Galactose-replacement unmasks the biochemical consequences of the G11778A mitochondrial DNA mutation of LHON in patient-derived fibroblasts.

Leber's hereditary optic neuropathy (LHON) is a visual impairment associated with mutations of mitochondrial genes encoding elements of the electron transport chain. While much is known about the genetics of LHON, the cellular pathophysiology leading to retinal ganglion cell degeneration and subsequent vision loss is poorly understood. The impacts of the G11778A mutation of LHON on bioenergetics, redox balance and cell proliferation were examined in patient-derived fibroblasts. Replacement of glucose with galactose in the culture media reveals a deficit in the proliferation of G11778A fibroblasts, imparts a reduction in ATP biosynthesis, and a reduction in capacity to accommodate exogenous oxidative stress. While steady-state ROS levels were unaffected by the LHON mutation, cell survival was diminished in response to exogenous H2O2.

Leber Hereditary Optic Neuropathy in Southwestern Ontario: A Growing List of Mutations.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a rare but bilaterally blinding disease. Three characteristic disease-causing point mutations, and other less common mutations, are most often found on the mitochondrially encoded genes of NADH-ubiquinone oxidoreductase core subunits (MT-ND). The purpose of this study is to provide an overview of LHON mutations in Southwestern Ontario and to describe the associated demographic and clinical characteristics. METHODS: A retrospective genetic and clinical chart review was performed from January 2015 to 2020. Patients were identified within a mitochondrial mutation database and included if a mutation was detected on the MT-ND1, -ND4, or -ND6 genes. A clinical chart review was done on all available patients. RESULTS: Forty-five of 63 patients identified had classic disease-causing mutations (6.7% m.3460G>A, 44.4% m.11778G>A, and 48.9% m.14484T>C). Several of the remaining 18 patients had rare mutations previously documented in association with LHON. Of the 14 patients with clinical charts accessible for review, 12 had symptomatic disease, and all but one had bilateral optic neuropathies. Nine patients had classic LHON mutations and 3 had possible novel mutations; 7 were males; 9 had final visual acuity ≤ 20/200 in at least one eye; and 6 of those had ≤20/400 in both eyes. CONCLUSIONS: This study adds to the literature on LHON in Canada, and specifically Southwestern Ontario. The demographic and clinical data regarding LHON in this geographic location, as well as possible novel disease-causing mutations, provide important information to aid clinicians in recognizing cases of LHON that may otherwise be disregarded.

Quantitative Optical Coherence Tomography Angiography in Patients with Moyamoya Vasculopathy: A Pilot Study.

Moyamoya (MM) disease is a chronic cerebrovascular disease that can lead to progressive stenosis of the terminal portions of the internal carotid arteries and their proximal branches. We sought to investigate and quantify retinal vascular changes in patients with MM vasculopathy (MMV) using optical coherence tomography angiography (OCTA) compared to healthy controls. Our findings reveal retinal microvascular changes in patients with MMV and highlights the potential of OCTA imaging for the detection of subclinical retinal pathology.

Autism Spectrum Disorder in Pediatric Idiopathic Intracranial Hypertension.

In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged 2-18 years were identified by review of a pediatric neuro-ophthalmologist's database spanning from July 1993 to April 2013. ASD diagnoses were identified within this cohort by an ICD-9 diagnosis code search and database review. Three subjects had concurrent ASD diagnoses; all were non-obese males. Since the retrospective observational case series was performed in April 2013, we identified three additional IIH cases in boys with ASD. Our experience suggests that IIH may be a comorbidity of ASD, particularly in non-obese boys.

INVESTIGATING MICROANGIOPATHY USING SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH SUSAC SYNDROME.

