Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P <1.06 x 10(- 7), of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.Peer reviewe

DNA methylation and body mass index from birth to adolescence : meta-analyses of epigenome-wide association studies

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P <1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.Peer reviewe

Direct carotid-cavernous sinus fistula

A 40-year-old man presented with decreased vision and redness in his left eye. He had a significant trauma to the left side of his face about one year ago, but did not seek medical attention. External examination showed significant proptosis of the left eye (Figure 1) and conjunctival injection and corkscrew episcleral vessels (Figure 2). Ocular motility was full in both eyes (Figure 3) and dilated examination showed left optic disc pallor, tortuous venules, and attenuated arterioles (Figure 4). CT scan of the orbits showed left proptosis (Figure 5), enlarged cavernous sinuses, superior ophthalmic veins, and extraocular muscles on the left (Figure 6). Similar findings were seen on coronal (Figure 7) and sagittal slices (Figure 8). A catheter angiogram was performed and showed evidence of Borden type II direct left carotid-cavernous sinus fistula shunting into bilateral cavernous sinuses (Figure 9). He was treated with transarterial coil embolization (Figure 10) and post-coiling catheter angiogram showed complete obliteration of the carotid cavernous sinus fistula without residual arteriovenous shunting (Figures 11 and 12).VBneurodiscarotidcavernousfistula

Sequential non-arteritic anterior ischemic optic neuropathy (NAION)

A 68-year old woman with hypertension, obstructive sleep apnea and obesity was seen in neuro-ophthalmology consultation for vision loss in the right eye. She had right optic disc edema with a small optic disc hemorrhage a small, crowded optic disc in the left eye known as a "disc-at-risk" (Figure 1). Humphrey 24-2 SITA-Fast visual fields showed non-specific points of depression in the left eye (Figure 2). She had normal laboratory investigations including complete blood count (CBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and was diagnosed with right NAION. She lost vision in her left eye 2 weeks later and had new optic disc edema in the left eye with optic disc hemorrhages (Figures 3 and 4). Humphrey 24-2 SITA-Fast visual fields show a right superior altitudinal defect and inferior points of depression in the left eye (Figure 5). Repeat CBC, ESR, and CRP were normal and was diagnosed with sequential NAION. She was seen in follow-up 1 month later and had mild improvement in her vision in the right eye, but no change in her left eye. There was resolution of the optic disc edema and optic disc pallor in both eyes at that time (Figures 6 and 7). Humphrey 24-2 SITA-Fast visual fields were unreliable due to fixation losses and a high number of false positives (Figure 8). Optic coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), which includes the ganglion cell layer and inner plexiform layer, showed inferior loss of the GCC corresponding to the superior visual field defect in the right eye and superior GCC loss corresponding to the inferior visual field defect in the left eye (Figures 9 and 10). [[Figure 1. Optic disc photos of both eyes demonstrating right optic disc edema and a left small, crowded optic nerve ("disc-at-risk"). ; ; Figure 2. Humphrey 24-2 SITA-Fast visual fields showing non-specific depressed points in the left eye above and below the horizontal. There are also non-specific depressed points in the right eye.; ; Figure 3. Optic disc photos demonstrating right optic disc edema and new left optic disc edema with optic disc hemorrhages. ; ; Figure 4. Comparison of optic disc photos from the initial visit to the follow-up visit 2 weeks later. ; ; Figure 5. Humphrey 24-2 SITA-Fast visual fields show a right superior altitudinal defect and inferior points of depression in the left eye. ; ; Figure 6. Optic disc photos showing bilateral optic disc pallor.; ; Figure 7. Optic disc photos from her previous visits shown for comparison. There has been resolution of the optic disc edema and optic disc pallor in both eyes.; ; Figure 8. Humphrey 24-2 SITA-Fast visual fields were unreliable due to high false negatives and fixation losses. ; ; Figure 9. Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) shows mild thinning superiorly in both eyes and OCT macular ganglion cell analysis shows inferior ganglion cell complex (GCC) thinning in the right eye and superior GCC thinning in the left eye. ; ; Figure 10. The inferior ganglion cell complex (GCC) thinning in the right eye corresponds to the superior visual field defect and the superior GCC thinning in the left eye corresponds to the inferior visual field defect in the left eye. The previous reliable visual fields were used for this figure. ]]KBDdoonanteriorischemicopticneuropath

