Choriocapillaris and Retinal Vascular Alterations in Presymptomatic Alzheimer's Disease.

Purpose: To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aß42/tau ratios. Methods: Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aß42/tau (PAT) ratio of <2.7132, indicative of presymptomatic Alzheimer's disease (AD), and 10 had a normal Aß42/tau (NAT) ratio of ≥2.7132. OCTA en face images of the superficial vascular complex (SVC) and deep vascular complex were binarized and skeletonized to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en face OCTA slab of the CC. The above parameters were compared between CH-PATs and CH-NATs. Results: Compared to CH-NATs, CH-PATs showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs. Conclusions: Swept-source OCTA analysis of the SVC and CC suggests a significant vascular loss at the CH stage of pre-AD that might be an indicator of a neurodegenerative process initiated by the impaired clearance of Aß42 in the blood vessel wall and by phosphorylated tau accumulation in the perivascular spaces, a process that most likely mirrors that in the brain. If confirmed in larger longitudinal studies, OCTA retinal and inner choroidal metrics may be important biomarkers for assessing presymptomatic AD.

Establishing induced pluripotent stem cell lines from two dominant optic atrophy patients with distinct OPA1 mutations and clinical pathologies.

Dominant optic atrophy (DOA) is an inherited disease that leads to the loss of retinal ganglion cells (RGCs), the projection neurons that relay visual information from the retina to the brain through the optic nerve. The majority of DOA cases can be attributed to mutations in optic atrophy 1 (OPA1), a nuclear gene encoding a mitochondrial-targeted protein that plays important roles in maintaining mitochondrial structure, dynamics, and bioenergetics. Although OPA1 is ubiquitously expressed in all human tissues, RGCs appear to be the primary cell type affected by OPA1 mutations. DOA has not been extensively studied in human RGCs due to the general unavailability of retinal tissues. However, recent advances in stem cell biology have made it possible to produce human RGCs from pluripotent stem cells (PSCs). To aid in establishing DOA disease models based on human PSC-derived RGCs, we have generated iPSC lines from two DOA patients who carry distinct OPA1 mutations and present very different disease symptoms. Studies using these OPA1 mutant RGCs can be correlated with clinical features in the patients to provide insights into DOA disease mechanisms.

Peripapillary Vitreous Traction Syndrome: Expanding the Spectrum of Anterior Optic Neuropathies.

BACKGROUND: Peripapillary vitreous traction (PVT) occurring without any underlying eye disease has been contemplated as a distinct entity from nonarteritic ischemic optic neuropathy (NAION) for many years and is sometimes difficult to differentiate from classical NAION. We report 6 new cases to analyze the clinical features of PVT syndrome that would expand the clinical spectrum of anterior optic neuropathies. METHODS: Prospective case series. RESULTS: PVT syndrome seems to affect optic discs with a small area with a small cup-to-disc (C/D) ratio. The C/D ratio does not significantly increase in the chronic stage, as in NAION. Vitreous traction without detachment can either lead to mild retinal nerve fiber layer (RNFL) injury with attendant ganglion cell layer/inner plexiform layer (GCL/IPL) thinning in 29% or no injury at all in 71%. Eighty-six percent had good visual acuity (VA) and had no relative afferent pupillary defect (RAPD), whereas 14% had a transient RAPD; 71% had no color defect. Vitreous detachment after a period of severe and persistent traction can lead to more damage to the optic nerve head and RNFL that may look like NAION. Our hypothesized mechanically induced injury to the superficial optic nerve head may not lead to much visual impairment. In our study, no further therapeutic interventions were required. CONCLUSIONS: Based on our analysis of previously published cases and our own prospective case series of 6 patients, the PVT syndrome falls within the spectrum of anterior optic neuropathies, often affecting small optic discs with a small C/D ratio. Vitreous traction can lead to a partial or complete anterior optic neuropathy. The PVT syndrome may be a "more" anterior optic neuropathy distinct from classical NAION.

Altering neuronal circuitry with 4-aminopyridine for visual improvement in Leber's hereditary optic neuropathy (LHON).