PURPOSE: To determine whether optical coherence tomography angiography is of diagnostic utility for Susac syndrome (SuS) by quantifying microvascular retinal changes. METHODS: We enrolled 18 eyes of 9 healthy controls and 18 eyes of 9 patients with chronic SuS (12 had previous branch retinal artery occlusions and 6 were clinically unaffected). Images of the fovea were taken using an optical coherence tomography angiography system. Analysis included vessel density, fractal dimension, vessel diameter, and measurements of the foveal avascular zone (area, eccentricity, acircularity index, and axis ratio) in deep and superficial retinal layers. RESULTS: Skeleton density and inner ring vessel density were significantly lower in patients with SuS (skeleton density: Susac 0.11 ± 0.01 vs. controls 0.12 ± 0.01, P = 0.027. VD: SuS 0.39 ± 0.04 vs. controls 0.42 ± 0.02, P = 0.041). Eccentricity and axis ratio were significantly higher in patients with SuS (EC: Susac 0.61 ± 0.11, controls 0.51 ± 0.10, P = 0.003; axis ratio: Susac 1.57 ± 0.28, controls 1.39 ± 0.11, P = 0.005). SuS eyes (affected and unaffected) had poorer outcomes of the remaining vascular parameters compared with controls (P > 0.05). CONCLUSION: Optical coherence tomography angiography identified chronic microvascular changes in the eyes of patients with chronic SuS. Even clinically unaffected SuS eyes showed poorer vascular parameters. Although further research is needed, this noninvasive imaging modality seems to have the potential to serve as a valuable additive diagnostic tool.

Is There an Association between Herpetic Infections and Giant Cell Arteritis? A Population-Based Study.

Recent data suggests that herpes zoster (HZ) and herpes simplex virus (HSV) may be one of the underlying immunological triggers for giant cell arteritis (GCA). However, there is limited population-based data to support this. Our goal was to determine if herpetic infections increase the likelihood of GCA in the British Columbia (BC) population. The background prevalence of GCA was compared to the prevalence of GCA in subjects with HZ and HSV using diagnostic billing code data from an online BC database (BC Data ScoutTM). BC residents ≥30 years old at the time of diagnosis from January 2000 to January 2019 were included. The relevant International Classification of Disease codes was used to identify patients with GCA, HZ, and HSV. Comparisons were made using two-sample Z tests. There were 4315 GCA diagnoses, from a total population of 3,026,005 subjects. The prevalence of GCA was 143 per 100,000 people. In terms of herpetic infections, 850 GCA cases were identified in 249,900 subjects with HZ versus 310 diagnoses of GCA in 163,170 subjects with HSV. The prevalence of GCA in subjects with HZ (0.340%) was significantly higher than the prevalence of GCA (0.143%) in the general population (p < 0.00001). The prevalence of GCA in HSV subjects (0.190%) was also significantly higher (p < 0.00001) than the population prevalence but lower than (p < 0.00001) the GCA with HZ prevalence. The likelihood of GCA appears to increase with herpetic infections, more significantly with HZ.

Homonymous hemiatrophy of ganglion cell layer from retrochiasmal lesions in the visual pathway.

OBJECTIVE: To determine the temporal evolution, morphology, and frequency of macular ganglion cell atrophy in patients with retrochiasmal lesions of the visual pathway. METHODS: In a consecutive retrospective case series, we identified 47 patients with homonymous hemianopia and accessible macular optical coherence tomography scans. We estimated the time of lesion onset and the location of the lesion within the afferent visual pathway. Using semiautomatic layer segmentation, we determined ganglion cell layer thickness in areas projecting to the side of the retrochiasmal lesion and compared it with ganglion cell layer thickness on the healthy side. RESULTS: We found that retrochiasmal lesions at any level may be associated with an atrophy of ganglion cells. This atrophy respects the vertical midline through the fovea and thus the anatomic separation of the nasal and temporal visual field. The vertical line separating the affected from the unaffected side has significantly less tilt as compared with the disc-fovea angle. Lesions of the optic tract are associated with earlier macular ganglion cell atrophy than retrogeniculate lesions. Macular ganglion cell atrophy may be present in cases with normal peripapillary nerve fiber layer analysis and vice versa. CONCLUSIONS: Macular ganglion cell layer thickness shows a topographic hemiatrophy in retrochiasmal lesions, which manifests earlier for tract lesions than for retrogeniculate lesions. This additional examination of ganglion cell homonymous hemiatrophy has a higher sensitivity in detecting retrograde transsynaptic degeneration than the analysis of the peripapillary nerve fiber layer alone.

Magnetic Resonance Imaging Findings in Pediatric Pseudotumor Cerebri Syndrome.

