Case Report: Unilateral Cranial Nerve VI Palsy Secondary to Intracranial Hypotension.

SIGNIFICANCE: Intracranial hypotension is a condition that occurs from a cerebrospinal fluid leak. Various visual symptoms have been associated with this condition. Cranial nerve VI (CN VI) palsies are the most common ocular manifestation, as the abducens nerve is prone to injury because of its intracranial anatomical course. PURPOSE: This case report presents a CN VI palsy secondary to intracranial hypotension from ventriculoperitoneal shunt overfiltration. Diagnosis, treatment, and management considerations are discussed. No identifiable health information was included in this case report. CASE REPORT: A 70-year-old White man was referred to the eye clinic for evaluation of binocular horizontal diplopia. The patient had a recent history of a left ventriculoperitoneal shunt for a persistent cerebrospinal fluid leak after complex mastoid surgery. The patient was also symptomatic for positional headaches, which improved in a recumbent position. He was diagnosed with a left CN VI palsy secondary to intracranial hypotension from a ventriculoperitoneal shunt overfiltration. The patient was followed up by neurosurgery for shunt adjustments to resolve the overfiltration. Binocular horizontal diplopia was managed conservatively with Fresnel prism. CONCLUSIONS: Intracranial hypotension should be considered in patients presenting with cranial nerve palsies and positional headaches. Obtaining neuroimaging and comanaging with neurology or neurosurgery are advised to make prompt diagnosis and treatment. Careful clinical monitoring and conservative diplopia therapy are recommended as visual symptoms improve upon resolution of the cerebrospinal fluid leak.

Neuro-ophthalmic complications of immune checkpoint inhibitor therapy: Current status and future directions.

Since 2011, use of immune checkpoint inhibitors (ICI) in cancer immunotherapy dramatically expanded, both alone and in combination with either a different cancer treatment or with two different ICIs. With this increase in use have come a myriad of adverse effects from enhanced immune activation, including ophthalmic and neurologic immune related adverse events (irAE). Neuro-ophthalmic immune related adverse events (NOirAE) associated with use of ICIs are increasingly recognized and their severity may actually limit use of potentially life-saving immunotherapy. NOirAEs comprise a wide variety of presentations involving both the central and peripheral nervous system. They cause afferent or efferent visual dysfunction, including among them optic neuropathy and edema, orbital inflammatory disease, and ocular myasthenia. While treatment for irAEs typically involves immunosuppression with corticosteroids, there is no expert consensus regarding best practices for treatment of NOirAEs and whether to stop ICI immunotherapy for the cancer or not. This state-of-the-art review explores the pathophysiologic basis for NOirAEs, provides a framework for categorizing them within neuro-ophthalmology, and discusses what is needed to close the current knowledge gaps in diagnosis and management of an increasing population of cancer patients requiring neuro-ophthalmic care.

