Serum and Cerebrospinal Fluid Testing in Optic Neuropathy Patients with Malignant Tumors.

PURPOSE: To evaluate the value of serum and cerebrospinal fluid (CSF) testing in optic neuropathy (ON) patients with malignant tumors. METHODS: Fourteen patients clinically diagnosed as ON with malignant tumors but without intracranial or orbital mass in MRI were included in this study. Detailed medical records including medical history, complete ophthalmic examination, colour fundus photography, visual field test, orbital MRI examination, serum and CSF testing data were collected and analyzed. The diagnosis of paraneoplastic optic neuropathy (PON) based on the 2004 recommended criteria of the paraneoplastic syndrome- Euronetwork consortium for paraneoplastic neurological disorders, and current adaption for neuropathies. All patients underwent serum tests for pathogens and autoantibodies including antinuclear antibodies, anticardiolipin antibodies, antineutrophil cytoplasmic antibodies, AQP4-Ab and MOG-Ab, as well as CSF tests for malignant cells under microscope. Serum paraneoplastic antibodies were detected in PON patients. Monkey cerebellar tissue-based assay was used to detect unknown serum anti-neuron antibodies in PON patients with negative paraneoplastic antibody testing results. RESULTS: Fourteen ON patients were classified as four groups based on their clinical and MRI characteristics, as well as serum and CSF testing results: [1] definite PON, 6 cases (11 eyes); [2] possible PON, 3 case (5 eyes); [3] meningeal carcinomatosis-associated optic neuropathy (MCON), 4 cases (6 eyes); [4] infiltrative optic neuropathy (ION), 2 cases (2 eyes). Malignant cells were found under microscope in CSF samples from MCON and ION patients, contrast to no malignant cells in CSF samples from PON cases. All 14 ON patients with malignant tumors showed negative results in serum tests for pathogens and autoantibodies. Serum paraneoplastic antibodies were tested in PON patients, anti- CV2, anti-Yo, and anti- amphiphysin were detected positive in 2, 1, and 1 case, respectively, in definite PON group, whereas no serum paraneoplastic antibody detected in possible PON group. Two unknown serum antineuronal antibodies (an anti- Purkinje cell antibody and an anti-granular cell antibody) were detected using monkey cerebellar tissue-based assay in 2 of 5 PON patients with negative paraneoplastic antibody test results. CONCLUSIONS: Serum and CSF tests are of great importance in differentiating different subtypes of ON with malignant tumors. Current diagnosis of PON still depends on combination of clinical and MRI manifestations, as well as serum and CSF tests. Tissue-based assay may help to detect new biomarkers for ON etiology and diagnosis.

Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy.

Radiation-induced optic neuropathy (RION) is a devastating complication following external beam radiation therapy (EBRT) that leads to acute vision loss. To date, no efficient, available treatment for this complication, due partly to the lack of understanding regarding the developmental processes behind RION. Here, we report radiation caused changes in mitochondrial dynamics by regulating the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission-1 (Fis1). Concurrent with an excessive production of reactive oxygen species (ROS), both neuronal injury and visual dysfunction resulted. Further, our findings delineate an important mechanism by which cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of Drp1 (Ser616) regulates defects in mitochondrial dynamics associated with neuronal injury in the development of RION. Both the pharmacological inhibition of Cdk5 by roscovitine and the inhibition of Drp1 by mdivi-1 inhibited mitochondrial fission and the production of ROS associated with radiation-induced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.

Yield of screening blood work and MRI of the brain and orbits in the work-up of unilateral chronic optic neuropathy.