In this retrospective, interventional, longitudinal small case series, we looked at the visual effects of pharmacologic intervention with 4-aminopyridine (4-AP) in chronic Leber's Hereditary Optic Neuropathy (LHON) patients who are non-responders to idebenone. We illustrate, as examples, the visual progression of three LHON patients with 4-AP as add-on therapy to idebenone. Each patient had a different primary LHON mutation and was treated with idebenone within one year of onset. No response to idebenone at 300 mg orally three times a day ranged from less than one year to 2.5 years, and the addition of 4-AP at 10 mg orally two times a day ranged from 24 to 29 months. Outcome measures included best-corrected distance visual acuity, color vision, automated perimetry, the average retinal nerve fiber layer (RNFL) thickness, and the full-field photopic negative response (PhNR) amplitude. The 19-year-old man with the LHON mutation 11778A > G had no response to the addition of 4-AP to idebenone. The 27-year-old man with the LHON mutation 3460A > G experienced a significant response to 4-AP. Finally, the 40-year-old man with the LHON mutation 14484 T > C had a milder response. Although this case series was too small to demonstrate the efficacy of idebenone with add-on 4AP, it allowed us to consider a new hypothesis that neuronal activity generated from 4-AP can add more potential for visual recovery in LHON patients.

The m.3890G>A/MT-ND1 mtDNA rare pathogenic variant: Expanding clinical and MRI phenotypes.

INTRODUCTION: Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues. CASES PRESENTATION: The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI. DISCUSSION: Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity. CONCLUSION: The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features.

Glaucoma as Neurodegeneration in the Brain.

Glaucoma, a group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence from human and animal studies have shown that glaucoma shares some common neurodegenerative pathways with Alzheimer's disease (AD) and other tauopathies, such as chronic traumatic encephalopathy (CTE) and frontotemporal dementia. This hypothesis is based on the focal adhesion pathway hypothesis and the spreading hypothesis of tau. Not only has the Apolipoprotein E (APOE) gene been shown to be associated with AD, but also with primary open angle glaucoma (POAG). This review will highlight the relevant literature in the past 20 years from PubMed that show the pathogenic overlap between POAG and AD. Neurodegenerative pathways that contribute to transsynaptic neurodegeneration in AD and other tauopathies might also be similar to those in glaucomatous neurodegeneration.

Past, present and future role of retinal imaging in neurodegenerative disease.

Retinal imaging technology is rapidly advancing and can provide ever-increasing amounts of information about the structure, function and molecular composition of retinal tissue in humans in vivo. Most importantly, this information can be obtained rapidly, non-invasively and in many cases using Food and Drug Administration-approved devices that are commercially available. Technologies such as optical coherence tomography have dramatically changed our understanding of retinal disease and in many cases have significantly improved their clinical management. Since the retina is an extension of the brain and shares a common embryological origin with the central nervous system, there has also been intense interest in leveraging the expanding armamentarium of retinal imaging technology to understand, diagnose and monitor neurological diseases. This is particularly appealing because of the high spatial resolution, relatively low-cost and wide availability of retinal imaging modalities such as fundus photography or OCT compared to brain imaging modalities such as magnetic resonance imaging or positron emission tomography. The purpose of this article is to review and synthesize current research about retinal imaging in neurodegenerative disease by providing examples from the literature and elaborating on limitations, challenges and future directions. We begin by providing a general background of the most relevant retinal imaging modalities to ensure that the reader has a foundation on which to understand the clinical studies that are subsequently discussed. We then review the application and results of retinal imaging methodologies to several prevalent neurodegenerative diseases where extensive work has been done including sporadic late onset Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. We also discuss Autosomal Dominant Alzheimer's Disease and cerebrovascular small vessel disease, where the application of retinal imaging holds promise but data is currently scarce. Although cerebrovascular disease is not generally considered a neurodegenerative process, it is both a confounder and contributor to neurodegenerative disease processes that requires more attention. Finally, we discuss ongoing efforts to overcome the limitations in the field and unmet clinical and scientific needs.

Indirect Traumatic Optic Neuropathy in Mild Chronic Traumatic Brain Injury.

