Literature Commentary: Take Two!

In this section of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss thefollowing 6 articles:1. Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, Ciccarelli O. Inclusion of optic nerve involvement indissemination in space criteria for multiple sclerosis. Neurology. 2018;91:e1130-e1134.2. Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraineattacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025.3. Rotenstein LS, Torre M, Ramos MA, Rosales RC, Guille C, Sen S, Mata DA. Prevalence of burnout amongphysicians: a systematic review. JAMA. 2018;320:1131-1150.4. Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, Takahashi T, Whittam D, Leite MI, Misu T,Yoshiki T, Messina S, Elsone L, Majed M, Flanagan E, Gadoth A, Huebert C, Sagen J, Greenberg BM, Levy M,Banerjee A, Weinshenker B, Pittock SJ. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018;91:e1642-e1651.5. Raynowska J, Miskin DP, Pramanik B, Asiry S, Anderson T, Boockvar J, Najjar S, Harel A. Retinal vasculopathywith cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS. Neurology. 2018;91:e1423-e1428.6. O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of preclinical Alzheimer disease withoptical coherence tomographic angiographyfindings. JAMA Ophthalmol. 2018;136:1242-1248.

Literature Commentary: June Issue Double Feature Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary: Take Two! In this section of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, Ciccarelli O. Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis. Neurology. 2018;91:e1130-e1134. 2. Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025. 3. Rotenstein LS, Torre M, Ramos MA, Rosales RC, Guille C, Sen S, Mata DA. Prevalence of burnout among physicians: a systematic review. JAMA. 2018;320:1131-1150. 4. Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, Takahashi T, Whittam D, Leite MI, Misu T, Yoshiki T, Messina S, Elsone L, Majed M, Flanagan E, Gadoth A, Huebert C, Sagen J, Greenberg BM, Levy M, Banerjee A, Weinshenker B, Pittock SJ. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG- positive NMOSD. Neurology. 2018;91:e1642-e1651. 5. Raynowska J, Miskin DP, Pramanik B, Asiry S, Anderson T, Boockvar J, Najjar S, Harel A. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS. Neurology. 2018;91:e1423-e1428. 6. O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of preclinical Alzheimer disease with optical coherence tomographic angiography findings. JAMA Ophthalmol. 2018;136:1242-1248. Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, Ciccarelli O. Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis. Neurology. 2018;91:e1130-e1134 Objective: To investigate the effect of including optic nerve involvement in dissemination in space (DIS) criteria for diagnosis of multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS). Methods: We studied 160 patients with CIS: 129 with optic neuritis (ON) and 31 with non-ON CIS. MRI brain/spinal cord was performed at the time of presentation and a follow-up MRI brain after 3-12 months. We evaluated optic nerve involvement clinically or with visual evoked potentials (n = 42). We investigated the performance of the McDonald 2017 DIS criteria and modified DIS criteria including optic nerve involvement for development of clinically definite MS after w15 years. Results: In the ON group, including symptomatic optic nerve involvement identified additional 15 patients with DIS. The modified DIS criteria that included optic nerve involvement were more sensitive (95% vs 83%) and more accurate (81% vs 78%) than the McDonald 2017 DIS criteria, but less specific (57% vs 68%). In combination with dissemination in time criteria, the modified DIS criteria remained more sensitive (83% vs 74%) and accurate (81% vs 75%), and the specificity was the same (77%). Including asymptomatic optic nerve involvement in DIS, the non-ON group did not identify any additional patients, and the performance of the McDonald 2017 criteria and the modified criteria was the same. Conclusion: The inclusion of symptomatic optic nerve involvement in DIS in patients with ON improved the overall performance of MS diagnostic criteria. Including asymptomatic optic nerve involvement in DIS in patients with a non-ON CIS may be of limited value. Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 Classification of Evidence: This study provides Class III evidence that for patients with suspected MS, inclusion of symptomatic optic nerve involvement in DIS criteria improves the overall performance of diagnostic criteria for MS. COMMENTS I don't think it's unreasonable to state that most, if not all, ophthalmologists and neurologists are aware that optic neuritis (ON) is a very common presentation of a clinically isolated syndrome (CIS) that can herald the diagnosis of multiple sclerosis (MS). But what may not be as well known is that in the fourth and most recent edition of the McDonald criteria for diagnosing MS, the optic nerve is not a criterion for magnetic resonance imaging (MRI) evidence of dissemination in space (DIS) (1). In fact, the authors of the 2017 McDonald criteria wrote ". the Panel recommended including symptomatic and asymptomatic MRI lesions in the determination of DIS and DIT (Panel 5). An exception relates to lesions in the optic nerve in a patient presenting with optic neuritis, as the panel felt evidence was insufficient to support inclusion of the optic nerve as a site to determine DIS in these patients." The MRI definition of DIS requires $1 T2hyperintense lesions characteristic of MS in $2 of 4 regions of the central nervous system (CNS): 1. Supratentorial periventricular 2. Supratentorial cortical or juxtacortical 3. Infratentorial 4. Spinal cord The optic nerve was left out in the cold! 279 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature This prospective study investigated the effect of diagnosing MS in a patient with ON using the optic nerve as an anatomical site in the 2017 McDonald criteria. Of the 104 patients with ON and an abnormal MRI, 80% (n = 83) had evidence of DIS based on the 2017 McDonald criteria. If the optic nerve (symptomatic or asymptomatic) was added as the fifth CNS area, an additional 15 patients or 94% (n = 98) met the modified DIS criteria. No additional cases of MS were diagnosed with the optic nerve added in the DIS criteria for those patients (n = 31) with no ON, although 3 patients had asymptomatic (based on clinical or VEP) optic nerve involvement. One aspect of the statistical analysis that confused me and maybe you can help me with this Mark is why did the authors use the denominator of 129 total patients with ON and not the 104 patients with ON and abnormal MRI? In particular, I am referring to the paragraph with the heading "optic neuritis group" in the results section and Table 2. Am I missing something because the definition of DIS requires at least 1 lesion in 2 or more anatomical CNS regions? By definition, having a normal MRI in the setting of any CIS such as ON is not MS, and so in my mind, the denominator in the ON group should have been 104 and not 129. I wonder if optical coherence tomography (OCT) was included as an imaging study in the DIS criteria if even more patients could be diagnosed with MS (i.e., increase sensitivity), but of course with the good comes the bad of decreasing the specificity. The editorial accompanying the article by Gass and Costello is a very nice read (2). -M. Tariq Bhatti, MD 1. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162-173. 2. Gass A, Costello FE. Optic neuritis in the diagnosis of MS: more than meets the eye. Neurology. 2018;91:545-546. In answer to your question, although they mention 129 patients, the actual calculations they did used 104 as the denominator (98/104 = 94%). I also think there is some confusion in the article from what they call a normal MRI, which is a normal brain and spine MRI, but not specifying or including the optic nerve involvement. In fact, when they talk about optic nerve involvement in these patients, they mean either clinically or MRI or VEP. I think optic nerve involvement should count as DIS. There is no reason to exclude it from MS diagnostic criteria. However, there is one huge caveat-it has to be diagnosed by an experienced clinician and not based on VEP or OCT because we have to ensure that diseases such as ischemic 280 optic neuropathy, glaucoma, myopia, etc., are not misconstrued as optic nerve involvement. -Mark L. Moster, MD Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025 No abstract COMMENTS I found this a very interesting pilot study and hope you did too Mark because I hate to waste a single second of your valuable time. I understand the study only involved 10 patients, but as a proof-of-concept study, I think it carries some merit and will be a spring board for a more robust clinical trial. The authors conducted a randomized, crossover, placebo controlled study to determine the effect size of timolol maleate (0.5%) eyedrops as an abortive migraine therapy. Ten patients were instructed to instill 1 drop of timolol or artificial tears into each eye at the onset and 30 minutes after the migraine. After 2 months, the drop regimen was reversed. To determine a treatment effect, the number of migraine attacks was recorded, and a 2-question questionnaire was administered to rate the severity of migraine attacks (0-3 scale) and rate the effectiveness of each drop (1-4 scale). In