BACKGROUND/OBJECTIVES: No guidelines exist for the investigation of treatable causes of chronic optic neuropathy, including sarcoidosis, lupus, and syphilis. The purpose of this study was to determine the diagnostic yield of screening blood work (ACE (Angiotensin Converting Enzyme) for sarcoidosis, Antinuclear Antibodies (ANA) for lupus, CMIA (chemiluminescence microparticle enzyme immunoassay) for syphilis) and contrast-enhanced MRI brain and orbits in atypical unilateral chronic optic neuropathy. SUBJECTS/METHODS: Retrospective review from February 2012 to June 2018 at a neuro-ophthalmology practice. Six hundred and eighty-three consecutive charts with optic neuropathy were reviewed. Inclusion criteria were unilateral chronic optic neuropathy and a work-up including contrast-enhanced MRI brain and orbits, CBC, ESR, CRP, ANA, CMIA, and ACE. Exclusion criteria were optic nerve swelling in either eye on initial assessment or an established cause of optic neuropathy. The main outcome measure was diagnostic yield. RESULTS: Fifty-seven patients were included. One patient had elevated ACE, seven had positive ANA titers, and three had positive CMIA. Zero patients were diagnosed with sarcoidosis, one patient was diagnosed with lupus-related optic neuropathy, and one patient was diagnosed with syphilitic optic neuropathy. The diagnostic yield of ACE was 0%, ANA was 1.75%, and CMIA was 1.75%. MRI revealed planum sphenoidale meningioma causing compressive optic neuropathy in one patient, giving it a diagnostic yield of 1.82%. CONCLUSION: Routine screening blood work (ACE, ANA, CMIA) and MRI brain and orbits for chronic idiopathic unilateral optic neuropathy has low diagnostic yield, especially if clinical suspicion for syphilis, lupus, and sarcoidosis is low. MRI should still be performed in all cases in order to rule out compressive lesions.

CV2/CRMP5-antibody-related Paraneoplastic Optic Neuropathy Associated with Small-cell Lung Cancer.

A 61-year-old woman who had smoked for 41 years developed subacute dizziness, ataxic gait, opsoclonus, and right visual impairment. She had right optic disc swelling and optic nerve gadolinium enhancement on magnetic resonance imaging. She had small-cell lung cancer (SCLC), with CV2/collapsin response mediator protein (CRMP) 5 and HuD antibodies in her serum and cerebrospinal fluid. She was diagnosed with paraneoplastic optic neuropathy (PON) accompanied by paraneoplastic opsoclonus-ataxia syndrome. Her symptoms improved after removing the SCLC. Classical PON is rare in Japan. We recommend assaying for CV2/CRMP5 antibodies and searching for cancer in elderly patients with subacute painless visual impairment.

Nutritional Optic Neuropathy Caused by Copper Deficiency After Bariatric Surgery.

A 47-year-old woman developed severe bilateral visual loss 4 years after a Roux-en-Y gastric bypass and 24 years after vertical banded gastroplasty. Her serum copper level was 35 µg/dL (normal, 80-155 µg/dL). She was prescribed elemental copper tablets. Because her methylmalonic acid was slightly elevated, she received vitamin B12 injections as well. Five weeks later, she reported that her vision had improved and, at 10 months, her vision had recovered from 20/400 bilaterally to 20/25 in each eye. This case highlights the importance of checking copper levels in addition to the "more routine" vitamin levels, such as B1, B6, B12, E, and serum folate in patients with suspected nutritional optic neuropathy after bariatric surgery, particularly if it involved a bypass procedure.

Retinal Nerve Fiber Layer Thickness is Decreased in Patients With Hematologic Malignancy.

PURPOSE: To investigate whether retinal nerve fiber layer (RNFL) thickness is decreased in patients with hematologic malignancy using optical coherence tomography (OCT). PATIENTS AND METHODS: This prospective, observational cross-sectional study included 65 eyes from 34 patients with hematologic malignancy and 72 healthy control eyes. OCT-measured RNFL thickness parameters (average, 4 quadrants, and 12 clock-hour thickness) and RNFL defect in red-free photo were compared between patients with hematologic malignancy and controls. RESULTS: Among average, quadrant, and clock-hour map, the only 11-o'clock RNFL in patients with hematologic malignancy was statistically thinner than in controls (P=0.021). The RNFL defect was detected in 21/65 (32.3%) patients with hematologic malignancy and in 5/72 (6.9%) controls (P<0.001). In patients with hematologic malignancy, the mean RNFL thickness was significantly lower in the severe and moderate anemia groups compared with the mild anemia group (P=0.011). In the generalized estimating equations model, the mean hemoglobin level was associated with RNFL thickness while correcting for inter-eye correlation, age, and refraction error (coefficient=3.685, P=0.006). CONCLUSIONS: The RNFL defect was frequently observed, and the RNFL was thinner in severe anemic patients with hematologic malignancy. These results suggest that chronic anemia may be a factor of RNFL loss.

Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery.