Illusory Visual Spread

Illusory visual spread is a form of visual perseveration resulting in images appearing to spread beyond it normal confines. In this video we describe a patient with Parkinson's disease and dementia, who developed various forms of visual hallucination including palinopsia and illusory visual spread. We review the literature and discuss the pathophysiology of this rare condition

Typical idiopathic intracranial hypertension: optic nerve appearance and brain MRI findings

A 24-year old African American woman was referred for bilateral optic disc edema that was incidentally noted on a routine eye examination. She had excellent visual function and dilated examination showed bilateral optic disc edema with peripapillary wrinkles in the right eye and pseudodrusen in the left eye (Figure 1). Optical coherence tomography of the optic nerve demonstrated the peripapillary wrinkles in the inner retina (Figure 2). Humphrey 24-2 SITA-Fast visual fields were normal (Figure 3). MRI and MRV of the with contrast were performed (Figures 4 and 5) and showed a partially empty sella (Figure 6), caudal displacement of the cerebellar tonsils (Figure 7), flattening of the posterior globes (Figure 8), distention of the CSF spaces around the optic nerves (Figure 9), and narrowing of the distal transverse sinuses (Figure 10), consistent with intracranial hypertension. The patient had a lumbar puncture, which confirmed an elevated opening pressure of 39 cm of water with normal cerebrospinal fluid contents leading to the diagnosis of idiopathic intracranial hypertension. Treatment with acetazolamide and weight loss was initiated and she was seen in follow-up at 3 months, 6 months, and 1 year after her initial visit. Her optic disc edema gradually resolved (Figure 11) and she continued to maintain excellent visual function (Figure 12). [[Number of Figures and legend for each: 12 figures included. Figure 1. Optic disc photos of both eyes demonstrating bilateral optic disc edema with peripapillary wrinkles in the right eye and pseudodrusen in the left eye. Figure 2. Spectralis optic coherence tomography of the optic nerve shows peripapillary wrinkles on the surface of the inner retina of the right eye. Figure 3. Humphrey 24-2 SITA-Fast visual fields. Figure 4. Sagittal T1, axial T2 FLAIR, and coronal T2 MRI images. Figure 5. MRV of the head with contrast. Figure 6. Sagittal T1 MRI shows a partially empty sella. A normal appearing sella is shown for reference. Figure 7. Sagittal T1 MRI shows caudal displacement of the cerebellar tonsils. A normal appearing sagittal T1 MRI is shown for comparison. Figure 8. Axial FLAIR MRI shows flattening of the posterior globes. Normally appearing globes are included for comparison. Figure 9. Coronal T2 MRI shows distention of the CSF spaces around the optic nerves. Normal appearing optic nerves and surrounding CSF spaces are shown for comparison. Figure 10. MRV of the brain shows narrowing of the distal transverse sinuses. Figure 11. Optic disc photos at follow-up visits show resolution of the optic disc edema. Figure 12. Optic disc photos are shown with accompanying pattern deviation from the 24-2 SITA-Fast Humphrey visual fields. She maintained excellent visual function at each follow-up visit. ]]KBDneurodisidiopathicintracranialhypertensio

Vitreopapillary traction

A 64-year-old woman was referred for bilateral optic disc edema. Examination of her optic nerves showed indistinct margins at the nasal aspect of both eyes (Figure 1). Humphrey 24-2 SITA-Fast visual fields showed non-specific depressed points in both eyes (Figure 2). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) showed a normal RNFL thickness, but there were areas of vitreopapillary traction evident from the B-scans (Figure 3). Spectralis OCT of the optic nerve of right eye (Figure 4) and left eye (Figure 5) showed areas of vitreopapillary traction in the nasal portion of both optic discs. OCT of the macular showed epiretinal membranes in both eyes (Figure 6)