Purpose: To analyze the clinical presentation and optical coherence tomography (OCT) findings in indirect traumatic optic neuropathy (ITON) in veterans with chronic mild traumatic brain injury (mTBI). Methods: This retrospective study is the first to describe the OCT pattern of subclinical to mild ITON in veterans with chronic mTBI. The thicknesses of the macular ganglion cell layer (mGCL), peripapillary retinal nerve fiber layer (pRNFL), and subfoveal choroidal layer were analyzed in young veterans who had mTBI of >6 months' duration and either blunt head injury or improvised explosive device (IED) concussions. Results: Three major OCT findings were demonstrated: (1) temporal pRNFL thinning was associated with subclinical TON in the eyes of chronic mTBI patients compared with controls; within mTBI subjects, nasal mGCL thinning at the 3-mm modified Early Treatment Diabetic Retinopathy Study circle diameter distance from the fovea correlated with the corresponding temporal retinal nerve fiber layer thinning; (2) inner (1 mm) superior thinning was greater than that of the temporal mGCL in blunt head injury and could potentially distinguish it from IED concussive head trauma; and (3) subfoveal choroidal thinning was significantly worse in eyes of mTBI patients compared with those of controls. Conclusions: These OCT findings may contribute to the understanding of the spectrum of visual injuries resulting from head trauma.

Current concepts and strategies in the diagnosis and management of idiopathic intracranial hypertension in adults.

Since obesity has become an epidemic in industrialized nations, idiopathic intracranial hypertension (IIH) is now a more common neuro-ophthalmic disorder that causes visual loss and headaches. This review highlights the new diagnostic criteria for IIH and the new insights into the pathophysiologic mechanisms of IIH. Key diagnostic and monitoring techniques for papilledema include not only neuroimaging and the measurement of cerebrospinal fluid (CSF) pressure, but also perimetry, optical coherence tomography, and ocular sonography. The main findings of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) support acetazolamide as the mainstay for medical therapy. CSF diversion procedures, endovascular venous sinus stenting, and optic nerve sheath fenestration are all surgical options when IIH is refractory to medical treatment or when it presents fulminantly. Future clinical trials comparing these procedures will help develop better paradigms in the surgical management of IIH.

Incidence and predictors of dural venous sinus pressure gradient in idiopathic intracranial hypertension and non-idiopathic intracranial hypertension headache patients: results from 164 cerebral venograms.

OBJECTIVE Cerebral venous pressure gradient (CVPG) from dural venous sinus stenosis is implicated in headache syndromes such as idiopathic intracranial hypertension (IIH). The incidence of CVPG in headache patients has not been reported. METHODS The authors reviewed all cerebral venograms with manometry performed for headache between January 2008 and May 2015. Patient demographics, headache etiology, intracranial pressure (ICP) measurements, and radiographic and manometric results were recorded. CVPG was defined as a difference ≥ 8 mm Hg by venographic manometry. RESULTS One hundred sixty-four venograms were performed in 155 patients. There were no procedural complications. Ninety-six procedures (58.5%) were for patients with IIH. The overall incidence of CVPG was 25.6% (42 of 164 procedures): 35.4% (34 of 96 procedures) in IIH patients and 11.8% (8 of 68 procedures) in non-IIH patients. Sixty procedures (36.6%) were performed in patients with preexisting shunts. Seventy-seven patients (49.7%) had procedures preceded by an ICP measurement within 4 weeks of venography, and in 66 (85.7%) of these patients, the ICP had been found to be elevated. CVPG was seen in 8.3% (n = 5) of the procedures in the 60 patients with a preexisting shunt and in 0% (n = 0) of the 11 procedures in the 77 patients with normal ICP (p < 0.001 for both). Noninvasive imaging (MR venography, CT venography) was assessed prior to venography in 112 (68.3%) of 164 cases, and dural venous sinus abnormalities were demonstrated in 73 (65.2%) of these cases; there was a trend toward CVPG (p = 0.07). Multivariate analysis demonstrated an increased likelihood of CVPG in patients with IIH (OR 4.97, 95% CI 1.71-14.47) and a decreased likelihood in patients with a preexisting shunt (OR 0.09, 95% CI 0.02-0.44). CONCLUSIONS CVPG is uncommon in IIH patients, rare in those with preexisting shunts, and absent in those with normal ICP.