Malabsorptive bariatric surgery is rapidly becoming a major cause of copper deficiency given the increasing prevalence of these procedures for morbid obesity. Acquired copper deficiency can present with clinically significant hematologic and neurological manifestations. Although hematologic manifestations of copper deficiency are rapidly reversible, significant neurological improvement after copper supplementation therapy is unusual and many patients remain debilitated and may only experience, at best, stabilization of the neurological manifestations. Here we present a case of an undiagnosed copper deficiency several years after bariatric gastric bypass surgery, in a patient who concomitantly used zinc-containing denture cream for several years, associated with anemia, neutropenia, myelopathy, respiratory failure, and bilateral optic neuropathy, which caused major vision loss. This patient was also a heterozygote carrier of the 5,10-methylenetetrahydrofolate reductase A1298C gene polymorphism, which may affect copper metabolism. Intravenous copper repletion resulted in rapid correction of hematologic indices. However, neurological manifestations, including vision loss responded only modestly to copper supplementation, despite achieving normal blood copper concentrations. Clinicians should consider copper deficiency in patients at risk, as in this case, as a delayed diagnosis can lead to irreversible disability due to neurological manifestations.

Optic neuropathy among a prison population in Papua New Guinea.

PURPOSE: To estimate the prevalence of optic neuropathy (ON) among prisoners in a provincial prison in Papua New Guinea, and to explore risk factors for this condition among this population. METHODS: Cross-sectional observation study of 148 male prisoners aged ≥18 years using an interview-based questionnaire, assessment of visual and nervous system function, ocular examination, and blood analysis (α-tocopherol, ß-carotene, lutein, folate, homocysteine, holotranscobalamin II, riboflavin, selenium, thiamin, and vitamins A, B(12) and C). Likelihood of the presence of ON was based on ordered groups determined by weighted combination of optic nerve head appearance and visual dysfunction (acuity, field, color perception). Main outcome measures were prevalence and associations of ON. RESULTS: Sample prevalence of clinical ON was 10.4% (95% confidence interval [CI], 6.2-16.8). No cases were found of unexplained non-visual nervous system dysfunction, including peripheral neuropathy. Increasing age (p = 0.001), length of current (p = 0.002) and lifetime (p = 0.03) incarceration, and duration of smoking by current smokers (p = 0.001) were associated with increased ON likelihood. However, when age-controlled, the smoking duration association was not maintained (p = 0.6). Prisoners were folate deficient. Adjusting for age and duration of current incarceration, whole blood (p = 0.02) and red blood cell (p = 0.04) folate concentrations were inversely associated with ON likelihood. No association was found for any other assessed demographic, lifestyle or biochemical measure. CONCLUSIONS: A cluster of ON associated with folate deficiency has been identified. Recommendations for dietary change and micronutrient supplementation have been made.

Serum cytokine alteration is associated with optic neuropathy in human primary open angle glaucoma.

PURPOSE: The purpose of this study is to compare human serum levels of TH1 and TH2 cytokines between 2 stages of primary open-angle glaucoma (POAG) and nonglaucomatous controls. METHODS: Thirty-two patients with primary POAG and 26 normal control subjects were enrolled into this study. The 32 patients with POAG were divided into 2 subgroups according to their mean defect (MD) with MD better than -12 dB and worse than -12 dB on the visual field. Enzyme-linked immunosorbent assay was used to assay for the levels of TH1 cytokines serum soluble interleukin-2 receptor (sIL-2R), interleukin (IL)-2, IL-12p40, IL-12p70, IL-23, tumor necrosis factor (TNF)-alpha, interferon-gamma, and TH2 cytokines IL-4, IL-6 in the peripheral serum. RESULTS: Patients with mild glaucomatous neuropathy exhibited significant elevations in IL-4 (P<0.0001) and IL-6 (P=0.0302) compared with the controls, whereas higher concentrations of IL-4 (P<0.0001) and IL-6 (P=0.0084) were found in patients with severe glaucomatous neuropathy. The level of IL-12p70 was significantly increased in both the MD >/=12 dB (P<0.0001) and MD <12 dB (P<0.0001) groups. A significant decrease in TNF-alpha levels were observed in MD <12 dB group compared with the controls (P=0.0464), and TNF-alpha levels in MD <12 dB group were lower than MD >/=12 dB group (P=0.0328). No significant differences in serum concentrations of IL-2, sIL-2R IL-12p40, IL-23 and interferon-gamma were found between MD <12 dB group, MD >or=12 dB group, and control group. CONCLUSIONS: Significant alterations of serum TH1 and TH2 cytokines are associated with glaucoma, suggesting the possibility that abnormal immune environments contribute to the glaucomatous neuropathy of POAG.