terms of migraine attacks that were scored none or mild, 57% were with placebo compared with 78% with timolol. The total mean percentage of migraine attacks was more frequent with timolol (11.8%) compared with placebo (8%). Timolol was felt to be more overall effective than placebo at the masked exit survey (2.4 vs 1.4, respectively). Only 25% of the patients would consider replacing timolol with their previous abortive therapy, and 55% would consider adding it to their abortive therapy. Although the effects measured were not very robust, the authors suggested a future clinical trial with no less than 86 patients. -M. Tariq Bhatti, MD This is an exciting study for me, and the result is surprising because beta blockers are preventative migraine treatments and not abortive treatment. This is a very small study, with mild benefit in favor of timolol, and I believe the results warrant a larger clinical trial. Glaucoma and migraine have an association with each other. It would be interesting to know whether topical timolol decreases migraine in glaucoma patients as well. -Mark L. Moster, MD Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature Rotenstein LS, Torre M, Ramos MA, Rosales RC, Guille C, Sen S, Mata DA. Prevalence of burnout among physicians: a systematic review. JAMA. 2018;320:1131-1150 Importance: Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout prevalence among physicians would have important health policy implications, but the overall prevalence is unknown. Objective: To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout. Data Sources and Study Selection: Systematic search of EMBASE, ERIC, MEDLINE/PubMed, psycARTICLES, and psycINFO for studies on the prevalence of burnout in practicing physicians (i.e., excluding physicians in training) published before June 1, 2018. Data Extraction and Synthesis: Burnout prevalence and study characteristics were extracted independently by 3 investigators. Although meta-analytic pooling was planned, variation in study designs and burnout ascertainment methods, as well as statistical heterogeneity, made quantitative pooling inappropriate. Therefore, studies were summarized descriptively and assessed qualitatively. Main Outcomes and Measures: Point or period prevalence of burnout assessed by questionnaire. Results: Burnout prevalence data were extracted from 182 studies involving 109,628 individuals in 45 countries published between 1991 and 2018. In all, 85.7% (156/182) of studies used a version of the Maslach Burnout Inventory (MBI) to assess burnout. Studies variably reported prevalence estimates of overall burnout or burnout subcomponents: 67.0% (122/182) on overall burnout, 72.0% (131/182) on emotional exhaustion, 68.1% (124/182) on depersonalization, and 63.2% (115/182) on low personal accomplishment. Studies used at least 142 unique definitions for meeting overall burnout or burnout subscale criteria, indicating substantial disagreement in the literature on what constituted burnout. Studies variably defined burnout based on predefined cutoff scores or sample quantiles and used markedly different cutoff definitions. Among studies using instruments based on the MBI, there were at least 47 distinct definitions of overall burnout prevalence and 29, 26, and 26 definitions of emotional exhaustion, depersonalization, and low personal accomplishment prevalence, respectively. Overall burnout prevalence ranged from 0% to 80.5%. Emotional exhaustion, depersonalization, and low personal accomplishment prevalence ranged from 0% to 86.2%, 0% to 89.9%, and 0% to 87.1%, respectively. Because of inconsistencies in definitions of and assessment methods for burnout across studies, associations between burnout and sex, age, geography, time, specialty, and depressive symptoms could not be reliably determined. Conclusions and Relevance: In this systematic review, there was substantial variability in prevalence estimates of burnout among practicing physicians and marked variation in burnout definitions, assessment methods, and study quality. These findings preclude definitive conclusions about the prevalence of burnout and highlight the importance of developing a consensus definition of burnout and of standardizing measurement tools to assess the effects of chronic occupational stress on physicians. Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 COMMENTS I am going to take a slight departure from what we normally do, and instead of dealing with patient care, I want to take this opportunity to talk about physician care. Physician burnout has become a hot topic and a very important topic that can be found in both medical journals and the lay press (1). I must admit that I learned a lot reading this article in addition to the other article in the same issue and the editorial that accompanied these 2 articles (2,3). No doubt we physicians have a problem, but before we can find a solution to this problem, we need to better understand the problem. Here is what I learned from this systemic review of the literature on the prevalence of physician burnout: 1. There are arbitrary and variable definitions of burnout 2. The instruments used to assess burnout have been dichotomized but more appropriately should be seen as a continuous scale to measure physician stress. 3. The Maslach Burnout Inventory (MBI), composed of 3 components (emotional exhaustion, depersonalization, and low personal accomplishment) with each component rated on a 7-point scale, is the most commonly used method to assess physician burnout but requires further studies to establish its validity for physicians. 4. It remains unclear whether physician burnout is a distinct entity or a subtype or symptom of another disease such as depression. 5. The exact cause of physician burnout is not known and much more work needs to be performed to understand the complex underlying causes. Schwenk and Gold stated in their editorial: "The physician has become the patient, but the profession has started to act on the patient's symptom before there is any actual understanding of its pathophysiology, origins, consequences, and effective approaches to prevention and treatment" (3). -M. Tariq Bhatti, MD 1. Xu R. The Burnout Crisis in American Medicine. Available at: https:// www.theatlantic.com/health/archive/2018/05/the-burnout-crisis-inhealth-care/559880/. Accessed December 31, 2018. 2. Dyrbye LN, Burke SE, Hardeman RR, et al. Association of clinical specialty with symptoms of burnout and career choice regret among US resident physicians. JAMA. 2018;320:1114-1130. 3. Schwenk TL, Gold KJ. Physician burnout-A serious symptom, but of what? JAMA. 2018;320:1109-1110. Burnout is currently a large problem for physicians, but as this article points out, we don't have adequate criteria to diagnose it because of the very variable ways it has been studied and characterized. Burnout has been blamed on many things: electronic medical records, lack of time with 281 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature patients, increasing regulation of decision making, etc. However, as the editorial points out, we need to really study the condition to understand and treat it. While writing this comment, I received an email from Doximity with an article about physicians leaving the practice of medicine, with 426 comments from physicians, mostly supporting the notion that physicians are "victims" in our current system. I then decided to review my email inbox from the last 6 months and found an average of 5 emails per month about physician burnout, besides those that I had deleted. These emails come from sources such as American Academy of Ophthalmology, American Academy of Neurology, Medscape, and Doximity. In reports that have compared the percentage of physicians with burnout by specialty, neurologists are on the high end and ophthalmologists on the low end of percentage with burnout. We also don't know how physicians compare with other nonmedical fields and whether we are unique. Despite all that we don't yet know or understand, there is a big problem of burnout, and we can't continue with a system where a lot of physicians feel the 3 things studied in the assessment of burnout: emotional exhaustion, depersonalization, and lack of a sense of accomplishment. -Mark L. Moster, MD Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, Takahashi T, Whittam D, Leite MI, Misu T, Yoshiki T, Messina S, Elsone L, Majed M, Flanagan E, Gadoth A, Huebert C, Sagen J, Greenberg BM, Levy M, Banerjee A, Weinshenker B, Pittock SJ. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018;91:e1642-e1651 Objective: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4- immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS). Methods: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG- positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers. Results: Analysis of an international database for AQP4IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, 282 and hiccups (102, 65%) lasted a median of 14 days (2- 365). Symptoms consistently and completely resolved after immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort. Conclusion: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials. COMMENTS Area postrema syndrome (APS) is one of the hallmark presentations of neuromyelitis optica spectrum disorder (NMOSD). What this article does is characterize the frequency, severity, and duration of the symptoms of APS. The first important take home message is that