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.

Combination Model of Thyrotrophin Receptor Antibody and Volumetric Orbital Apex Crowding Index as an Indicator of Dysthyroid Optic Neuropathy.

BACKGROUND: Dysthyroid optic neuropathy (DON) is one of the most serious vision-threatening complications of thyroid eye disease (TED); however, accurate and established diagnostic tools for DON are yet lacking. The present study was aimed at identifying new diagnostic factors for the accurate diagnosis of DON. METHODS: This retrospective cross-sectional study included 25 TED patients (50 eyes) with enlarged extraocular muscles, no previous anti-inflammatory therapy, and the absence of other vision-affecting diseases between May 2017 and August 2019. Baseline data, such as gender, age, ophthalmological history, thyroid disease and management, TED history including clinical features, management, and long-term results, ophthalmological examinations, serology examinations, and single-photon emission computed tomography/computed tomography (SPECT/CT) results, were extracted. The diagnostic criteria were as follows: (1) best-corrected visual acuity (BCVA) loss coexisting with either of the following-increased latency or reduction of amplitude on visual evoked potential (VEP), impaired color vision, visual field defects, contrast sensitivity impairment, and optic disk swelling-and (2) Barrett's index ≥ 60% in CT. Univariate and multivariate logistic regression analyses assessed the differences in age, gender, eyes, medical history, clinical activity, thyroid hormone and antibodies, uptake ratio (UR) of extraocular muscles in SPECT/CT, and volumetric orbital apex crowding index (VACI) using the generalized estimation equation. Consequently, the receiver operating characteristic curve (ROC) of the significant factors was constructed. RESULTS: Univariate analysis revealed significant differences in the clinical activity, free triiodothyronine (FT3), free thyroxine (FT4), thyrotrophin receptor antibody (TRAb) levels, the UR of superior and medial rectus, and VACI between DON and TED (without DON) groups. Multivariate regression analysis revealed that TRAb and VACI were significantly different. ROC analysis showed that the univariate models of TRAb or VACI and the multivariate model were effective indicators of DON, while the multivariate model had the highest area under the ROC curve. CONCLUSION: A combination of TRAb and VACI is an effective indicator for DON.

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.

[Optic neuropathy in positive anti-MOG antibody syndrome]. / Neuropathie optique dans le syndrome des anticorps anti MOG positif.

INTRODUCTION: The diagnosis of optic neuritis (ON), or inflammation of the optic nerve, is based on clinical findings: first marked by rapidly progressive visual decline associated with eye pain accentuated by eye movements; abnormalities of color perception and/or contrast sensitivity may also be reported. In this case, inflammatory neuropathies are associated with anti-MOG antibodies. MOGs, oligodendrocytic glycoproteins involved in the production of myelin, were identified nearly three decades ago in association with demyelinating ON. The first series were reported in children following demyelinating neurological manifestations, particularly in ADEM (acute demyelinating encephalomyelitis) or multiple sclerosis (MS) [1]. Anti-MOGs are associated with neuropathies in the phenotypic setting of the neuromyelitis optica (NO) spectrum, and anti-Aquaporin 4 antibodies (AQP4) are negative by definition. Thus, anti-MOG could explain up to 30 % of cases of seronegative optic neuritis; their presence thus represents a significant diagnostic aid for the clinician, especially during a first neurological episode [1]. The first short published series in AQP4-/MOG+populations revealed primarily ophthalmological involvement with a good prognosis for recovery [1]. Knowledge of these antigens is important; it may permit not only an understanding of the physiopathology but also the stratification of patients in terms of prognosis and response to treatment [2]. Thus, the early diagnosis of anti-MOG positive ON must prompt aggressive initial treatment and a more or less maintenance therapy to prevent recurrence. The role of the ophthalmologist remains paramount, since most cases present with purely ocular involvement. MATERIALS AND METHODS: We report herein the clinical, ophthalmological, laboratory and radiological data for 25 patients (45 eyes) managed between February 2011 and January 2017. All of our patients had optic neuritis associated with anti-MOG antibodies. All patients underwent the following testing: - Visual acuity; - Humphrey and/or Goldmann visual field; - Non-mydriatic fundus photography; - Optic disc OCT; - 3 Tesla orbital-cerebral MRI with and without contrast; - Standard and immunological laboratory testing for anti-MOG and anti AQP4 antibodies by Western Blot and ELISA. RESULTS: The male: female ratio of the population was 0.92 (13 women and 12 men). The average age at onset was 35.68 years (15 to 60 years); 40 % of the subjects were between 31 and 40 years old. The initial symptoms leading to consultation were mostly visual acuity (80 %) and pain (88 %). Involvement was bilateral in 80 % of cases (5 unilateral). Initial visual acuity was poor; 52 % of eyes were less than or equal to count fingers. The course was favorable however, with visual acuity returning to 10-12/10 after 6 months of follow-up (84 % of eyes). Orbital/cerebral MRI with attention to the visual pathways revealed involvement of the anterior visual pathways with gadolinium uptake in 92 % of cases. Of the 35 eyes initially considered affected, the main initial diagnoses were: - 36 % retro-bulbar optic neuritis (RBON); - 40 % anterior optic neuritis (AON); - 24 % other; of which 16 % were initially diagnosed as acute anterior ischemic optic neuropathy (AAION). 96 % of patients received corticosteroid treatment in the acute phase. 16 % required plasma exchange sessions. Maintenance therapy was proposed for only 36 % of the population. CONCLUSION: Optic neuritis is a pathology frequently encountered in ophthalmology; a good knowledge of symptoms and clinical signs is essential for early diagnosis and optimal management. The identification of autoantibodies, including anti-MOG antibodies, is important for patient management and is part of the required testing for all cases of optic neuritis, in order to adapt the treatment of the acute episode and to provide maintenance therapy to avoid recurrence.