High-titer collapsin response-mediating protein-associated (CRMP-5) paraneoplastic optic neuropathy and Vitritis as the only clinical manifestations in a patient with small cell lung carcinoma.

Paraneoplastic optic neuropathy (PON) is a rare syndrome usually associated with small cell lung carcinoma. In the 27 rigorously reported cases, neurologic manifestations other than visual loss have been present in all but 2. In the single case in which vision improved in response to treatment of the cancer, the collapsin response-mediating protein (CRMP)-5 titer did not change, and the ophthalmic examination was not detailed. We describe a patient with optic neuropathy and vitritis as the only clinical manifestations of PON marked by an extremely high titer of CRMP-5 antibody. Treatment of the underlying small cell lung cancer coincided with resolution of the visual abnormalities and a dramatic decrease in the CRMP-5 titer.

Optic neuropathy from folic acid deficiency without alcohol abuse.

A 47-year-old woman with a 2-month history of bilateral progressive visual loss was found to have a bilateral retrobulbar optic neuropathy. Her serum vitamin B(12) concentration and hemoglobin level were normal, but her serum folic acid concentration was decreased. The patient had a minimal alcohol intake and moderate tobacco use that had been unchanged for over 20 years; however, she had markedly altered her diet 4 years earlier in the setting of clinical depression. After treatment with oral folic acid and diet modification without change in her tobacco or alcohol use, the patient's visual function returned to normal. This case supports the role of folic acid deficiency as an important cause of some cases of nutritional optic neuropathy.

Seasonal variations of antioxidant imbalance in Cuban healthy men.

OBJECTIVE: To determine the antioxidant imbalance in healthy Cuban men 2y after the end of the epidemic neuropathy (50 862 cases from 1991 to 1993) and to evaluate its change over 1 y. DESIGN: Prospective study. SETTING: La Lisa health centres (Havana, Cuba). SUBJECTS: One-hundred and ninety-nine healthy middle-aged men were selected and 106 completed the study. Subjects were studied at 3 month intervals over 1 year. INTERVENTIONS: No invervention. MAIN OUTCOME MEASURES: An assessment of dietary intake and the determination of blood lipid peroxides (TBARS), glutathione, diglutathione, glutathione peroxidase, superoxide dismutase, vitamin E, carotenoids, copper, zinc and selenium were performed at each period. RESULTS: While dietary zinc, vitamins C and E, carotenoids and fat dietary intakes and blood concentrations were low for adult men compared to international reference ranges, serum TBARS concentrations were high at every period. Some significant seasonal variations were observed. The lowest carotenoids (P < 0.002) and vitamin C(P = 0.0001) intakes, serum beta-carotene (P = 0.0001) and lutein/zeaxanthin (P < 0.05) concentrations, and the highest blood TBARS (P = 0.0001) and diglutathione (P < 0.001) concentrations were observed at the end of the rainy season (October). This period seemed to pose the greatest risk of antioxidant imbalance. CONCLUSIONS: Cuban men still represent a vulnerable population in terms of antioxidant imbalance. A national program of vegetable growing and increase in fruit and vegetable consumption is now evaluated in Cuba.

Deficiencia de folato y concentraciones elevadas de formato en suero y líquido cefalorraquídeo de pacientes con neuropatía óptica epidémica / Folic acid deficiency and increased concentrations of formate in serum and cerebrospinal fluid of patients with epidemic optical neuropathy

We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del RÝo province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50 of samples and high formate concentration levels in almost 25 of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.

Precocious puberty in children with neurofibromatosis type 1.