many of these patients were misdiagnosed. Forty four patients had gastrointestinal workups without coming to a diagnosis of NMOSD. In addition, they do not respond to the typical symptomatic treatments, such as antiemetics. However, they responded rapidly to steroids or plasmapheresis. Isolated APS is the initial presentation in 7.1-10.3% of patients. In addition, APS associated with other symptoms (i.e., optic neuritis, within 30 days of the APS) was the initial presentation in 8.2%-15.9%. The authors speculate that since APS responds to steroids and precedes the other symptoms, perhaps treatment of APS expeditiously will prevent these other symptoms. Isolated bouts of APS occur in the subsequent course of NMOSD in 9.4%-14.5% and with other neurologic symptoms in 8.9%-18.8%. The severity of symptoms in APS was graded with a repurposed score called the PUQE score (PregnancyUnique Quantification of Emesis and Nausea) with an added hiccup component. In 100 US patients with NMOSD who had 157 APS attacks, 30 (19%) were mild, 37 (24%) were moderate, and 90 (57%) were severe. The symptoms lasted for a median of 14 days (2-365) and a median of 5 episodes of vomiting daily (2-40). Before this article, my knowledge of the syndrome was of prolonged vomiting or hiccups, and the detail provided will aid in evaluating patients with NMOSD. -Mark L. Moster, MD I agree with you Mark that this article provides some very important details regarding the clinical syndrome of APS. In practical terms as neuro-ophthalmologists, of course these patients will not be presenting to us because of their nausea, vomiting, or hiccups. Therefore, what we should be asking all our patients with optic neuritis aside from the typical questions about weakness, paresthesia, L'hermitte phenomenon, etc., is whether there is a history Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature of nausea, vomiting, or hiccups because it can be a valuable clue to NMSOD. -M. Tariq Bhatti, MD Raynowska J, Miskin DP, Pramanik B, Asiry S, Anderson T, Boockvar J, Najjar S, Harel A. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS. Neurology. 2018;91:e1423-e1428 Objective: We report a series of 2 brothers who each developed tumefactive brain lesions, initially believed to have brain tumors or tumefactive multiple sclerosis (MS), but who were ultimately diagnosed with a rare autosomal dominant condition known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Methods: Case series and literature review. Results: We present 2 brothers who developed tumefactive right frontal brain lesions leading to gait disturbances and cognitive changes. Both brothers also had nonspecific brain calcifications and T2-hyperintense lesions, and both had ophthalmic and liver disease of unclear etiology. The first brother had been extensively evaluated by various specialists, underwent inconclusive brain and liver biopsies, and was ultimately unsuccessfully treated for a diagnosis of tumefactive MS. The second brother also underwent unrevealing evaluation with CSF analysis and brain biopsy. Further family history revealed that the patients' father developed a tumefactive brain lesion in the 1980s and had been diagnosed with CNS vasculitis. Given the familial link, RVCL was suspected, and genetic analysis confirmed the diagnosis with a 3-prime repair exonuclease 1 (TREX1) C-terminal mutation. Conclusion: The presence of tumefactive brain lesions, nonspecific brain calcifications, liver disease, and retinal vasculopathy, coupled with suggestive family history, led to the RVCL diagnosis. This report contributes to the limited understanding of RVCL, which can cause brain lesions that mimic gliomas or tumefactive MS. Recognition of this entity may prevent unnecessary invasive procedures and inappropriate therapeutic interventions, and would allow for proper counseling of family members. COMMENTS This is a report of 2 brothers who had a classic presentation for retinal vasculopathy with cerebral leukoencephalopathy (RVCL), who nonetheless underwent brain and liver biopsy because of the clinicians' lack of familiarity with the disease. My reason for choosing to review this article is the likelihood that I (and many practitioners dealing with visual loss) might miss the diagnosis in the next patient we consult on with RVCL. RVCL presents acutely in middle age, so a genetic disease is not first on the list, and it presents with a mass lesion, so tumor or multiple sclerosis (MS) leads the Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 differential diagnosis list. The clues are the retinal vasculopathy, not really detailed in this article, the liver disease, brain calcifications, and the family history. An excellent review of the condition