Temporal Artery Biopsy in the Workup of Giant Cell Arteritis: Diagnostic Considerations in a Veterans Administration Cohort.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in the American population older than 50 years and is a sight-threatening and life-threatening disease. It is definitively diagnosed with a temporal artery biopsy. Although there are many studies focusing on the clinical presentation and laboratory values in diagnosing GCA in the general population, studies focusing on the veteran population are lacking. This is the first study describing the diagnostic features of GCA in the US military veterans. METHODS: We performed a retrospective chart review in the Veterans Information Systems and Technology Architecture Computerized Patient Record System (CPRS 1.0, Department of Veterans Affairs Health Data Systems). Anatomic pathology reports from temporal artery biopsies (TABs) were collected, as well as the clinical presentation and laboratory values for each case. Frequency, sensitivity, and specificity were calculated for clinical variables, such as new-onset headache and vision changes, including diplopia, ischemic vision loss/optic disc disease, and amaurosis fugax. A logistic regression (LR) prediction model was then developed to compare veteran risk factors with those of the general population. RESULTS: Of 292 patients, 40 had positive TABs (13.7%). The average age of subjects with positive TABs was 73 ± 8.8 years (mean ± SD). The average erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with positive TABs (69.1 mm/hr and 56.6 mg/L, respectively) were significantly higher than ESR and CRP in patients with negative TABs (50.5 mm/hr, P = 0.0016 and 32.2 mg/L, P = 0.0394, respectively). Mean platelet levels were much higher (317.6 × 10/L) in patients with positive TABs than platelet levels in those with negative TABs (260.6 × 10/L, P = 0.0005). CRP was the most sensitive variable at 83.3%, followed by ESR with a sensitivity of 80% and new-onset headache with a sensitivity of 62.5%. Jaw claudication and polymyalgia rheumatica (PMR) were most specific (81.3% and 89.3%, respectively). Headache was the most common presenting symptom overall (71.6%), followed by vision changes (50.3%), scalp tenderness (25.7%), jaw claudication (20.9%), and PMR-related symptoms (12.7%). The LR prediction model included scalp tenderness, log (CRP), log (platelets), vision changes, and age, with 50% sensitivity and 88.36% specificity. Platelets (odds ratio [OR] = 4.309, P = 0.049), CRP (OR = 1.504, P = 0.022) and scalp tenderness (OR = 3.860, P = 0.016) were statistically significant predictors of a positive TAB in this population. CONCLUSIONS: Veterans Administration (VA) patients present with symptomatology similar to that of the general population. A positive biopsy was found in female veterans more frequently than in their male counterparts. Platelet count and scalp tenderness were most predictive. Our LR model provided a highly specific method for detecting GCA in the veteran population at this institution, but further studies are needed to determine the generalizability of the model. This retrospective study serves as a basis for future multicenter VA-wide studies to characterize the unique features in this population.

Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort.

BACKGROUND: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Vision Loss from Choroidal and Pituitary Metastases Secondary to Renal Cell Carcinoma: A Case Report.

A 62-year-old male with a history of metastatic clear cell renal cell carcinoma (ccRCC) presented with decreased vision to 20/50 in the left eye. Fundus examination revealed an elevated, amelanotic mass lesion in the superotemporal macula, without involvement of the central macula by subretinal fluid or tumour. Given incongruity between the fundus findings and the degree of visual impairment, visual field testing was obtained, revealing a bitemporal hemianopia. Magnetic resonance imaging demonstrated optic chiasm compression by a pituitary mass, which had previously been overlooked on computed tomography imaging. Biopsy confirmed metastatic ccRCC to the pituitary, which presented simultaneously with the presumed choroidal metastasis.

Lipoic acid in secondary progressive MS: A randomized controlled pilot trial.

OBJECTIVE: To determine whether lipoic acid (LA), an endogenously produced antioxidant, slowed the whole-brain atrophy rate and was safe in secondary progressive MS (SPMS). METHODS: Patients with SPMS aged 40-70 years enrolled in a single center, 2-year, double-blind, randomized trial of daily oral 1,200 mg LA vs placebo. Primary outcome was change in annualized percent change brain volume (PCBV). Secondary outcomes were changes in rates of atrophy of segmented brain, spinal cord, and retinal substructures, disability, quality of life, and safety. Intention-to-treat analysis used linear mixed models. RESULTS: Participation occurred between May 2, 2011, and August 14, 2015. Study arms of LA (n = 27) and placebo (n = 24) were matched with mean age of 58.5 (SD 5.9) years, 61% women, mean disease duration of 29.6 (SD 9.5) years, and median Expanded Disability Status Score of 6.0 (interquartile range 1.75). After 2 years, the annualized PCBV was significantly less in the LA arm compared with placebo (-0.21 [standard error of the coefficient estimate (SEE) 0.14] vs -0.65 [SEE 0.10], 95% confidence interval [CI] 0.157-0.727, p = 0.002). Improved Timed 25-Foot Walk was almost but not significantly better in the LA than in the control group (-0.535 [SEE 0.358] vs 0.137 [SEE 0.247], 95% CI -1.37 to 0.03, p = 0.06). Significantly more gastrointestinal upset and fewer falls occurred in LA patients. Unexpected renal failure (n = 1) and glomerulonephritis (n = 1) occurred in the LA cohort. Compliance, measured by pill counts, was 87%. CONCLUSIONS: LA demonstrated a 68% reduction in annualized PCBV and suggested a clinical benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years. CLINICALTRIALSGOV IDENTIFIER: NCT01188811. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with SPMS, LA reduces the rate of brain atrophy.