Trauma-Associated Leber Hereditary Optic Neuropathy.

A 19-year-old man developed visual loss in the left eye 1 day following a martial arts kick to the head. Vision worsened over a week, when visual loss was noted in the right eye without further trauma. The fundus was initially normal, but visual field testing showed temporal depression right eye with diffuse depression left eye, and traumatic chiasmopathy was suspected. Magnetic resonance imaging (MRI) of the brain demonstrated an enlarged chiasm with intrinsic signal abnormality, but no enhancement. Treatment with intravenous corticosteroids and hyperbaric oxygen therapy did not result in visual improvement. Ancillary testing for atypical optic neuritis was negative, but testing for LHON was positive for the 11778 mutation. This case raises the question of trauma as a precipitating factor for LHON and illustrates the rare occurrence of intrinsic signal abnormalities of the chiasm in this disorder.

Causes of isolated recurrent ipsilateral sixth nerve palsies in older adults: a case series and review of the literature.

PURPOSE: The etiology of recurrent isolated sixth nerve palsies in older adults has not been well described in the literature. Sixth nerve palsies presenting with a chronic, relapsing, and remitting course are uncommon, but can herald a diagnosis of high morbidity and mortality in the older population. PATIENTS AND METHODS: Our method was a retrospective case series study. A review of clinical records of 782 patients ≥50 years of age diagnosed with recurrent sixth nerve palsies was performed over a 10-year period from 1995-2005 in a neuro-ophthalmology clinic in Reno, Nevada. A review of the current literature regarding similar cases was also performed on PubMed. RESULTS: Seven patients ≥50 years of age with chronic, recurrent sixth nerve palsies were identified. Five were males and two were females. Four of seven (57%) patients had structural lesions located in the parasellar or petrous apex cavernous sinus regions. One of seven (14.29%) had a recurrent painful ophthalmoplegic neuropathy (International Headache Society [IHS] 13.9), previously termed ophthalmoplegic migraine; one of seven (14.29%) presented with an intracavernous carotid artery aneurysm; and one of seven (14.29%) presented with microvascular disease. CONCLUSION: The clinical presentation of an isolated recurrent diplopia from a sixth nerve palsy should prompt the neurologist or ophthalmologist to order a magnetic resonance imaging (MRI) scan of the brain with and without gadolinium as part of the initial workup to rule out a non-microvascular cause, such as a compressive lesion, which can increase morbidity and mortality in adults >50 years of age.

Neuro-ophthalmic features of the neurocutaneous syndromes.

This review highlights the diagnostic criteria and neuro-ophthalmic symptoms and signs of the more commonly seen neurocutaneous disorders, including NF1 and NF2, tuberous sclerosis, VHL disease, Sturge-Weber disease, and AT. The distinct neuro-ophthalmic features in each of these hereditary and congenital disorders play an important role in clinical diagnosis.

Early diagnosis, monitoring, and treatment of optic neuritis.

BACKGROUND: About half of multiple sclerosis patients present with optic neuritis (ON) as a clinically isolated syndrome (CIS). In the Optic Neuritis Treatment Trial study, 28% of patients with ON and an abnormal brain magnetic resonance imaging (MRI) did not have a relapse at the end of 15 years. It is still difficult to predict which CIS patients will go on to develop clinically definite multiple sclerosis and which will have a benign course. REVIEW SUMMARY: This review focuses on more advanced methods of detecting and quantifying ON in multiple sclerosis that have been developed in the past 15 years, especially on recent developments in optical coherence tomography measurement of the retinal nerve fiber layer and its role in monitoring axonal loss in the course of the disease. New clinical trial methods of measuring visual acuity include high-contrast visual acuity testing with the Early Treatment Diabetic Retinopathy Study charts, low-contrast letter acuity, and contrast sensitivity testing. More advanced neuroimaging techniques include magnetization transfer imaging and diffusion tensor imaging to quantify visual pathway lesions. Other tests of visual function, such as multifocal visual-evoked potentials and functional MRI, have been shown to be more sensitive than conventional visual-evoked potentials or MRI in detecting early, subtle visual impairment in ON and early recovery of visual function related to cortical plasticity. Newer agents are currently being investigated for CIS in ongoing clinical trials. CONCLUSIONS: Better methods are being developed for the earlier diagnosis, monitoring, and treatment of ON. In the future, CIS patients may be stratified according to their risk of development of clinically definite multiple sclerosis and therefore, receive the appropriate treatment.