BACKGROUND: Revised diagnostic criteria for pseudotumor cerebri syndrome require three of four neuroimaging findings in the absence of papilledema. We examined the sensitivity and specificity of three or more of four of these magnetic resonance imaging (MRI) findings for pseudotumor cerebri syndrome in children. METHODS: As part of clinical care, patients in whom there was suspicion for pseudotumor cerebri syndrome underwent neurological and fundoscopic examinations, lumbar puncture, MRI, or magnetic resonance venogram. For this retrospective study, we used this information to classify 119 subjects into definite (n = 66) or probable pseudotumor cerebri syndrome (n = 12), elevated opening pressure without papilledema (n = 23), or controls who had normal opening pressure without papilledema (n = 24). A neuroradiologist, unaware of the clinical findings or original MRI report, reviewed MRIs for pituitary gland flattening, flattening of the posterior sclera, optic nerve sheath distention, and transverse venous sinus stenosis. RESULTS: The presence of three or more MRI findings has a sensitivity of 62% (95% confidence interval: 47% to 75%) and a specificity of 95% (95% confidence interval: 77% to 100%), compared with controls. Two of three (transverse venous sinus stenosis, pituitary gland flattening, flattening of the posterior sclera) had a similar sensitivity and specificity. Transverse venous sinus stenosis alone had a slightly higher sensitivity (74%, 95% confidence interval: 60% to 85%) and specificity (100%, 95% confidence interval: 80% to 100%). CONCLUSIONS: In children, three of four of the proposed neuroimaging criteria and transverse venous sinus stenosis alone have a moderate sensitivity and robust specificity for pseudotumor cerebri syndrome. MRIs should be reviewed for these criteria, and their presence should raise suspicion for pseudotumor cerebri syndrome in children, particularly if the presence of papilledema is uncertain.

Retrospective, Multicenter Comparison of the Clinical Presentation of Patients Presenting With Diplopia From Giant Cell Arteritis vs Other Causes.

BACKGROUND: Although giant cell arteritis (GCA) is a well-known cause of transient and permanent vision loss, diplopia as a presenting symptom of this condition is uncommon. We compared symptoms and signs of patients presenting with diplopia from GCA to those from other causes. METHODS: This was a multicenter, retrospective study comparing the clinical characteristics of patients presenting with diplopia from GCA with age-matched controls. Demographic information, review of symptoms, ophthalmic examination, and laboratory data of biopsy-proven patients with GCA were compared with those of age-matched controls presenting with diplopia. RESULTS: A total of 27 patients presented with diplopia from GCA, 19 with constant diplopia, and 8 with transient diplopia. All patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies. Patients with GCA were more likely to describe other accompanying visual symptoms (58% vs 25%, P = 0.008), a greater number of systemic GCA symptoms (3.5, GCA vs 0.6, controls, P < 0.001) such as headache (94% [17/18] vs 39% [23/67]; P < 0.001), jaw claudication (80% [12/15] vs 0% [0/36]; P < 0.001), and scalp tenderness (44% [7/16] vs 7% [3/43]; P < 0.001). Ocular ischemic lesions (26% vs 1%, P < 0.001) were also common in patients with diplopia from GCA. Inflammatory markers were elevated significantly in patients with GCA vs controls (erythrocyte sedimentation rate: 91% [10/11] vs 12% [3/25], P < 0.001; C-reactive protein: 89% [8/9] vs 11% [2/19], P < 0.001). CONCLUSIONS: GCA is a rare but serious cause of diplopia among older adults and must be differentiated from other more common benign etiologies. Our study suggests that most patients with diplopia from GCA have concerning systemic symptoms and/or elevated inflammatory markers that should trigger further work-up. Moreover, careful ophthalmoscopic examination should be performed to look for presence of ocular ischemic lesions in older patients presenting with acute diplopia.

Headache Characteristics in Children With Pseudotumor Cerebri Syndrome, Elevated Opening Pressure Without Papilledema, and Normal Opening Pressure: A Retrospective Cohort Study.

BACKGROUND: Certain headache characteristics and associated symptoms are commonly attributed to increased intracranial pressure, but they have not been systematically studied among children in the context of revised diagnostic criteria for pseudotumor cerebri syndrome (PTCS). METHODS: We performed a retrospective cohort study of patients treated for suspected or confirmed PTCS. Charts were reviewed for PTCS and headache diagnostic criteria and associated characteristics. Chi-squared or Fisher's exact tests were used to compare the frequency of headache characteristics between groups. RESULTS: One hundred and twenty-seven individuals were identified: 61 had definite PTCS, 10 had probable PTCS, 31 had elevated opening pressure (OP) without papilledema, and 25 had normal OP without papilledema. Eleven children had no headache (6 with definite PTCS, 5 with probable PTCS). Headache pattern was episodic in 49% (95% CI: 34-64%) of those with definite PTCS, 18% (95% CI 6-37%) of those with elevated OP without papilledema, and 16% (5-36%) of those with normal OP without papilledema. Headache location was more likely to involve the head along with neck or shoulders in those with definite PTCS compared with elevated OP without papilledema (OR = 7.2, 95% CI: 1.9-27.6) and normal OP (OR = 4.5, 95% CI: 1.3-15.6) groups. DISCUSSION: While missing data and small cohort size are limitations, this study suggests that headache in PTCS is more likely to involve the head along with neck/shoulders, and that headache in PTCS may be episodic or constant. Headache is occasionally absent in PTCS.