Diabetic Optic Neuropathy and Its Risk Factors in Chinese Patients With Diabetic Retinopathy.

Purpose: To investigate diabetic optic neuropathy (DON) prevalence and risk factors in Chinese diabetic retinopathy (DR) patients. Methods: This retrospective study included 1067 eyes (550 patients) that underwent ocular imaging. The diabetes duration, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and high-density lipoprotein (HDL) were also recorded simultaneously. Results: A total of 410 eyes with DON and 657 eyes without DON were included (38.4% DON prevalence). DON eyes were classified as having diabetic papillopathy (DP), optic disc neovascularization (NVD), anterior ischemic optic neuropathy (AION), or optic atrophy (OA). Proliferative DR eyes had a higher DON prevalence than nonproliferative DR eyes (P < 0.001). Diabetes duration, SBP, and HbA1c were higher in DON patients than in non-DON patients (all P < 0.001). Additionally, HDL was lower in patients with DON (0.74 ± 0.13 mM) than in those without DON (1.00 ± 0.24 mM, P < 0.001). HbA1c levels were greater in AION patients (10.00 ± 1.53% [85.76 ± 16.71 mmol/mol]) than in DP patients (8.78 ± 1.97% [72.45 ± 21.55 mmol/mol], P = 0.017); central foveal thickness (CFT) significantly varied among groups (P < 0.001). Increased age, diabetes duration, SBP, CFT, and DR severity were risk factors for DON; and increased HbA1c was a risk factor for NVD, AION, and OA (all P < 0.05). Conclusions: Our study results strengthen the argument that increased age, diabetes duration, SBP, CFT, DR severity, and HbA1c are all risk factors for DON in patients with DR.

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.

Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies.

BACKGROUND: Key clinical features of chronic relapsing inflammatory optic neuropathy (CRION) include relapsing inflammatory optic neuritis (ON) and steroid dependency, both of which have been reported among patients with myelin oligodendrocyte glycoprotein antibodies (MOG-Abs). We investigated the relevance of the presence of serum MOG-IgG with the current diagnostic criteria for CRION among patients with idiopathic inflammatory optic neuritis (iON). METHODS: Retrospective reviews of a database prospectively collated between 2011 and 2017 from the tertiary referral center for multiple sclerosis and neuromyelitis optica were performed. Sixty-four patients with iON, who did not meet the diagnostic criteria for multiple sclerosis, neuromyelitis optica (NMO) spectrum disorder with/without NMO-IgG, or acute disseminated encephalomyelitis and who had no symptomatic central nervous system (CNS) lesions other than on the optic nerve, were included from a cohort of 615 patients with inflammatory demyelinating diseases of the CNS. Fulfillment of the current diagnostic criteria for CRION, assay results for the serum IgG1 MOG-Ab, and characteristics of CRION patients with MOG-IgG were compared to those of non-CRION patients with MOG-IgG. RESULTS: Twelve iON patients fulfilled the current diagnostic criteria for CRION, 11 patients were positive for MOG-IgG, and one patient was borderline. Among the other 52 iON patients not meeting the criteria for CRION, 14 had relapsing disease courses and 38 had monophasic courses, of which MOG-IgG positivity were 0% and 29%, respectively. CRION patients with MOG-IgG had more relapsing disease courses (first steroid-dependent worsening/relapse in 2.3 months, range 0.4-7.0) and poorer optical coherence tomography outcomes at follow-up than non-CRION patients with MOG-IgG. However, patients in the two groups did not differ in terms of age of onset, sex, or steroid treatment duration after initial attack. CONCLUSIONS: CRION, according to the current diagnostic criteria, is a relapsing optic neuritis associated with MOG-IgG. Among iON patients with MOG-IgG, the absence of steroid-dependent attacks in the early stages of the disease may predict a long-term non-relapsing disease course and a more favorable outcome.