Recent advances in optic neuritis related to multiple sclerosis.

More advanced methods of detecting and quantifying optic neuritis (ON) in multiple sclerosis have been developed in the past 15 years. This review focuses on developments in optical coherence tomography (OCT) measurement of the retinal nerve fibre layer (RNFL) and its role in monitoring axonal loss in the course of the disease. New clinical trial methods of measuring visual acuity (VA) include high-contrast VA testing with Early Treatment Diabetic Retinopathy Study charts, low-contrast letter acuity and contrast sensitivity testing. Multi-focal visual evoked potentials have been used to detect early, subtle visual impairment in ON and early recovery of visual function. New technical developments in OCT may help advance our knowledge in studying the relationship between optic nerve/retinal atrophy and brain atrophy in clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis and primary progressive multiple sclerosis. The treatment of CIS patients is still debatable.

Short-lasting unilateral neuralgiform headache with autonomic symptoms syndrome as the initial manifestation of idiopathic hypertrophic cranial pachymeningitis.

This is the first report of 2 patients presenting with short-lasting unilateral neuralgiform headache with autonomic symptoms as the initial manifestation of idiopathic hypertrophic cranial pachymeningitis. They both had acute retro-orbital pain ipsilateral to the dural thickening on magnetic resonance imaging of brain, and one had transient miosis as an additional parasympathetic feature. Short-lasting unilateral neuralgiform headache with autonomic symptoms syndrome may be associated with secondary central nervous system pathology, and neuroimaging should be considered in all patients with trigeminal autonomic cephalalgia.

Infliximab and anterior optic neuropathy: case report and review of the literature.

BACKGROUND: Anti-tumor necrosis factor alpha (TNF alpha) agents have been increasingly used to treat patients with Crohn's disease, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and persistent uveitis. We describe a 68-year-old man with Crohn's esophagitis who developed a possible bilateral toxic anterior optic neuropathy during infliximab infusion. METHODS: This is an observational case report, with review of the PubMed literature from 1977 to present. RESULTS: This 68-year-old man with a 2-year history of Crohn's esophagitis developed acute bilateral visual loss during his third infliximab infusion. His clinical features and laboratory tests were characteristic for a bilateral anterior optic neuropathy. Only three cases of possible infliximab-associated anterior optic neuropathy have been reported in the literature to date. CONCLUSION: It is important to consider the possibility of anterior optic neuropathy, in addition to retrobulbar optic neuritis, in patients who experience sudden-onset visual loss while being treated with infliximab.

Mycophenolate mofetil for ocular myasthenia.

OBJECTIVE: To study the safety and tolerability of mycophenolate mofetil (MM), since this steroid-sparing immunomodulatory agent with less side effects, compared to corticosteroids, may be considered for long-term management of ocular myasthenia (OMG). METHODS: Consecutive patients with OMG started on MM between December 2000 and December 2002 were followed up to December 2006. RESULTS: All of the 31 patients with OMG were treated with prednisone at 40-60 mg/d while MM was increased up to the target of 1.0 g/d. After symptoms completely resolved, all patients were then tapered off prednisone over a period of 4 weeks. Eighty-seven percent (27/31) of patients continued on MM during the study. Mycophenolate mofetil discontinuation occurred in 4/31 (13%) of patients within the first four months of starting the drug. Of the patients who continued on MM, 93% (25/27) remained at stage I of the disease. The 7% (2/27) of patients on MM who generalized in our study did so by 2 years and were treated with additional prednisone. MM-related adverse events included nausea in 9 of 31 patients, diarrhea in 5 of 31 patients, and vomiting in 1/31 patients. No cases of infections, cytopenias, or malignancies were observed. CONCLUSIONS: Eighty-seven percent of OMG patients on corticosteroids who were switched to MM remained at Stage I of the disease over a mean period of 4.2 years. MM at 1.0 g/d was safe and tolerable as a long-term immunosuppressant for OMG.