Baseline retinal nerve fiber layer thickness and macular volume quantified by OCT in the North American phase 3 fingolimod trial for relapsing-remitting multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) demonstrate thinning of peripapillary retinal nerve fiber layer (RNFL) and decreased macular volume as measured by optical coherence tomography (OCT). To our knowledge, there are no previous reports from a large MS OCT database with strict quality control measures that quantitate RNFL and macula in patients with relapsing-remitting multiple sclerosis. METHODS: The University of California Davis OCT Reading Center gathered OCT data at baseline as part of the North American phase 3 trial of fingolimod (Gilenya). Average RNFL thickness (RNFLT) and macular volume (TMV) were measured using time domain OCT (TD-OCT). RNFL quadrants, clock hours, and macular subfields were included. With strict quality control and accounting for signal strength differences, scans were categorized as "reduced" or "not reduced" for each field, based on being less than 5th percentile for age-matched controls derived from the normative database in the scanner software. Patients were deemed "abnormal" if at least 1 eye had reduced values for a given parameter. Patients with abnormalities in corresponding RNFL and macular subfields were compared by cross-tabulation. RESULTS: The TD-OCT data were prospectively collected from 939 of the 1,083 trial patients, 712 of whom met all final quality and data inclusion criteria. Of the final cohort, 242 (34.0%) demonstrated reduced (less than 5th percentile) average RNFLT in at least 1 eye. One hundred seventy-eight (25.0%) patients had reduced TMV. One hundred twenty-eight (18.0%) demonstrated both reduced TMV and RNFLT in the same eye, whereas 42 (5.8%) had reduced TMV and RNFLT in both eyes. Of the 242 patients with reduced average RNFL thickness, 128 (52.9%) also had reduced TMV. Fifty patients had reduced TMV in the absence of reduced RNFLT in at least 1 eye, a cohort prevalence of 7.0%. Quadrant and subfield analysis showed a predominance of temporal and inferior RNFL thinning, with inferior macular thinning corresponding best to RNFL thinning. CONCLUSION: RNFL and macular thinning/volume loss is common at baseline in relapsing-remitting multiple sclerosis, as measured by TD-OCT. When the RNFL is thin, the macular volume is reduced in more than half of the patients. There is a population of reduced TMV without any reduction in RNFLT. Documenting the prevalence and distribution of these structural abnormalities supports recent reports and suggests new retinal areas to probe for functional vision changes in MS.

Analysis of multiple sclerosis cerebrospinal fluid reveals a continuum of clonally related antibody-secreting cells that are predominantly plasma blasts.

Fluorescence-activated cell sorting (FACS) analysis of B cell subtypes in 17 CSF samples from 15 patients with clinically-definite MS revealed that CD19+ B cells accounted for 2 to 11% (mean 5%) and CD138+ cells constituted 0 to 5% (mean 2%) of total CSF lymphocytes. Further stratification of CD138+ cells based on expression levels of CD19 showed that CD138+19+ plasma blasts constituted 89+/-2% (mean+/-SE) of the CD138+ cell population (P<0.00001), with more mature plasma cells (CD138+19-) constituting the remaining 11+/-2%. Sequence analysis of immunoglobulin variable regions in single CD138+19+ and CD138+19- cells sorted from MS CSF identified many of the same clonal populations in both populations, indicating a continuum of clonally related plasma cell subtypes of which CD138+19+ plasma blasts are most abundant.

VH4 gene segments dominate the intrathecal humoral immune response in multiple sclerosis.