Clinical and Prognostic Significance of Cerebrospinal Fluid Opening and Closing Pressures in Pediatric Pseudotumor Cerebri Syndrome.

BACKGROUND: The purpose of this study was to determine the prognostic utility of closing pressure and volume of cerebrospinal fluid removed with respect to papilledema resolution and headache improvement in pediatric pseudotumor cerebri syndrome. METHODS: This is a retrospective observational study of 93 children with definite pseudotumor cerebri syndrome. The primary outcome measure was time to resolution of papilledema, and the secondary outcome measure was time to resolution of headache. RESULTS: There were no significant differences in gender, age, or body mass index z score observed between subjects with (N = 35) and without (N = 58) documented closing pressure. The median time to resolution of papilledema was not statistically different between children above or equal to and those below the median closing pressure (170 mm of cerebrospinal fluid, n = 31, P = 0.391) or the volume of median cerebrospinal fluid removed (16 mL, n = 19, P = 0.155). There was no statistically significant difference detected in days of headache between the children with opening pressure above and equal to the median (400 mm of cerebrospinal fluid) and the children with opening pressure below the median (n = 44, P = 0.634). CONCLUSIONS: No significant association between closing pressure, amount of cerebrospinal fluid removed, and time to resolution of papilledema due to pseudotumor cerebri syndrome was detected. The diagnostic and therapeutic purposes of either measuring the closing pressure or maximizing the volume of cerebrospinal fluid removed were not evident in these analyses.

Pediatric Pseudotumor Cerebri Syndrome: Diagnosis, Classification, and Underlying Pathophysiology.

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure in the setting of normal brain parenchyma and cerebrospinal fluid. PTCS can occur in the pediatric and adult populations and, if untreated, may lead to permanent visual loss. In this review, discussion will focus on PTCS in the pediatric population and will outline its distinct epidemiology and key elements of diagnosis, evaluation and management. Finally, although the precise mechanisms are unclear, the underlying pathophysiology will be considered.

Pediatric Pseudotumor Cerebri Syndrome.

Idiopathic intracranial hypertension, otherwise known as primary pseudotumor cerebri syndrome (PTCS), most frequently occurs in obese women of childbearing age. However, children may be affected as well. This review will address recent findings regarding demographics, diagnosis, and treatment of pediatric PTCS. Prepubertal children with primary PTCS have an equal sex distribution and less frequent obesity compared with adult patients. However, female gender and obesity are risk factors for primary PTCS in postpubertal children. Compared with adults, children with PTCS more frequently present with ocular motility deficits and more often have associated medical conditions that increase the risk of developing PTCS. Visual field testing may be unreliable, and the optimal modality to monitor visual function is unknown. MRI shows signs of elevated intracranial pressure (ICP) in children with PTCS similar to that of adults. It has now been established that elevated ICP in children ≤18 years old is greater than 25 cm H20 in nonobese, nonsedated children, and greater than 28 cm H2O in the remainder. Optical coherence tomography (OCT) may be used to distinguish pseudopapilledema from papilledema, monitor response to treatment in preverbal children, and identify patients with PTCS at risk for permanent visual loss. However, the precise role of OCT in the management of pediatric PTCS remains to be determined.

Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: Nested case-control study.

