophthalmol 1994; 39: 169- 210. 265. Newman NJ, Capone A, Leeper HF, et al. Clinical and subclinical ophthalmic findings with retinol deficiency. Ophthalmology 1994; 101: 1077- 83. 266. Doraiswamy PM, Massey EW, Enright K, Palese VJ, La-monica D, Boyko O. Wernicke- Korsakoff syndrome caused by psychogenic food refusal: MR findings. AJNR 1994; 15: 594- 6. 267. Shogry MEC, Curnes JT. Mamillary body enhancement on MR as the only sign of acute Wernicke encephalopathy. AJNR 1994; 15: 172- 4. 268. D'Aprile P, Gentile MA, Carella A. Enhanced MR in the acute phase of Wernicke encephalopathy. A] NR 1994; 15: 591- 3. 269. Leib ML, Odel JG, Cooney MJ. Orbital polymyositis and giant cell myocarditis. Ophthalmology 1994; 101: 950- 4. 270. Scinto LFM, Daffner KR, Dressier D, et al. A potential noninvasive neurobiological test for alzheimer's disease. Science 1994; 266: 1051^. 271. Idiaquez J, Alvarez G, Villagra R, San Martin RA. Cholin-ergenic supersensitivity of the iris in alzheimer's disease. / Neurol Neurosurg Psychiatry 1994; 57: 1544- 5. / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 |