A characteristic feature of the CNS inflammatory response in multiple sclerosis (MS) is the intrathecal synthesis of IgG and the presence of oligoclonal bands. A strong correlation between CD138(+) plasma blast numbers in MS cerebrospinal fluid (CeSF) and intrathecal IgG synthesis suggests that these cells are the major Ab-secreting cell type in MS CeSF. Sequencing of V regions from CD138(+) cells in MS CeSF has revealed somatically mutated and expanded IgG clonotypes consistent with an Ag-targeted response. In the present study, single-cell RT-PCR analysis of CD138(+) cells from 11 MS patients representing differing clinical courses and stages of disease identified expansion of CD138(+) cells with functionally rearranged V(H)4 gene segments as an overriding feature of MS CeSF repertoires. V(H)4 dominance was attributed to the preferential selection of specific V(H)4 genes, particularly gene segment V(H)4-39, which displayed a significant enrichment in CeSF compared with MS peripheral blood B cells. A modest increase in V(H)4 prevalence among MS peripheral blood IgG memory cells was also noted, suggesting that factors shaping the CD138 repertoire in CeSF might also influence the peripheral IgG memory cell pool. These results indicate a highly restricted B cell response in MS. Identifying the targets of CeSF plasma cells may yield insights into disease pathogenesis.

Delayed visual attention caused by high myopic refractive error.

Delayed visual maturation (DVM) is usually a retrospective diagnosis given to infants who are born with no or poor visually-directed behavior, despite normal acuity on objective testing, but who recover months later. This condition can be organized into several types based on associated neurodevelopmental or ocular findings, but the etiology of DVM is probably complex and involves multiple possible origins. Here we report two infants who presented with delayed visual maturation (attention). They were visually unresponsive at birth but were later found to have high myopic errors. Patient 1 had -4 D right eye, -5 D left eye. Patient 2 had -9 D o.u. Upon spectacle correction at 5 and 4 months, respectively, both infants immediately displayed visually-directed behavior, suggesting that a high refractive error was the cause of inattention in these patients. These findings could add to knowledge surrounding DVM and the diagnosis of apparently blind infants. Findings presented here also indicate the importance of prompt refractive error measurement in such cases.

Regulation of antiprotease and antimicrobial protein secretion by airway submucosal gland serous cells.

Airway submucosal gland serous cells express the cystic fibrosis transmembrane conductance regulator (CFTR) and secrete antimicrobial, anti-inflammatory, and antioxidant molecules. In cystic fibrosis, diminished gland secretion may impair innate airway host defenses. We used Calu-3 cells as a serous cell model to study the types of proteins released, the pathways that release them, and the possible involvement of CFTR activity in protein release. Many proteins were secreted constitutively into the apical fluid and showed increased release to agonists. We identified some of them by high pressure liquid chromatography-mass spectrometry and reverse transcriptase PCR, including lysozyme, siderocalin (the protein NGAL), which inhibits bacterial growth by binding iron-containing siderophores, HSC-71, which is thought to have anti-inflammatory properties, and the serine protease inhibitors alpha-1-antitrypsin and alpha-1-antichymotrypsin, which may function as antimicrobials as well as play a potential role in diminishing the activation of epithelial Na(+) channels by serine proteases. We used an enzyme-linked immunosorbent assay to quantify lysozyme secretion by Calu-3 cells in response to various agonists and inhibitors. Forskolin increased the lysozyme secretion rate (J(lyz)) from 32 to 77 ng/hr/cm(2) (n = 36, p < 0.005). Thapsigargin increased J(lyz) from 40 to 63 ng/h/cm(2) (n = 16, p < 0.005), and forskolin plus thapsigargin further increased the forskolin-stimulated J(lyz) by 48% (n = 9, p < 0.05). 1-Ethyl-benzimidazolinone and carbachol were less effective. Glibenclamide inhibited basal and stimulated J(lyz), but clotrimazole was without effect. CFTR(inh)172 caused a small (15%) but significant inhibition of forskolin-stimulated J(lyz) without affecting basal J(lyz). Thus, Calu-3 cells secrete diverse proteins that in aggregate would be expected to suppress microbial growth, protect the airways from damage, and limit the activation of epithelial Na(+) channels via serine proteases.