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.

Diagnosis and classification of autoimmune optic neuropathy.

The spectrum of autoimmune optic neuropathies (ON) is extending. The phenotypic spectrum includes single isolated optic neuritis (SION), relapsing isolated optic neuritis (RION), chronic relapsing inflammatory optic neuropathy (CRION), the neuromyelitis optica (NMO) spectrum disorder, multiple sclerosis associated optic neuritis (MSON) and unclassified optic neuritis (UCON) forms. Epidemiological data suggests a slight female predominance. The ethnic heritage is relevant as Caucasian patients are more likely to suffer from MSON, whilst SION, RION, CRION and NMO are more frequent in non-Caucasian patients. Importantly, prognosis for recovery of visual function is good in MSON, but poorer in NMO and CRION which also have a high chance for recurrent episodes. Testing for serum anti-AQP4 autoantibodies is advised in all patients with severe, atypical or recurrent ON because of the high diagnostic specificity. The diagnostic specificity may be aided by testing for glial biomarkers in the CSF and prognostic accuracy by testing for biomarkers for neuroaxonal degeneration. Optical coherence tomography is a highly accurate tool to document the final outcome. The current clinical classification criteria rely on the phenotype, response to treatment and presence of anti-AQP4 autoantibodies.

Cobalamin deficiency: clinical picture and radiological findings.

Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, psychiatric and neurological disorders. Hematological presentation of cobalamin deficiency ranges from the incidental increase of mean corpuscular volume and neutrophil hypersegmentation to symptoms due to severe anemia, such as angor, dyspnea on exertion, fatigue or symptoms related to congestive heart failure, such as ankle edema, orthopnea and nocturia. Neuropsychiatric symptoms may precede hematologic signs and are represented by myelopathy, neuropathy, dementia and, less often, optic nerve atrophy. The spinal cord manifestation, subacute combined degeneration (SCD), is characterized by symmetric dysesthesia, disturbance of position sense and spastic paraparesis or tetraparesis. The most consistent MRI finding is a symmetrical abnormally increased T2 signal intensity confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord. Isolated peripheral neuropathy is less frequent, but likely overlooked. Vitamin B12 deficiency has been correlated negatively with cognitive functioning in healthy elderly subjects. Symptoms include slow mentation, memory impairment, attention deficits and dementia. Optic neuropathy occurs occasionally in adult patient. It is characterized by symmetric, painless and progressive visual loss. Parenteral replacement therapy should be started soon after the vitamin deficiency has been established.

Evaluation of peripapillary retinal nerve fiber layer thickness in patients with vitamin B12 deficiency using spectral domain optical coherence tomography.

PURPOSE: To compare peripapillary retinal nerve fiber layer (RNFL) thicknesses measured by Cirrus HD optical coherence tomography (OCT) of patients with vitamin B12 deficiency with healthy controls and to evaluate the correlation between the peripapillary RNFL thickness and plasma vitamin B12 levels. MATERIALS AND METHODS: Forty-five patients (19 male and 26 female) with a diagnosis of vitamin B12 deficiency (patient group) and 45 age- and sex- matched healthy subjects (control group) were consecutively enrolled in this study. Average, temporal, nasal, inferior, and superior quadrant peripapillary RNFL thicknesses of each subject were obtained using the Cirrus HD OCT. Disc area (DA) and rim area (RA), central subfield thickness (CST), cube volume (CV), and cube average thickness (CAT) were also measured. RESULTS: Mean age of each group was 33.1 ± 6.5 years (range: 21-45 years). Mean plasma vitamin B12 level was 114.8 ± 34.0 pg/mL in the patient group and was 405.1 ± 20.0 pg/mL in the control group (p < 0.001). The patient and control groups were similar regarding axial length, plasma folate levels, DA, RA, CST, CV, CAT, and RNFL thicknesses in superior, nasal, and inferior quadrants. However, average RNFL and RNFL in temporal quadrant were significantly thinner in the patient group than in the control group (p = 0.013 and p < 0.001, respectively). In addition, temporal (r = 0.356, p = 0.001) and average (r = 0.212, p = 0.045) peripapillary RNFL thicknesses were correlated with plasma vitamin B12 levels. CONCLUSION: We have shown that, as in other non-glaucomatous optic neuropathies, temporal quadrant RNFL thickness was thinner in patients with vitamin B12 deficiency and it was correlated with plasma vitamin B12 levels. Further studies are warranted to clarify the clinical relevance of these findings and the effects of vitamin B12 replacement therapy.

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.