We undertook a comprehensive study of children with neurofibromatosis type 1 (NF-1) cared for in a large multidisciplinary clinic to determine the prevalence of precocious puberty and its relationship to optic pathway tumors (OPTs). Precocious puberty was diagnosed in 7 of 219 children with NF-1 (5 boys and 2 girls) examined between Jan. 1, 1985, and April 20, 1993. All seven children had OPTs involving the optic chiasm; they represented 39% of children with NF-1 and chiasmal tumors (95% confidence interval, 17% to 64%). Eleven prepubertal children (aged 2 to 10 years) with NF-1 and OPTs, and age- and sex-matched NF-1 control subjects without OPTs, underwent luteinizing hormone-releasing hormone (LH-RH) stimulation tests. Two boys with OPTs had pubertal luteinizing hormone (LH) responses, and testosterone levels > 10 ng/dl. Basal LH levels were also elevated in these two boys when tested with a very sensitive immunochemiluminometric assay. None of the children without an OPT had either a pubertal response to LH-RH or an elevated basal LH level. We conclude that precocious puberty in children with NF-1 is found exclusively in those who have OPTs involving the optic chiasm; it is a common complication in those children. With the use of a highly sensitive LH assay, biochemical evidence of hypothalamic-pituitary-gonadal axis activation may be demonstrated, even without provocative testing.

Fibrinogen, cholesterol and smoking as risk factors for non-arteritic anterior ischaemic optic neuropathy.

Non-arteritic anterior ischaemic optic neuropathy (AION) is thought to be due to occlusion of the posterior ciliary circulation. Raised lipid and fibrinogen concentrations are recognised risk factors for vessel occlusion in cardiovascular disease and stroke but, although suspected as risk factors in non-arteritic AION, they have not been studied in this condition. We therefore performed a case-control study on 41 patients with non-arteritic AION, looking at these and other atherosclerotic risk factors. The odds ratio of cholesterol being > 6.5 mmol/l in non-arteritic AION was 2.7 (95% confidence interval 1.09 to 6.65; p < 0.05) and of fibrinogen being > 3.6 g/l was 5 (2.66 to 9.39; p < 0.05). Smoking was also found to be significantly associated with non-arteritic AION, the odds ratio being 16 (3.23 to 79.23; p < 0.001). These were the only risk factors found to be significantly associated with non-arteritic AION. This raises the possibility that appropriate medical management of these factors could be given to prevent recurrence in the fellow eye.

Visual functions and trace element metabolism in tobacco-toxic optic neuropathy.

Visual functions and nutrition metabolic characteristics were studied in 8 subjects (16 eyes) with tobacco-toxic optic neuropathy (TTON). Their visual functions tested by psychophysical and electrophysiologic methods showed that 1: 1. central vision diminished in 16 eyes, 2. dyschromatopsias were found in 14 tested eyes, 3. bilateral symmetrical central or cecocentral scotomas were the visual field characteristics in all cases, 4. PVEP were severe abnormal in 3 spatial frequencies in all cases and 56.3% of 15' checkboard PVEP showed flat responses, which indicated the impairment of optic nerve dominated by the central field. However, the preserved visual responses could be obtained by FVEP test in 14 tested eyes even though their visual acuity were between the range of 0.02-0.2 and flat PVEP responses. The II and III wave latencies of primary stage were more prolonged than those of control group (P < 0.01), which further indicated the preferential demyelination corresponding to the papillomacular bundles, 5. ERG showed slightly attenuated amplitudes in 5 of 8 tested eyes, which indicated the secondary and mild retinal lesion. On the other hand, TTON occurred on a background of long-term, heavy smoking, drinking, emaciation and malnutrition bodies with low serum zinc level.

Red cell reduced glutathione and tobacco smoke-induced optic neuropathy.

Cigarette smoke contains detectable amounts of cyanide, regardless of the type of cigarette. The very high levels of this compound in plasma of amblyopic smokers suggests that cyanide causes optic neuropathy. The detoxification of cyanide in man occurs through various metabolic pathway; the most important are those that use sulfur to transform cyanide into thiocyanate. One of the richest sources of reduced sulfhydryl groups is reduced glutathione (GSH). For this reason we investigated red cell GSH levels in non-smokers, in healthy smokers and in smokers affected by optic neuropathy to ascertain whether this compound is a marker of the disease. Red cell GSH levels in the non-smokers group were similar to those of affected smokers. On the contrary, GSH levels in healthy smokers were significantly more elevated. During therapy with vitamin E we noted that the concentration of GSH decreased with the progression of the disease and increased with recovery. Moreover, there was a good correlation between GSH levels and clinical findings. Our findings demonstrate that GSH plays a key role in the detoxification of cyanide and so it could be a marker of tobacco smoke-induced optic neuropathy.