OBJECTIVE: To quantify the risk of secondary pseudotumor cerebri syndrome (PTCS) with fluoroquinolones. METHODS: A case-control study of people 15-60 years of age from the LifeLink Database (QuintilesIMS, Parsippany, NJ) was conducted. Cases had the first ICD-9-CM code for benign intracranial hypertension (BIH) as well as having received a procedure code for an MRI or CT scan and a lumbar puncture within 15 days or 30 days of the BIH code. For each case, 10 controls were selected using density-based sampling. Current users of fluoroquinolones received a prescription within 15 days or 30 days of the date of the diagnosis. For the sensitivity analysis, risk periods for 30 and 60 days were also examined. Adjusted rate ratios (RRs) were computed from a conditional logistic regression model. RESULTS: From a cohort of 6,110,723 people, there were 339 cases of PTCS and 3,390 corresponding controls. In the primary analysis, the adjusted RR for current users of fluoroquinolones for both the 15-day and 30-day definitions were 5.67 (95% confidence interval [CI] 2.72-11.83) and 4.15 (95% CI 2.29-7.50), respectively. The risk with tetracycline antibiotics was also increased, with RRs for 15 and 30 days of current use of 2.68 (0.89-8.11) and 3.64 (1.67-7.91), respectively. CONCLUSION: Our study suggests an increase in the risk of PTCS with current users of fluoroquinolones. Although this adverse event is rare, patients who experience symptoms of raised intracranial pressure including headaches, tinnitus, and double vision while taking fluoroquinolones should seek medical attention.

Inflammatory Orbitopathy Associated With Ipilimumab.

In this case report, the clinical presentation of an inflammatory orbitopathy seen following treatment with ipilimumab is described. After 3 rounds of ipilimumab (10 mg/kg) treatment for Stage III metastatic melanoma, the subject of this case report developed acute eye pain and proptosis. At initial presentation, she had marked proptosis and diffuse severe ophthalmoparesis. After treatment with high-dose steroids, over a period of 6 months, the symptoms gradually resolved fully. Although the condition may mimic thyroid-associated orbitopathy, imaging and laboratory features suggest that the orbitopathy associated with ipilimumab is not a secondary effect of thyroid dysfunction but a distinct inflammatory condition. The authors conclude that immune-related side effects can occur with biologic agents used to treat malignancies and these side-effects can involve the eye. This case illustrates the occurrence of an inflammatory orbitopathy associated with ipilimumab treatment.

Pediatric Idiopathic Intracranial Hypertension: Age, Gender, and Anthropometric Features at Diagnosis in a Large, Retrospective, Multisite Cohort.

PURPOSE: To examine anthropometric and maturational characteristics at diagnosis in pediatric idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, international, multisite study. PARTICIPANTS: Pediatric patients (2-18 years of age at diagnosis) with IIH. MAIN OUTCOME MEASURES: Body mass index (BMI), height, and weight Z-scores; sexual maturation. METHODS: Cases of IIH were identified retrospectively based on diagnostic code, pediatric neuro-ophthalmologist databases, or both and updated diagnostic criteria (2013) were applied to confirm definite IIH. Anthropometric measurements were converted into age- and gender-specific height, weight, and BMI Z-scores CDC 2000 growth charts. When available, sexual maturation was noted. RESULTS: Two hundred thirty-three cases of definite IIH were identified across 8 sites. In boys, a moderate association between age and BMI Z-scores was noted (Pearson's correlation coefficient, 0.50; 95% confidence interval [CI], 0.30-0.66; P < 0.001; n = 72), and in girls, a weak association was noted (Pearson's correlation coefficient, 0.34; 95% CI, 0.20-0.47; P < 0.001; n = 161). The average patient was more likely to be overweight at diagnosis at age 6.7 years in girls and 8.7 years in boys, and obese at diagnosis at age 12.5 years in girls and 12.4 years in boys. Compared with age- and gender-matched reference values, early adolescent patients were taller for age (P = 0.002 in girls and P = 0.02 in boys). Data on Tanner staging, menarchal status, or both were available in 25% of cases (n = 57/233). Prepubertal participants (n = 12) had lower average BMI Z-scores (0.95±1.98) compared with pubertal participants (n = 45; 1.92±0.60), but this result did not reach statistical significance (P = 0.09). CONCLUSIONS: With updated diagnostic criteria and pediatric-specific assessments, the present study identifies 3 subgroups of pediatric IIH: a young group that is not overweight, an early adolescent group that is either overweight or obese, and a late adolescent group that is mostly obese. Data also suggest that the early adolescent group with IIH may be taller than age- and gender-matched reference values. Understanding these features of pediatric IIH may help to illuminate the complex pathogenesis of this condition.

A baby with a lot of nerve.

An infant presented with bilateral disk edema and an acute left sixth cranial nerve (CN VI) palsy because of pseudotumor cerebri (PTC). PTC is rare in infants where it is often associated with endocrine abnormalities, medications, viral infections, systemic conditions, and nutritional etiologies such as vitamin A toxicity. We report a case of PTC in an infant associated with hypervitaminosis A with an unlikely source-a common prenatal vitamin.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.