Optical coherence tomography of the retinal nerve fiber layer

A normal optical coherence tomography (OCT) of the macula is shown highlighting the position of a single retinal ganglion cell and its axon in the retinal nerve fiber layer (Figure 1). The topographical relationship of retinal ganglion cells in the retina to the visual field and position in the anterior visual pathways is demonstrated in Figure 2. A normal OCT of the retinal nerve fiber layer (RNFL) is shown and the various components of a Cirrus OCT of the RNFL printout are explained (Figure 3). Case examples highlighting the use of OCT of the RNFL in a patient with a left optic tract lesion (Figures 4, 5, 6), right optic neuritis (Figures 7, 8, 9), idiopathic intracranial pressure with worsening papilledema (Figures 10, 11, 12) and non-organic vision loss (Figures 13 and 14) are illustrated. Potential pitfalls in interpreting the OCT of the RNFL are described and case examples are shown of a patient with IIH and an off-centered scan in the right eye (Figures 15 and 16), a patient with IIH and a segmentation error in the right eye due to severe optic disc edema (Figures 17, 18) and a patient with bilateral optic neuropathies from non-arteritic anterior ischemic optic neuropathy and an RNFL thickness in the "normal" range in the left eye, but an abnormal left optic nerve (Figures 19 and 20).VBnflaopticalcoherencetomography; EXAMrnf

Typical idiopathic optic neuritis

This is a case of a typical optic neuritis in a 41-year-old woman presenting with vision loss and pain with eye movements in the right eye. Optic disc photos at presentation showed subtle hyperemia in the right eye (Figure 1) and optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) was mildly elevated in the right eye whereas OCT of the ganglion cell layer (GCL) was normal (Figure 2). Humphrey visual fields (24-2 SITA Fast) showed a cecocentral scotoma in the right eye (Figure 3) and MRI of the orbits (Axial T1 with fat suppression, post-contrast) showed enhancement of the right intraorbital optic nerve (Figure 4). MRI of the brain and spine were normal without any white matter lesions (Figure 5). She was treated with intravenous methylprednisolone 1 gram per day for 3 days followed by an oral prednisone taper and her vision returned to baseline after about 6 weeks. Optic disc photos 6 months after presentation showed temporal pallor in the right eye (Figure 6) and OCT of the RNFL showed temporal thinning and reduced macular GCL thickness in the right eye (Figure 7). Humphrey visual fields (24-2 SITA Fast) showed were normal in both eyes (Figure 8). OCT angiography was available for review and showed reduction in the superficial peripapillary capillary network temporally in the right eye corresponding to the area of RNFL thinning (Figure 9). Because her MRI of the brain was normal without any white matter lesions, her 15-year risk of multiple sclerosis in 25% based on the optic neuritis treatment trial. Figure 1. Optic disc photos at presentation showed subtle hyperemia in the right eye.; ; Figure 2. Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) was mildly elevated in the right eye whereas OCT of the ganglion cell layer (GCL) was normal.; ; Figure 3. Humphrey visual fields (24-2 SITA Fast) showed a cecocentral scotoma in the right eye.; ; Figure 4. MRI of the orbits (Axial T1 with fat suppression, post-contrast) showed enhancement of the right intraorbital optic nerve.; ; Figure 5. MRI of the brain and spine were normal without any white matter lesions.; ; Figure 6. Optic disc photos 6 months after presentation showed temporal pallor in the right eye.; ; Figure 7. OCT of the RNFL showed temporal thinning and reduced macular GCL thickness in the right eye.; ; Figure 8. Humphrey visual fields (24-2 SITA Fast) showed were normal in both eyes 6 months after presentation.; ; Figure 9. OCT anriography was available for review and showed reduction in the superficial peripapillary capillary network temporally in the right eye corresponding to the area of RNFL thinning.KBDidiopathicopticneuriti