in 78 patients is by Stam et al in 2016 in Brain (1) that I'd like to summarize. Other names for the condition are cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS). That article defines the genetic, clinical, radiological, and pathological spectrum of RVCL, which can prevent unnecessary brain and liver biopsies. There are 5 different TREX mutations described in families with RVCL. The retinopathy typically begins in the early 40s and is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots and later by perifoveal capillary obliteration and neovascularization. Pathological examination of the retina at autopsy (n = 8) was consistent with scattered microinfarcts with retinal arteries with thickened hyalinized walls and focal areas of disruption of the ganglion cells and inner nuclear layer of the retina. Some patients had retinal hemorrhage and neovascularization. Brain presentations include focal deficits, cognitive dysfunction, psychiatric disease, and seizures. Death occurs at a mean of 53 years of age, 9 years after onset of symptoms. MRI lesions include hyperintense, white-matter lesions with or without nodular enhancement (92%), rimenhancing mass lesions (71%), and white-matter calcifications (52%). Systemic features were present in 62/63 (98%) and included liver disease (70%), anemia (74%), nephropathy (49%), hypertension (58%), mild Raynaud phenomenon (42%), and gastrointestinal bleeding (12%). So, in addition to neuromyelitis optica spectrum disorder, MS, and Susac disease, we must add RVCL to our differential for visual loss and brain disease. Although rare, I suspect there are many undiagnosed cases because of lack of awareness of RVCL. I really wanted to review these cases when realizing I would likely miss the diagnosis, although you and I reviewed an article on it in the December 2016 Literature Commentary section of JNO. -Mark L. Moster, MD 1. Stam AH, Kothari PH, Shaikh A, Gschwendter A, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016;139:2909-2922. I try so hard to teach you things Mark, and it just seems to go in one ear and out the other. I know your memory span is quite short, but golly gee willikers, it was only in 2 years ago when we discussed RVCL. But no worries, it is always good to re-review uncommon diseases to help us remember them. 283 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature I want to point out a couple of things about this article. First, in case 1, the patient was noted to have only bilateral optic disc pallor with no comment on the retina but will assume was normal. Therefore, it seems that RVCL does not require overt clinical manifestations of retinal vascular disease. Second, and an extension of my first point is, I wonder if an intravenous fluorescein angiography could detect subtle retinal vascular changes not seen on clinical examination similar to what we see sometimes in Susac disease? I am going to try really hard to keep RVCL in the differential diagnosis of a patient with an optic neuropathy, retinopathy, and cerebropathy (is that even a word?). -M. Tariq Bhatti, MD Tariq, I don't think we can assume the retina was normal in case 1. The patient was cared for by neurologists, and it's not clear that an ophthalmologist examined the patient. -Mark L. Moster, MD O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of preclinical Alzheimer disease with optical coherence tomographic angiography findings. JAMA Ophthalmol. 2018;136:1242-1248 Importance: Biomarker testing for asymptomatic, preclinical Alzheimer disease (AD) is invasive and expensive. Optical coherence tomographic angiography (OCTA) is a noninvasive technique that allows analysis of retinal and microvascular anatomy, which is altered in early-stage AD. Objective: To determine whether OCTA can detect early retinal alterations in cognitively normal study participants with preclinical AD diagnosed by criterion standard biomarker testing. Design, Setting, and Participants: This case-control study included 32 participants recruited from the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St. Louis, Missouri. Results of extensive neuropsychometric testing determined that all participants were cognitively normal. Participants underwent positron emission tomography (PET) and/or cerebral spinal fluid testing to determine biomarker status. Individuals with previous ophthalmic disease, media opacity, diabetes, or uncontrolled hypertension were excluded. Data were collected from July 1, 2016, through September 30, 2017, and analyzed from July 30, 2016, through December 31, 2017. Main Outcomes and Measures: Automated measurements of retinal nerve fiber layer thickness, ganglion cell layer thickness, inner and outer foveal thickness, vascular