Clare L. Fraser

The investigation of acute optic neuritis: a review and proposed protocol

Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials.

Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study

BACKGROUND Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. METHODS In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. FINDINGS 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume. INTERPRETATION Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. FUNDING Instituto de Salud Carlos III.

Efficacy of Intravenous Tissue-Type Plasminogen Activator in Central Retinal Artery Occlusion Report From a Randomized, Controlled Trial

Background and Purpose— Central retinal artery occlusion is caused by a platelet-fibrin thrombus or embolic occlusion and is a stroke of the eye. Observational studies suggest that thrombolytics may restore ocular perfusion and visual function. We hypothesized that intravenous tissue-type plasminogen activator (tPA) administered within 24 hours of symptom onset might restore ocular perfusion and visual function. Methods— A placebo-controlled, randomized trial of intravenous tPA versus intravenous saline was performed in patients with clinically defined central retinal artery occlusion within 24 hours of symptom onset. tPA was administered at a total dose of 0.9 mg/kg, with 10% given as a 1-minute bolus and the remainder over 1 hour. An improvement of visual acuity of 3 lines or more was considered significant. Results— Twenty-five percent (2 of 8) of the tPA group experienced the primary outcome at 1 week after tPA versus none of the placebo group. One patient had an intracranial hemorrhage. The visual acuity improvement of these 2 patients was not sustained at 6 months. In both patients, tPA was administered within 6 hours of symptom onset. Conclusions— Although essentially a negative study, it does add to the evidence base of reperfusion in central retinal artery occlusion by showing that the time window for intervention is likely to be <6 hours. Reocclusion is a potential problem and may require adjuvant anticoagulation. Future studies should concentrate on determining the efficacy of thrombolytics in the <6-hour time window. Clinical Trial Registration— URL: http://www.anzctr.org.au. Unique identifier: 83102.

The syndrome of pseudotumour cerebri and idiopathic intracranial hypertension

PURPOSE OF REVIEW Idiopathic intracranial hypertension (IIH) is a condition in which raised intracranial pressure is associated with a high body mass index, and in those societies in which the prevalence of obesity is increasing the disorder is of increasing importance. It is one cause of the syndrome of pseudotumour cerebri but the cause and the link with a rise in body weight are not understood. Furthermore the treatment of the more severe, sight-threatening cases is controversial. RECENT FINDINGS A major theme in recent years has been an attempt to identify the underlying mechanism of IIH. Some theories - such as the dural sinus stenosis theory - seem to ignore the relationship with weight gain; others have proposed a direct link between obesity and raised intracranial pressure through a specific fat distribution in the body; others through the production of lipokines; and yet others have suggested a converse causation with raised intracranial pressure giving rise to obesity. Uncontrolled case series continue to demonstrate the success of interventions such as cerebrospinal fluid diversion procedures, venous sinus stenting and bariatric surgery but there are no level 1 clinical trials. SUMMARY Interest in IIH is increasing and currently generating numerous studies but there is no consensus view on either cause or management.

Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm.

The diagnosis of Horner’s syndrome (HS) can be difficult, as patients rarely present with the classic triad of ptosis, miosis, and anhydrosis. Frequently, there are no associated symptoms to help determine or localise the underlying pathology. The onset of anisocoria may also be uncertain, with many cases referred after incidental discovery on routine optometric assessment. Although the textbooks discuss the use of cocaine, apraclonidine, and hydroxyamphetamine to diagnose and localise HS, in addition to reported false positive and negative results, these pharmacological agents are rarely available during acute assessment or in general ophthalmic departments. Typically, a week is required between using cocaine or apraclonidine for diagnosis and localisation of HS with hydroxyamphetamine, leaving the clinician with the decision of which investigations to request and with what urgency. Modern imaging modalities have advanced significantly and become more readily available since many of the established management algorithms were written. We thus propose a practical and safe combined clinical and radiological diagnostic protocol for HS that can be applied in most clinical settings.

Diagnostic Accuracy and Use of Nonmydriatic Ocular Fundus Photography by Emergency Physicians: Phase II of the FOTO-ED Study

STUDY OBJECTIVE During the first phase of the Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department study, 13% (44/350; 95% confidence interval [CI] 9% to 17%) of patients had an ocular fundus finding, such as papilledema, relevant to their emergency department (ED) management found by nonmydriatic ocular fundus photography reviewed by neuro-ophthalmologists. All of these findings were missed by emergency physicians, who examined only 14% of enrolled patients by direct ophthalmoscopy. In the present study, we evaluate the sensitivity of nonmydriatic ocular fundus photography, an alternative to direct ophthalmoscopy, for relevant findings when photographs are made available for use by emergency physicians during routine clinical care. METHODS Three hundred fifty-four patients presenting to our ED with headache, focal neurologic deficit, visual change, or diastolic blood pressure greater than or equal to 120 mm Hg had nonmydriatic fundus photography obtained (Kowa nonmydriatic α-D). Photographs were placed on the electronic medical record for emergency physician review. Identification of relevant findings on photographs by emergency physicians was compared with a reference standard of neuro-ophthalmologist review. RESULTS Emergency physicians reviewed photographs of 239 patients (68%). Thirty-five patients (10%; 95% CI 7% to 13%) had relevant findings identified by neuro-ophthalmologist review (6 disc edema, 6 grade III/IV hypertensive retinopathy, 7 isolated hemorrhages, 15 optic disc pallor, and 1 retinal vascular occlusion). Emergency physicians identified 16 of 35 relevant findings (sensitivity 46%; 95% CI 29% to 63%) and also identified 289 of 319 normal findings (specificity 91%; 95% CI 87% to 94%). Emergency physicians reported that photographs were helpful for 125 patients (35%). CONCLUSION Emergency physicians used nonmydriatic fundus photographs more frequently than they performed direct ophthalmoscopy, and their detection of relevant abnormalities improved. Ocular fundus photography often assisted ED care even when results were normal. Nonmydriatic ocular fundus photography offers a promising alternative to direct ophthalmoscopy.

Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next‐Generation Sequencing

Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next‐generation sequencing (NGS) of 32 cataract‐associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two‐thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal‐dominant or X‐linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases.

Nonmydriatic ocular fundus photography among headache patients in an emergency department

Objectives: Determine the frequency of and the predictive factors for abnormal ocular fundus findings among emergency department (ED) headache patients. Methods: Cross-sectional study of prospectively enrolled adult patients presenting to our ED with a chief complaint of headache. Ocular fundus photographs were obtained using a nonmydriatic fundus camera that does not require pupillary dilation. Demographic and neuroimaging information was collected. Photographs were reviewed independently by 2 neuroophthalmologists for findings relevant to acute care. The results were analyzed using univariate statistics and logistic regression modeling. Results: We included 497 patients (median age: 40 years, 73% women), among whom 42 (8.5%, 95% confidence interval: 6%–11%) had ocular fundus abnormalities. Of these 42 patients, 12 had disc edema, 9 had optic nerve pallor, 6 had grade III/IV hypertensive retinopathy, and 15 had isolated retinal hemorrhages. Body mass index ≥35 kg/m2 (odds ratio [OR]: 2.3, p = 0.02), younger age (OR: 0.7 per 10-year increase, p = 0.02), and higher mean arterial blood pressure (OR: 1.3 per 10-mm Hg increase, p = 0.003) were predictive of abnormal retinal photography. Patients with an abnormal fundus had a higher percentage of hospital admission (21% vs 10%, p = 0.04). Among the 34 patients with abnormal ocular fundi who had brain imaging, 14 (41%) had normal imaging. Conclusions: Ocular fundus abnormalities were found in 8.5% of patients with headache presenting to our ED. Predictors of abnormal funduscopic findings included higher body mass index, younger age, and higher blood pressure. Our study confirms the importance of funduscopic examination in patients with headache, particularly in the ED, and reaffirms the utility of nonmydriatic fundus photography in this setting.

Obstructive Sleep Apnea and Optic Neuropathy: Is There a Link?

Over the last decade, there has been an emerging interest in the link between obstructive sleep apnea (OSA) and ocular health. Though the evidence for OSA playing a role in cerebrovascular disease risk seems clear, the same cannot be said for optic neuropathies. The association between OSA and glaucoma or non-arteritic anterior ischemic optic neuropathy (NAION) has been postulated to be secondary to direct hypoxia or mechanisms of optic nerve head vascular dysregulation. Papilledema and increased intracranial pressure have also been reported in OSA and are thought to be due to increased cerebral perfusion pressure and cerebral venous dilation secondary to hypoxia and hypercapnia. This article reviews the evidence for possible pathophysiological links between OSA and optic nerve pathology. The epidemiologic and clinical evidence for an association, direct or indirect, between OSA and glaucoma, non-arteritic anterior ischemic optic neuropathy (NAION), and papilledema or idiopathic intracranial hypertension is presented.Over the last decade, there has been an emerging interest in the link between obstructive sleep apnea (OSA) and ocular health. Though the evidence for OSA playing a role in cerebrovascular disease risk seems clear, the same cannot be said for optic neuropathies. The association between OSA and glaucoma or non-arteritic anterior ischemic optic neuropathy (NAION) has been postulated to be secondary to direct hypoxia or mechanisms of optic nerve head vascular dysregulation. Papilledema and increased intracranial pressure have also been reported in OSA and are thought to be due to increased cerebral perfusion pressure and cerebral venous dilation secondary to hypoxia and hypercapnia. This article reviews the evidence for possible pathophysiological links between OSA and optic nerve pathology. The epidemiologic and clinical evidence for an association, direct or indirect, between OSA and glaucoma, non-arteritic anterior ischemic optic neuropathy (NAION), and papilledema or idiopathic intracranial hypertension is presented.

Minocycline-Induced Fulminant Intracranial Hypertension

OBJECTIVE To describe the clinical course of an unusually severe case of minocycline-induced intracranial hypertension. DESIGN Case study. SETTING Academic medical center. PATIENT Twelve-year-old girl with a fulminant course of intracranial hypertension. INTERVENTIONS Magnetic resonance imaging and venography of the brain, lumbar puncture, and optic nerve sheath fenestration. RESULTS Although the patient ceased minocycline treatment, there was ongoing and rapid worsening of symptoms and vision loss. Lumbar puncture, which normally acts as a temporizing measure to preserve vision, failed to prevent, and may even have precipitated, further deterioration in vision, necessitating surgical intervention with optic nerve sheath fenestration. CONCLUSION Minocycline can cause a fulminant syndrome of elevated intracranial pressure, with severe vision loss, even after the medication has been discontinued.