density, macular volume, and foveal avascular zone were collected using an OCTA system from both eyes of all participants. Separate model III analyses of covariance were used to analyze individual data outcome. Results: Fifty-eight eyes from 30 participants (53% female; mean [SD] age, 74.5 [5.6] years; age range, 62-92 years) were included in the analysis. One participant was African 284 American and 29 were white. Fourteen participants had biomarkers positive for AD and thus a diagnosis of preclinical AD (mean [SD] age, 73.5 [4.7] years); 16 without biomarkers served as a control group (mean [SD] age, 75.4 [6.6] years). The foveal avascular zone was increased in the biomarker-positive group compared with controls (mean [SD], 0.364 [0.095] vs 0.275 [0.060] mm2; P = 0.002). Mean (SD) inner foveal thickness was decreased in the biomarker-positive group (66.0 [9.9] vs 75.4 [10.6] mm; P = 0.03). Conclusions and Relevance: This study suggests that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities in addition to architectural alterations, and that these changes occur at earlier stages of AD than has previously been demonstrated. Longitudinal studies in larger cohorts are needed to determine whether this finding has value in identifying preclinical AD. COMMENTS There has been a lot of banter about the eye in neurodegenerative diseases, particularly Alzheimer disease (AD). Although people at risk may be identified by abnormal positron emission tomography (PET) amyloid imaging or lumbar puncture, these are either expensive or invasive. The search for a more affordable noninvasive biomarker has focused on the eye, and in particular on the retina as an extension of the brain. AD changes have been found in retina and if somehow looking at the retina can tell who is developing AD before symptoms, there is a window for treatment. Admittedly, we don't have any adequate treatment for AD, but one of the recent clinical trials of BAN2401 might show promise of decreasing brain amyloid and slowing down cognitive decline. This article by Greg Van Stavern's group sheds some more light on the topic. They used optical coherence tomography (OCT) and OCT angiography (OCTA) in a group of preclinical AD patients with abnormal PET scans for Pittsburgh Compound B (PiB)or fluorine 18-labeled florbetapir (18F-AV-45) and/or lumbar punctures with cerebrospinal (CSF)-positive Ab42 compared with those with negative biomarkers. They found an enlarged foveal avascular zone and a decrease in inner foveal thickness in the subjects with positive biomarkers. However, they point out that there is considerable overlap in distribution, which makes the findings of lesser clinical use. My take is that OCTA and most of the other retinal abnormalities described in AD (e.g., thinning of retinal nerve fiber layer or ganglion cell layer) are not specific to AD and therefore not candidates for biomarker status. Until imaging of specific biomarkers for amyloid or tau protein matures, our now traditional methods of retinal imaging will be sensitive but not specific. They might be helpful in monitoring patients after a definitive diagnosis but not in the initial differential diagnosis. -Mark L. Moster, MD Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature First, let me first congratulate my friend Greg Van Stavern and his group on this very provocative study. I choose this article to discuss at our recent resident journal club, and it sparked a lot of discussion and ideas for future studies among the trainees. As you mentioned, Mark, there has been a focus of using the eye as a biomarker or surrogate for what is going on in the brain. In particular, this is not the first time that the eye has been used as a potential signal for AD. Do you remember the excitement of pupillary dilation with dilute tropicamide drops as a marker of AD? It turned out to be all hype (1). Certainly, more studies will need to be performed to determine whether OCT/OCTA can assess the risk of developing AD. -M. Tariq Bhatti, MD Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 279-285 1. Kardon RH. Drop the Alzheimer's drop test. Neurology. 1998;50:588-591. SPECIAL COMMENTS We want to thank Dr. Lanning Kline for being an amazing Editor-In-Chief. He not only elevated the status of JNO with all his hard work, but also was wonderful to work with and for. He will be missed. I wiped the tears from Mark's eyes, patted his head, and reminded him that JNO is now in the dynamic and very capable leadership of Laura Balcer. We very much look forward to working with Laura and thank her for the continued opportunity to work on Literature Commentary. -M. Tariq Bhatti and Mark L. Moster 285 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.